TY - THES A1 - Meyer, Sören T1 - Toxicity and toxicokinetics of arsenolipids and their metabolites Y1 - 2015 ER - TY - JOUR A1 - Kumar, Kevin K. A1 - Goodwin, Cody R. A1 - Uhouse, Michael A. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael A. A1 - McLean, John A. A1 - Bowman, Aaron B. T1 - Untargeted metabolic profiling identifies interactions between JF - Metallomics : integrated biometal science Y1 - 2015 U6 - https://doi.org/10.1039/c4mt00223g SN - 1756-5901 SN - 1756-591X VL - 7 IS - 2 SP - 363 EP - 370 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Chen, Pan A1 - DeWitt, Margaret R. A1 - Bornhorst, Julia A1 - Soares, Felix A. A1 - Mukhopadhyay, Somshuvra A1 - Bowman, Aaron B. A1 - Aschner, Michael A. T1 - Age- and manganese-dependent modulation of dopaminergic phenotypes in a JF - Metallomics : integrated biometal science Y1 - 2015 U6 - https://doi.org/10.1039/c4mt00292j SN - 1756-5901 SN - 1756-591X VL - 7 IS - 2 SP - 289 EP - 298 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Dschietzig, Thomas Bernd A1 - Krause-Relle, Katharina A1 - Hennequin, Maud A1 - von Websky, Karoline A1 - Rahnenfuhrer, Jan A1 - Ruppert, Jana A1 - Groena, Hans Juergen A1 - Armbruster, Franz Paul A1 - Bathgate, Ross A. D. A1 - Aschenbach, Joerg R. A1 - Forssmann, Wolf-Georg A1 - Hocher, Berthold T1 - Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes JF - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie N2 - Background/Aims: In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide - is a candidate drug for both. Methods: Low-dose (32 mu g/kg/day) and high-dose (320 mu g/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Results: Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-beta pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. Conclusions: We investigated a model showing early DN without overt tubulo-interstitial fibrosis and activation of the TGF-beta-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes. KW - Diabetic nephropathy KW - Diabetic cardiomyopathy KW - Fibrosis KW - Inflammation KW - Relaxin Y1 - 2015 U6 - https://doi.org/10.1159/000368484 SN - 1420-4096 SN - 1423-0143 VL - 40 IS - 1 SP - 77 EP - 88 PB - Karger CY - Basel ER - TY - JOUR A1 - Chakraborty, Sudipta A1 - Chen, Pan A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Schumacher, Fabian A1 - Kleuser, Burkhard A1 - Bowman, Aaron B. A1 - Aschner, Michael A. T1 - Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C-elegans JF - Metallomics : integrated biometal science Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00052a SN - 1756-5901 SN - 1756-591X VL - 7 IS - 5 SP - 847 EP - 856 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Hasselhoff, Görge K. T1 - Midrash Unbound. Transformations and Innovations JF - Zeitschrift für Religions- und Geistesgeschichte Y1 - 2015 SN - 0044-3441 VL - 67 IS - 2 SP - 205 EP - 206 PB - Brill CY - Leiden ER - TY - JOUR A1 - Crone, Barbara A1 - Aschner, Michael A. A1 - Schwerdtle, Tanja A1 - Karst, Uwe A1 - Bornhorst, Julia T1 - Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS JF - Metallomics : integrated biometal science N2 - cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 mm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose) metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00096c SN - 1756-5901 SN - 1756-591X VL - 7 IS - 7 SP - 1189 EP - 1195 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Meyer, Sören A1 - Raber, Georg A1 - Ebert, Franziska A1 - Leffers, L. A1 - Mueller, Sandra Maria A1 - Taleshi, M. S. A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - In vitro toxicological characterisation of arsenic-containing fatty acids and three of their metabolites JF - Toxicology research N2 - Arsenic-containing fatty acids are a group of fat-soluble arsenic species (arsenolipids) which are present in marine fish and other seafood. Recently, it has been shown that arsenic-containing hydrocarbons, another group of arsenolipids, exert toxicity in similar concentrations comparable to arsenite although the toxic modes of action differ. Hence, a