@phdthesis{Meyer2015, author = {Meyer, S{\"o}ren}, title = {Toxicity and toxicokinetics of arsenolipids and their metabolites}, school = {Universit{\"a}t Potsdam}, pages = {152, VIII}, year = {2015}, language = {en} } @phdthesis{Prandi2015, author = {Prandi, Simone}, title = {Characterization of the expression and function of bitter taste receptor genes in gastrointestinal tissues}, school = {Universit{\"a}t Potsdam}, pages = {165}, year = {2015}, language = {en} } @phdthesis{Scherwinski2015, author = {Scherwinski, Ann-Christin}, title = {Die Phyllosph{\"a}re}, school = {Universit{\"a}t Potsdam}, pages = {83}, year = {2015}, language = {de} } @phdthesis{Jacobs2015, author = {Jacobs, Simone}, title = {Biological mechanisms of the association between proportions of fatty acids in erythrocyte membranes and type 2 diabetes risk in the EPIC-Potsdam-Study}, pages = {157}, year = {2015}, language = {en} } @phdthesis{Frenzel2015, author = {Frenzel, Sabine}, title = {Die Rolle der Umamirezeptoruntereinheit Tas1r1 jenseits ihrer gustatorischen Bedeutung}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-79502}, school = {Universit{\"a}t Potsdam}, pages = {XV, 172}, year = {2015}, abstract = {Aminos{\"a}uren sind lebensnotwendige Molek{\"u}le f{\"u}r alle Organismen. Ihre Erkennung im K{\"o}rper erm{\"o}glicht eine bedarfsgerechte Regulation ihrer Aufnahme und ihrer Verwertung. Welcher Chemosensor f{\"u}r diese Erkennung jedoch hauptverantwortlich ist, ist bisher unklar. In der vorliegenden Arbeit wurde die Rolle der Umamigeschmacksrezeptoruntereinheit Tas1r1 jenseits ihrer gustatorischen Bedeutung f{\"u}r die Aminos{\"a}uredetektion in der Mundh{\"o}hle untersucht. In der histologischen Tas1r1-Expressionsanalyse nichtgustatorischer Gewebe der Mauslinie Tas1r1-Cre/ROSA26-tdRFP wurde {\"u}ber die Detektion des Reporterproteins tdRFP die Expression des Tas1r1 in allen untersuchten Geweben (Speiser{\"o}hre, Magen, Darm, Bauchspeicheldr{\"u}se, Leber, Niere, Muskel- und Fettgewebe, Milz, Thymus, Lymphknoten, Lunge sowie Hoden) nachgewiesen. Mit Ausnahme von D{\"u}nndarm und Hoden gelang hierbei der Nachweis erstmals spezifisch auf zellul{\"a}rer Ebene. Caecum und Lymphknoten wurden zudem neu als Expressionsorte des Tas1r1 identifiziert. Trotz der beobachteten weiten Verbreitung des Tas1r1 im Organismus - unter anderem auch in Geweben, die f{\"u}r den Proteinstoffwechsel besonders relevant sind - waren im Zuge der durchgef{\"u}hrten Untersuchung potentieller extraoraler Funktionen des Rezeptors durch ph{\"a}notypische Charakterisierung der Mauslinie Tas1r1-BLiR nur schwache Auswirkungen auf Aminos{\"a}urestoffwechsel bzw. Stickstoffhaushalt im Falle eines Tas1r1-Knockouts detektierbar. W{\"a}hrend sich Ern{\"a}hrungsverhalten, Gesamtphysiologie, Gewebemorphologie sowie Futterverdaulichkeit unver{\"a}ndert zeigten, war die renale Stickstoffausscheidung bei Tas1r1-Knockout-M{\"a}usen auf eiweißarmer sowie auf eiweißreicher Di{\"a}t signifikant verringert. Eine {\"U}berdeckung der Auswirkungen des Tas1r1-Knockouts aufgrund kompensatorischer Effekte durch den Aminos{\"a}uresensor CaSR oder den Peptidsensor Gpr93 war nicht nachweisbar. Es bleibt offen, ob andere Mechanismen oder andere Chemosensoren an einer Kompensation beteiligt sind oder aber Tas1r1 in extraoralem Gewebe andere Funktionen als die der Aminos{\"a}uredetektion {\"u}bernimmt. Unterschiede im extraoralen Expressionsmuster der beiden Umamirezeptor-untereinheiten Tas1r1 und Tasr3 lassen Spekulationen {\"u}ber andere Partner, Liganden und Funktionen zu.}, language = {de} } @phdthesis{Bojahr2015, author = {Bojahr, Juliane}, title = {Aktivierung des humanen S{\"u}ßgeschmacksrezeptors im zellbasierten Testsystem}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-93331}, school = {Universit{\"a}t Potsdam}, pages = {XIII, 174}, year = {2015}, abstract = {Zellbasierte heterologe Expressionssysteme bieten ein einfaches und schnelles Verfahren, um neue S{\"u}ßstoffe oder S{\"u}ßverst{\"a}rker zu finden. Unter Verwendung eines solchen Testsystems, konnte ich in Zusammenarbeit mit der Symrise AG, Holzminden und dem Institut f{\"u}r Pflanzenbiochemie in Halle/Saale die vietnamesische Pflanze Mycetia balansae als Quelle eines neuen S{\"u}ßstoffs identifizieren. Deren Hauptkomponenten, genannt Balansine, aktivieren spezifisch den humanen S{\"u}ßrezeptor. Chim{\"a}re Rezeptoren zeigten, dass die amino-terminalen Dom{\"a}nen der S{\"u}ßrezeptoruntereinheiten, welche ein Großteil der Liganden des S{\"u}ßrezeptors binden, f{\"u}r dessen Aktivierung durch Balansin A nicht notwendig sind. Voraussetzung f{\"u}r die Anwendung zellbasierter Testsysteme zum Auffinden neuer S{\"u}ßstoffe ist jedoch, dass s{\"u}ße Substanzen gesichert identifiziert werden, w{\"a}hrend nicht s{\"u}ße Substanzen zuverl{\"a}ssig keine Rezeptoraktivierung aufweisen. W{\"a}hrend in HEK293 TAS1R2 TAS1R3To Galpha15i3-Zellen S{\"u}ßrezeptoraktivierung gegen{\"u}ber nicht s{\"u}ß schmeckenden Substanzen beobachtet wurde, konnte mit den HEK293PEAKrapid Galpha15-Zellen ein zuverl{\"a}ssiges Testsystem identifiziert, welches den S{\"u}ßgeschmack der untersuchten Substanzen widerspiegelte. Es fanden sich keine Hinweise, dass akzessorische Proteine oder verwandte Rezeptoren des S{\"u}ßrezeptors das unterschiedliche Verhalten der Zellen verursachen. Es konnte gezeigt werden, dass die Verwendung unterschiedlicher G-Proteine die Signalamplituden des S{\"u}ßrezeptors beeinflusst, die Unterschiede zwischen den Zellsystemen jedoch nicht vollst{\"a}ndig erkl{\"a}rt. Keine der untersuchten Galpha-Proteinchim{\"a}ren spiegelte die intrinsische S{\"u}ße der Substanzen wider. Wenn auch nicht urs{\"a}chlich f{\"u}r die Diskrepanz zwischen S{\"u}ßrezeptoraktivierung in vitro und S{\"u}ßgeschmack in vivo, so weisen die Ergebnisse dieser Arbeit auf eine Interaktion der S{\"u}ßrezeptoruntereinheiten mit dem humanen Calcium-sensing Rezeptor hin. Vanillin und Ethylvanillin konnten als neue Agonisten des Calcium-sensing Rezeptors identifiziert werden. Wie die vorliegende Arbeit zeigt, k{\"o}nnen sich kleine Unterschiede im Zellhintergrund deutlich auf die Funktionsweise heterolog exprimierter Rezeptoren auswirken. Dies zeigt wie wichtig die Wahl der Zellen f{\"u}r solche Screeningsysteme ist.}, language = {de} } @phdthesis{Brachs2015, author = {Brachs, Maria}, title = {Genome wide expression analysis and metabolic mechanisms predicting body weight maintenance}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-100767}, school = {Universit{\"a}t Potsdam}, pages = {106}, year = {2015}, abstract = {Obesity is a major health problem for many developing and industrial countries. Increasing rates reach almost 50 \% of the population in some countries and related metabolic diseases including cardiovascular events and T2DM are challenging the health systems. Adiposity, an increase in body fat mass, is a major hallmark of obesity. Adipose tissue is long known not only to store lipids but also to influence whole-body metabolism including food intake, energy expenditure and insulin sensitivity. Adipocytes can store lipids and thereby protect other tissue from lipotoxic damage. However, if the energy intake is higher than the energy expenditure over a sustained time period, adipose tissue will expand. This can lead to an impaired adipose tissue function resulting in higher levels of plasma lipids, which can affect other tissue like skeletal muscle, finally leading