@article{BeckmannKadowSchumacheretal.2018,
  author    = {Beckmann, Nadine and Kadow, Stephanie and Schumacher, Fabian and Goethert, Joachim R. and Kesper, Stefanie and Draeger, Annette and Schulz-Schaeffer, Walter J. and Wang, Jiang and Becker, Jan U. and Kramer, Melanie and Kuehn, Claudine and Kleuser, Burkhard and Becker, Katrin Anne and Gulbins, Erich and Carpinteiro, Alexander},
  title     = {Pathological manifestations of Farber disease in a new mouse model},
  series = {Biological chemistry},
  volume    = {399},
  journal   = {Biological chemistry},
  number    = {10},
  publisher = {De Gruyter},
  address   = {Berlin},
  issn      = {1431-6730},
  doi       = {10.1515/hsz-2018-0170},
  pages     = {1183 -- 1202},
  year      = {2018},
  abstract  = {Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments are clinically available and affected patients have a severely shortened lifespan. Due to the low incidence, the pathogenesis of FD is still poorly understood. Here, we report a novel acid ceramidase mutant mouse model that enables the study of pathogenic mechanisms of FD and ceramide accumulation. Asah1(tmEx1) mice were generated by deletion of the acid ceramidase signal peptide sequence. The effects on lysosomal targeting and activity of the enzyme were assessed. Ceramide and sphingomyelin levels were quantified by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and disease manifestations in several organ systems were analyzed by histology and biochemistry. We show that deletion of the signal peptide sequence disrupts lysosomal targeting and enzyme activity, resulting in ceramide and sphingomyelin accumulation. The affected mice fail to thrive and die early. Histiocytic infiltrations were observed in many tissues, as well as lung inflammation, liver fibrosis, muscular disease manifestations and mild kidney injury. Our new mouse model mirrors human FD and thus offers further insights into the pathogenesis of this disease. In the future, it may also facilitate the development of urgently needed therapies.},
  language  = {en}
}
@article{WienholdMacriNouaillesetal.2018,
  author    = {Wienhold, Sandra-Maria and Macri, Mario and Nouailles, Geraldine and Dietert, Kristina and Gurtner, Corinne and Gruber, Achim D. and Heimesaat, Markus M. and Lienau, Jasmin and Schumacher, Fabian and Kleuser, Burkhard and Opitz, Bastian and Suttorp, Norbert and Witzenrath, Martin and M{\"u}ller-Redetzky, Holger C.},
  title     = {Ventilator-induced lung injury is aggravated by antibiotic mediated microbiota depletion in mice},
  series = {Critical Care},
  volume    = {22},
  journal   = {Critical Care},
  number    = {282},
  publisher = {BMC},
  address   = {London},
  issn      = {1466-609X},
  doi       = {10.1186/s13054-018-2213-8},
  pages     = {12},
  year      = {2018},
  abstract  = {BackgroundAntibiotic exposure alters the microbiota, which can impact the inflammatory immune responses. Critically ill patients frequently receive antibiotic treatment and are often subjected to mechanical ventilation, which may induce local and systemic inflammatory responses and development of ventilator-induced lung injury (VILI). The aim of this study was to investigate whether disruption of the microbiota by antibiotic therapy prior to mechanical ventilation affects pulmonary inflammatory responses and thereby the development of VILI.MethodsMice underwent 6-8weeks of enteral antibiotic combination treatment until absence of cultivable bacteria in fecal samples was confirmed. Control mice were housed equally throughout this period. VILI was induced 3 days after completing the antibiotic treatment protocol, by high tidal volume (HTV) ventilation (34ml/kg; positive end-expiratory pressure=2 cmH(2)O) for 4h. Differences in lung function, oxygenation index, pulmonary vascular leakage, macroscopic assessment of lung injury, and leukocyte and lymphocyte differentiation were assessed. Control groups of mice ventilated with low tidal volume and non-ventilated mice were analyzed accordingly.ResultsAntibiotic-induced microbiota depletion prior to HTV ventilation led to aggravation of VILI, as shown by increased pulmonary permeability, increased oxygenation index, decreased pulmonary compliance, enhanced macroscopic lung injury, and increased cytokine/chemokine levels in lung homogenates.ConclusionsDepletion of the microbiota by broad-spectrum antibiotics prior to HTV ventilation renders mice more susceptible to developing VILI, which could be clinically relevant for critically ill patients frequently receiving broad-spectrum antibiotics.},