risk assessment of arsenolipids is urgently needed. In this study the cellular toxicity of a saturated (AsFA 362) and an unsaturated (AsFA 388) arsenic-containing fatty acid and three of their proposed metabolites (DMA(V), DMAPr and thio-DMAPr) were investigated in human liver cells (HepG2). Even though both arsenic-containing fatty acids were less toxic as compared to arsenic-containing hydrocarbons and arsenite, significant effects were observable at mu M concentrations. DMA(V) causes effects in a similar concentration range and it could be seen that it is metabolised to its highly toxic thio analogue thio-DMA(V) in HepG2 cells. Nevertheless, DMAPr and thio-DMAPr did not exert any cytotoxicity. In summary, our data indicate that risks to human health related to the presence of arsenic-containing fatty acids in marine food cannot be excluded. This stresses the need for a full in vitro and in vivo toxicological characterisation of these arsenolipids. Y1 - 2015 U6 - https://doi.org/10.1039/c5tx00122f SN - 2045-452X SN - 2045-4538 VL - 4 IS - 5 SP - 1289 EP - 1296 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Peng, Tao A1 - Zhu, Ganghua A1 - Dong, Yunpeng A1 - Zeng, Junjie A1 - Li, Wei A1 - Guo, Weiwei A1 - Chen, Yong A1 - Duan, Maoli A1 - Hocher, Berthold A1 - Xie, Dinghua T1 - BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Previous studies have shown that BMP4 may play an important part in the development of auditory neurons (ANs), which are degenerated in sensorineural hearing loss. However, whether BMP4 can promote sensory fate specification from mesenchymal stromal cells (MSCs) is unknown so far. Methods: MSCs isolated from Sprague-Dawley (SD) rats were confirmed by expression of MSC markers using flow cytometry and adipogenesis/osteogenesis using differentiation assays. MSCs treated with a complex of neurotrophic factors (BMP4 group and non-BMP4 group) were induced into auditory neuron-like cells, then the differences between the two groups were analyzed in morphological observation, cell growth curve, qRT-PCR, and immunofluorescence. Results: Flow cytometric analysis showed that the isolated cells expressed typical MSC surface markers. After adipogenic and osteogenic induction, the cells were stained by oil red O and Alizarin Red. The neuronal induced cells were in the growth plateau and had special forms of neurons. In the presence of BMP4, the inner ear genes NF-M, Neurog1, GluR4, NeuroD, Calretinin, NeuN, Tau, and GATA3 were up-regulated in MSCs. Conclusions: MSCs have the capacity to differentiate into auditory neuron-like cells in vitro. As an effective inducer, BMP4 may play a key role in transdifferentiation. KW - differentiation KW - auditory neurons KW - BMP4 Y1 - 2015 U6 - https://doi.org/10.7754/Clin.Lab.2015.150217 SN - 1433-6510 VL - 61 IS - 9 SP - 1171 EP - 1178 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER - TY - JOUR A1 - Lohren, Hanna A1 - Bornhorst, Julia A1 - Galla, Hans-Joachim A1 - Schwerdtle, Tanja T1 - The blood-cerebrospinal fluid barrier - first evidence for an active transport of organic mercury compounds out of the brain JF - Metallomics : integrated biometal science N2 - Exposure to organic mercury compounds promotes primarily neurological effects. Although methylmercury is recognized as a potent neurotoxicant, its transfer into the central nervous system (CNS) is not fully evaluated. While methylmercury and thiomersal pass the blood-brain barrier, limited data are available regarding the second brain regulating interface, the blood-cerebrospinal fluid (CSF) barrier. This novel study was designed to investigate the effects of organic as well as inorganic mercury compounds on, and their transfer across, a porcine in vitro model of the blood-CSF barrier for the first time. The barrier system is significantly more sensitive towards organic Hg compounds as compared to inorganic compounds regarding the endpoints cytotoxicity and barrier integrity. Whereas there are low transfer rates from the blood side to the CSF side, our results strongly indicate an active transfer of the organic mercury compounds out of the CSF. These results are the first to demonstrate an efflux of organic mercury compounds regarding the CNS and provide a completely new approach in the understanding of mercury compounds specific transport. Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00171d SN - 1756-5901 SN - 1756-591X VL - 7 IS - 10 SP - 1420 EP - 1430 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Lohren, Hanna A1 - Blagojevic, Lara A1 - Fitkau, Romy A1 - Ebert, Franziska A1 - Schildknecht, Stefan A1 - Leist, Marcel A1 - Schwerdtle, Tanja T1 - Toxicity of organic and inorganic mercury species in human neurons and human astrocytes JF - Journal of trace elements in medicine and biology N2 - Organic mercury (Hg) species exert their toxicity primarily in the central nervous system. The food relevant Hg species methylmercury (MeHg) has been frequently studied regarding its neurotoxic effects in vitro and in vivo. Neurotoxicity of thiomersal, which is used as a preservative in medical preparations, is to date less characterised. Due to dealkylation of organic Hg or oxidation of elemental Hg, inorganic Hg is present in the brain albeit these species are not able to readily cross the blood brain barrier. This study compared for the first time toxic effects of organic MeHg chloride (MeHgCl) and thiomersal as well as inorganic mercury chloride (HgCl2) in differentiated human neurons (LUHMES) and human astrocytes (CCF-STTG1). The three Hg species differ in their degree and mechanism of toxicity in those two types of brain cells. Generally, neurons are more susceptible to Hg species induced cytotoxicity as compared to astrocytes. This might be due to the massive cellular mercury uptake in the differentiated neurons. The organic compounds exerted stronger cytotoxic effects as compared to inorganic HgCl2. In contrast to HgCl2 exposure, organic Hg compounds seem to induce the apoptotic cascade in neurons following low-level exposure. No indicators for apoptosis were identified for both inorganic and organic mercury species in astrocytes. Our studies clearly demonstrate species-specific toxic mechanisms. A mixed exposure towards all Hg species in the brain can be assumed. Thus, prospectively coexposure studies as well as cocultures of neurons and astrocytes could provide additional information in the investigation of Hg induced neurotoxicity. KW - Methylmercury KW - Thiomersal KW - Mercuric mercury KW - Human differentiated neurons KW - Cytotoxicity KW - Apoptosis Y1 - 2015 U6 - https://doi.org/10.1016/j.jtemb.2015.06.008 SN - 0946-672X VL - 32 SP - 200 EP - 208 PB - Elsevier CY - Jena ER - TY - INPR A1 - Seelaender, Marilia A1 - Laviano, A. A1 - Busquets, S. A1 - Püschel, Gerhard Paul A1 - Margaria, T. A1 - Batista Jr., Miguel Luiz T1 - Inflammation in Cachexia T2 - Mediators of inflammation Y1 - 2015 U6 - https://doi.org/10.1155/2015/536954 SN - 0962-9351 SN - 1466-1861 PB - Hindawi Publishing Corp. CY - New York ER - TY - JOUR A1 - Tsuprykov, Oleg A1 - Chaykovska, Lyubov A1 - Kretschmer, Axel A1 - Stasch, Johannes-Peter A1 - Pfab, Thiemo A1 - Krause-Relle, Katharina A1 - Reichetzeder, Christoph A1 - Kalk, Philipp A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Endothelin-1 overexpression improves renal function in eNOS knockout mice JF - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology N2 - Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel KW - Chronic kidney disease KW - Endothelial nitric oxide synthase KW - Endothelin KW - Mice KW - Nitric oxide Y1 - 2015 U6 - https://doi.org/10.1159/000438516 SN - 1015-8987 SN - 1421-9778 VL - 37 IS - 4 SP - 1474 EP - 1490 PB - Karger CY - Basel ER - TY - JOUR A1 - Bruno, Gennaro A1 - Cencetti, Francesca A1 - Pertici, Irene A1 - Japtok, Lukasz A1 - Bernacchioni, Caterina A1 - Donati, Chiara A1 - Bruni, Paola T1 - CTGF/CCN2 exerts profibrotic action in myoblasts via the up-regulation of sphingosine kinase-1/S1P(3) signaling axis: Implications in the action mechanism of TGF beta JF - Biochimica et biophysica acta : Molecular and cell biology of