TY  - JOUR
A1  - Winckler, Silvia
A1  - Krueger, Rolf
A1  - Schnitzler, Thomas
A1  - Zang, Werner
A1  - Fischer, Rainer
A1  - Biselli, Manfred
T1  - A sensitive monitoring system for mammalian cell cultivation processes: a PAT approach
JF  - Bioprocess and biosystems engineering
N2  - Biopharmaceuticals such as antibodies are produced in cultivated mammalian cells, which must be monitored to comply with good manufacturing practice. We, therefore, developed a fully automated system comprising a specific exhaust gas analyzer, inline analytics and a corresponding algorithm to precisely determine the oxygen uptake rate, carbon dioxide evolution rate, carbon dioxide transfer rate, transfer quotient and respiratory quotient without interrupting the ongoing cultivation, in order to assess its reproducibility. The system was verified using chemical simulation experiments and was able to measure the respiratory activity of hybridoma cells and DG44 cells (derived from Chinese hamster ovary cells) with satisfactory results at a minimum viable cell density of ~2.0 × 10⁵ cells ml⁻¹. The system was suitable for both batch and fed-batch cultivations in bubble-aerated and membrane-aerated reactors, with and without the control of pH and dissolved oxygen.
Y1  - 2014
U6  - http://dx.doi.org/10.1007/s00449-013-1062-8
SN  - 1615-7591 (Print) 1615-7605 (Online)
VL  - 37
IS  - 5
SP  - 901
EP  - 912
PB  - Springer
CY  - Berlin, Heidelberg
ER  - 
TY  - JOUR
A1  - Heinze, Daniel
A1  - Mang, Thomas
A1  - Peter, Karin
A1  - Möller, Martin
A1  - Weichold, Oliver
T1  - Synthesis of low molecular weight poly(vinyl acetate) and its application as plasticizer
JF  - Journal of applied polymer science
N2  - Poly(vinyl acetate), PVAc, with a degree of polymerization Xn = 10 was prepared by chain-transfer radical polymerization using carbon tetrachloride and used as oligomeric plasticizer for commercial PVAc. However, the chlorinated chain ends cause a low thermal stability requiring mild Cl/H substitution. The product exhibits high thermal stability and excellent melt-compounding properties. Blends of oligomeric and commercial PVAc show single glass transition temperatures which decrease with higher oligomer content and exhibit small negative deviations from Fox' linear additivity rule. This indicates plasticization and miscibility being mainly due to entropic effects. Injection-moulded thick specimens show ductile behaviour at oligomer contents >10 wt %, while sheets with a thickness of 0.2–0.5 mm appear flexible already at 7.5 wt %. The oxygen permeability coefficients are an order of magnitude lower than those of low-density polyethylene. Due to the sum of their properties, the plasticized sheets present a promising alternative in the preparation of barrier materials.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/app.40226
SN  - 1097-4628 (E-Journal); 0021-8995 (Print)
VL  - 131
IS  - 9
SP  - Article No. 40226
PB  - Wiley
CY  - New York
ER  - 
TY  - JOUR
A1  - Wang, Ren-Qi
A1  - Druckenmüller, Katharina
A1  - Elbers, Gereon
A1  - Guenther, Klaus
A1  - Croué, Jean-Philippe
T1  - Analysis of aquatic-phase natural organic matter by optimized LDI-MS method
JF  - Journal of mass spectrometry
N2  - The composition and physiochemical properties of aquatic-phase natural organic matter (NOM) are most important problems for both environmental studies and water industry. Laser desorption/ionization (LDI) mass spectrometry facilitated successful examinations of NOM, as humic and fulvic acids in NOM are readily ionized by the nitrogen laser. In this study, hydrophobic NOMs (HPO NOMs) from river, reservoir and waste water were characterized by this technique. The effect of analytical variables like concentration, solvent composition and laser energy was investigated. The exact masses of small molecular NOM moieties in the range of 200–1200 m/z were determined in reflectron mode. In addition, spectra of post-source-decay experiments in this range showed that some compounds from different natural NOMs had the same fragmental ions. In the large mass range of 1200–15 000 Da, macromolecules and their aggregates were found in HPO NOMs from natural waters. Highly humic HPO exhibited mass peaks larger than 8000 Da. On the other hand, the waste water and reservoir water mainly had relatively smaller molecules of about 2000 Da. The LDI-MS measurements indicated that highly humic river waters were able to form large aggregates and membrane foulants, while the HPO NOMs from waste water and reservoir water were unlikely to form large aggregates. Copyright © 2014 John Wiley & Sons, Ltd.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/jms.3321
SN  - 1096-9888
VL  - 49
IS  - 2
SP  - 154
EP  - 160
PB  - Wiley
CY  - Bognor Regis
ER  - 
TY  - JOUR
A1  - Heine, A.
