TY - THES A1 - Meyer, Sören T1 - Toxicity and toxicokinetics of arsenolipids and their metabolites Y1 - 2015 ER - TY - THES A1 - Prandi, Simone T1 - Characterization of the expression and function of bitter taste receptor genes in gastrointestinal tissues Y1 - 2015 ER - TY - THES A1 - Scherwinski, Ann-Christin T1 - Die Phyllosphäre BT - eine Reservoir für humaneffektive Bakterien Y1 - 2015 ER - TY - THES A1 - Jacobs, Simone T1 - Biological mechanisms of the association between proportions of fatty acids in erythrocyte membranes and type 2 diabetes risk in the EPIC-Potsdam-Study Y1 - 2015 ER - TY - THES A1 - Frenzel, Sabine T1 - Die Rolle der Umamirezeptoruntereinheit Tas1r1 jenseits ihrer gustatorischen Bedeutung T1 - The role of the umami receptor subunit Tas1r1 beyond its gustatory importance BT - Analyse ihrer Expression und Funktion in nichtgustatorischen Geweben gentechnisch modifizierter Mauslinien N2 - Aminosäuren sind lebensnotwendige Moleküle für alle Organismen. Ihre Erkennung im Körper ermöglicht eine bedarfsgerechte Regulation ihrer Aufnahme und ihrer Verwertung. Welcher Chemosensor für diese Erkennung jedoch hauptverantwortlich ist, ist bisher unklar. In der vorliegenden Arbeit wurde die Rolle der Umamigeschmacksrezeptoruntereinheit Tas1r1 jenseits ihrer gustatorischen Bedeutung für die Aminosäuredetektion in der Mundhöhle untersucht. In der histologischen Tas1r1-Expressionsanalyse nichtgustatorischer Gewebe der Mauslinie Tas1r1-Cre/ROSA26-tdRFP wurde über die Detektion des Reporterproteins tdRFP die Expression des Tas1r1 in allen untersuchten Geweben (Speiseröhre, Magen, Darm, Bauchspeicheldrüse, Leber, Niere, Muskel- und Fettgewebe, Milz, Thymus, Lymphknoten, Lunge sowie Hoden) nachgewiesen. Mit Ausnahme von Dünndarm und Hoden gelang hierbei der Nachweis erstmals spezifisch auf zellulärer 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 für den Proteinstoffwechsel besonders relevant sind – waren im Zuge der durchgeführten Untersuchung potentieller extraoraler Funktionen des Rezeptors durch phänotypische Charakterisierung der Mauslinie Tas1r1-BLiR nur schwache Auswirkungen auf Aminosäurestoffwechsel bzw. Stickstoffhaushalt im Falle eines Tas1r1-Knockouts detektierbar. Während sich Ernährungsverhalten, Gesamtphysiologie, Gewebemorphologie sowie Futterverdaulichkeit unverändert zeigten, war die renale Stickstoffausscheidung bei Tas1r1-Knockout-Mäusen auf eiweißarmer sowie auf eiweißreicher Diät signifikant verringert. Eine Überdeckung der Auswirkungen des Tas1r1-Knockouts aufgrund kompensatorischer Effekte durch den Aminosäuresensor 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 Aminosäuredetektion übernimmt. Unterschiede im extraoralen Expressionsmuster der beiden Umamirezeptor-untereinheiten Tas1r1 und Tasr3 lassen Spekulationen über andere Partner, Liganden und Funktionen zu. N2 - Amino acids are important nutrients for each organism. Recognition of amino acids in the body enables an adequate regulation of their absorption and use. Until now, it is ambiguous which chemosensor is mainly responsible for this recognition. In the present work, the role of the umami taste receptor subunit Tas1r1 was examined beyond its gustatory importance for the amino acid detection in the oral cavity. By a histological expression analysis of non-gustatory tissues of the mouse strain Tas1r1-Cre/ROSA26-tdRFP, Tas1r1 expression has been proven in all of the analysed tissues (oesophagus, stomach, intestine, pancreas, liver, kidney, muscle and fat tissues, spleen, thymus, lymph nodes, lung and testes) via the detection of the reporter protein tdRFP. With the exception of small intestine and testes, the proof succeeded for the first time specifically at the cellular level. Moreover, caecum and lymph nodes were newly identified as expression sites of Tas1r1. Despite the observed widespread distribution of Tas1r1 in the organism – including tissues which are particularly relevant in protein