lipids N2 - The matricellular protein connective tissue growth factor (CTGF/CCN2) is recognized as key player in the onset of fibrosis in various tissues, including skeletal muscle. In many circumstances, CTGF has been shown to be induced by transforming growth factor beta (TGF beta) and accounting, at least in part, for its biological action. In this study it was verified that in cultured myoblasts CTGF/CCN2 causes their transdifferentiation into myofibroblasts by up-regulating the expression of fibrosis marker proteins alpha-smooth muscle actin and transgelin. Interestingly, it was also found that the profibrotic effect exerted by CTGF/CCN2 was mediated by the sphingosine kinase (SK)-1/S1P(3) signaling axis specifically induced by the treatment with the profibrotic cue. Following CTGF/CCN2-induced up-regulation, S1P(3) became the SIP receptor subtype expressed at the highest degree, at least at mRNA level, and was thus capable of readdressing the sphingosine 1-phosphate signaling towards fibrosis rather than myogenic differentiation. Another interesting finding is that CTGF/CCN2 silencing prevented the TGF beta-dependent up-regulation of SKI/S1P(3) signaling axis and strongly reduced the profibrotic effect exerted by TGF beta, pointing at a crucial role of endogenous CTGF/CCN2 generated following TGF beta challenge in the transmission of at least part of its profibrotic effect These results provide new insights into the molecular mechanism by which CTGF/CCN2 drives its biological action and strengthen the concept that SK1/S1P(3) axis plays a critical role in the onset of fibrotic cell phenotype. (C) 2014 Elsevier B.V. All rights reserved. KW - Sphingosine kinase KW - S1P(3) receptor KW - Connective tissue growth factor KW - Myoblasts KW - Transforming growth factor beta Y1 - 2015 U6 - https://doi.org/10.1016/j.bbalip.2014.11.011 SN - 1388-1981 SN - 0006-3002 VL - 1851 IS - 2 SP - 194 EP - 202 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Chen, Xiaomin A1 - Baldermann, Susanne A1 - Cao, Shuyan A1 - Lu, Yao A1 - Liu, Caixia A1 - Hirata, Hiroshi A1 - Watanabe, Naoharu T1 - Developmental patterns of emission of scent compounds and related gene expression in roses of the cultivar Rosa x hybrida cv. 'Yves Piaget' JF - Plant physiology and biochemistry : an official journal of the Federation of European Societies of Plant Physiology N2 - 2-Phenylethanol (2PE) and 3,5-dimethoxytoluene (DMT) are characteristic scent compounds in specific roses such as Rosa x hybrida cv. 'Yves Piaget'. We analyzed the endogenous concentrations and emission of 2PE and DMT during the unfurling process in different floral organs, as well as changes in transcript levels of the two key genes, PAR and OOMT2. The emission of both 2PE and DMT increased during floral development to reach peaks at the fully unfurled stage. The relative transcripts of PAR and OOMT2 also increased during floral development. Whereas the maximum for OOMT2 was found at the fully unfurled stage (stage 4), similar expression levels of PAR were detected at stage 4 and the senescence stage (stage 6). The results demonstrate a positive correlation between the expression levels of PAR and OOMT2 and the emission of 2PE and DMT. In addition, endogenous volatiles and relative transcripts showed tissue- and development-specific patterns. (C) 2014 Elsevier Masson SAS. All rights reserved. KW - 2-Phenylethanol KW - 3,5-Dimethoxytoluene KW - Floral scent compound KW - Rosa x level Y1 - 2015 U6 - https://doi.org/10.1016/j.plaphy.2014.12.016 SN - 0981-9428 VL - 87 SP - 109 EP - 114 PB - Elsevier CY - Paris ER - TY - CHAP A1 - Wiesner, Melanie A1 - Barknowitz, Gitte A1 - Florian, Simone A1 - Haack, Michael A1 - Lehmann, Carsten A1 - Lippmann, Doris A1 - Mewis, Inga A1 - Schumacher, Fabian A1 - Brigelius-Flohé, Regina A1 - Schreiner, Monika A1 - Glatt, Hansruedi T1 - Pak Choi Fed to Mice: Formation of DNA Adducts and Influence on Xenobiotic-Metabolizing Enzymes T2 - NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY Y1 - 2015 SN - 0028-1298 SN - 1432-1912 VL - 388 SP - S68 