to metabolic complications. Several studies showed beneficial metabolic effects of weight reduction in obese subjects immediately after weight loss. However, weight regain is frequently observed along with potential negative effects on cardiovascular risk factors and a high intra-individual response. We performed a body weight maintenance study investigating the mechanisms of weight maintenance after intended WR. Therefore we used a low caloric diet followed by a 12-month life-style intervention. Comprehensive phenotyping including fat and muscle biopsies was conducted to investigate hormonal as well as metabolic influences on body weight regulation. In this study, we showed that weight reduction has numerous potentially beneficial effects on metabolic parameters. After 3-month WR subjects showed significant weight and fat mass reduction, lower TG levels as well as higher insulin sensitivity. Using RNA-Seq to analyse whole fat and muscle transcriptome a strong impact of weight reduction on adipose tissue gene expression was observed. Gene expression alterations over weight reduction included several cellular metabolic genes involved in lipid and glucose metabolism as well as insulin signalling and regulatory pathways. These changes were also associated with anthropometric parameters assigning body composition. Our data indicated that weight reduction leads to a decreased expression of several lipid catabolic as well as anabolic genes. Long-term body weight maintenance might be influenced by several parameters including hormones, metabolic intermediates as well as the transcriptional landscape of metabolic active tissues. Our data showed that genes involved in biosynthesis of unsaturated fatty acids might influence the BMI 18-month after a weight reduction phase. This was further supported by analysing metabolic parameters including RQ and FFA levels. We could show that subjects maintaining their lost body weight had a higher RQ and lower FFA levels, indicating increased metabolic flexibility in subjects. Using this transcriptomic approach we hypothesize that low expression levels of lipid synthetic genes in adipose tissue together with a higher mitochondrial activity in skeletal muscle tissue might be beneficial in terms of body weight maintenance.}, language = {en} } @unpublished{SeelaenderLavianoBusquetsetal.2015, author = {Seelaender, Marilia and Laviano, A. and Busquets, S. and P{\"u}schel, Gerhard Paul and Margaria, T. and Batista Jr., Miguel Luiz}, title = {Inflammation in Cachexia}, series = {Mediators of inflammation}, journal = {Mediators of inflammation}, publisher = {Hindawi Publishing Corp.}, address = {New York}, issn = {0962-9351}, doi = {10.1155/2015/536954}, pages = {2}, year = {2015}, language = {en} } @article{GereckeScholtkaLoewensteinetal.2015, author = {Gerecke, Christian and Scholtka, Bettina and Loewenstein, Yvonne and Fait, Isabel and Gottschalk, Uwe and Rogoll, Dorothee and Melcher, Ralph and Kleuser, Burkhard}, title = {Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer}, series = {Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft}, volume = {141}, journal = {Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft}, number = {12}, publisher = {Springer}, address = {New York}, issn = {0171-5216}, doi = {10.1007/s00432-015-1972-8}, pages = {2097 -- 2107}, year = {2015}, abstract = {Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer. Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9). A high methylation frequency of VIM (55.6 \%) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD). The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.}, language = {en} } @article{SchraplauScheweNeuschaeferRubeetal.2015, author = {Schraplau, Anne and Schewe, Bettina and Neusch{\"a}fer-Rube, Frank and Ringel, Sebastian and Neuber, Corinna and Kleuser, Burkhard and P{\"u}schel, Gerhard Paul}, title = {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}, series = {Toxicology}, volume = {328}, journal = {Toxicology}, publisher = {Elsevier}, address = {Clare}, issn = {0300-483X}, doi = {10.1016/j.tox.2014.12.004}, pages = {21 -- 28}, year = {2015}, abstract = {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.}, language = {en} } @article{KanaSopGouadoAchuetal.2015, author = {Kana-Sop, Marie Modestine and Gouado, Inocent and Achu, Mercy Bih and Van Camp, John and Zollo, Paul Henri Amvam and Schweigert, Florian J. and Oberleas, Donald and Ekoe, Tetanye}, title = {The Influence of Iron and Zinc Supplementation on the Bioavailability of Provitamin A Carotenoids from Papaya Following Consumption of a Vitamin A-Deficient Diet}, series = {Journal of nutritional science and vitaminology}, volume = {61}, journal = {Journal of nutritional science and vitaminology}, number = {3}, publisher = {Univ. of Tokyo Pr.}, address = {Tokyo}, issn = {0301-4800}, pages = {205 -- 214}, year = {2015}, abstract = {Iron deficiency anemia, zinc and vitamin A deficiencies are serious public health problems in Cameroon, as in many developing countries. Local vegetables which are sources of provitamin A carotenoids (PACs) can be used to improve vitamin A intakes. However, traditional meals are often unable to cover zinc and iron needs. The aim of this study was to determine the bioavailability of 3 PACs (alpha-carotene, beta-carotene, and beta-cryptoxanthin) in young men, who were fed with a vitamin A-free diet and received iron and zinc supplementation. Twelve healthy participants were divided into three groups and were supplemented with elemental iron (20 mg of iron fumarate), 20 mg of zinc sulfate or iron + zinc (20 mg of iron in the morning and 20 mg of zinc in the evening) for 11 d. They were given a vitamin A- and PAC-free diet from the 6th to the 11th day, followed by a test meal containing 0.55 kg of freshly peeled papaya as a source of PACs. Blood samples were collected four times successively on the 11th day (the test meal day), at TO (just after the test meal), after 2 h (T2), after 4 h (T4) and after 7 h (T7). Ultracentrifugation was used to isolate serum chylomicrons. Retinol appearance and PAC postprandial concentrations were determined. The supplementation with zinc, iron and iron+zinc influenced the chylomicron appearance of retinol and PACs differently as reflected by retention times and maximum absorption peaks. Iron led to highest retinol levels in the chylomicron. Zinc and iron+zinc supplements were best for optimal intact appearance of alpha-carotene, beta-carotene and beta-cryptoxanthin respectively. Supplementation with iron led to the greatest bioavailability of PACs from papaya and its conversion to retinol.}, language = {en} } @article{DanquahDobruckyFranketal.2015, author = {Danquah, Ina and Dobrucky, C. Lydia and Frank, Laura K. and Henze, Andrea and Amoako, Yaw A. and Bedu-Addo, George and Raila, Jens and Schulze, Matthias Bernd and Mockenhaupt, Frank P. and Schweigert, Florian J.}, title = {Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana}, series = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, volume = {102}, journal = {The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.}, number = {1}, publisher = {American Society for Nutrition, Inc.