metabolism – only slight effects on amino acid metabolism and nitrogen balance respectively were detectable in the course of examinations of potentially extraoral functions of the receptor by a phenotypical characterization of the mouse strain Tas1r1-BLiR. The renal nitrogen excretion of Tas1r1 knockout mice on low protein and also high protein diet was significantly reduced, whereas dietary habit, overall physiology, tissue morphology and food digestibility remained unchanged. A superposition of the Tas1r1 knockout impact due to compensatory effects by the amino acid sensor CaSR or the peptide sensor Gpr93 was unverifiable. It remains open whether other mechanisms or chemosensors are involved in compensation or whether Tas1r1 takes over other functions in extraoral tissues than the amino acid detection. Differences in the extraoral expression pattern of the two umami receptor subunits Tas1r1 and Tas1r3 leave room for speculations about other partners, ligands and functions. KW - Tas1r1 KW - Geschmacksrezeptor KW - taste receptor KW - umami KW - umami KW - Tas1r1 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-79502 ER - TY - THES A1 - Bojahr, Juliane T1 - Aktivierung des humanen Süßgeschmacksrezeptors im zellbasierten Testsystem T1 - Human sweet taste receptor activation in cell based assay N2 - Zellbasierte heterologe Expressionssysteme bieten ein einfaches und schnelles Verfahren, um neue Süßstoffe oder Süßverstärker zu finden. Unter Verwendung eines solchen Testsystems, konnte ich in Zusammenarbeit mit der Symrise AG, Holzminden und dem Institut für Pflanzenbiochemie in Halle/Saale die vietnamesische Pflanze Mycetia balansae als Quelle eines neuen Süßstoffs identifizieren. Deren Hauptkomponenten, genannt Balansine, aktivieren spezifisch den humanen Süßrezeptor. Chimäre Rezeptoren zeigten, dass die amino-terminalen Domänen der Süßrezeptoruntereinheiten, welche ein Großteil der Liganden des Süßrezeptors binden, für dessen Aktivierung durch Balansin A nicht notwendig sind. Voraussetzung für die Anwendung zellbasierter Testsysteme zum Auffinden neuer Süßstoffe ist jedoch, dass süße Substanzen gesichert identifiziert werden, während nicht süße Substanzen zuverlässig keine Rezeptoraktivierung aufweisen. Während in HEK293 TAS1R2 TAS1R3To Galpha15i3-Zellen Süßrezeptoraktivierung gegenüber nicht süß schmeckenden Substanzen beobachtet wurde, konnte mit den HEK293PEAKrapid Galpha15-Zellen ein zuverlässiges Testsystem identifiziert, welches den Süßgeschmack der untersuchten Substanzen widerspiegelte. Es fanden sich keine Hinweise, dass akzessorische Proteine oder verwandte Rezeptoren des Süßrezeptors das unterschiedliche Verhalten der Zellen verursachen. Es konnte gezeigt werden, dass die Verwendung unterschiedlicher G-Proteine die Signalamplituden des Süßrezeptors beeinflusst, die Unterschiede zwischen den Zellsystemen jedoch nicht vollständig erklärt. Keine der untersuchten Galpha-Proteinchimären spiegelte die intrinsische Süße der Substanzen wider. Wenn auch nicht ursächlich für die Diskrepanz zwischen Süßrezeptoraktivierung in vitro und Süßgeschmack in vivo, so weisen die Ergebnisse dieser Arbeit auf eine Interaktion der Süßrezeptoruntereinheiten 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, können sich kleine Unterschiede im Zellhintergrund deutlich auf die Funktionsweise heterolog exprimierter Rezeptoren auswirken. Dies zeigt wie wichtig die Wahl der Zellen für solche Screeningsysteme ist. N2 - Screening for new sweeteners or sweet taste modulators by the use of heterologous expression systems is an easy and fast way without time- and cost-intensive sensory studies. Using such cell based expression systems we could show that the main components of the so far undescribed Vietnamese plant Mycetia balansae activate specifically the human sweet taste receptor TAS1R2-TAS1R3. Analysis of chimeric receptors revealed that the TAS1R2-TAS1R3 amino-terminal domain is not involved