  language  = {en}
}
@article{MuellerFinkeEbertetal.2018,
  author    = {M{\"u}ller, S. M. and Finke, Hannah and Ebert, Franziska and Kopp, Johannes Florian and Schumacher, Fabian and Kleuser, Burkhard and Francesconi, Kevin A. and Raber, G. and Schwerdtle, Tanja},
  title     = {Arsenic-containing hydrocarbons},
  series = {Archives of toxicology : official journal of EUROTOX},
  volume    = {92},
  journal   = {Archives of toxicology : official journal of EUROTOX},
  number    = {5},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {0340-5761},
  doi       = {10.1007/s00204-018-2194-z},
  pages     = {1751 -- 1765},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{GulbinsSchumacherBeckeretal.2018,
  author    = {Gulbins, Anne and Schumacher, Fabian and Becker, Katrin Anne and Wilker, Barbara and Soddemann, Matthias and Boldrin, Francesco and M{\"u}ller, Christian P. and Edwards, Michael J. and Goodman, Michael and Caldwell, Charles C. and Kleuser, Burkhard and Kornhuber, Johannes and Szabo, Ildiko and Gulbins, Erich},
  title     = {Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide},
  series = {Molecular psychiatry},
  volume    = {23},
  journal   = {Molecular psychiatry},
  number    = {12},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {1359-4184},
  doi       = {10.1038/s41380-018-0090-9},
  pages     = {2324 -- 2346},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{ZabihiGraffSchumacheretal.2018,
  author    = {Zabihi, Fatemeh and Graff, Patrick and Schumacher, Fabian and Kleuser, Burkhard and Hedtrich, Sarah and Haag, Rainer},
  title     = {Synthesis of poly(lactide-co-glycerol) as a biodegradable and biocompatible polymer with high loading capacity for dermal drug delivery},
  series = {Nanoscale},
  volume    = {10},
  journal   = {Nanoscale},
  number    = {35},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {2040-3364},
  doi       = {10.1039/c8nr05536j},
  pages     = {16848 -- 16856},
  year      = {2018},
  abstract  = {Due to the low cutaneous bioavailability of tacrolimus (TAC), penetration enhancers are used to improve its penetration into the skin. However, poor loading capacity, non-biodegradability, toxicity, and in some cases inefficient skin penetration are challenging issues that hamper their applications for the dermal TAC delivery. Here we present poly(lactide-co-glycerol) (PLG) as a water soluble, biodegradable, and biocompatible TAC-carrier with high loading capacity (14.5\% w/w for TAC) and high drug delivery efficiencies into the skin. PLG was synthesized by cationic ring-opening copolymerization of a mixture of glycidol and lactide and showed 35 nm and 300 nm average sizes in aqueous solutions before and after loading of TAC, respectively. Delivery experiments on human skin, quantified by fluorescence microscopy and LC-MS/MS, showed a high ability for PLG to deposit Nile red and TAC into the stratum corneum and viable epidermis of skin in comparison with Protopic (R) (0.03\% w/w, TAC ointment). The cutaneous distribution profile of delivered TAC proved that 80\%, 16\%, and 4\% of the cutaneous drug level was deposited in the stratum corneum, viable epidermis, and upper dermis, respectively. TAC delivered by PLG was able to efficiently decrease the IL-2 and TSLP expressions in human skin models. Taking advantage of the excellent physicochemical and biological properties of PLG, it can be used for efficient dermal TAC delivery and potential treatment of inflammatory skin diseases.},
  language  = {en}
}
@misc{SchwerbelKamitzJaehnertetal.2018,
  author    = {Schwerbel, Kristin and Kamitz, Anne and Jaehnert, Markus and Gottmann, P. and Schumacher, Fabian and Kleuser, Burkhard and Haltenhof, T. and Heyd, F. and Roden, Michael and Chadt, Alexandra and Al-Hasani, Hadi and Jonas, W. and Vogel, Heike and Sch{\"u}rmann, Annette},
  title     = {Two immune-related GTPases prevent from hepatic fat accumulation by inducing autophagy},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {61},
  journal   = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  pages     = {S259 -- S259},
  year      = {2018},
  language  = {en}
}
@article{GutbierSchoenrockEhrleretal.2018,
