TY  - JOUR
A1  - Collenburg, Lena
A1  - Walter, Tim
A1  - Burgert, Anne
A1  - Mueller, Nora
A1  - Seibel, Juergen
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Sauer, Markus
A1  - Schneider-Schaulies, Sibylle
T1  - A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells
JF  - The journal of immunology
N2  - Sphingolipids are major components of the plasma membrane. In particular, ceramide serves as an essential building hub for complex sphingolipids, but also as an organizer of membrane domains segregating receptors and signalosomes. Sphingomyelin breakdown as a result of sphingomyelinase activation after ligation of a variety of receptors is the predominant source of ceramides released at the plasma membrane. This especially applies to T lymphocytes where formation of ceramide-enriched membrane microdomains modulates TCR signaling. Because ceramide release and redistribution occur very rapidly in response to receptor ligation, novel tools to further study these processes in living T cells are urgently needed. To meet this demand, we synthesized nontoxic, azido-functionalized ceramides allowing for bio-orthogonal click-reactions to fluorescently label incorporated ceramides, and thus investigate formation of ceramide-enriched domains. Azido-functionalized C-6-ceramides were incorporated into and localized within plasma membrane microdomains and proximal vesicles in T cells. They segregated into clusters after TCR, and especially CD28 ligation, indicating efficient sorting into plasma membrane domains associated with T cell activation; this was abolished upon sphingomyelinase inhibition. Importantly, T cell activation was not abrogated upon incorporation of the compound, which was efficiently excluded from the immune synapse center as has previously been seen in Ab-based studies using fixed cells. Therefore, the functionalized ceramides are novel, highly potent tools to study the subcellular redistribution of ceramides in the course of T cell activation. Moreover, they will certainly also be generally applicable to studies addressing rapid stimulation-mediated ceramide release in living cells.
Y1  - 2016
U6  - https://doi.org/10.4049/jimmunol.1502447
SN  - 0022-1767
SN  - 1550-6606
VL  - 196
SP  - 3951
EP  - 3962
PB  - American Assoc. of Immunologists
CY  - Bethesda
ER  - 
TY  - CHAP
A1  - Baranyai, Dorothea
A1  - Goedtel-Armbrust, Ute
A1  - Nestler, Sebastian
A1  - Kleuser, Burkhard
A1  - Wojnowski, Leszek
T1  - A role for cutaneous CYP3A in vitamin D homeostasis?
T2  - NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Y1  - 2014
SN  - 0028-1298
SN  - 1432-1912
VL  - 387
SP  - S27
EP  - S27
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Solger, Franziska
A1  - Kunz, Tobias C.
A1  - Fink, Julian
A1  - Paprotka, Kerstin
A1  - Pfister, Pauline
A1  - Hagen, Franziska
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Seibel, Jürgen
A1  - Rudel, Thomas
T1  - A role of sphingosine in the intracellular survival of Neisseria gonorrhoeae
JF  - Frontiers in Cellular and Infection Microbiology
N2  - Obligate human pathogenic Neisseria gonorrhoeae are the second most frequent bacterial cause of sexually transmitted diseases. These bacteria invade different mucosal tissues and occasionally disseminate into the bloodstream. Invasion into epithelial cells requires the activation of host cell receptors by the formation of ceramide-rich platforms. Here, we investigated the role of sphingosine in the invasion and intracellular survival of gonococci. Sphingosine exhibited an anti-gonococcal activity in vitro. We used specific sphingosine analogs and click chemistry to visualize sphingosine in infected cells. Sphingosine localized to the membrane of intracellular gonococci. Inhibitor studies and the application of a sphingosine derivative indicated that increased sphingosine levels reduced the intracellular survival of gonococci. We demonstrate here, that sphingosine can target intracellular bacteria and may therefore exert a direct bactericidal effect inside cells.
KW  - Neisseria gonorrhoeae
KW  - sphingosine
KW  - sphingolipids
KW  - sphingosine kinases
KW  - invasion
KW  - survival
KW  - click chemistry
Y1  - 2020
U6  - https://doi.org/10.3389/fcimb.2020.00215
SN  - 2235-2988
VL  - 10
PB  - Frontiers Media
CY  - Lausanne
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  - GEN
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1400 
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-515661
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Lang, Judith
A1  - Bohn, Patrick
A1  - Bhat, Hilal
A1  - Jastrow, Holger
A1  - Walkenfort, Bernd
A1  - Cansiz, Feyza
A1  - Fink, Julian
A1  - Bauer, Michael
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Lang, Karl S.
T1  - Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease
JF  - Nature Communications
N2  - Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1(-/-) mice results in replication of HSV-1 and Asah1(-/-) mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.
KW  - immunology
KW  - infection
KW  - membrane fusion
KW  - phagocytosis
KW  - sphingolipids
Y1  - 2020
U6  - https://doi.org/10.1038/s41467-020-15072-8
SN  - 2041-1723
VL  - 11
IS  - 1
SP  - 1
EP  - 15
PB  - Nature Publishing Group UK
CY  - London
ER  - 
TY  - JOUR
A1  - Zeitler, Stefanie
A1  - Ye, Lian
A1  - Andreyeva, Aksana
A1  - Schumacher, Fabian
A1  - Monti, Juliana
A1  - Nürnberg, Bernd
A1  - Nowak, Gabriel
A1  - Kleuser, Burkhard
A1  - Reichel, Martin
A1  - Fejtova, Anna
A1  - Kornhuber, Johannes
A1  - Rhein, Cosima
A1  - Friedland, Kristina
T1  - Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity
JF  - Journal of neurochemistry
N2  - Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM‐induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non‐selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John’s wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin‐induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6‐mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration‐related way. This effect was confirmed in whole‐cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin‐1–positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine‐tuning their physical properties.