}, address = {Bethesda}, issn = {0002-9165}, doi = {10.3945/ajcn.114.101345}, pages = {207 -- 214}, year = {2015}, abstract = {Background: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension. Objective: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard. Design: A hospital-based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol. Results: VAD (retinol <1.05 mu mol/L) was present in 10\% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95\% CI: 0.08, 0,17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72\%) and prealbumin (22\%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30\%; urinary albumin: 5\%) but not to inflammation. Conclusions: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status.}, language = {en} } @article{ZirafiKimStaendkeretal.2015, author = {Zirafi, Onofrio and Kim, Kyeong-Ae and St{\"a}ndker, Ludger and Mohr, Katharina B. and Sauter, Daniel and Heigele, Anke and Kluge, Silvia F. and Wiercinska, Eliza and Chudziak, Doreen and Richter, Rudolf and M{\"o}pps, Barbara and Gierschik, Peter and Vas, Virag and Geiger, Hartmut and Lamla, Markus and Weil, Tanja and Burster, Timo and Zgraja, Andreas and Daubeuf, Francois and Frossard, Nelly and Hachet-Haas, Muriel and Heunisch, Fabian and Reichetzeder, Christoph and Galzi, Jean-Luc and Perez-Castells, Javier and Canales-Mayordomo, Angeles and Jimenez-Barbero, Jesus and Gimenez-Gallego, Guillermo and Schneider, Marion and Shorter, James and Telenti, Amalio and Hocher, Berthold and Forssmann, Wolf-Georg and Bonig, Halvard and Kirchhoff, Frank and M{\"u}nch, Jan}, title = {Discovery and Characterization of an Endogenous CXCR4 Antagonist}, series = {Cell reports}, volume = {11}, journal = {Cell reports}, number = {5}, publisher = {Cell Press}, address = {Cambridge}, issn = {2211-1247}, doi = {10.1016/j.celrep.2015.03.061}, pages = {737 -- 747}, year = {2015}, abstract = {CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.}, language = {en} } @article{MaschirowKhalafAlAubaidyetal.2015, author = {Maschirow, Laura and Khalaf, Kinda and Al-Aubaidy, Hayder A. and Jelinek, Herbert F.}, title = {Inflammation, coagulation, endothelial dysfunction and oxidative stress in prediabetes - Biomarkers as a possible tool for early disease detection for rural screening}, series = {Clinical biochemistry : official journal of the Canadian Society of Clinical Chemists}, volume = {48}, journal = {Clinical biochemistry : official journal of the Canadian Society of Clinical Chemists}, number = {9}, publisher = {Elsevier}, address = {Oxford}, issn = {0009-9120}, doi = {10.1016/j.clinbiochem.2015.02.015}, pages = {581 -- 585}, year = {2015}, abstract = {Objectives: This study aims to increase understanding of the connection between oxidative stress and inflammation in diabetes disease progression to provide a basis for investigating improved diagnostic possibilities, treatment and prevention of prediabetes. Design and methods: Differences in the level of biochemical markers of oxidative stress (erythrocyte GSH/GSSG and urinary 8-isoprostane), inflammation (CRP, IL-6), endothelial dysfunction (plasma homocysteine, urinary 8-hydroxy-2-deoxy-guanosine) and coagulation/fibrinolysis (C5a, D-Dimer) were determined in prediabetes and control subjects. Results: While no difference was found in the 8-isoprostane levels between the two groups, the erythrocyte GSH/GSSG ratio was significantly reduced in the prediabetes group compared to control, indicating increased oxidative stress in the prediabetic state. Both urinary 8-OHdG and surprisingly also plasma homocysteine were significantly elevated in the prediabetes group, indicating endothelial dysfunction. The inflammation markers were slightly elevated in the prediabetic subjects and the same trend was found for the coagulation/fibrinolysis markers C5a and D-Dimer. These results were however not significant. Conclusions: The small elevation of blood glucose levels in the prediabetic state may have a detectable influence on endothelial function as indicated by changes to 8-OHdG, indicating an increased DNA-damage and homocysteine release from endothelial cells. Increased oxidative stress as indicated by the reduced GSH/GSSG ratio is likely to be the link between the moderate hyperglycaemia in prediabetes and pathological changes in endothelial function, which in the long-term may promote atherogenesis and result in the development of cardiovascular disease. Early detection of prediabetes is essential to avoid diabetes development and the associated complications like cardiovascular disease. The GSH/GSSG ratio and biomarkers like urinary 8-OHdG and plasma homocysteine offer a possible tool for the assessment of prediabetes in prevention screenings. (C) 2015 The Authors. The Canadian Society of Clinical Chemists. Published by Elsevier Inc.}, language = {en} } @misc{PrueferKleuservanderGiet2015, author = {Pr{\"u}fer, Nicole and Kleuser, Burkhard and van der Giet, Markus}, title = {The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality}, series = {Biological chemistry}, volume = {396}, journal = {Biological chemistry}, number = {6-7}, publisher = {De Gruyter}, address = {Berlin}, issn = {1431-6730}, doi = {10.1515/hsz-2014-0192}, pages = {573 -- 583}, year = {2015}, abstract = {The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL's anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL's protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL's biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function.}, language = {en} } @article{SatwikoIkedaNakayamaetal.2015, author = {Satwiko, Muhammad Gahan and Ikeda, Koji and Nakayama, Kazuhiko and Yagi, Keiko and Hocher, Berthold and Hirata, Ken-Ichi and Emoto, Noriaki}, title = {Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension}, series = {Biochemical and biophysical research communications}, volume = {465}, journal = {Biochemical and biophysical research communications}, number = {3}, publisher = {Elsevier}, address = {San Diego}, issn = {0006-291X}, doi = {10.1016/j.bbrc.2015.08.002}, pages = {356 -- 362}, year = {2015}, abstract = {Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.}, language = {en} } @article{FruscalzoLonderoDriuletal.2015, author = {Fruscalzo, Arrigo and Londero, Ambrogio P. and Driul, Lorenza and Henze, Andrea and Tonutti, Laura and Ceraudo, Maria and Zanotti, Giuseppe and Berni, Rodolfo and Schweigert, Florian J. and Raila, Jens}, title = {First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus}, series = {Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine}, volume = {53}, journal = {Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine}, number = {10}, publisher = {De Gruyter}, address = {Berlin}, issn = {1434-6621}, doi = {10.1515/cclm-2014-0929}, pages = {1643 -- 1651}, year = {2015}, abstract = {Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy. Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean +/- SD: TTR 3.96 +/- 0.89 mu mol/L vs. 4.68 +/- 1.21 mu mol/L, RBP4 1.13 +/- 0.25 mu mol/L vs. 1.33 +/- 0.38 mu mol/L and ROH 1.33 +/- 0.17 mu mol/L vs. 1.62 +/- 0.29 mu mol/L, p < 0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p < 0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95\% CI 0.87-0.98, p < 0.05). Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.