EP - S68 PB - Springer CY - New York ER - TY - JOUR A1 - Schraplau, Anne A1 - Schewe, Bettina A1 - Neuschäfer-Rube, Frank A1 - Ringel, Sebastian A1 - Neuber, Corinna A1 - Kleuser, Burkhard A1 - Püschel, Gerhard Paul T1 - Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital JF - Toxicology N2 - Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. (C) 2014 Elsevier Ireland Ltd. All rights reserved. KW - Endocrine disruption KW - Xenobesity KW - Aryl-hydrocarbon receptor KW - Cyp2b1 KW - Thyroid hormone KW - UDP-glucuronosyltransferase Y1 - 2015 U6 - https://doi.org/10.1016/j.tox.2014.12.004 SN - 0300-483X VL - 328 SP - 21 EP - 28 PB - Elsevier CY - Clare ER - TY - JOUR A1 - van der Valk, Ralf J. P. A1 - Kreiner-Moller, Eskil A1 - Kooijman, Marjolein N. A1 - Guxens, Monica A1 - Stergiakouli, Evangelia A1 - Saaf, Annika A1 - Bradfield, Jonathan P. A1 - Geller, Frank A1 - Hayes, M. Geoffrey A1 - Cousminer, Diana L. A1 - Koerner, Antje A1 - Thiering, Elisabeth A1 - Curtin, John A. A1 - Myhre, Ronny A1 - Huikari, Ville A1 - Joro, Raimo A1 - Kerkhof, Marjan A1 - Warrington, Nicole M. A1 - Pitkanen, Niina A1 - Ntalla, Ioanna A1 - Horikoshi, Momoko A1 - Veijola, Riitta A1 - Freathy, Rachel M. A1 - Teo, Yik-Ying A1 - Barton, Sheila J. A1 - Evans, David M. A1 - Kemp, John P. A1 - St Pourcain, Beate A1 - Ring, Susan M. A1 - Smith, George Davey A1 - Bergstrom, Anna A1 - Kull, Inger A1 - Hakonarson, Hakon A1 - Mentch, Frank D. A1 - Bisgaard, Hans A1 - Chawes, Bo Lund Krogsgaard A1 - Stokholm, Jakob A1 - Waage, Johannes A1 - Eriksen, Patrick A1 - Sevelsted, Astrid A1 - Melbye, Mads A1 - van Duijn, Cornelia M. A1 - Medina-Gomez, Carolina A1 - Hofman, Albert A1 - de Jongste, Johan C. A1 - Taal, H. Rob A1 - Uitterlinden, Andre G. A1 - Armstrong, Loren L. A1 - Eriksson, Johan A1 - Palotie, Aarno A1 - Bustamante, Mariona A1 - Estivill, Xavier A1 - Gonzalez, Juan R. A1 - Llop, Sabrina A1 - Kiess, Wieland A1 - Mahajan, Anubha A1 - Flexeder, Claudia A1 - Tiesler, Carla M. T. A1 - Murray, Clare S. A1 - Simpson, Angela A1 - Magnus, Per A1 - Sengpiel, Verena A1 - Hartikainen, Anna-Liisa A1 - Keinanen-Kiukaanniemi, Sirkka A1 - Lewin, Alexandra A1 - Alves, Alexessander Da Silva Couto A1 - Blakemore, Alexandra I. F. A1 - Buxton, Jessica L. A1 - Kaakinen, Marika A1 - Rodriguez, Alina A1 - Sebert, Sylvain A1 - Vaarasmaki, Marja A1 - Lakka, Timo A1 - Lindi, Virpi A1 - Gehring, Ulrike A1 - Postma, Dirkje S. A1 - Ang, Wei A1 - Newnham, John P. A1 - Lyytikainen, Leo-Pekka A1 - Pahkala, Katja A1 - Raitakari, Olli T. A1 - Panoutsopoulou, Kalliope A1 - Zeggini, Eleftheria A1 - Boomsma, Dorret I. A1 - Groen-Blokhuis, Maria A1 - Ilonen, Jorma A1 - Franke, Lude A1 - Hirschhorn, Joel N. A1 - Pers, Tune H. A1 - Liang, Liming A1 - Huang, Jinyan A1 - Hocher, Berthold A1 - Knip, Mikael A1 - Saw, Seang-Mei A1 - Holloway, John W. A1 - Melen, Erik A1 - Grant, Struan F. A. A1 - Feenstra, Bjarke A1 - Lowe, William L. A1 - Widen, Elisabeth A1 - Sergeyev, Elena A1 - Grallert, Harald A1 - Custovic, Adnan A1 - Jacobsson, Bo A1 - Jarvelin, Marjo-Riitta A1 - Atalay, Mustafa A1 - Koppelman, Gerard H. A1 - Pennell, Craig E. A1 - Niinikoski, Harri A1 - Dedoussis, George V. A1 - Mccarthy, Mark I. A1 - Frayling, Timothy M. A1 - Sunyer, Jordi A1 - Timpson, Nicholas J. A1 - Rivadeneira, Fernando A1 - Bonnelykke, Klaus A1 - Jaddoe, Vincent W. V. T1 - A novel common variant in DCST2 is associated with length in early life and height in adulthood JF - Human molecular genetics N2 - Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height. Y1 - 2015 U6 - https://doi.org/10.1093/hmg/ddu510 SN - 0964-6906 SN - 1460-2083 VL - 24 IS - 4 SP - 1155 EP - 1168 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Draude, Felix A1 - Körsgen, Martin A1 - Pelster, Andreas A1 - Schwerdtle, Tanja A1 - Müthing, Johannes A1 - Arlinghaus, Heinrich F. T1 - Characterization of freeze-fractured epithelial plasma membranes on nanometer scale with ToF-SIMS JF - Analytical & bioanalytical chemistry N2 - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used to characterize the freeze-fracturing