  author    = {Gutbier, Birgitt and Sch{\"o}nrock, Stefanie M. and Ehrler, Carolin and Haberberger, Rainer and Dietert, Kristina and Gruber, Achim D. and Kummer, Wolfgang and Michalick, Laura and Kuebler, Wolfgang M. and Hocke, Andreas C. and Szymanski, Kolja and Letsiou, Eleftheria and L{\"u}th, Anja and Schumacher, Fabian and Kleuser, Burkhard and Mitchell, Timothy J. and Bertrams, Wilhelm and Schmeck, Bernd and Treue, Denise and Klauschen, Frederick and Bauer, Torsten T. and T{\"o}nnies, Mario and Weissmann, Norbert and Hippenstiel, Stefan and Suttorp, Norbert and Witzenrath, Martin},
  title     = {Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2},
  series = {Critical care medicine},
  volume    = {46},
  journal   = {Critical care medicine},
  number    = {3},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  organization    = {CAPNETZ Study Grp},
  issn      = {0090-3493},
  doi       = {10.1097/CCM.0000000000002916},
  pages     = {e258 -- e267},
  year      = {2018},
  abstract  = {Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.},
  language  = {en}
}
@misc{ReichelRheinHofmannetal.2018,
  author    = {Reichel, Martin and Rhein, Cosima and Hofmann, Lena M. and Monti, Juliana and Japtok, Lukasz and Langgartner, Dominik and F{\"u}chsl, Andrea M. and Kleuser, Burkhard and Gulbins, Erich and Hellerbrand, Claus and Reber, Stefan O. and Kornhuber, Johannes},
  title     = {Chronic psychosocial stress in mice is associated with increased acid sphingomyelinase activity in liver and serum and with hepatic C16:0-ceramide accumulation},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe},
  number    = {1120},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-44624},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-446241},
  pages     = {10},
  year      = {2018},
  abstract  = {Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28\% (P = 0.006) and secretory Asm activity by 47\% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40\% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-alpha (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.},
  language  = {en}
}
@article{ReichelRheinHofmannetal.2018,
  author    = {Reichel, Martin and Rhein, Cosima and Hofmann, Lena M. and Monti, Juliana and Japtok, Lukasz and Langgartner, Dominik and F{\"u}chsl, Andrea M. and Kleuser, Burkhard and Gulbins, Erich and Hellerbrand, Claus and Reber, Stefan O. and Kornhuber, Johannes},
  title     = {Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation},
  series = {Frontiers in Psychiatry},
  volume    = {9},
  journal   = {Frontiers in Psychiatry},
  publisher = {Frontiers Research Foundation},
  address   = {Lausanne},
  issn      = {1664-0640},
  doi       = {10.3389/fpsyt.2018.00496},
  pages     = {8},
  year      = {2018},
  abstract  = {Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28\% (P = 0.006) and secretory Asm activity by 47\% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40\% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-alpha (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.},
  language  = {en}
}
@article{LaegerCastanoMartinezWernoetal.2018,
  author    = {Laeger, Thomas and Castano-Martinez, Teresa and Werno, Martin W. and Japtok, Lukasz and Baumeier, Christian and Jonas, Wenke and Kleuser, Burkhard and Sch{\"u}rmann, Annette},
  title     = {Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {61},
  journal   = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  number    = {6},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  doi       = {10.1007/s00125-018-4595-1},
  pages     = {1459 -- 1469},
  year      = {2018},
  abstract  = {Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ\%; CON) or low (4 kJ\%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.},
  language  = {en}
}
@article{RadbruchPischonOstrowskietal.2017,
  author    = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.},
  title     = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin},
  series = {Nanoscale Research Letters},
  volume    = {12},
  journal   = {Nanoscale Research Letters},
  number    = {64},
  publisher = {Springer},
  address   = {New York},
  issn      = {1556-276X},
  doi       = {10.1186/s11671-017-1835-0},
  pages     = {12},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{SahleGereckeKleuseretal.2017,
  author    = {Sahle, Fitsum Feleke and Gerecke, Christian and Kleuser, Burkhard and Bodmeier, Roland},
  title     = {Formulation and comparative in vitro evaluation of various dexamethasone-loaded pH-sensitive polymeric nanoparticles intended for dermal applications},
  series = {International Journal of Pharmaceutics},
  volume    = {516},