KW  - acid sphingomyelinase
KW  - antidepressants
KW  - ceramide
KW  - hyperforin
KW  - lipid rafts
KW  - TRPC6
Y1  - 2019
U6  - https://doi.org/10.1111/jnc.14823
SN  - 0022-3042
SN  - 1471-4159
VL  - 150
IS  - 6
SP  - 678
EP  - 690
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - GEN
A1  - Beckmann, Nadine
A1  - Becker, Katrin Anne
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Kramer, Melanie
A1  - Kühn, Claudine
A1  - Schulz-Schaeffer, Walter J.
A1  - Edwards, Michael J.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Acid sphingomyelinase deficiency ameliorates Farber disease
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1087 
KW  - Farber disease
KW  - lysosomal storage disorders
KW  - acid ceramidase
KW  - acid sphingomyelinase
KW  - amitriptyline
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441282
SN  - 1866-8372
IS  - 1087
ER  - 
TY  - JOUR
A1  - Beckmann, Nadine
A1  - Becker, Katrin Anne
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Kramer, Melanie
A1  - Kuehn, Claudine
A1  - Schulz-Schaeffer, Walter J.
A1  - Edwards, Michael J.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Acid Sphingomyelinase Deficiency Ameliorates Farber Disease
JF  - International journal of molecular sciences
N2  - Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
KW  - Farber disease
KW  - lysosomal storage disorders
KW  - acid ceramidase
KW  - acid sphingomyelinase
KW  - amitriptyline
Y1  - 2019
U6  - https://doi.org/10.3390/ijms20246253
SN  - 1422-0067
VL  - 20
IS  - 24
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Hoehn, Richard S.
A1  - Jernigan, Peter L.
A1  - Japtok, Lukasz
A1  - Chang, Alex L.
A1  - Midura, Emily F.
A1  - Caldwell, Charles C.
A1  - Kleuser, Burkhard
A1  - Lentsch, Alex B.
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Pritts, Timothy A.
T1  - Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation
JF  - Annals of surgery : a monthly review of surgical science and practice
N2  - 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.
KW  - acid sphingomyelinase
KW  - blood banking
KW  - ceramide
KW  - lung inflammation
KW  - microparticle
Y1  - 2017
U6  - https://doi.org/10.1097/SLA.0000000000001648
SN  - 0003-4932
SN  - 1528-1140
VL  - 265
IS  - 1
SP  - 218
EP  - 226
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - McVey, Mark J.
A1  - Kim, Michael
A1  - Tabuchi, Arata
A1  - Srbely, Victoria
A1  - Japtok, Lukasz
A1  - Arenz, Christoph
A1  - Rotstein, Ori
A1  - Kleuser, Burkhard
A1  - Semple, John W.
A1  - Kuebler, Wolfgang M.
T1  - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets
JF  - American journal of physiology : Lung cellular and molecular physiology
N2  - 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.
KW  - transfusion-related acute lung injury
KW  - ceramide
KW  - acid sphingomyelinase
KW  - platelets
KW  - storage
Y1  - 2017
U6  - https://doi.org/10.1152/ajplung.00317.2016
SN  - 1040-0605
SN  - 1522-1504
VL  - 312
IS  - 5
SP  - 625
EP  - 637
PB  - American Physiological Society
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Gulbins, Erich
A1  - Palmada, Monica
A1  - Reichel, Martin
A1  - Lueth, Anja
A1  - Boehmer, Christoph
A1  - Amato, Davide
A1  - Mueller, Christian P.
A1  - Tischbirek, Carsten H.
A1  - Groemer, Teja W.
A1  - Tabatabai, Ghazaleh
A1  - Becker, Katrin Anne
A1  - Tripal, Philipp
A1  - Staedtler, Sven
A1  - Ackermann, Teresa F.
A1  - van Brederode, Johannes
A1  - Alzheimer, Christian
A1  - Weller, Michael
A1  - Lang, Undine E.
A1  - Kleuser, Burkhard
A1  - Grassme, Heike
A1  - Kornhuber, Johannes
T1  - Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs
JF  - Nature medicine
N2  - Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
Y1  - 2013
U6  - https://doi.org/10.1038/nm.3214
SN  - 1078-8956
VL  - 19
IS  - 7
SP  - 934
EP  - +
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Reichel, Martin
A1  - Hoenig, Stefanie
A1  - Liebisch, Gerhard
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Schmitz, Gerd
A1  - Kornhuber, Johannes
T1  - Alterations of plasma glycerophospholipid and sphingolipid species in male alcohol-dependent patients
JF  - Biochimica et biophysica acta : Molecular and cell biology of lipids
N2  - Background: Alcohol abuse is a major risk factor for somatic and neuropsychiatric diseases. Despite their potential clinical importance, little is known about the alterations of plasma glycerophospholipid (GPL) and sphingolipid (SPL) species associated with alcohol abuse.
 Methods: Plasma GPL and SPL species were quantified using electrospray ionization tandem mass spectrometry in samples from 23 male alcohol-dependent patients before and after detoxification, as well as from 20 healthy male controls.
 Results: A comparison of alcohol-dependent patients with controls revealed higher phosphatidylcholine (PC; P-value = 0.008) and phosphatidylinositol (PI; P-value = 0.001) concentrations in patients before detoxification, and higher PI (P-value = 0.001) and phosphatidylethanolamine (PE)-based plasmalogen (PEP; P-value = 0.003) concentrations after detoxification. Lysophosphatidylcholines (LPC) were increased by acute intoxication (P-value = 0.002). Sphingomyelin (SM) concentration increased during detoxification (P-value = 0.011). The concentration of SM 23:0 was lower in patients (P-value = 2.79 x 10(-5)), and the concentrations of ceramide Cer d18:1/16:0 and Cer d18:1/18:0 were higher in patients (P-value = 2.45 x 10(-5) and 3.73 x 10(-5)). Activity of lysosomal acid sphingomyelinase (ASM) in patients correlated positively with the concentrations of eight LPC species, while activity of secreted ASM was inversely correlated with several PE, PI and PC species, and positively correlated with the molar ratio of PC to SM (Pearson's r = 0.432; P-value = 0.039).