A1  - Herrmann, G.
A1  - Selmer, Thorsten
A1  - Terwesten, F.
A1  - Buckel, W.
A1  - Reuter, K.
T1  - High resolution crystal structure of clostridium propionicum β-Alanyl-CoA:Ammonia Lyase, a new member of the "Hot Dog Fold" protein superfamily
JF  - Proteins
N2  - Clostridium propionicum is the only organism known to ferment β-alanine, a constituent of coenzyme A (CoA) and the phosphopantetheinyl prosthetic group of holo-acyl carrier protein. The first step in the fermentation is a CoA-transfer to β-alanine. Subsequently, the resulting β-alanyl-CoA is deaminated by the enzyme β-alanyl-CoA:ammonia lyase (Acl) to reversibly form ammonia and acrylyl-CoA. We have determined the crystal structure of Acl in its apo-form at a resolution of 0.97 Å as well as in complex with CoA at a resolution of 1.59 Å. The structures reveal that the enyzme belongs to a superfamily of proteins exhibiting a so called “hot dog fold” which is characterized by a five-stranded antiparallel β-sheet with a long α-helix packed against it. The functional unit of all “hot dog fold” proteins is a homodimer containing two equivalent substrate binding sites which are established by the dimer interface. In the case of Acl, three functional dimers combine to a homohexamer strongly resembling the homohexamer formed by YciA-like acyl-CoA thioesterases. Here, we propose an enzymatic mechanism based on the crystal structure of the Acl·CoA complex and molecular docking. Proteins 2014; 82:2041–2053. © 2014 Wiley Periodicals, Inc.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/prot.24557
SN  - 1097-0134 (E-Journal); 0887-3585 (Print)
VL  - 82
IS  - 9
SP  - 2041
EP  - 2053
PB  - Wiley-Liss
CY  - New York
ER  - 
TY  - JOUR
A1  - Takenaga, Shoko
A1  - Biselli, Manfred
A1  - Schnitzler, Thomas
A1  - Öhlschläger, Peter
A1  - Wagner, Torsten
A1  - Schöning, Michael Josef
T1  - Toward multi-analyte bioarray sensors: LAPS-based on-chip determination of a Michaelis–Menten-like kinetics for cell culturing
JF  - Physica status solidi A : Applications and materials science
N2  - The metabolic activity of Chinese hamster ovary (CHO) cells was observed using a light-addressable potentiometric sensor (LAPS). The dependency toward different glucose concentrations (17–200 mM) follows a Michaelis–Menten kinetics trajectory with Kₘ = 32.8 mM, and the obtained Kₘ value in this experiment was compared with that found in literature. In addition, the pH shift induced by glucose metabolism of tumor cells transfected with the HPV-16 genome (C3 cells) was successfully observed. These results indicate the possibility to determine the tumor cells metabolism with a LAPS-based measurement device.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/pssa.201330464
SN  - 1521-396X (E); 1862-6319 (E-Journal); 0031-8965 (Print); 1862-6300 (Print)
VL  - 211
IS  - 6
SP  - 1410
EP  - 1415
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Whitehead, Mark
A1  - Öhlschläger, Peter
A1  - Almajhdi, Fahad N.
A1  - Alloza, Leonor
A1  - Marzábal, Pablo
A1  - Meyers, Ann E.
A1  - Hitzeroth, Inga I.
A1  - Rybicki, Edward P.