}, language = {en} } @inproceedings{ReichetzedervonWebskyTsuprykovetal.2015, author = {Reichetzeder, Christoph and von Websky, Karoline and Tsuprykov, Oleg and Antonenko, V. and Samarin, Azin Mohagheghi and Hocher, Berthold}, title = {Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {58}, booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, pages = {S34 -- S35}, year = {2015}, language = {en} } @article{LuckertHesselLenzeetal.2015, author = {Luckert, Claudia and Hessel, Stefanie and Lenze, Dido and Lampen, Alfonso}, title = {Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis}, series = {Toxicology in vitro}, volume = {29}, journal = {Toxicology in vitro}, number = {7}, publisher = {Elsevier}, address = {Oxford}, issn = {0887-2333}, doi = {10.1016/j.tiv.2015.06.021}, pages = {1669 -- 1682}, year = {2015}, abstract = {1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 mu M of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a vertical bar fold change vertical bar of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NF kappa B and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPAR alpha/gamma/delta were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. (C) 2015 Elsevier Ltd. All rights reserved.}, language = {en} } @article{NiehoffBauerKroegeretal.2015, author = {Niehoff, Ann-Christin and Bauer, Oliver Bolle and Kr{\"o}ger, Sabrina and Fingerhut, Stefanie and Schulz, Jacqueline and Meyer, S{\"o}ren and Sperling, Michael and Jeibmann, Astrid and Schwerdtle, Tanja and Karst, Uwe}, title = {Quantitative Bioimaging to Investigate the Uptake of Mercury Species in Drosophila melanogaster}, series = {Analytical chemistry}, volume = {87}, journal = {Analytical chemistry}, number = {20}, publisher = {American Chemical Society}, address = {Washington}, issn = {0003-2700}, doi = {10.1021/acs.analchem.5b02500}, pages = {10392 -- 10396}, year = {2015}, abstract = {The uptake of mercury species in the model organism Drosophila melanogaster was investigated by elemental bioimaging using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS). The mercury distribution in Drosophila melanogaster was analyzed for the three species mercury(II) chloride, methylmercury chloride, and thimerosal after intoxication. A respective analytical method was developed and applied to the analysis of the entire Drosophila melanogaster first, before a particular focus was directed to the cerebral areas of larvae and adult flies. For quantification of mercury, matrix-matched standards based on gelatin were prepared. Challenges of spatially dissolved mercury determination, namely, strong evaporation issues of the analytes and an inhomogeneous distribution of mercury in the standards due to interactions with cysteine containing proteins of the gelatin were successfully addressed by complexation with meso-2,3-dimercaptosuccinic acid (DMSA). No mercury was detected in the cerebral region for mercury(II) chloride, whereas both organic species showed the ability to cross the blood brain barrier. Quantitatively, the mercury level in the brain exceeded the fed concentration indicating mercury enrichment, which was approximately 3 times higher for methylmercury chloride than for thimerosal.}, language = {en} } @article{LuckertHesselLampenetal.2015, author = {Luckert, Claudia and Hessel, Stefanie and Lampen, Alfonso and Braeuning, Albert}, title = {Utility of an appropriate reporter assay: Heliotrine interferes with GAL4/upstream activation sequence-driven reporter gene systems}, series = {Analytical biochemistry : methods in the biological sciences}, volume = {487}, journal = {Analytical biochemistry : methods in the biological sciences}, publisher = {Elsevier}, address = {San Diego}, issn = {0003-2697}, doi = {10.1016/j.ab.2015.07.009}, pages = {45 -- 48}, year = {2015}, abstract = {Reporter gene assays are widely used for the assessment of transcription factor activation following xenobiotic exposure of cells. A critical issue with such assays is the possibility of interference of test compounds with the test system, for example, by direct inhibition of the reporter enzyme. Here we show that the pyrrolizidine alkaloid heliotrine interferes with reporter signals derived from GAL4-based nuclear receptor transactivation assays by a mechanism independent of luciferase enzyme inhibition. These data highlight the necessity to conduct proper control experiments in order to avoid perturbation of reporter assays by test chemicals. (C) 2015 Elsevier Inc. All rights reserved.}, language = {en} } @article{MeyerRaberEbertetal.2015, author = {Meyer, S{\"o}ren and Raber, Georg and Ebert, Franziska and Taleshi, Mojtaba S. and Francesconi, Kevin A. and Schwerdtle, Tanja}, title = {Arsenic-containing hydrocarbons and arsenic-containing fatty acids: Transfer across and presystemic metabolism in the Caco-2 intestinal barrier model}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {59}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {10}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201500286}, pages = {2044 -- 2056}, year = {2015}, abstract = {Scope: Arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) represent two classes of arsenolipids occurring naturally in marine food. Toxicological data are yet scarce and an assessment regarding the risk to human health has not been possible. Here, we investigated the transfer and presystemic metabolism of five arsenolipids in an intestinal barrier model. Methods and results: Three AsHCs and two AsFAs were applied to the Caco-2 intestinal barrier model. Thereby, the short-chain AsHCs reached up to 50\% permeability. Transport is likely to occur via passive diffusion. The AsFAs showed lower intestinal bioavailability, but respective permeabilities were still two to five times higher as compared to arsenobetaine or arsenosugars. Interestingly, AsFAs were effectively biotransformed while passing the in vitro intestinal barrier, whereas AsHCs were transported to the blood-facing compartment essentially unchanged. Conclusion: AsFAs can be presystemically metabolised and the amount of transferred arsenic is lower than that for AsHCs. In contrast, AsHCs are likely to be highly intestinally bioavailable to humans. Since AsHCs exert strong toxicity in vitro and in vivo, toxicity studies with experimental animals as well as a human exposure assessment are needed to assess the risk to human health related to the presence of AsHCs in seafood.}, language = {en} } @article{ReichelHoenigLiebischetal.2015, author = {Reichel, Martin and Hoenig, Stefanie and Liebisch, Gerhard and L{\"u}th, Anja and Kleuser, Burkhard and Gulbins, Erich and Schmitz, Gerd and Kornhuber, Johannes}, title = {Alterations of plasma glycerophospholipid and sphingolipid species in male alcohol-dependent patients}, series = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, volume = {1851}, journal = {Biochimica et biophysica acta : Molecular and cell biology of lipids}, number = {11}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1388-1981}, doi = {10.1016/j.bbalip.2015.08.005}, pages = {1501 -- 1510}, year = {2015}, abstract = {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.