process of human epithelial PANC-1 and UROtsa cells. For this purpose, phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and phosphatidylserine standard samples were investigated to find specific signals with both high specificity and signal intensity. The results were used to investigate single cells of subconfluent cell layers prepared with a special silicon wafer sandwich preparation technique. This freeze-fracturing technique strips cell membranes off the cells, isolating them on opposing silicon wafer substrates. Criteria were found for defining regions with stripped off cell membranes and, on the opposing wafer, complementary regions with the remaining cells. Measured ethanolamine/choline and serine/choline ratios in these regions clearly showed that in the freeze-fracturing process, the lipid bilayer of the plasma membrane is split along its central zone. Accordingly, only the outer lipid monolayer is stripped off the cell, while the inner lipid monolayer remains attached to the cell on the opposing wafer, thus allowing detailed analysis of a single lipid monolayer. Furthermore, it could be shown that using different washing procedures did not influence the transmembrane lipid distribution. Under optimized preparation conditions, it became feasible to detect lipids with a lateral resolution of approximately 100 nm. The data indicate that ToF-SIMS would be a very useful technique to study with very high lateral resolution changes in lipid composition caused, for example, by lipid storage diseases or pharmaceuticals that interfere with the lipid metabolism. KW - ToF-SIMS imaging KW - Life science KW - Lipid KW - Freeze-fracturing KW - Membrane KW - Transmembrane asymmetry Y1 - 2015 U6 - https://doi.org/10.1007/s00216-014-8334-2 SN - 1618-2642 SN - 1618-2650 VL - 407 IS - 8 SP - 2203 EP - 2211 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Ong, Albert C. M. A1 - von Websky, Karoline A1 - Hocher, Berthold T1 - Endothelin and Tubulointerstitial Renal Disease JF - Seminars in nephrology N2 - All components of the endothelin (ET) system are present in renal tubular cells. In this review, we summarize current knowledge about ET and the most common tubular diseases: acute kidney injury (AKI) and polycystic kidney disease. AKI originally was called acute tubular necrosis, pointing to the most prominent morphologic findings. Similarly, cysts in polycystic kidney disease, and especially in autosomal-dominant polycystic kidney disease, are of tubular origin. Preclinical studies have indicated that the ET system and particularly ETA receptors are involved in the pathogenesis of ischemia-reperfusion injury, although these findings have not been translated to clinical studies. The ET system also has been implicated in radiocontrast-dye-induced AKI, however, ET-receptor blockade in a large human study was not successful. The ET system is activated in sepsis models of AKI; the effectiveness of ET blocking agents in preclinical studies is variable depending on the model and the ET-receptor antagonist used. Numerous studies have shown that the ET system plays an important role in the complex pathophysiology associated with cyst formation and disease progression in polycystic kidney disease. However, results from selective targeting of ET-receptor subtypes in animal models of polycystic kidney disease have proved disappointing and do not support clinical trials. These studies have shown that a critical balance between ETA and ETB receptor action is necessary to maintain structure and function in the cystic kidney. In summary, ETs have been implicated in the pathogenesis of several renal tubulointerstitial diseases, however, experimental animal findings have not yet led to use of ET blockers in human beings. (C) 2015 Elsevier Inc. All rights reserved. KW - Endothelin KW - acute kidney injury KW - polycystic kidney disease KW - ADPKD KW - ET-1 KW - ETA KW - ETB Y1 - 2015 U6 - https://doi.org/10.1016/j.semnephrol.2015.03.004 SN - 0270-9295 SN - 1558-4488 VL - 35 IS - 2 SP - 197 EP - 207 PB - Elsevier CY - Philadelphia ER -