 Conclusion: Plasma concentrations of numerous GPL and SPL species were altered in alcohol-dependent patients. These molecules might serve as potential biomarkers to improve the diagnosis of patients and to indicate health risks associated with alcohol abuse. Our study further indicates that there are strong interactions between plasma GPL concentrations and SPL metabolism. (C) 2015 Elsevier B.V. All rights reserved.
KW  - Acid sphingomyelinase
KW  - Alcohol dependence
KW  - Anxiety
KW  - Cardiovascular
KW  - Case-control study
KW  - Ceramide
KW  - Clinical
KW  - Depression
KW  - Diagnostic
KW  - Disease
KW  - Glycerophospholipids
KW  - Lysophosphatidylcholines
KW  - Mass spectrometry
KW  - Phosphatidylcholines
KW  - Phosphatidylinositols
KW  - Plasma
KW  - Plasmalogens
KW  - Sphingolipids
KW  - Sphingomyelin
KW  - Tandem mass spectrometry
Y1  - 2015
U6  - https://doi.org/10.1016/j.bbalip.2015.08.005
SN  - 1388-1981
SN  - 0006-3002
VL  - 1851
IS  - 11
SP  - 1501
EP  - 1510
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Putra, Sulistyo Emantoko Dwi
A1  - Neuber, Corinna
A1  - Reichetzeder, Christoph
A1  - Hocher, Berthold
A1  - Kleuser, Burkhard
T1  - Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background: DNA-methylation is a common epigenetic tool which plays a crucial role in gene regulation and is essential for cell differentiation and embryonic development. The placenta is an important organ where gene activity can be regulated by epigenetic DNA modifications, including DNA methylation. This is of interest as, the placenta is the interface between the fetus and its environment, the mother. Exposure to environmental toxins and nutrition during pregnancy may alter DNA methylation of the placenta and subsequently placental function and as a result the phenotype of the offspring. The aim of this study was to develop a reliable method to quantify DNA methylation in large clinical studies. This will be a tool to analyze the degree of DNA methylation in the human placenta in relationship to clinical readouts. Methods: Liquid chromatography-electrospray ionization/multi-stage mass spectrometry (LC-ESI/MS/MS) technique was used for the quantification of the 5dmC/dG ratio in placentas from 248 healthy pregnancies. We were able to demonstrate that this method is a reliable and stable way to determine global placental DNA methylation in large clinical trials. Results/Conclusion: The degree of placental DNA methylation seen in our pilot study varies substantially from 2% to 5%. The clinical implications of this variation need to be demonstrated in adequately powered large studies.
KW  - Pregnancy
KW  - Placenta
KW  - Methylation
KW  - Global
KW  - LC-MS/MS
KW  - Fetal programming
KW  - Clinical
Y1  - 2014
U6  - https://doi.org/10.1159/000358666
SN  - 1015-8987
SN  - 1421-9778
VL  - 33
IS  - 4
SP  - 945
EP  - 952
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Gulbins, Anne
A1  - Schumacher, Fabian
A1  - Becker, Katrin Anne
A1  - Wilker, Barbara
A1  - Soddemann, Matthias
A1  - Boldrin, Francesco
A1  - Müller, Christian P.
A1  - Edwards, Michael J.
A1  - Goodman, Michael
A1  - Caldwell, Charles C.
A1  - Kleuser, Burkhard
A1  - Kornhuber, Johannes
A1  - Szabo, Ildiko
A1  - Gulbins, Erich
T1  - Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide
JF  - Molecular psychiatry
N2  - Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
Y1  - 2018
U6  - https://doi.org/10.1038/s41380-018-0090-9
SN  - 1359-4184
SN  - 1476-5578
VL  - 23
IS  - 12
SP  - 2324
EP  - 2346
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - JOUR
A1  - Müller, S. M.
A1  - Finke, Hannah
A1  - Ebert, Franziska
A1  - Kopp, Johannes Florian
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Francesconi, Kevin A.
A1  - Raber, G.
A1  - Schwerdtle, Tanja
T1  - Arsenic-containing hydrocarbons
BT  - effects on gene expression, epigenetics, and biotransformation in HepG2 cells
JF  - Archives of toxicology : official journal of EUROTOX
N2  - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine-5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids.
KW  - Arsenolipids
KW  - Gene expression
KW  - Arsenic-containing hydrocarbons
KW  - Global DNA methylation
KW  - Arsenic speciation
KW  - Metabolism
Y1  - 2018
U6  - https://doi.org/10.1007/s00204-018-2194-z
SN  - 0340-5761
SN  - 1432-0738
VL  - 92
IS  - 5
SP  - 1751
EP  - 1765
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - GEN
A1  - Polzin, Amin
A1  - Rassaf, Tienush
A1  - Boehm, Andreas
A1  - Lueth, Anja
A1  - Kleuser, Burkhard
A1  - Zeus, Tobias
A1  - Kelm, Malte
A1  - Kroemer, Heyo K.
A1  - Schroer, Karsten
A1  - Rauch, Bernhard H.