in the sweet taste receptor activation by balansin A, one of the main components of Mycetia balansae. The usage of such heterologous expression systems strongly depends on their predictive value, e.g. neither false-positives nor false-negatives shall occur when screening for new sweeteners. However, HEK293 TAS1R2 TAS1R3To Galpha15i3 cells showed sweet taste receptor activation for substances that were not perceived as sweet by a sensory panel. The analysis of further cell based systems revealed the HEK293PEAKrapid Galpha15 cell line as a reliable test system that reflected the sweet taste of the analyzed test compounds. These cell systems differ in their heterologously expressed G protein. Nevertheless, this does not explain the different responses of the cell systems. Although the G protein influences their signal amplitudes, none of the analyzed G protein chimeras showed an activation pattern that reflected the sweet taste of the test compounds. No indication was found that accessory proteins or related receptors like the calcium sensing receptor or the GPRC6A are responsible for the different behavior of these cell systems. First hints for an interaction of the human calcium sensing receptor and the sweet taste receptor subunits were observed. Vanillin and Ethylvanillin were identified as new calcium sensing receptor agonists. It appears as small differences in cellular background can strongly influence on the function of heterologously expressed receptors. KW - Süßrezeptor KW - Süßgeschmack KW - Süßstoff KW - Rezeptorscreening KW - sweet taste KW - sweet taste receptor KW - sweetener KW - taste receptor screening KW - HEK293 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-93331 ER - TY - THES A1 - Brachs, Maria T1 - Genome wide expression analysis and metabolic mechanisms predicting body weight maintenance T1 - Genomweite Expressions-Analyse und metabolische Mechanismen bestimmen den Körpergewichtserhalt N2 - 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. N2 - Die Adipositas hat sich in den letzten Jahren zu einem deutlichen Gesundheitsproblem in Industrie- und Entwicklungsländern entwickelt. So sind in einigen Länder bis zu 50 % der Bevölkerung übergewichtig und Begleiterkrankungen wie Herzkreislauferkrankungen und Typ 2 Diabetes belasten das Gesundheitssystem. Ein Anstieg der Körperfettmasse spielt bei der Adipositas eine große Rolle. Mittlerweile ist bekannt, dass Fettgewebe nicht nur Lipide speichert, sondern auch den Gesamtmetabolismus wie Nahrungsaufnahme, Energieumsatz und Insulinsensitivität beeinflusst. Lipide werden in Adipozyten gespeichert und verhindern so eine vermehrte Fetteinlagerung in andere Gewebe. Somit stellt das Fettgewebe ein wichtiges Organ dar, das andere periphere Gewebe vor dem toxischen Effekt erhöhter Lipidspiegel schütz. Ist über einen längeren Zeitraum die Energiezufuhr höher als der Energieverbrauch, kommt es zu einer Expansion des Fettgewebes. Dies kann im weiteren Verlauf zu einer Dysfunktion der Adipozyten und des Fettgewebes führen. Erhöhte Lipidspiegel können dann nicht mehr im Fettgewebe gespeichert werden und es kommt zu einer Anreicherung in der Peripherie. Vor allem das Muskelgewebe und die Leber sind hiervon betroffen, was zu weiteren metabolischen Komplikationen führt. Eine Gewichtsreduktion führt in adipösen Personen zu einer Verbesserung zahlreicher metabolischer Parameter. Diverse Studien zeigten jedoch, dass nur ein geringer Anteil dieser Personen in der Lage waren, das reduzierte Körpergewicht zu erhalten. Diese Wiederzunahme des Körpergewichts führt unter anderem zu einer Erhöhung des kardiovaskulären Risikos. Im Allgemeinen ist eine hohe Variabilität bei der Gewichtsreduktion und der Wiederzunahme zu beobachten. Diese Arbeit basiert auf Daten einer Studie, die Effekte einer Gewichtsreduktion auf den Gewichtserhalt untersucht. Nach einer 3-monatigen Gewichtsreduktion mittels einer niederkalorischen Diät wurden die Probanden