T1  - Human papillomavirus (HPV) type 16 E7 protein bodies cause tumour regression in mice
JF  - BMC cancer
Y1  - 2014
U6  - http://dx.doi.org/10.1186/1471-2407-14-367
SN  - 1471-2407
IS  - 14:367
SP  - 1
EP  - 15
PB  - BioMed Central
CY  - London
ER  - 
TY  - JOUR
A1  - Küppers, Tobias
A1  - Steffen, Victoria
A1  - Hellmuth, Hendrik
A1  - O'Connell, Timothy
A1  - Bongaerts, Johannes
A1  - Maurer, Karl-Heinz
A1  - Wiechert, Wolfgang
T1  - Developing a new production host from a blueprint: Bacillus pumilus as an industrial enzyme producer
JF  - Microbial cell factories
Y1  - 2014
U6  - http://dx.doi.org/10.1186/1475-2859-13-46
SN  - 1475-2859 (E-Journal)
VL  - 13
SP  - Article No. 46
PB  - BioMed Central
CY  - London
ER  - 
TY  - JOUR
A1  - Guo, Yuanyuan
A1  - Miyamoto, Ko-ichiro
A1  - Wagner, Torsten
A1  - Schöning, Michael Josef
A1  - Yoshinobu, Tatsuo
T1  - Theoretical study and simulation of light-addressable potentiometric sensors
JF  - Physica status solidi (A) : applications and materials
N2  - The light-addressable potentiometric sensor (LAPS) is a semiconductor-based potentiometric sensor using a light probe with an ability of detecting the concentration of biochemical species in a spatially resolved manner. As an important biomedical sensor, research has been conducted to improve its performance, for instance, to realize high-speed measurement. In this work, the idea of facilitating the device-level simulation, instead of using an equivalent-circuit model, is presented for detailed analysis and optimization of the performance of the LAPS. Both carrier distribution and photocurrent response have been simulated to provide new insight into both amplitude-mode and phase-mode operations of the LAPS. Various device parameters can be examined to effectively design and optimize the LAPS structures and setups for enhanced performance.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/pssa.201330354
SN  - 0031-8965
VL  - 211
IS  - 6
SP  - 1467
EP  - 1472
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Ratke, Lorenz
A1  - Milow, Barbara
A1  - Lisinski, Susanne
A1  - Hoepfner, Sandra
T1  - On an effect of fine ceramic particles on the structure of aerogels
JF  - Microgravity science and technology
Y1  - 2014
U6  - http://dx.doi.org/10.1007/s12217-014-9380-2
SN  - 0938-0108 ; 1875-0494
VL  - 26
SP  - 103
EP  - 110
PB  - Springer Nature
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Handtke, Stefan
A1  - Volland, Sonja
A1  - Methling, Karen
A1  - Albrecht, Dirk
A1  - Becher, Dörte
A1  - Nehls, Jenny
A1  - Bongaerts, Johannes
A1  - Maurer, Karl-Heinz
A1  - Lalk, Michael
A1  - Liesegang, Heiko
A1  - Voigt, Birgit
A1  - Daniel, Rolf
A1  - Hecker, Michael
T1  - Cell physiology of the biotechnological relevant bacterium Bacillus pumilus - An omics-based approach
JF  - Journal of Biotechnology
N2  - Members of the species Bacillus pumilus get more and more in focus of the biotechnological industry as potential new production strains. Based on exoproteome analysis, B. pumilus strain Jo2, possessing a high secretion capability, was chosen for an omics-based investigation. The proteome and metabolome of B. pumilus cells growing either in minimal or complex medium was analyzed. In total, 1542 proteins were identified in growing B. pumilus cells, among them 1182 cytosolic proteins, 297 membrane and lipoproteins and 63 secreted proteins. This accounts for about 43% of the 3616 proteins encoded in the B. pumilus Jo2 genome sequence. By using GC–MS, IP-LC/MS and H NMR methods numerous metabolites were analyzed and assigned to reconstructed metabolic pathways. In the genome sequence a functional secretion system including the components of the Sec- and Tat-secretion machinery was found. Analysis of the exoproteome revealed secretion of about 70 proteins with predicted secretion signals. In addition, selected production-relevant genome features such as restriction modification systems and NRPS clusters of B. pumilus Jo2 are discussed.