T1  - Aspirin inhibits release of platelet-derived sphingosine-1-phosphate in
 acute myocardial infarction
T2  - INTERNATIONAL JOURNAL OF CARDIOLOGY
KW  - Sphingosine-1-phosphate
KW  - Acute coronary syndrome
KW  - Platelets
KW  - Aspirin
Y1  - 2013
U6  - https://doi.org/10.1016/j.ijcard.2013.10.050
SN  - 0167-5273
SN  - 1874-1754
VL  - 170
IS  - 2
SP  - E23
EP  - E24
PB  - ELSEVIER IRELAND LTD
CY  - CLARE
ER  - 
TY  - JOUR
A1  - Fink, Julian
A1  - Schumacher, Fabian
A1  - Schlegel, Jan
A1  - Stenzel, Philipp
A1  - Wigger, Dominik
A1  - Sauer, Markus
A1  - Kleuser, Burkhard
A1  - Seibel, Jürgen
T1  - Azidosphinganine enables metabolic labeling and detection of sphingolipid de novo synthesis
JF  - Organic & biomolecular chemistry : an international journal of synthetic, physical and biomolecular organic chemistry
N2  - Here were report the combination of biocompatible click chemistry of omega-azidosphinganine with fluorescence microscopy and mass spectrometry as a powerful tool to elaborate the sphingolipid metabolism. The azide probe was efficiently synthesized over 13 steps starting from l-serine in an overall yield of 20% and was used for live-cell fluorescence imaging of the endoplasmic reticulum in living cells by bioorthogonal click reaction with a DBCO-labeled fluorophore revealing that the incorporated analogue is mainly localized in the endoplasmic membrane like the endogenous species. A LC-MS(/MS)-based microsomal in vitro assay confirmed that omega-azidosphinganine mimics the natural species enabling the identification and analysis of metabolic breakdown products of sphinganine as a key starting intermediate in the complex sphingolipid biosynthetic pathways. Furthermore, the sphinganine-fluorophore conjugate after click reaction was enzymatically tolerated to form its dihydroceramide and ceramide metabolites. Thus, omega-azidosphinganine represents a useful biofunctional tool for metabolic investigations both by in vivo fluorescence imaging of the sphingolipid subcellular localization in the ER and by in vitro high-resolution mass spectrometry analysis. This should reveal novel insights of the molecular mechanisms sphingolipids and their processing enzymes have e.g. in infection.
Y1  - 2021
U6  - https://doi.org/10.1039/d0ob02592e
SN  - 1477-0520
SN  - 1477-0539
VL  - 19
IS  - 10
SP  - 2203
EP  - 2212
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - GEN
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1405 
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516289
SN  - 1866-8372
IS  - 1
ER  - 
TY  - JOUR
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
JF  - Scientific Reports
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-57725-0
SN  - 2045-2322
VL  - 10
IS  - 1
SP  - 1
EP  - 10
PB  - Springer Nature
CY  - London
ER  - 
TY  - JOUR
A1  - Gerecke, Christian
A1  - Edlich, Alexander
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Zhang, Nan
A1  - Said, Andre
A1  - Yealland, Guy
A1  - Lohan, Silke B.
A1  - Neumann, Falko
A1  - Meinke, Martina C.
A1  - Ma, Nan
A1  - Calderon, Marcelo
A1  - Hedtrich, Sarah
A1  - Schaefer-Korting, Monika
A1  - Kleuser, Burkhard
T1  - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes
JF  - Nanotoxicology
N2  - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.
KW  - Drug delivery
KW  - nanoparticles
KW  - particle characterization
KW  - keratinocytes
KW  - nanotoxicology
Y1  - 2017
U6  - https://doi.org/10.1080/17435390.2017.1292371
SN  - 1743-5390
SN  - 1743-5404
VL  - 11
SP  - 267
EP  - 277
PB  - Routledge, Taylor & Francis Group
CY  - Abingdon
ER  - 
TY  - GEN
A1  - Gerecke, Christian
A1  - Edlich, Alexander
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Zhang, Nan
A1  - Said, Andre
A1  - Yealland, Guy
A1  - Lohan, Silke B.
A1  - Neumann, Falko
A1  - Meinke, Martina C.
A1  - Ma, Nan
A1  - Calderón, Marcelo
A1  - Hedtrich, Sarah
A1  - Schäfer-Korting, Monika
A1  - Kleuser, Burkhard
T1  - Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes
N2  - Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 335 
KW  - Drug delivery
KW  - nanoparticles
KW  - particle characterization
KW  - keratinocytes
KW  - nanotoxicology
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-395325
ER  - 
TY  - GEN
A1  - Giulbudagian, Michael
A1  - Yealland, Guy
A1  - Hönzke, Stefan
A1  - Edlich, Alexander
A1  - Geisendörfer, Birte
A1  - Kleuser, Burkhard
A1  - Hedtrich, Sarah
A1  - Calderón, Marcelo
T1  - Breaking the barrier
BT  - potent anti-inflammatory activity following efficient topical delivery of etanercept using thermoresponsive nanogels
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Topical administration permits targeted, sustained delivery of therapeutics to human skin. Delivery to the skin, however, is typically limited to lipophilic molecules with molecular weight of < 500 Da, capable of crossing the stratum corneum. Nevertheless, there are indications protein delivery may be possible in barrier deficient skin, a condition found in several inflammatory skin diseases such as psoriasis, using novel nanocarrier systems.