in Kontroll- und Interventionsgruppe eingeteilt. Anthropometrische sowie metabolische Parameter inklusive Muskel- und Fettgewebsbiopsien wurden erfasst. In dieser Studie konnte gezeigt werden, dass eine Gewichtsreduktion verschiedenste positive Auswirkungen auf den Metabolismus der Teilnehmer hat. Die Probanden zeigten nach 3-monatiger Gewichtsreduktion eine signifikante Reduktion des Körpergewichts und der Fettmasse, erniedrigte Triglyzerid Spiegel und eine verbesserte Insulinsensitivität. Mittels RNA-Seq konnten wir zusätzlich zeigen, dass eine Gewichtsreduktion deutliche Auswirkungen auf das Transkriptom des Fettgewebes besitzt. Unter anderem wurden Genexpressionsveränderungen im Bereich zell-metabolischer Gene wie Lipid- und Glukosestoffwechsel als auch im Bereich des Insulinsignalweges und regulatorischer Gene ermittelt. Diese Expressionsveränderungen zeigten auch einen Zusammenhang mit dem BMI. Unsere Daten weisen darauf hin, dass eine Gewichtsreduktion zu einer Erniedrigung der Expression von Genen im Fettstoffwechsel führt. Ein langfristiger Gewichtserhalt wird durch zahlreiche Parameter wie Hormone, Stoffwechselintermediate und vermutlich auch den transkriptionellen Zustand im metabolisch aktiven Gewebe beeinflusst. Die hier gezeigten Daten deuten darauf hin, dass Gene beteiligt in der Biosynthese von ungesättigten Fettsäuren den BMI 18 Monate nach einer Gewichtsreduktion beeinflussen. Weitere Analysen in Bezug auf den RQ und die FFA Spiegel bestätigen diese Daten. Wir konnten zeigen, dass der Gewichtserhalt mit einem erhöhten RQ und niedrigen FFA Spiegel korrelierten. Dies könnte auf eine erhöhte metabolische Flexibilität in Personen mit Gewichtserhalt hinweisen. Aufgrund dieser Daten spekulieren wir, dass eine niedrige Expression von Lipidsynthese-Genen im Fettgewebe zusammen mit einer erhöhten mitochondrialen Aktivität im Skeletmuskel einen positiven Einfluss auf einen langfristigen Gewichtserhalt besitzt. KW - obesity KW - body weight loss KW - RNA Sequencing KW - body weight maintenance KW - Adipositas KW - Körpergewichtsverlust KW - RNA Sequenzierung KW - Körpergewichsterhalt Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-100767 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 - Gerecke, Christian A1 - Scholtka, Bettina A1 - Loewenstein, Yvonne A1 - Fait, Isabel A1 - Gottschalk, Uwe A1 - Rogoll, Dorothee A1 - Melcher, Ralph A1 - Kleuser, Burkhard T1 - Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer JF - Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft N2 - 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. KW - Epigenetic KW - DNA methylation KW - Colon cancer KW - Colitis KW - Gastrointestinal tract KW - Biomarker Y1 - 2015 U6 - https://doi.org/10.1007/s00432-015-1972-8 SN - 0171-5216 SN - 1432-1335 VL - 141 IS - 12 SP - 2097 EP - 2107 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 - THES A1 - Partosch, Falko T1 - Computergestützte Analysen in der Toxikologie T1 - Computer-assisted analyses in toxicology BT - Anwendung von In-silico-Modellen und Nutzen in der Risikobewertung BT - application of in silico models and their use in risk assessment N2 - 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 Strukturaktivitätsbeziehungen (QSAR) über eine neue Herangehensweise an das gängige Konzept zur Festlegung von Grenzwerten bis hin zu computerbasierten Modellierungen zum Alkohol- und Bisphenol-A-Stoffwechsel. Das Kapitel über QSAR befasst sich im Wesentlichen mit der Erstellung und Analyse einer Datenbank mit 878 Substanzen, die sich aus Tierversuchsstudien aus dem Archiv des Bundesinstituts für Risikobewertung zusammensetzt. Das Design wurde dabei an eine bereits bestehende Datenbank angepasst, um so einen möglichst großen Datenpool zu generieren. In der Analyse konnte u.a. gezeigt werden, dass Stoffe mit niedrigerem Molekulargewicht ein erhöhtes Potential für toxikologische Schäden aufwiesen als größere Moleküle. Mit Hilfe des sogenannten TTC-Konzepts können Grenzwerte für Stoffe geringer Exposition festgelegt werden, zu denen keine toxikologischen Daten zur Verfügung stehen. In dieser Arbeit wurden für die Stoffe dreier Datenbanken entsprechende Grenzwerte festgelegt. Es erfolgte zunächst eine gängige strukturbasierte Aufteilung der Substanzen in die Kategorien "nicht toxisch", "möglicherweise 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 Toxizität nicht bestimmbar ist, ist sie sehr groß. Daher wurden in dieser Arbeit die ersten beiden Klassen zusammengelgt, um einen größeren Datenpool zu ermöglichen. 