  journal   = {International Journal of Pharmaceutics},
  number    = {1-2},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0378-5173},
  doi       = {10.1016/j.ijpharm.2016.11.029},
  pages     = {21 -- 31},
  year      = {2017},
  abstract  = {pH-sensitive nanoparticles have a great potential for dermal and transfollicular drug delivery. In this study, pH-sensitive, dexamethasone-loaded Eudragit (R) L 100, Eudragit (R) L 100-55, Eudragit (R) S 100, HPMCP-50, HPMCP-55 and cellulose acetate phthalate nanoparticles were prepared by nanoprecipitation and characterized. The pH-dependent swelling, erosion, dissolution and drug release kinetics were investigated in vitro using dynamic light scattering and Franz diffusion cells, respectively. Their toxicity potential was assessed by the ROS and MTT assays. 100-700 nm nanoparticles with high drug loading and entrapment efficiency were obtained. The nanoparticles bear no toxicity potential. Cellulose phthalates nanoparticles were more sensitive to pH than acrylates nanoparticles. They dissolved in 10 mM pH 7.5 buffer and released > 80\% of the drug within 7 h. The acrylate nanoparticles dissolved in 40 mM pH 7.5 buffer and released 65-70\% of the drug within 7 h. The nanoparticles remained intact in 10 and 40 mM pH 6.0 buffers (HPMCP nanoparticles dissolved in 40 mM pH 6.0 buffer) and released slowly. The nanoparticles properties could be modulated by blending the different polymers. In conclusion, various pH-sensitive nanoparticles that could release differently on the skin surface and dissolve and release in the hair follicles were obtained.},
  language  = {en}
}
@misc{Kleuser2017,
  author    = {Kleuser, Burkhard},
  title     = {Medikamentennebenwirkungen auf Haut und Schleimhaut - allergische oder pharmakologisch erkl{\"a}rbare Reaktionen},
  series = {Allergologie},
  volume    = {40},
  journal   = {Allergologie},
  number    = {10},
  publisher = {Dustri-Verlag},
  address   = {Deisenhofen-M{\"u}nchen},
  issn      = {0344-5062},
  pages     = {420 -- 421},
  year      = {2017},
  language  = {de}
}
@article{KakkasserySkosyrskiLuethetal.2017,
  author    = {Kakkassery, Vinodh and Skosyrski, S. and L{\"u}th, A. and Kleuser, Burkhard and van der Giet, Maria and Tate, R. and Reinhard, J. and Faissner, Andreas and Joachim, Stephanie Christine and Kociok, N.},
  title     = {Etoposide Upregulates Survival Favoring Sphingosine-1-Phosphate in Etoposide-Resistant Retinoblastoma Cells},
  series = {Pathology \& Oncology Research},
  volume    = {25},
  journal   = {Pathology \& Oncology Research},
  number    = {1},
  publisher = {Springer},
  address   = {Dordrecht},
  issn      = {1219-4956},
  doi       = {10.1007/s12253-017-0360-x},
  pages     = {391 -- 399},
  year      = {2017},
  abstract  = {Improved knowledge of retinoblastoma chemotherapy resistance is needed to raise treatment efficiency. The objective of this study was to test whether etoposide alters glucosyl-ceramide, ceramide, sphingosine, and sphingosine-1-phosphate (sphingosine-1-P) levels in parental retinoblastoma cells (WERI Rb1) or their etoposide-resistant subclones (WERI EtoR). WERI Rb1 and WERI EtoR were incubated with 400 ng/ml etoposide for 24 h. Levels of glucosyl-ceramides, ceramides, sphingosine, sphingosine-1-P were detected by Q-TOF mass spectrometry. Statistical analysis was done by ANOVA followed by Tukey post-hoc test (p < 0.05). The mRNA expression of sphingolipid pathways enzymes in WERI Rb1, WERI EtoR and four human retinoblastoma tissue samples was analyzed by quantitative real-time PCR. Pathways enzymes mRNA expression confirmed similarities of human sphingolipid metabolism in both cell lines and tissue samples, but different relative expression. Significant up-regulation of sphingosine was seen in both cell lines (p < 0.001). Only sphingosine-1-P up-regulation was significantly increased in WERI EtoR (p < 0.01), but not in WERI Rb1 (p > 0.2). Both cell lines upregulate pro-apoptotic sphingosine after etoposide incubation, but only WERI EtoR produces additional survival favorable sphingosine-1-P. These data may suggest a role of sphingosine-1-P in retinoblastoma chemotherapy resistance, although this seems not to be the only resistance mechanism.},
  language  = {en}
}
@misc{HocherReichetzederDwiPutraetal.2017,
  author    = {Hocher, Berthold and Reichetzeder, Christoph and Dwi Putra, Sulistyo Emantoko and Slowinski, Torsten and Neuber, Corinna and Kleuser, Burkhard and Pfab, Thiemo},