Methods: Water in water thermo-nanoprecipitation; dynamic light scattering; zeta potential measurement; nanoparticle tracking analysis; atomic force microscopy; cryogenic transmission electron microscopy; UV absorption; centrifugal separation membranes; bicinchoninic acid assay; circular dichroism; TNF alpha binding ELISA; inflammatory skin equivalent construction; human skin biopsies; immunohistochemistry; fluorescence microscopy; western blot; monocyte derived Langerhans cells; ELISA

Results: Here, we report the novel synthesis of thermoresponsive nanogels (tNG) and the stable encapsulation of the anti-TNFa fusion protein etanercept (ETR) (similar to 150 kDa) without alteration to its structure, as well as temperature triggered release from the tNGs. Novel tNG synthesis without the use of organic solvents was conducted, permitting in situ encapsulation of protein during assembly, something that holds great promise for easy manufacture and storage. Topical application of ETR loaded tNGs to inflammatory skin equivalents or tape striped human skin resulted in efficient ETR delivery throughout the SC and into the viable epidermis that correlated with clear anti-inflammatory effects. Notably, effective ETR delivery depended on temperature triggered release following topical application.

Conclusion: Together these results indicate tNGs hold promise as a biocompatible and easy to manufacture vehicle for stable protein encapsulation and topical delivery into barrier-deficient skin.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1030 
KW  - thermoresponsive-nanogel
KW  - topical
KW  - anti-inflammatory therapy
KW  - etanercept
KW  - skin equivalents
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-459301
SN  - 1866-8372
IS  - 1030
SP  - 450
EP  - 463
ER  - 
TY  - JOUR
A1  - Giulbudagian, Michael
A1  - Yealland, Guy
A1  - Hönzke, S.
A1  - Edlich, A.
A1  - Geisendörfer, Birte
A1  - Kleuser, Burkhard
A1  - Hedtrich, Sarah
A1  - Calderon, Marcelo
T1  - Breaking the Barrier
BT  - potent anti-inflammatory activity following efficient topical delivery of etanercept using thermoresponsive nanogels
JF  - Theranostics
N2  - Topical administration permits targeted, sustained delivery of therapeutics to human skin. Delivery to the skin, however, is typically limited to lipophilic molecules with molecular weight of < 500 Da, capable of crossing the stratum corneum. Nevertheless, there are indications protein delivery may be possible in barrier deficient skin, a condition found in several inflammatory skin diseases such as psoriasis, using novel nanocarrier systems. Methods: Water in water thermo-nanoprecipitation; dynamic light scattering; zeta potential measurement; nanoparticle tracking analysis; atomic force microscopy; cryogenic transmission electron microscopy; UV absorption; centrifugal separation membranes; bicinchoninic acid assay; circular dichroism; TNF alpha binding ELISA; inflammatory skin equivalent construction; human skin biopsies; immunohistochemistry; fluorescence microscopy; western blot; monocyte derived Langerhans cells; ELISA Results: Here, we report the novel synthesis of thermoresponsive nanogels (tNG) and the stable encapsulation of the anti-TNFa fusion protein etanercept (ETR) (similar to 150 kDa) without alteration to its structure, as well as temperature triggered release from the tNGs. Novel tNG synthesis without the use of organic solvents was conducted, permitting in situ encapsulation of protein during assembly, something that holds great promise for easy manufacture and storage. Topical application of ETR loaded tNGs to inflammatory skin equivalents or tape striped human skin resulted in efficient ETR delivery throughout the SC and into the viable epidermis that correlated with clear anti-inflammatory effects. Notably, effective ETR delivery depended on temperature triggered release following topical application. Conclusion: Together these results indicate tNGs hold promise as a biocompatible and easy to manufacture vehicle for stable protein encapsulation and topical delivery into barrier-deficient skin.
KW  - thermoresponsive-nanogel
KW  - topical
KW  - anti-inflammatory therapy
KW  - etanercept
KW  - skin equivalents
Y1  - 2018
U6  - https://doi.org/10.7150/thno.21668
SN  - 1838-7640
VL  - 8
IS  - 2
SP  - 450
EP  - 463
PB  - Ivyspring International Publisher
CY  - Lake haven
ER  - 
TY  - JOUR
A1  - Beckmann, Nadine
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Nomellini, Vanessa
A1  - Caldwell, Charles C.
T1  - Burn injury impairs neutrophil chemotaxis through increased ceramide
JF  - Shock : injury, inflammation, and sepsis, laboratory and clinical approaches
N2  - Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis toward CXCL1 ex vivo. Additionally, we observed a reduced recruitment of neutrophils to the peritoneal after elicitation 7 days after injury. We demonstrate that neutrophil ceramide levels increase after burn injury, and this is associated with decreased expression of CXCR2 and blunted chemotaxis. A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn.
KW  - Acid sphingomyelinase
KW  - Akt
KW  - burn injury
KW  - ceramide
KW  - CXCR2
KW  - immune
KW  - dysfunction
KW  - neutrophil chemotaxis
KW  - PTEN
Y1  - 2021
U6  - https://doi.org/10.1097/SHK.0000000000001693
SN  - 1073-2322
SN  - 1540-0514
VL  - 56
IS  - 1
SP  - 125
EP  - 132
PB  - Lippincott Williams & Wilkins
CY  - Hagerstown, Md.
ER  - 
TY  - JOUR
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
JF  - Scientific reports
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
KW  - n-acetyl-cysteine
KW  - s-glutathionylation
KW  - force-field
KW  - c. elegans
KW  - life-span
KW  - protein
KW  - cells
KW  - menadione
KW  - disease
KW  - binding
Y1  - 2016
U6  - https://doi.org/10.1038/srep37346
SN  - 2045-2322
VL  - 6
PB  - Nature Publishing Group
CY  - London
ER  - 
TY  - GEN
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 312 
KW  - binding
KW  - c. elegans
KW  - cells
KW  - disease
KW  - force-field
KW  - life-span
KW  - menadione
KW  - n-acetyl-cysteine
KW  - protein
KW  - s-glutathionylation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-103674
ER  - 
TY  - JOUR
A1  - Henze, Andrea
A1  - Homann, Thomas
A1  - Rohn, Isabelle
A1  - Aschner, Michael A.