}, language = {en} } @article{ReinkensmeierBasslerSchlueteretal.2015, author = {Reinkensmeier, Annika and Bassler, Sara and Schlueter, Oliver and Rohn, Sascha and Rawel, Harshadrai Manilal}, title = {Characterization of individual proteins in pea protein isolates and air classified samples}, series = {Food research international}, volume = {76}, journal = {Food research international}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0963-9969}, doi = {10.1016/j.foodres.2015.05.009}, pages = {160 -- 167}, year = {2015}, abstract = {Generally, pea proteins are extracted at comparatively acidic or basic pH values to provide a basis for protein isolate production. Such processing steps result in partial denaturation of the proteins rendering them in most cases insoluble at food processing pH conditions and limiting their application in food products. Here, the comparison of the solubility properties of pea proteins in protein enriched fractions deriving from air classification is reported. Protein content, solubility, and physicochemical parameters of different fractions of the pea (Pisum sativum) variety 'Salamanca' were investigated as a function of pH using SDS-PAGE and surface hydrophobicity. Whole pea flour (20\% protein), air classified, protein-enriched pea flour (48\% protein), pea flour made from hulls (2.8\% protein), and pea protein isolate (81\% protein) served as test materials. Fractionation and pH value affected the composition and surface hydrophobicity of the proteins as well as the content of trypsin inhibitors. All samples showed a high buffering capacity in the range of pH 4 to 10. The direct comparison documents the comparatively better protein quality of the air classified, protein enriched pea fraction. The solubility of the pea protein isolate can be improved by using selected additives, giving new possibilities for plant protein application. Relevant technofunctional properties were determined and compared with two commercially available pea-based products (whole pea flour and an isolate). Water binding capacity was highest for the commercially available pea flour followed by the pea hull flour. Fat binding capacity remained more or less unchanged. (C) 2015 Elsevier Ltd. All rights reserved.}, language = {en} } @article{GroopCooperPerkovicetal.2015, author = {Groop, Per-Henrik and Cooper, Mark E. and Perkovic, Vlado and Sharma, Kumar and Schernthaner, Guntram and Haneda, Masakazu and Hocher, Berthold and Gordat, Maud and Cescutti, Jessica and Woerle, Hans-Juergen and von Eynatten, Maximilian}, title = {Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D trial}, series = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease}, volume = {12}, journal = {Diabetes \& vascular disease research : official journal of the International Society of Diabetes and Vascular Disease}, number = {6}, publisher = {Sage Publ.}, address = {London}, issn = {1479-1641}, doi = {10.1177/1479164115579002}, pages = {455 -- 462}, year = {2015}, abstract = {Efficacy, Safety \& Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5mg or placebo in addition to their stable glucose-lowering background therapy for 24weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24weeks with =0.05. MARLINA-T2D is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.}, language = {en} } @article{BaierPurschkeSchmittetal.2015, author = {Baier, Daniel and Purschke, Benedict and Schmitt, Christophe and Rawel, Harshadrai Manilal and Knorr, Dietrich}, title = {Effect of high pressure - low temperature treatments on structural characteristics of whey proteins and micellar caseins}, series = {Food chemistry}, volume = {187}, journal = {Food chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0308-8146}, doi = {10.1016/j.foodchem.2015.04.049}, pages = {354 -- 363}, year = {2015}, abstract = {In this study, structural changes in micellar caseins and whey proteins due to high pressure - low temperature treatments (HPLT) were investigated and compared to changes caused by high pressure treatments at room temperature. Whey protein isolate (WPI) solutions as well as micellar casein (MC) dispersions and mixtures were treated at 500 MPa (pH 7.0 and 5.8) at room temperature, -15 degrees C and -35 degrees C. Surface hydrophobicity and accessible thiol groups remained nearly unchanged after HPLT treatments whereas HP treatments at room temperature caused an unfolding of the WPI, resulting in an increase in surface hydrophobicity and exposure of the thiol groups. For HPLT treatments, distinct changes in the secondary structure (increase in the amount of beta-sheets) were observed while the tertiary structure remained unchanged. Large flocs, stabilized by hydrophobic interactions and hydrogen bonds, were formed in casein containing samples due to HPLT treatments. Depending on the pH and the applied HPLT treatment parameters, these interactions differed significantly from the interactions determined in native micelles. (C) 2015 Elsevier Ltd. All rights reserved.}, language = {en} } @article{SchmidtPourteauCandanetal.2015, author = {Schmidt, Alexander and Pourteau, Amaury and Candan, Osman and Oberh{\"a}nsli, Roland}, title = {Lu-Hf geochronology on cm-sized garnets using microsampling: New constraints on garnet growth rates and duration of metamorphism during continental collision (Menderes Massif, Turkey)}, series = {Earth \& planetary science letters}, volume = {432}, journal = {Earth \& planetary science letters}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0012-821X}, doi = {10.1016/j.epsl.2015.09.015}, pages = {24 -- 35}, year = {2015}, abstract = {This study shows Lu-Hf geochronology of zoned garnet crystals contained in mica schists from the southern Menderes Massif, Turkey. Selected samples are four 3-5 cm large garnet megacrysts of which several consecutive garnet shells have been sampled with a micro-saw and analyzed for dating. The results are used to extract growth rates of garnet, and also to improve the time constraint for Alpine-aged overprint of the Pan-African basement in the Menderes Massif. The new data provides a precise age determination for prograde Barrovian metamorphism in the southern Menderes Massif, which so far was placed between 63 and 27 Ma on the basis of mica Rb-Sr and Ar-Ar dating. This study provides new constraints crucial to the understanding of the tectonic evolution of southwest Anatolia and the Aegean realm, as it yields a shorter outline for Alpine aged continental collision.}, language = {en} } @article{DraudeKoersgenPelsteretal.2015, author = {Draude, Felix and K{\"o}rsgen, Martin and Pelster, Andreas and Schwerdtle, Tanja and M{\"u}thing, Johannes and Arlinghaus, Heinrich F.}, title = {Characterization of freeze-fractured epithelial plasma membranes on nanometer scale with ToF-SIMS}, series = {Analytical \& bioanalytical chemistry}, volume = {407}, journal = {Analytical \& bioanalytical chemistry}, number = {8}, publisher = {Springer}, address = {Heidelberg}, issn = {1618-2642}, doi = {10.1007/s00216-014-8334-2}, pages = {2203 -- 2211}, year = {2015}, abstract = {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.