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 können. Mittels physiologisch basiertem kinetischem Modelling ist es möglich, Vorgänge im menschlichen Körper mit Hilfe spezieller Software nachzuvollziehen. Durch diese Vorgehensweise können Expositionen von Chemikalien simuliert werden. In einem Teil der Arbeit wurden Alkoholexpositionen von gestillten Neugeborenen simuliert, deren Mütter unmittelbar zuvor alkoholische Getränke 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 für Säuglinge zugelassenes alkoholhaltiges pflanzliches Arzneimittel simuliert. Hier wurden Spitzenkonzentrationen von 0,0141 Promille erreicht. Daher scheinen Empfehlungen wie gelegentlicher Konsum ohne schädigende Wirkung auf das Kind wissenschaftlich fundiert zu sein. Ein weiteres Kinetik-Modell befasste sich mit dem Stoffwechsel von Bisphenol A. Teils widersprüchliche Daten zur Belastung mit BPA in der wissenschaftlichen Literatur führen wiederholt zu Anregungen, den Grenzwert der Chemikalie anzupassen. Die Funktionalität der am Metabolismus beteiligten Enzyme kann je nach Individuum unterschiedlich ausgeprägt sein. Mittels Modellings konnte hier gezeigt werden, dass dies maßgeblich dazu führt, 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 für diverse toxikologische Fragestellungen leisten. N2 - In the last few years alternative methods to animal testing have gained in importance, particularly in the context of EU wide REACH legislation. The alternative methods are divided into in vitro and in silico methods. In this work, different concepts of in silico toxicology are discussed. The topics in this dissertation range from quantitative structure-activity relation- ships (QSAR) via a new approach to the common TTC concept to modeling of alcohol and bisphenol A metabolism. The chapter on QSAR is essentially concerned with the creation and analysis of a database of the German Federal Institute for Risk Assessment (BfR). The design of the database has been adapted to the design of an existing database to gain a relative large pool of data. It was found for example that substances with lower molecular weight have increased potential for toxicologically relevant damage compared to larger molecules. The TTC concept allows the user to set thresholds for substances of low level exposure when no experimental toxicological data is available. In this work, thresholds were determined for the substances of three different databases. At first substances were identified by their structure and assigned to the categories “nontoxic”, “possibly toxic” and “significantly toxic”. Depending on the category in which an unknown substance is classified, the corresponding threshold applies for it. Since the allocation to com- mon Cramer classes is done very conservatively, substances are rarely assigned to the second class. For this reason, the chemicals of the second and the third class were merged here. A further new approach was the determination of an internal threshold. This allows to subtract out the route of exposure and to apply established thresholds of oral exposure to substances that are absorbed through the skin for example. Physiologically based kinetic modeling is used to simulate physiological processes in the human body and therefore allows to understand kinetic processes. As a result, exposures to chemicals after intake into the