A1  - Link, Christopher D.
A1  - Kleuser, Burkhard
A1  - Schweigert, Florian J.
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin
JF  - Scientific reports
N2  - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time-and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling.
Y1  - 2016
U6  - https://doi.org/10.1038/srep37346
SN  - 2045-2322
VL  - 6
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - JOUR
A1  - Keller, Johannes
A1  - Catala-Lehnen, Philip
A1  - Huebner, Antje K.
A1  - Jeschke, Anke
A1  - Heckt, Timo
A1  - Lueth, Anja
A1  - Krause, Matthias
A1  - Koehne, Till
A1  - Albers, Joachim
A1  - Schulze, Jochen
A1  - Schilling, Sarah
A1  - Haberland, Michael
A1  - Denninger, Hannah
A1  - Neven, Mona
A1  - Hermans-Borgmeyer, Irm
A1  - Streichert, Thomas
A1  - Breer, Stefan
A1  - Barvencik, Florian
A1  - Levkau, Bodo
A1  - Rathkolb, Birgit
A1  - Wolf, Eckhard
A1  - Calzada-Wack, Julia
A1  - Neff, Frauke
A1  - Gailus-Durner, Valerie
A1  - Fuchs, Helmut
A1  - de Angelis, Martin Hrabe
A1  - Klutmann, Susanne
A1  - Tsourdi, Elena
A1  - Hofbauer, Lorenz C.
A1  - Kleuser, Burkhard
A1  - Chun, Jerold
A1  - Schinke, Thorsten
A1  - Amling, Michael
T1  - Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts
JF  - Nature Communications
N2  - The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P(3). Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P(3)-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
Y1  - 2014
U6  - https://doi.org/10.1038/ncomms6215
SN  - 2041-1723
VL  - 5
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - GEN
A1  - Wardelmann, Kristina
A1  - Rath, Michaela
A1  - Castro, José Pedro
A1  - Blümel, Sabine
A1  - Schell, Mareike
A1  - Hauffe, Robert
A1  - Schumacher, Fabian
A1  - Flore, Tanina
A1  - Ritter, Katrin
A1  - Wernitz, Andreas
A1  - Hosoi, Toru
A1  - Ozawa, Koichiro
A1  - Kleuser, Burkhard
A1  - Weiß, Jürgen
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1165 
KW  - brain insulin signaling
KW  - mitochondria
KW  - oxidative stress
KW  - fatty acid metabolism
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-522985
SN  - 1866-8372
IS  - 5
ER  - 
TY  - JOUR
A1  - Wardelmann, Kristina
A1  - Rath, Michaela
A1  - Castro, José Pedro
A1  - Blümel, Sabine
A1  - Schell, Mareike
A1  - Hauffe, Robert
A1  - Schumacher, Fabian
A1  - Flore, Tanina
A1  - Ritter, Katrin
A1  - Wernitz, Andreas
A1  - Hosoi, Toru
A1  - Ozawa, Koichiro
A1  - Kleuser, Burkhard
A1  - Weiß, Jürgen
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
JF  - Antioxidants
N2  - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
KW  - brain insulin signaling
KW  - mitochondria
KW  - oxidative stress
KW  - fatty acid metabolism
Y1  - 2021
U6  - https://doi.org/10.3390/antiox10050711
SN  - 2076-3921
VL  - 10
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - GEN
A1  - Naser, Eyad
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Mohamed, Zainelabdeen H.
A1  - Kappe, Christian
A1  - Hessler, Gabriele
A1  - Pollmeier, Barbara
A1  - Kleuser, Burkhard
A1  - Arenz, Christoph
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Characterization of the small molecule ARC39
BT  - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1407 
KW  - sphingolipids
KW  - sphingomyelin
KW  - cerami-des
KW  - lipid metabolism
KW  - enzymology
KW  - lysosome
KW  - lysosomal hydrolases
KW  - acid ceramidase
KW  - bisphosphonates
KW  - functional inhibitors of acid sphin-gomyelinase
KW  - 1-aminodecylidene bis-phosphonic acid
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-516635
SN  - 1866-8372
IS  - 6
ER  - 
TY  - JOUR
A1  - Naser, Eyad
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Mohamed, Zainelabdeen H.
A1  - Kappe, Christian
A1  - Hessler, Gabriele
A1  - Pollmeier, Barbara
A1  - Kleuser, Burkhard
A1  - Arenz, Christoph
A1  - Becker, Katrin Anne
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Characterization of the small molecule ARC39
BT  - a direct and specific inhibitor of acid sphingomyelinase in vitro[S]
JF  - Journal of Lipid Research
N2  - Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.
KW  - sphingolipids
KW  - sphingomyelin
KW  - cerami-des
KW  - lipid metabolism
KW  - enzymology
KW  - lysosome
KW  - lysosomal hydrolases
KW  - acid ceramidase
KW  - bisphosphonates
KW  - functional inhibitors of acid sphin-gomyelinase
KW  - 1-aminodecylidene bis-phosphonic acid
Y1  - 2021
U6  - https://doi.org/10.1194/jlr.RA120000682
SN  - 1539-7262
SN  - 0022-2275
VL  - 61
IS  - 6
SP  - 896
EP  - 910
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - GEN
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
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 538 
KW  - hepatic ischemia-reperfusion
KW  - liver-regeneration
KW  - injury
KW  - ischemia/reperfusion
KW  - neutrophil
KW  - ceramide
KW  - homolog
KW  - mice
KW  - mechanisms
KW  - recovery
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-410885
SN  - 1866-8372
IS  - 538
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  - GEN
A1  - Nojima, Hiroyuki
A1  - Konishi, Takanori
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
T2  - Hepatology : official journal of the American Association for the Study of Liver Diseases
Y1  - 2016
SN  - 0270-9139
SN  - 1527-3350
VL  - 64
SP  - 165A
EP  - 165A
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - GEN
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
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1120 
KW  - chronic psychosocial stress
KW  - acid sphingomyelinase
KW  - ceramide
KW  - sphingolipid metabolism
KW  - chronic subordinate colony housing (CSC)
KW  - liver metabolism
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-446241
SN  - 1866-8372
IS  - 1120
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  - Ahlberg, Sebastian
A1  - Rancan, Fiorenza
A1  - Epple, Matthias
A1  - Loza, Kateryna
A1  - Höppe, David
A1  - Lademann, Jürgen
A1  - Vogt, Annika
A1  - Kleuser, Burkhard
A1  - Gerecke, Christian
A1  - Meinke, Martina C.