}, language = {en} } @phdthesis{Baumeier2015, author = {Baumeier, Christian}, title = {Dietary and Pharmacological Strategies for the Prevention and Treatment of Type 2 Diabetes in a Diabetes-Susceptible Mouse Model}, school = {Universit{\"a}t Potsdam}, pages = {148}, year = {2015}, language = {en} } @phdthesis{Bendadani2015, author = {Bendadani, Carolin}, title = {1-Methylpyren: Biotransformation und Gentoxizit{\"a}t}, school = {Universit{\"a}t Potsdam}, pages = {188}, year = {2015}, language = {en} } @phdthesis{Hiller2015, author = {Hiller, Franziska}, title = {Effekte des Selenstatus und des Selenoproteins Glutathionperoxidase 2 auf die experimentelle Colitis in M{\"a}usen}, school = {Universit{\"a}t Potsdam}, pages = {99}, year = {2015}, language = {de} } @phdthesis{Sarem2015, author = {Sarem, Zeinab}, title = {Regulation of IGF-1 bioactivity by dietary hormones, impact of glucagon and insulin-induced hypoglycemia}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-82198}, school = {Universit{\"a}t Potsdam}, pages = {IX, 64, IV, XIII}, year = {2015}, abstract = {Der Zusammenhang zwischen Ern{\"a}hrung und der Entwicklung von chronischen Krankenheiten wie metabolischem Syndrom, Diabetes mellitus, Krebs und kardiovaskul{\"a}ren Erkrankungen wurde untersucht. Ver{\"a}nderungen der GH-IGF-1 Achse in Verbindung mit ern{\"a}hrungsbedingten Erkrankungen wurden fr{\"u}her beschrieben. Das Wechselspiel zwischen GH, gesamt IGF-1 und verschiedenen hemmenden und stimulierenden IGF-1 bindenden Proteinen (IGFBPs) bestimmt die IGF-1 Bioaktivit{\"a}t, die als die F{\"a}higkeit von IGF-1 die Phosphorylierung von seinem Rezeptor und folglich seinem Signalsweg zu induzieren, identifiziert ist. Deshalb reicht die Messung der IGF-1 Bioaktivit{\"a}t aus, um {\"A}nderungen des GH-IGF-1 Systems darzustellen. Studien deuten darauf hin, dass proteinreiche Di{\"a}t, gekennzeichnet durch erh{\"o}hte Glukagonsekretion, und Insulin-induzierte Hypoglyk{\"a}mie die Sterblichkeit erh{\"o}hen, und die Mechanismen sind unklar. Sowohl Glukagon als auch Insulin-induzierte Hypoglyk{\"a}mie stimulieren die GH Sekretion. Das Ziel der vorliegenden Studie war, die Wirkung von Glucagon und Insulin-induzierter Hypoglyk{\"a}mie auf die IGF-1 -Bioaktivit{\"a}t als m{\"o}gliche Mechanismen zu characterizieren. In einer doppelblinden, Placebo-kontrollierten Studie wurde Glukagon intramuskul{\"a}r 13 Patienten mit T1DM (6 M{\"a}nner / 7 Frauen; [ BMI ] : 24,8 ± 0,95 kg / m2) , 11 {\"u}bergewichtigen Teilnehmern (OP ; 5/6 ; 34,4 ± 1,7 kg / m2) und 13 gesunden schlanken Teilnehmern (LP ; 6/7 ; 21,7 ± 0,6 kg / m2) administriert. Zw{\"o}lf {\"u}bergewichtige Teilnehmer (OP ; 6/6 ; 34,4 ± 1,7 kg / m2) und 13 gesunde schlanke Teilnehmer (LP ; 6/7 ; 21,7 ± 0,6 kg / m2) f{\"u}hrten Insulintoleranztests in einer weiteren doppelblinden, Plazebo- kontrollierten Studie durch. {\"A}nderungen des GH, gesamt-IGF-1, der IGF-bindenden Proteinen ( IGFBPs ) und der IGF-1-Bioaktivit{\"a}t wurden durch das zellbasierte KIRA-Verfahren gemessen. Außerdem wurde die Wechselwirkung zwischen den metabolischen Hormonen (Glucagon und Insulin) und GH-IGF-1-System auf der Transkriptionsebene mit prim{\"a}ren Maus-Hepatozyten untersucht. In dieser Arbeit verringerte Glukagon die IGF-1-Bioaktivit{\"a}t bei den Menschen unabh{\"a}ngig von k{\"o}rpereigenen Insulinspiegeln, h{\"o}chstwahrscheinlich durch Modulation des IGFBP-1 und -2. Die Glukagon-induzierte Reduktion der IGF-1-Bioaktivit{\"a}t stellt einen neuen Mechanismus der Wirkung von Glucagon auf die GH-Sekretion dar und kann als m{\"o}gliche Erkl{\"a}rung f{\"u}r die negativen Auswirkungen der proteinreichen Di{\"a}t im Zusammenhang auf das erh{\"o}hte kardiovaskul{\"a}re Risiko und die Mortalit{\"a}t vorgeschlagen werden. Zus{\"a}tzlich wurde die Insulin-induzierten Hypoglyk{\"a}mie eine Abnahme der IGF-1-Bioaktivit{\"a}t durch Hochregulierung von IGFBP-2 zugeordnet. Diese Ergebnisse k{\"o}nnen auf m{\"o}gliche und wenig erforschte Mechanismen zur Erl{\"a}uterung der starken Assoziation zwischen Hypoglyk{\"a}mie und erh{\"o}hter kardiovaskul{\"a}rer Mortalit{\"a}t bei diabetischen Patienten beziehen.}, language = {en} } @phdthesis{Sachse2015, author = {Sachse, Benjamin Christian Daniel}, title = {Metabolische Aktivierung und Inaktivierung der genotoxischen Nahrungsmittelinhaltsstoffe 5-Hydroxymethylfurfural und Furfurylalkohol in Mensch, Maus und Ratte}, pages = {I-IV, 172, i-v}, year = {2015}, language = {de} } @phdthesis{Fayyaz2015, author = {Fayyaz, Susann}, title = {Bedeutung bioaktiver Lipidderivate bei der Entstehung hepatischer Insulinresistenz}, pages = {173}, year = {2015}, language = {de} } @phdthesis{Lohren2015, author = {Lohren, Hanna}, title = {Mechanisms of mercury species-mediated neurotoxicity}, school = {Universit{\"a}t Potsdam}, pages = {141, viii}, year = {2015}, language = {en} } @phdthesis{Schiess2015, author = {Schiess, Sonja}, title = {Effects of glucotropaeolin and its breakdown product benzyl isothiocyanate on metabolic, endocrine, and inflammatory parameters in humans}, school = {Universit{\"a}t Potsdam}, pages = {115}, year = {2015}, language = {en} } @phdthesis{Honig2015, author = {Honig, Caroline}, title = {Optimal fibre trail for diabetes prevention}, school = {Universit{\"a}t Potsdam}, pages = {137}, year = {2015}, language = {de} } @article{TsuprykovChaykovskaKretschmeretal.2015, author = {Tsuprykov, Oleg and Chaykovska, Lyubov and Kretschmer, Axel and Stasch, Johannes-Peter and Pfab, Thiemo and Krause-Relle, Katharina and Reichetzeder, Christoph and Kalk, Philipp and Adamski, Jerzy and Hocher, Berthold}, title = {Endothelin-1 overexpression improves renal function in eNOS knockout mice}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {37}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000438516}, pages = {1474 -- 1490}, year = {2015}, abstract = {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}, language = {en} } @article{LohrenBlagojevicFitkauetal.2015, author = {Lohren, Hanna and Blagojevic, Lara and Fitkau, Romy and Ebert, Franziska and Schildknecht, Stefan and Leist, Marcel and Schwerdtle, Tanja}, title = {Toxicity of organic and inorganic mercury species in human neurons and human astrocytes}, series = {Journal of trace elements in medicine and biology}, volume = {32}, journal = {Journal of trace elements in medicine and biology}, publisher = {Elsevier}, address = {Jena}, issn = {0946-672X}, doi = {10.1016/j.jtemb.2015.06.008}, pages = {200 -- 208}, year = {2015}, abstract = {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.}, language = {en} } @article{IslamSchweigert2015, author = {Islam, Khan Md. Shaiful and Schweigert, Florian J.}, title = {Comparison of three spectrophotometric methods for analysis of egg yolk carotenoids}, series = {Food chemistry}, volume = {172}, journal = {Food chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0308-8146}, doi = {10.1016/j.foodchem.2014.09.045}, pages = {233 -- 237}, year = {2015}, abstract = {Carotenoids accumulated in the egg yolk are of importance for two reasons. Firstly they are important pigments influencing customer acceptance and secondly they are essential components with positive health effects either as antioxidants or as precursor of vitamin A. Different analytical methods are available to quantitatively identify carotenoids from egg yolk such as spectrophotometric methods described by AOAC (Association of Official Analytical Chemists) and HPLC (High Performance Liquid Chromatography). Both methods have in common that they are time consuming, need a laboratory environment and well trained technical operators. Recently, a rapid lab-independent spectrophotometric method (iCheck, BioAnalyt GmbH, Germany) has been introduced that claims to be less time consuming and easy to operate. The aim of the current study was therefore to compare the novel method with the two standard methods. Yolks of 80 eggs were analysed as aliquots by the three methods in parallel. While both spectrometric methods are only able measure total carotenoids as total beta-carotene, HPLC enables the determination of individual carotenoids such lutein, zeaxanthin, canthaxanthin, beta-carotene and beta-apocarotenoic ester. In general, total carotenoids levels as obtained by AOAC were in average 27\% higher than those obtained by HPLC. Carotenoid values obtained by the reference methods AOAC and HPLC are highly correlated with the iCheck method with r(2) of 0.99 and 0.94 for iCheck vs. AOAC and iCheck vs. HPLC, respectively (both p < 0.001). Bland Altman analysis showed that the novel iCheck method is comparable to the reference methods. In conclusion, the novel rapid and portable iCheck method is a valid and effective tool to determine total carotenoid of egg yolk under laboratory-independent conditions with little trained personal. (C) 2014 Elsevier Ltd. All rights reserved.