Y1  - 2014
U6  - http://dx.doi.org/10.1016/j.jbiotec.2014.08.028
SN  - 1873-4863 (E-Journal); 0168-1656 (Print)
IS  - 192(A)
SP  - 204
EP  - 214
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Nachtrodt, Frederik
A1  - Tietsch, Wolfgang
A1  - Mostacci, Domiziano
A1  - Scherer, Ulrich W.
T1  - Set-up and first operation of a plasma oven for treatment of low level radioactive wastes
JF  - Nuclear technology and radiation protection
Y1  - 2014
U6  - http://dx.doi.org/10.2298/NTRP140SS47N
SN  - 1451-3994
VL  - 29
IS  - Suppl.
SP  - 47
EP  - 51
PB  - VINČA Institute of Nuclear Sciences
CY  - Belgrad
ER  - 
TY  - JOUR
A1  - Raue, Markus
A1  - Wambach, M.
A1  - Glöggler, S.
A1  - Grefen, Dana
A1  - Kaufmann, R.
A1  - Abetz, C.
A1  - Georgopanos, P.
A1  - Handge, U. A.
A1  - Mang, Thomas
A1  - Blümich, B.
A1  - Abetz, V.
T1  - Investigation of historical hard rubber ornaments of Charles Goodyear
JF  - Macromolecular chemistry and physics
Y1  - 2014
SN  - 1022-1352
VL  - Vol. 215
IS  - No. 3
SP  - 245
EP  - 254
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Pasteur, Aline
A1  - Tippkötter, Nils
A1  - Kampeis, Percy
A1  - Ulber, Roland
T1  - Optimization of high gradient magnetic separation filter units for the purification of fermentation products
JF  - IEEE TRANSACTIONS ON MAGNETICS
N2  - High gradient magnetic separation (HGMS) has been established since the early 1970s. A more recent application of these systems is the use in bioprocesses. To integrate the HGMS in a fermentation process, it is necessary to optimize the separation matrix with regard to the magnetic separation characteristics and permeability of the non-magnetizable components of the fermentation broth. As part of the work presented here, a combined fluidic and magnetic force finite element model simulation was created using the software COMSOL Multiphysics and compared with separation experiments. Finally, as optimal lattice orientation of the separation matrix, a transversal rhombohedral arrangement was defined. The high suitability of the new filter matrix has been verified by separation experiments.
Y1  - 2014
U6  - http://dx.doi.org/10.1109/TMAG.2014.2325535
SN  - 0018-9464
N1  - Article Sequence Number: 5000607
INSPEC Accession Number: 14663042
VL  - 50
IS  - 10
SP  - Artikel 5000607
PB  - IEEE
CY  - New York, NY
ER  - 
TY  - JOUR
A1  - Tippkötter, Nils
A1  - Wollny, Steffen
A1  - Suck, Kirstin
A1  - Sohling, Ulrich
A1  - Ruf, Friedrich
A1  - Ulber, Roland
T1  - Recycling of spent oil bleaching earth as source of glycerol for the anaerobic production of acetone, butanol, and ethanol with Clostridium diolis and lipolytic Clostridium lundense
JF  - Engineering in Life Sciences
N2  - A major part of edible oil is subjected to bleaching procedures, primarily with minerals applied as adsorbers. Their recycling is currently done either by regaining the oil via organic solvent extraction or by using the spent bleaching earth (SBE) as additive for animal feed, etc. As a new method, the reutilization of the by-product SBE for the microbiologic formation of acetone, butanol, and ethanol (ABE) is presented as proof-of-concept. The SBE was taken from a palm oil cleaning process. The recycling concept is based on the application of lipolytic clostridia strains. Due to considerably long fermentation times, co-fermentation with Candida rugosa and enzymatic hydrolyses of the bound oil with a subsequent clostridia fermentation are shown as alternative routes. Anaerobic fermentations under comparison of different clostridia strains were performed with glycerol media, enzymatically hydrolyzed palm oil and SBE. Solutes, side product compositions and productivities were quantified via HPLC. A successful production of ABE solutes from SBE has been done with a yield of 0.15 g butanol per gram of bound glycerol. Thus, the biotechnological recycling of the waste stream is possible in principle. Inhibition of the substrate suspension has been observed. A chromatographic ion-exchange of substrates increased the biomass concentration.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/elsc.201300113