T1  - Comparison of different methods to study effects of silver nanoparticles on the pro- and antioxidant status of human keratinocytes and fibroblasts
JF  - Methods : focusing on rapidly developing techniques
KW  - Oxidative stress
KW  - Dichlorofluorescein assay
KW  - Electron paramagnetic resonance spectroscopy
KW  - HaCaT cells
KW  - Glutathione
KW  - Free radicals
Y1  - 2016
U6  - https://doi.org/10.1016/j.ymeth.2016.05.015
SN  - 1046-2023
SN  - 1095-9130
VL  - 109
SP  - 55
EP  - 63
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - JOUR
A1  - Frombach, Janna
A1  - Unbehauen, Michael
A1  - Kurniasih, Indah N.
A1  - Schumacher, Fabian
A1  - Volz, Pierre
A1  - Hadam, Sabrina
A1  - Rancan, Fiorenza
A1  - Blume-Peytavi, Ulrike
A1  - Kleuser, Burkhard
A1  - Haag, Rainer
A1  - Alexiev, Ulrike
A1  - Vogt, Annika
T1  - Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin
JF  - Journal of controlled release
N2  - In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 mu g DXM/cm(2) skin encapsulated in CMS-NC (12 nm diameter, 5.8% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25% CD1a(+) cells were found within the epidermal CMS-NC+ population compared to approximately 3% CD1a(+)/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial.
KW  - Drug delivery
KW  - Skin penetration
KW  - Cellular uptake
KW  - Nanoparticles
KW  - Dendritic cells
KW  - High resolution microscopy
Y1  - 2019
U6  - https://doi.org/10.1016/j.jconrel.2019.02.028
SN  - 0168-3659
SN  - 1873-4995
VL  - 299
SP  - 138
EP  - 148
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - CHAP
A1  - Natek, M.
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
A1  - Schäfer-Korting, M.
A1  - Weindl, G.
T1  - CpG-oligonucleotides modulate sphingosine-1-phosphate metabolism in normal human keratinocytes
T2  - The journal of investigative dermatology
Y1  - 2012
SN  - 0022-202X
VL  - 132
IS  - 5
SP  - S112
EP  - S112
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Edlich, Alexander
A1  - Volz, Pierre
A1  - Brodwolf, Robert
A1  - Unbehauen, Michael
A1  - Mundhenk, Lars
A1  - Gruber, Achim D.
A1  - Hedtrich, Sarah
A1  - Haag, Rainer
A1  - Alexiev, Ulrike
A1  - Kleuser, Burkhard
T1  - Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin
JF  - Biomaterials : biomaterials reviews online
N2  - Owing their unique chemical and physical properties core-multishell (CMS) nanocarriers are thought to underlie their exploitable biomedical use for a topical treatment of skin diseases. This highlights the need to consider not only the efficacy of CMS nanocarriers but also the potentially unpredictable and adverse consequences of their exposure thereto. As CMS nanocarriers are able to penetrate into viable layers of normal and stripped human skin ex vivo as well as in in vitro skin disease models the understanding of nanoparticle crosstalk with components of the immune system requires thorough investigation. Our studies highlight the biocompatible properties of CMS nanocarriers on Langerhans cells of the skin as they did neither induce cytotoxicity and genotoxicity nor cause reactive oxygen species (ROS) or an immunological response. Nevertheless, CMS nanocarriers were efficiently taken up by Langerhans cells via divergent endocytic pathways. Bioimaging of CMS nanocarriers by fluorescence lifetime imaging microscopy (FLIM) and flow cytometry indicated not only a localization within the lysosomes but also an energy-dependent exocytosis of unmodified CMS nanocarriers into the extracellular environment. (C) 2018 Elsevier Ltd. All rights reserved.
KW  - Core-multishell nanocarriers
KW  - Fluorescence lifetime imaging microscopy
KW  - Langerhans cells
KW  - Nanoparticle uptake
KW  - Nanotoxicology
Y1  - 2018
U6  - https://doi.org/10.1016/j.biomaterials.2018.01.058
SN  - 0142-9612
SN  - 1878-5905
VL  - 162
SP  - 60
EP  - 70
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - GEN
A1  - Bäumer, Wolfgang
A1  - Rossbach, Kristine
A1  - Mischke, Reinhard
A1  - Reines, Ilka
A1  - Langbein-Detsch, Ines
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
T1  - Decreased concentration and enhanced metabolism of sphingosine-1-Phosphate in lesional skin of dogs with atopic dermatitis  disturbed Sphingosine-1-Phosphate homeostasis in atopic Dermatitis
T2  - The journal of investigative dermatology
Y1  - 2011
U6  - https://doi.org/10.1038/jid.2010.252
SN  - 0022-202X
VL  - 131
IS  - 1
SP  - 266
EP  - 268
PB  - Nature Publ. Group
CY  - New York
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  - Radbruch, Moritz
A1  - Pischon, Hannah
A1  - Ostrowski, Anja
A1  - Volz, Pierre
A1  - Brodwolf, Robert
A1  - Neumann, Falko
A1  - Unbehauen, Michael
A1  - Kleuser, Burkhard
A1  - Haag, Rainer
A1  - Ma, Nan
A1  - Alexiev, Ulrike
A1  - Mundhenk, Lars
A1  - Gruber, Achim D.