}, language = {en} } @article{StaschSchlossmannHocher2015, author = {Stasch, Johannes-Peter and Schlossmann, Jens and Hocher, Berthold}, title = {Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence}, series = {Current opinion in pharmacology}, volume = {21}, journal = {Current opinion in pharmacology}, publisher = {Elsevier}, address = {Oxford}, issn = {1471-4892}, doi = {10.1016/j.coph.2014.12.014}, pages = {95 -- 104}, year = {2015}, abstract = {Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs sGC stimulators and activators are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments.}, language = {en} } @article{WieseEsatbeyogluWinterhalteretal.2015, author = {Wiese, Stefanie and Esatbeyoglu, Tuba and Winterhalter, Peter and Kruse, Hans-Peter and Winkler, Stephanie and Bub, Achim and Kulling, Sabine E.}, title = {Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: A randomized cross-over study in humans}, series = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, volume = {59}, journal = {Molecular nutrition \& food research : bioactivity, chemistry, immunology, microbiology, safety, technology}, number = {4}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1613-4125}, doi = {10.1002/mnfr.201400422}, pages = {610 -- 621}, year = {2015}, abstract = {Scope: Flavan-3-ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of (-)-epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross-over study in humans. Methods and results: Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC-MS and GC-MS/MS. Glucuronidated, sulfated, and methylated (-)-epicatechin and 5-(3',4'-dihydroxyphenyl)-valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4-hydroxy-5-(3',4'-dihydroxyphenyl) valeric acid and their conjugated metabolites were detected. The formation of 5-(3',4'-dihydroxyphenyl)-valerolactone and 4-hydroxy-5-(3',4'-dihydroxyphenyl) valeric acid varied largely between individuals as well as with the degree of polymerization of flavan-3-ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan-3-ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces. Conclusion: In addition to conjugated metabolites derived from the absorption of monomeric flavan-3-ols, 5-(3',4' -dihydroxyphenyl)-valerolactone represents an important in vivo metabolite of (-)-epicatechin and procyanidin B1 produced by the gut microbiota.}, language = {en} } @misc{OngvonWebskyHocher2015, author = {Ong, Albert C. M. and von Websky, Karoline and Hocher, Berthold}, title = {Endothelin and Tubulointerstitial Renal Disease}, series = {Seminars in nephrology}, volume = {35}, journal = {Seminars in nephrology}, number = {2}, publisher = {Elsevier}, address = {Philadelphia}, issn = {0270-9295}, doi = {10.1016/j.semnephrol.2015.03.004}, pages = {197 -- 207}, year = {2015}, abstract = {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.}, language = {en} } @inproceedings{ChenReichetzederFoelleretal.2015, author = {Chen, Hong and Reichetzeder, Christoph and F{\"o}ller, Michael and Slowinski, Torsten and Li, Jian and Chen, You-Peng and Lang, Florian and Hocher, Berthold}, title = {Maternal vitamin D deficiency and fetal programming}, series = {Acta physiologica : official journal of the Federation of European Physiological Societies}, volume = {213}, booktitle = {Acta physiologica : official journal of the Federation of European Physiological Societies}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {1748-1708}, pages = {155 -- 156}, year = {2015}, language = {en} } @article{vanderValkKreinerMollerKooijmanetal.2015, author = {van der Valk, Ralf J. P. and Kreiner-Moller, Eskil and Kooijman, Marjolein N. and Guxens, Monica and Stergiakouli, Evangelia and Saaf, Annika and Bradfield, Jonathan P. and Geller, Frank and Hayes, M. Geoffrey and Cousminer, Diana L. and Koerner, Antje and Thiering, Elisabeth and Curtin, John A. and Myhre, Ronny and Huikari, Ville and Joro, Raimo and Kerkhof, Marjan and Warrington, Nicole M. and Pitkanen, Niina and Ntalla, Ioanna and Horikoshi, Momoko and Veijola, Riitta and Freathy, Rachel M. and Teo, Yik-Ying and Barton, Sheila J. and Evans, David M. and Kemp, John P. and St Pourcain, Beate and Ring, Susan M. and Smith, George Davey and Bergstrom, Anna and Kull, Inger and Hakonarson, Hakon and Mentch, Frank D. and Bisgaard, Hans and Chawes, Bo Lund Krogsgaard and Stokholm, Jakob and Waage, Johannes and Eriksen, Patrick and Sevelsted, Astrid and Melbye, Mads and van Duijn, Cornelia M. and Medina-Gomez, Carolina and Hofman, Albert and de Jongste, Johan C. and Taal, H. Rob and Uitterlinden, Andre G. and Armstrong, Loren L. and Eriksson, Johan and Palotie, Aarno and Bustamante, Mariona and Estivill, Xavier and Gonzalez, Juan R. and Llop, Sabrina and Kiess, Wieland and Mahajan, Anubha and Flexeder, Claudia and Tiesler, Carla M. T. and Murray, Clare S. and Simpson, Angela and Magnus, Per and Sengpiel, Verena and Hartikainen, Anna-Liisa and Keinanen-Kiukaanniemi, Sirkka and Lewin, Alexandra and Alves, Alexessander Da Silva Couto and Blakemore, Alexandra I. F. and Buxton, Jessica L. and Kaakinen, Marika and Rodriguez, Alina and Sebert, Sylvain and Vaarasmaki, Marja and Lakka, Timo and Lindi, Virpi and Gehring, Ulrike and Postma, Dirkje S. and Ang, Wei and Newnham, John P. and Lyytikainen, Leo-Pekka and Pahkala, Katja and Raitakari, Olli T. and Panoutsopoulou, Kalliope and Zeggini, Eleftheria and Boomsma, Dorret I. and Groen-Blokhuis, Maria and Ilonen, Jorma and Franke, Lude and Hirschhorn, Joel N. and Pers, Tune H. and Liang, Liming and Huang, Jinyan and Hocher, Berthold and Knip, Mikael and Saw, Seang-Mei and Holloway, John W. and Melen, Erik and Grant, Struan F. A. and Feenstra, Bjarke and Lowe, William L. and Widen, Elisabeth and Sergeyev, Elena and Grallert, Harald and Custovic, Adnan and Jacobsson, Bo and Jarvelin, Marjo-Riitta and Atalay, Mustafa and Koppelman, Gerard H. and Pennell, Craig E. and Niinikoski, Harri and Dedoussis, George V. and Mccarthy, Mark I. and Frayling, Timothy M. and Sunyer, Jordi and Timpson, Nicholas J. and Rivadeneira, Fernando and Bonnelykke, Klaus and Jaddoe, Vincent W. V.}, title = {A novel common variant in DCST2 is associated with length in early life and height in adulthood}, series = {Human molecular genetics}, volume = {24}, journal = {Human molecular genetics}, number = {4}, publisher = {Oxford Univ. Press}, address = {Oxford}, organization = {Early Genetics Lifecourse, Genetic Invest ANthropometric, Early Growth Genetics EGG}, issn = {0964-6906}, doi = {10.1093/hmg/ddu510}, pages = {1155 -- 1168}, year = {2015}, abstract = {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.}, language = {en} } @article{DschietzigKrauseRelleHennequinetal.2015, author = {Dschietzig, Thomas Bernd and Krause-Relle, Katharina and Hennequin, Maud and von Websky, Karoline and Rahnenfuhrer, Jan and Ruppert, Jana and Groena, Hans Juergen and Armbruster, Franz Paul and Bathgate, Ross A. D. and Aschenbach, Joerg R. and Forssmann, Wolf-Georg and Hocher, Berthold}, title = {Relaxin-2 does not Ameliorate Nephropathy in an experimental model of Type-1 Diabetes}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, volume = {40}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000368484}, pages = {77 -- 88}, year = {2015}, abstract = {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.