body can be simulated. In the first part it was tried to simulate alcohol exposure of breast-fed babies, if the nursing mother had previously consumed various alcoholic beverages. In the model, it was shown that exposure of the child was consistently low. Peak concentrations were 0.0034 per mill in a newborn after consuming of a glass of wine. For comparison the exposure by an approved alcoholic herbal medicine for the treatment of flatulence in infants was simulated. Here, the peak concentrations reached 0.0141 per mill. Therefore, the findings appear to prove recommendations like “occasional consumption without damaging effect on the child” to be scientifically justified. Another kinetics model focused on polymorphisms of bisphenol A metabolizing enzymes. Conflicting evidence in the scientific literature on measured BPA concentrations in the blood led to consideration whether the TDI of 0.05 mg/kg bw/day imposed by the EFSA has to be corrected. There are known polymorphisms of the primary metabolizing enzyme. Via modeling it could be shown that these polymorphisms lead to individual plasma levels which vary by the factors of 4.7. Thus, this work contributes to the development and use of in silico models for various toxicological problems. KW - QSAR KW - Toxikokinetik KW - TTC KW - PBTK KW - Modelling KW - in silico KW - QSAR KW - toxicology KW - TTC KW - PBTK KW - in silico KW - kinetics KW - alcohol KW - BPA KW - Bisphenol A KW - polymorphism KW - PBPK KW - Kinetik KW - Alkohol KW - BPA KW - Bisphenol A KW - Polymorphismus Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-82334 ER - TY - JOUR A1 - Sagu Tchewonpi, Sorel A1 - Nso, Emmanuel Jong A1 - Homann, Thomas A1 - Kapseu, Cesar A1 - Rawel, Harshadrai Manilal T1 - Extraction and purification of beta-amylase from stems of Abrus precatorius by three phase partitioning JF - Food chemistry N2 - 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. KW - Purification KW - Beta-amylase KW - Abrus precatorius KW - Three phase partitioning KW - Doehlert design Y1 - 2015 U6 - https://doi.org/10.1016/j.foodchem.2015.03.028 SN - 0308-8146 SN - 1873-7072 VL - 183 SP - 144 EP - 153 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Kana-Sop, Marie Modestine A1 - Gouado, Inocent A1 - Achu, Mercy Bih A1 - Van Camp, John A1 - Zollo, Paul Henri Amvam A1 - Schweigert, Florian J. A1 - Oberleas, Donald A1 - Ekoe, Tetanye T1 - The Influence of Iron and Zinc Supplementation on the Bioavailability of Provitamin A Carotenoids from Papaya Following Consumption of a Vitamin A-Deficient Diet JF - Journal of nutritional science and vitaminology N2 - 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. KW - micronutrient deficiencies KW - zinc/iron supplementation KW - carotenoids bioavailability KW - Cameroon Y1 - 2015 SN - 0301-4800 SN - 1881-7742 VL - 61 IS - 3 SP - 205 EP - 214 PB - Univ. of Tokyo Pr. CY - Tokyo ER - TY - JOUR A1 - Danquah, Ina A1 - Dobrucky, C. Lydia A1 - Frank, Laura K. A1 - Henze, Andrea A1 - Amoako, Yaw A. A1 - Bedu-Addo, George A1 - Raila, Jens A1 - Schulze, Matthias Bernd A1 - Mockenhaupt, Frank P. A1 - Schweigert, Florian J. T1 - Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana JF - The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc. N2 - 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. KW - hypertension KW - inflammation KW - kidney dysfunction KW - type 2 diabetes KW - vitamin A deficiency Y1 - 2015 U6 - https://doi.org/10.3945/ajcn.114.101345 SN - 0002-9165 SN - 1938-3207 VL - 102 IS - 1 SP - 207 EP - 214 PB - American Society for Nutrition, Inc. CY - Bethesda ER - TY - JOUR A1 - Zirafi, Onofrio A1 - Kim, Kyeong-Ae A1 - Ständker, Ludger A1 - Mohr, Katharina B. A1 - Sauter, Daniel A1 - Heigele, Anke A1 - Kluge, Silvia F. A1 - Wiercinska, Eliza A1 - Chudziak, Doreen A1 - Richter, Rudolf A1 - Möpps, Barbara A1 - Gierschik, Peter A1 - Vas, Virag A1 - Geiger, Hartmut A1 - Lamla, Markus A1 - Weil, Tanja A1 - Burster, Timo A1 - Zgraja, Andreas A1 - Daubeuf, Francois A1 - Frossard, Nelly A1 - Hachet-Haas, Muriel A1 - Heunisch, Fabian A1 - Reichetzeder, Christoph A1 - Galzi, Jean-Luc A1 - Perez-Castells, Javier A1 - Canales-Mayordomo, Angeles A1 - Jimenez-Barbero, Jesus A1 - Gimenez-Gallego, Guillermo A1 - Schneider, Marion A1 - Shorter, James A1 - Telenti, Amalio A1 - Hocher, Berthold A1 - Forssmann, Wolf-Georg A1 - Bonig, Halvard A1 - Kirchhoff, Frank A1 - Münch, Jan T1 - Discovery and Characterization of an Endogenous CXCR4 Antagonist JF - Cell reports N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1016/j.celrep.2015.03.061 SN - 2211-1247 VL - 11 IS - 5 SP - 737 EP - 747 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Maschirow, Laura A1 - Khalaf, Kinda A1 - Al-Aubaidy, Hayder A. A1 - Jelinek, Herbert F. T1 - Inflammation, coagulation, endothelial dysfunction and oxidative stress in prediabetes - Biomarkers as a possible tool for early disease detection for rural screening JF - Clinical biochemistry : official journal of the Canadian Society of Clinical Chemists N2 - 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. KW - Prediabetes KW - Oxidative stress KW - Inflammation KW - Coagulation KW - Endothelial dysfunction Y1 - 2015 U6 - https://doi.org/10.1016/j.clinbiochem.2015.02.015 SN - 0009-9120 SN - 1873-2933 VL - 48 IS - 9 SP - 581 EP - 585 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Prüfer, Nicole A1 - Kleuser, Burkhard A1 - van der Giet, Markus T1 - The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality JF - Biological chemistry N2 - The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL's anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL's protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL's biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function. KW - atherosclerosis KW - high-density lipoprotein (HDL) KW - inflammation KW - serum amyloid A (SAA) KW - sphingosine-1-phosphate (S1P) Y1 - 2015 U6 - https://doi.org/10.1515/hsz-2014-0192 SN - 1431-6730 SN - 1437-4315 VL - 396 IS - 6-7 SP - 573 EP - 583 PB - De Gruyter CY - Berlin ER - TY - JOUR A1 - Satwiko, Muhammad Gahan A1 - Ikeda, Koji A1 - Nakayama, Kazuhiko A1 - Yagi, Keiko A1 - Hocher, Berthold A1 - Hirata, Ken-Ichi A1 - Emoto, Noriaki T1 - Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension JF - Biochemical and biophysical research communications N2 - 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. KW - Pulmonary arterial hypertension KW - Endothelin KW - Hypoxia KW - SU5416 Y1 - 2015 U6 - https://doi.org/10.1016/j.bbrc.2015.08.002 SN - 0006-291X SN - 1090-2104 VL - 465 IS - 3 SP - 356 EP - 362 PB - Elsevier CY - San Diego ER - TY - JOUR A1 - Fruscalzo, Arrigo A1 - Londero, Ambrogio P. A1 - Driul, Lorenza A1 - Henze, Andrea A1 - Tonutti, Laura A1 - Ceraudo, Maria A1 - Zanotti, Giuseppe A1 - Berni, Rodolfo A1 - Schweigert, Florian J. A1 - Raila, Jens T1 - First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus JF - 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 N2 - 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. KW - first trimester KW - gestational diabetes mellitus (GDM) KW - insulin KW - large for gestational age fetus (LGA) KW - protein microheterogeneity KW - retinol (ROH) KW - serum retinol binding protein (RBP4) KW - transthyretin (TTR) Y1 - 2015 U6 - https://doi.org/10.1515/cclm-2014-0929 SN - 1434-6621 SN - 1437-4331 VL - 53 IS - 10 SP - 1643 EP - 1651 PB - De Gruyter CY - Berlin ER - TY - CHAP A1 - Reichetzeder, Christoph A1 - von Websky, Karoline A1 - Tsuprykov, Oleg A1 - Antonenko, V. A1 - Samarin, Azin Mohagheghi A1 - Hocher, Berthold T1 - Effects of DPP-4 inhibition on glomerular and tubular function in a rat model of ischaemia-reperfusion injury T2 - Diabetologia : journal of the European Association for the Study of Diabetes (EASD) Y1 - 2015 SN - 0012-186X SN - 1432-0428 VL - 58 SP - S34 EP - S35 PB - Springer CY - New York ER -