T1  - Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin
JF  - Nanoscale Research Letters
N2  - Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment. Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection. Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis. Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.
KW  - CMS
KW  - Skin
KW  - Topical treatment
KW  - Dermal delivery
KW  - Atopic dermatitis
KW  - Oxazolone
KW  - Fluorescence lifetime imaging microscopy
KW  - Nanomaterials
KW  - Multi-domain nanoparticles
KW  - Penetration enhancement
Y1  - 2017
U6  - https://doi.org/10.1186/s11671-017-1835-0
SN  - 1556-276X
VL  - 12
IS  - 64
PB  - Springer
CY  - New York
ER  - 
TY  - GEN
A1  - Radbruch, Moritz
A1  - Pischon, Hannah
A1  - Ostrowski, Anja
A1  - Volz, Pierre
A1  - Brodwolf, Robert
A1  - Neumann, Falko
A1  - Unbehauen, Michael
A1  - Kleuser, Burkhard
A1  - Haag, Rainer
A1  - Ma, Nan
A1  - Alexiev, Ulrike
A1  - Mundhenk, Lars
A1  - Gruber, Achim D.
T1  - Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin
T2  - Postprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe
N2  - Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment.

Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection.

Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis.

Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 724 
KW  - CMS
KW  - skin
KW  - topical treatment
KW  - dermal delivery
KW  - atopic dermatitis
KW  - oxazolone
KW  - fluorescence lifetime imaging microscopy
KW  - nanomaterials
KW  - multi-domain nanoparticles
KW  - penetration enhancement
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-430136
SN  - 1866-8372
IS  - 724
ER  - 
TY  - GEN
A1  - Rancan, Fiorenza
A1  - Volkmann, Hildburg
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Stanko, Jessica Isolde
A1  - Kleuser, Burkhard
A1  - Blume-Peytavi, Ulrike
A1  - Calderón, Marcelo
A1  - Vogt, Annika
T1  - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
T2  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1339 
KW  - tacrolimus formulation
KW  - nanogels
KW  - skin penetration
KW  - drug delivery
KW  - human excised skin
KW  - Jurkat cells
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-473270
SN  - 1866-8372
IS  - 1339
ER  - 
TY  - JOUR
A1  - Rancan, Fiorenza
A1  - Volkmann, Hildburg
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Stanko, Jessica Isolde
A1  - Kleuser, Burkhard
A1  - Blume-Peytavi, Ulrike
A1  - Calderon, Marcelo
A1  - Vogt, Annika
T1  - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
JF  - Pharmaceutics : Molecular Diversity Preservation International
N2  - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
KW  - tacrolimus formulation
KW  - nanogels
KW  - skin penetration
KW  - drug delivery
KW  - human excised skin
KW  - Jurkat cells
Y1  - 2019
U6  - https://doi.org/10.3390/pharmaceutics11080394
SN  - 1999-4923
VL  - 11
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Laeger, Thomas
A1  - Castano-Martinez, Teresa
A1  - Werno, Martin W.
A1  - Japtok, Lukasz
A1  - Baumeier, Christian
A1  - Jonas, Wenke
A1  - Kleuser, Burkhard
A1  - Schürmann, Annette
T1  - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - 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.
KW  - Energy expenditure
KW  - FGF21
KW  - Hyperglycaemia
KW  - Insulin resistance
KW  - NZO
KW  - Obesity
KW  - Protein restriction
Y1  - 2018
U6  - https://doi.org/10.1007/s00125-018-4595-1
SN  - 0012-186X
SN  - 1432-0428
VL  - 61
IS  - 6
SP  - 1459
EP  - 1469
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Kleuser, Burkhard
T1  - Divergent role of sphingosine 1-phosphate in liver health and disease
JF  - International journal of molecular sciences
N2  - Two decades ago, sphingosine 1-phosphate (S1P) was discovered as a novel bioactive molecule that regulates a variety of cellular functions. The plethora of S1P-mediated effects is due to the fact that the sphingolipid not only modulates intracellular functions but also acts as a ligand of G protein-coupled receptors after secretion into the extracellular environment. In the plasma, S1P is found in high concentrations, modulating immune cell trafficking and vascular endothelial integrity. The liver is engaged in modulating the plasma S1P content, as it produces apolipoprotein M, which is a chaperone for the S1P transport. Moreover, the liver plays a substantial role in glucose and lipid homeostasis. A dysfunction of glucose and lipid metabolism is connected with the development of liver diseases such as hepatic insulin resistance, non-alcoholic fatty liver disease, or liver fibrosis. Recent studies indicate that S1P is involved in liver pathophysiology and contributes to the development of liver diseases. In this review, the current state of knowledge about S1P and its signaling in the liver is summarized with a specific focus on the dysregulation of S1P signaling in obesity-mediated liver diseases. Thus, the modulation of S1P signaling can be considered as a potential therapeutic target for the treatment of hepatic diseases.
KW  - sphingolipids
KW  - sphingosine kinase
KW  - fibrosis
KW  - non-alcoholic fatty liver disease
KW  - insulin resistance
KW  - liver fibrosis
Y1  - 2018
U6  - https://doi.org/10.3390/ijms19030722
SN  - 1422-0067
VL  - 19
IS  - 3
PB  - MDPI
CY  - Basel
ER  -