}, language = {en} } @article{MeyerRaberEbertetal.2015, author = {Meyer, S{\"o}ren and Raber, Georg and Ebert, Franziska and Leffers, L. and Mueller, Sandra Maria and Taleshi, M. S. and Francesconi, Kevin A. and Schwerdtle, Tanja}, title = {In vitro toxicological characterisation of arsenic-containing fatty acids and three of their metabolites}, series = {Toxicology research}, volume = {4}, journal = {Toxicology research}, number = {5}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {2045-452X}, doi = {10.1039/c5tx00122f}, pages = {1289 -- 1296}, year = {2015}, abstract = {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.}, language = {en} } @article{PengZhuDongetal.2015, author = {Peng, Tao and Zhu, Ganghua and Dong, Yunpeng and Zeng, Junjie and Li, Wei and Guo, Weiwei and Chen, Yong and Duan, Maoli and Hocher, Berthold and Xie, Dinghua}, title = {BMP4: a possible key factor in differentiation of auditory neuron-like cells from bone-derived mesenchymal stromal cells}, series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, volume = {61}, journal = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion}, number = {9}, publisher = {Clin Lab Publ., Verl. Klinisches Labor}, address = {Heidelberg}, issn = {1433-6510}, doi = {10.7754/Clin.Lab.2015.150217}, pages = {1171 -- 1178}, year = {2015}, abstract = {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.}, language = {en} } @phdthesis{Partosch2015, author = {Partosch, Falko}, title = {Computergest{\"u}tzte Analysen in der Toxikologie}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-82334}, school = {Universit{\"a}t Potsdam}, pages = {XVII, 131, ix}, year = {2015}, abstract = {Im Rahmen der EU-weiten REACH-Verordnung haben Alternativmethoden zum Tierversuch in der Toxikologie an Bedeutung gewonnen. Die Alternativmethoden gliedern sich auf in In-vitro- und In-silico-Methoden. In dieser Dissertation wurden verschiedene Konzepte der In-silico-Toxikologie behandelt. Die bearbeiteten Themen reichen von quantitativen Strukturaktivit{\"a}tsbeziehungen (QSAR) {\"u}ber eine neue Herangehensweise an das g{\"a}ngige Konzept zur Festlegung von Grenzwerten bis hin zu computerbasierten Modellierungen zum Alkohol- und Bisphenol-A-Stoffwechsel. Das Kapitel {\"u}ber QSAR befasst sich im Wesentlichen mit der Erstellung und Analyse einer Datenbank mit 878 Substanzen, die sich aus Tierversuchsstudien aus dem Archiv des Bundesinstituts f{\"u}r Risikobewertung zusammensetzt. Das Design wurde dabei an eine bereits bestehende Datenbank angepasst, um so einen m{\"o}glichst großen Datenpool zu generieren. In der Analyse konnte u.a. gezeigt werden, dass Stoffe mit niedrigerem Molekulargewicht ein erh{\"o}htes Potential f{\"u}r toxikologische Sch{\"a}den aufwiesen als gr{\"o}ßere Molek{\"u}le. Mit Hilfe des sogenannten TTC-Konzepts k{\"o}nnen Grenzwerte f{\"u}r Stoffe geringer Exposition festgelegt werden, zu denen keine toxikologischen Daten zur Verf{\"u}gung stehen. In dieser Arbeit wurden f{\"u}r die Stoffe dreier Datenbanken entsprechende Grenzwerte festgelegt. Es erfolgte zun{\"a}chst eine g{\"a}ngige strukturbasierte Aufteilung der Substanzen in die Kategorien "nicht toxisch", "m{\"o}glicherweise toxisch" und "eindeutig toxisch". Substanzen, die aufgrund ihrer Struktur in eine der drei Klassen eingeordnet werden, erhalten den entsprechenden Grenzwert. Da in die dritte Klasse auch Stoffe eingeordnet werden, deren Toxizit{\"a}t nicht bestimmbar ist, ist sie sehr groß. Daher wurden in dieser Arbeit die ersten beiden Klassen zusammengelgt, um einen gr{\"o}ßeren Datenpool zu erm{\"o}glichen. Eine weitere Neuerung umfasst die Erstellung eines internen Grenzwerts. Diese Vorgehensweise hat den Vorteil, dass der Expositionsweg herausgerechnet wird und somit beispielsweise Studien mit oraler Verabreichung mit Studien dermaler Verabreichung verglichen werden k{\"o}nnen. Mittels physiologisch basiertem kinetischem Modelling ist es m{\"o}glich, Vorg{\"a}nge im menschlichen K{\"o}rper mit Hilfe spezieller Software nachzuvollziehen. Durch diese Vorgehensweise k{\"o}nnen Expositionen von Chemikalien simuliert werden. In einem Teil der Arbeit wurden Alkoholexpositionen von gestillten Neugeborenen simuliert, deren M{\"u}tter unmittelbar zuvor alkoholische Getr{\"a}nke konsumiert hatten. Mit dem Modell konnte gezeigt werden, dass die Expositionen des Kindes durchweg gering waren. Nach einem Glas Wein wurden Spitzenkonzentrationen im Blut von Neugeborenen von 0,0034 Promille ermittelt. Zum Vergleich wurde die Exposition durch ein f{\"u}r S{\"a}uglinge zugelassenes alkoholhaltiges pflanzliches Arzneimittel simuliert. Hier wurden Spitzenkonzentrationen von 0,0141 Promille erreicht. Daher scheinen Empfehlungen wie gelegentlicher Konsum ohne sch{\"a}digende Wirkung auf das Kind wissenschaftlich fundiert zu sein. Ein weiteres Kinetik-Modell befasste sich mit dem Stoffwechsel von Bisphenol A. Teils widerspr{\"u}chliche Daten zur Belastung mit BPA in der wissenschaftlichen Literatur f{\"u}hren wiederholt zu Anregungen, den Grenzwert der Chemikalie anzupassen. Die Funktionalit{\"a}t der am Metabolismus beteiligten Enzyme kann je nach Individuum unterschiedlich ausgepr{\"a}gt sein. Mittels Modellings konnte hier gezeigt werden, dass dies maßgeblich dazu f{\"u}hrt, dass sich berechnete Plasmaspiegel von Individuen bis zu 4,7-fach unterscheiden. Die Arbeit konnte somit einen Beitrag zur Nutzung und Weiterentwicklung von In-silico-Modellen f{\"u}r diverse toxikologische Fragestellungen leisten.}, language = {de} } @article{SaguTchewonpiNsoHomannetal.2015, author = {Sagu Tchewonpi, Sorel and Nso, Emmanuel Jong and Homann, Thomas and Kapseu, Cesar and Rawel, Harshadrai Manilal}, title = {Extraction and purification of beta-amylase from stems of Abrus precatorius by three phase partitioning}, series = {Food chemistry}, volume = {183}, journal = {Food chemistry}, publisher = {Elsevier}, address = {Oxford}, issn = {0308-8146}, doi = {10.1016/j.foodchem.2015.03.028}, pages = {144 -- 153}, year = {2015}, abstract = {The stems of Abrus precatorius were used to extract a beta-amylase enriched fraction. A three phase partitioning method and a Doehlert design with 3 variables (ratio of crude extract/t-butanol, the ammonium sulphate saturation and pH) were used. The data was fitted in a second-order polynomial model and the parameters were optimized to enrich beta-amylase. Experimental responses for the modulation were recovery of activity and the purification factor. The optimal conditions were: a ratio of crude extract/t-butanol of 0.87 (v/v), saturation in ammonium sulphate of 49.46\% (w/v) and a pH of 5.2. An activity recovery of 156.2\% and a purification factor of 10.17 were found. The enriched enzyme was identified as a beta-amylase and its molecular weight was 60.1 kDa. K-m and V-max values were 79.37 mg/ml and 5.13 U/ml, respectively and the highest activity was registered at a temperature of 70 degrees C and a pH between 6 and 6.5. A significant stabilization of the beta-amylase was observed up to 65 degrees C. (C) 2015 Elsevier Ltd. All rights reserved.}, language = {en} }