SN  - 1618-2863
VL  - 14
IS  - 4
SP  - 425
EP  - 432
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Al-Kaidy, Huschyar
A1  - Duwe, Anna
A1  - Huster, Manuel
A1  - Muffler, Kai
A1  - Schlegel, Christin
A1  - Sieker, Tim
A1  - Stadtmüller, Ralf
A1  - Tippkötter, Nils
A1  - Ulber, Roland
T1  - Biotechnologie und Bioverfahrenstechnik – Vom ersten Ullmanns Artikel bis hin zu aktuellen Forschungsthemen
JF  - Chemie Ingenieur Technik
N2  - Biotechnologie und die mit ihr verbundenen technischen Prozesse prägen seit Jahrtausenden die Entwicklung der Menschheit. Ausgehend von empirischen Verfahren, insbesondere zur Herstellung von Lebensmitteln und täglichen Gebrauchsgütern, haben sich diese Disziplinen zu einem der innovativsten Zukunftsfelder entwickelt. Durch das immer detailliertere Verständnis zellulärer Vorgänge können mittlerweile Produktionsstämme gezielt optimiert werden. Im Zusammenspiel mit moderner Prozesstechnik können so eine Vielzahl von Bulk- und Feinchemikalien sowie Pharmazeutika effizient hergestellt werden. In diesem Artikel werden exemplarisch einige der aktuellen Trends vorgestellt.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/cite.201400083
SN  - 0009-286X
VL  - 86
IS  - 12
SP  - 2215
EP  - 2225
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Wiesen, Sebastian
A1  - Tippkötter, Nils
A1  - Muffler, Kai
A1  - Suck, Kirstin
A1  - Sohling, Ulrich
A1  - Ruf, Nils
A1  - Ulber, Roland
T1  - Adsorptive Vorbehandlung von Rohglycerin für die 1,3-Propandiol Fermentation mit Clostridium diolis
JF  - Chemie Ingenieur Technik
N2  - Bei der Gewinnung von Fettsäuren aus Pflanzenölen, z. B. zur Herstellung von Biopolymeren, oder bei der Biodiesel- und Seifenproduktion, fällt Glycerin als Nebenprodukt an. Bei der Biokonversion dieses Rohstoffes zu 1,3-Propandiol wird der Produktionsorganismus Clostridium diolis durch Verunreinigungen im Rohglycerin gehemmt. Als inhibierende Substanzen konnten freie Fettsäuren identifiziert werden. Mithilfe eines adsorptiven Aufarbeitungsverfahrens ist es gelungen, die Fettsäuren zu entfernen und die Konversionseffizienz zu 1,3-Propandiol zu erhöhen.
Y1  - 2014
U6  - http://dx.doi.org/10.1002/cite.201300080
N1  - Englischer Titel: Adsorptive Pretreatment of Crude Glycerol Prior to Fermentation to 1,3-Propanediole by Clostridium Diolis
VL  - 86
IS  - 1-2
SP  - 129
EP  - 135
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Tippkötter, Nils
A1  - Duwe, Anna-Maria
A1  - Wiesen, Sebastian
A1  - Sieker, Tim
A1  - Ulber, Roland
T1  - Enzymatic hydrolysis of beech wood lignocellulose at high solid contents and its utilization as substrate for the production of biobutanol and dicarboxylic acids
JF  - Bioresource Technology
N2  - The development of a cost-effective hydrolysis for crude cellulose is an essential part of biorefinery developments. To establish such high solid hydrolysis, a new solid state reactor with static mixing is used. However, concentrations >10% (w/w) cause a rate and yield reduction of enzymatic hydrolysis. By optimizing the synergetic activity of cellulolytic enzymes at solid concentrations of 9%, 17% and 23% (w/w) of crude Organosolv cellulose, glucose concentrations of 57, 113 and 152 g L⁻¹ are reached. However, the glucose yield decreases from 0.81 to 0.72gg⁻¹ at 17% (w/w). Optimal conditions for hydrolysis scale-up under minimal enzyme addition are identified. As result, at 23% (w/w) crude cellulose the glucose yield increases from 0.29 to 0.49gg⁻¹. As proof of its applicability, biobutanol, succinic and itaconic acid are produced with the crude hydrolysate. The potential of the substrate is proven e.g. by a high butanol yield of 0.33gg⁻¹.