  title     = {Increased global placental DNA methylation levels are associated with gestational diabetes},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-400914},
  pages     = {10},
  year      = {2017},
  abstract  = {Background: Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. Methods: Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. Results: Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46 \%; p = 0.013; ±SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9-5.3 \%), whereas the frequency in the fifth quintile was significantly higher (10.7 \%; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. Conclusions: This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors.},
  language  = {en}
}
@article{SchwiebsThomasKleuseretal.2017,
  author    = {Schwiebs, Anja and Thomas, Dominique Jeanette and Kleuser, Burkhard and Pfeilschifter, Josef and Radeke, Heinfried H.},
  title     = {Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells},
  series = {Mediators of inflammation},
  journal   = {Mediators of inflammation},
  publisher = {Hindawi Publishing Corp.},
  address   = {London},
  issn      = {0962-9351},
  doi       = {10.1155/2017/5187368},
  pages     = {10},
  year      = {2017},
  abstract  = {A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.},
  language  = {en}
}
@misc{RadbruchPischonOstrowskietal.2017,
  author    = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.},
  title     = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin},
  series = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe},
  number    = {724},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-43013},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-430136},
  pages     = {12},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}
@article{WallmeyerDietertSochorovaetal.2017,
  author    = {Wallmeyer, Leonie and Dietert, Kristina and Sochorova, Michaela and Gruber, Achim D. and Kleuser, Burkhard and Vavrova, Katerina and Hedtrich, Sarah},
  title     = {TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents},
  series = {Scientific reports},
  volume    = {7},
  journal   = {Scientific reports},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2045-2322},
  doi       = {10.1038/s41598-017-00670-2},
  pages     = {12},
  year      = {2017},
  abstract  = {Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4(+) T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.},
  language  = {en}
}
@article{ZhangSaidWischkeetal.2017,
  author    = {Zhang, Nan and Said, Andre and Wischke, Christian and Kral, Vivian and Brodwolf, Robert and Volz, Pierre and Boreham, Alexander and Gerecke, Christian and Li, Wenzhong and Neffe, Axel T. and Kleuser, Burkhard and Alexiev, Ulrike and Lendlein, Andreas and Sch{\"a}fer-Korting, Monika},
  title     = {Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles - Composition-dependent skin penetration enhancement of a dye probe and biocompatibility},
  series = {European Journal of Pharmaceutics and Biopharmaceutics},
  volume    = {116},
  journal   = {European Journal of Pharmaceutics and Biopharmaceutics},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0939-6411},
  doi       = {10.1016/j.ejpb.2016.10.019},
  pages     = {66 -- 75},
  year      = {2017},
  abstract  = {Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1\% and particle size ranged from 35 to 244 nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis. Hence, systematic variations of nanoparticle properties allows gaining insights into critical criteria for biocompatibility and functionality of novel nanocarriers for topical drug delivery and risks associated with environmental exposure.},
  language  = {en}
}
@article{GereckeEdlichGiulbudagianetal.2017,
  author    = {Gerecke, Christian and Edlich, Alexander and Giulbudagian, Michael and Schumacher, Fabian and Zhang, Nan and Said, Andre and Yealland, Guy and Lohan, Silke B. and Neumann, Falko and Meinke, Martina C. and Ma, Nan and Calderon, Marcelo and Hedtrich, Sarah and Schaefer-Korting, Monika and Kleuser, Burkhard},
  title     = {Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes},
  series = {Nanotoxicology},
  volume    = {11},
  journal   = {Nanotoxicology},
  publisher = {Routledge, Taylor \& Francis Group},
  address   = {Abingdon},
  issn      = {1743-5390},
  doi       = {10.1080/17435390.2017.1292371},
  pages     = {267 -- 277},
  year      = {2017},
  abstract  = {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.},
  language  = {en}
}