Y1  - 2014
U6  - http://dx.doi.org/10.1016/j.biortech.2014.06.052
VL  - 167
SP  - 447
EP  - 455
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Hoehr, Cornelia
A1  - Paulßen, Elisabeth
A1  - Benard, Francois
A1  - Lee, Chris Jaeil
A1  - Hou, Xinchi
A1  - Badesso, Brian
A1  - Ferguson, Simon
A1  - Miao, Qing
A1  - Yang, Hua
A1  - Buckley, Ken
A1  - Hanemaayer, Victoire
A1  - Zeisler, Stefan
A1  - Ruth, Thomas
A1  - Celler, Anna
A1  - Schaffer, Paul
T1  - ⁴⁴ᶢSc production using a water target on a 13 MeV cyclotron
JF  - Nuclear medicine and biology
N2  - Access to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t₁⸝₂ = 3.97 h, Eavg,β⁺ = 1.47 MeV, branching ratio = 94.27%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations.
Y1  - 2014
U6  - http://dx.doi.org/10.1016/j.nucmedbio.2013.12.016
SN  - 1872-9614
VL  - 41
IS  - 5
SP  - 401
EP  - 406
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Luisier, Raphaëlle
A1  - Lempiäinen, Harri
A1  - Scherbichler, Nina
A1  - Braeuning, Albert
A1  - Geissler, Miriam
A1  - Dubost, Valerie
A1  - Müller, Arne
A1  - Scheer, Nico
A1  - Chibout, Salah-Dine
A1  - Hara, Hisanori
A1  - Picard, Frank
A1  - Theil, Diethilde
A1  - Couttet, Philippe
A1  - Vitobello, Antonio
A1  - Grenet, Olivier
A1  - Grasl-Kraupp, Bettina
A1  - Ellinger-Ziegelbauer, Heidrung
A1  - Thomson, John P.
A1  - Meehan, Richard R.
A1  - Elcombe, Clifford R.
A1  - Henderson, Colin J.
A1  - Wolf, C. Roland
A1  - Schwarz, Michael
A1  - Moulin, Pierre
A1  - Terranova, Remi
A1  - Moggs, Jonathan G.
T1  - Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors
JF  - Toxicological Sciences
N2  - The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.
Y1  - 2014
U6  - http://dx.doi.org/https://doi.org/10.1093/toxsci/kfu038
SN  - 1094-2025
VL  - 139
IS  - 2
SP  - 501
EP  - 511
PB  - Oxford University Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Salpati, Laurent
A1  - Chu, Xiaoyan
A1  - Chen, Liangfu
A1  - Prasad, Bhagwat
A1  - Dallas, Shannon
A1  - Evers, Raymond
A1  - Mamaril-Fishman, Donna
A1  - Geier, Ethan G.
A1  - Kehler, Jonathan
A1  - Kunta, Jeevan
A1  - Mezler, Mario
A1  - Laplanche, Loic
A1  - Pang, Jodie
A1  - Soars, Matthew G.
A1  - Unadkat, Jashvant D.
A1  - van Waterschoot, Robert A.B.
A1  - Yabut, Jocelyn
A1  - Schinkel, Alfred H.
A1  - Scheer, Nico
A1  - Rode, Anja
T1  - Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins
JF  - Drug Metabolism and Disposition
N2  - Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography–tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans.
Y1  - 2014
U6  - http://dx.doi.org/10.1124/dmd.114.057976
SN  - 1521-009X
VL  - 42
IS  - 8
SP  - 1301
EP  - 1313
PB  - ASPET
CY  - Bethesda, Md.
ER  -