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  - https://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  - Scheer, Nico
A1  - Mclaughlin, Lesley A.
A1  - Rode, Anja
A1  - MacLeod, Alastair Kenneth
A1  - Henderson, Colin J.
A1  - Wolf, Roland C.
T1  - Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism
JF  - Drug Metabolism and Disposition
N2  - In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.
Y1  - 2014
U6  - https://doi.org/10.1124/dmd.114.057885
SN  - 1521-009X
VL  - 42
IS  - 6
SP  - 1022
EP  - 1030
PB  - ASPET
CY  - Bethesda, Md.
ER  - 
TY  - JOUR
A1  - Scheer, Nico
A1  - Henderson, Colin James
A1  - Kapelyukh, Yury
A1  - Rode, Anja
A1  - Mclaren, Aileen W.
A1  - MacLeod, Alastair Kenneth
A1  - Lin, De
A1  - Wright, Jayne
A1  - Stanley, Lesley
A1  - Wolf, C. Roland
T1  - An extensively humanised mouse model to predict pathways of drug disposition, drug/drug interactions, and to facilitate the design of clinical trials
JF  - Drug Metabolism and Disposition
Y1  - 2019
U6  - https://doi.org/10.1124/dmd.119.086397
IS  - Early view
ER  - 
TY  - JOUR
A1  - Wilson, Ian D.
A1  - Wilson, Claire E.
A1  - Scheer, Nico
A1  - Dickie, A.P.
A1  - Schreiter, K.
A1  - Wilson, E. M.
A1  - Riley, R. J.
A1  - Wehr, R.
A1  - Bial, J.
T1  - The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice
JF  - Biochemical pharmacology
Y1  - 2017
U6  - https://doi.org/10.1016/j.bcp.2017.03.015
SN  - 1873-2968
VL  - Volume 135
SP  - 139
EP  - 150
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Hough, Lindsay B.
A1  - Nalwalk, Julia W.
A1  - Ding, Xinxin
A1  - Scheer, Nico
T1  - Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms
JF  - Drug Metabolism and Disposition
Y1  - 2015
U6  - https://doi.org/10.1124/dmd.115.065490
SN  - 1521-009x
VL  - 43
IS  - 9
SP  - 1326
EP  - 1330
ER  - 
TY  - JOUR
A1  - Haeger, Gerrit
A1  - Probst, Johanna
A1  - Jaeger, Karl-Erich
A1  - Bongaerts, Johannes
A1  - Siegert, Petra
T1  - Novel aminoacylases from Streptomyces griseus DSM 40236 and their recombinant production in Streptomyces lividans
JF  - FEBS Open Bio
N2  - Amino acid-based surfactants are valuable compounds for cosmetic formulations. The chemical synthesis of acyl-amino acids is conventionally performed by the Schotten-Baumann reaction using fatty acyl chlorides, but aminoacylases have also been investigated for use in biocatalytic synthesis with free fatty acids. Aminoacylases and their properties are diverse; they belong to different peptidase families and show differences in substrate specificity and biocatalytic potential. Bacterial aminoacylases capable of synthesis have been isolated from Burkholderia, Mycolicibacterium, and Streptomyces. Although several proteases and peptidases from S. griseus have been described, no aminoacylases from this species have been identified yet. In this study, we investigated two novel enzymes produced by S. griseus DSM 40236ᵀ . We identified and cloned the respective genes and recombinantly expressed an α-aminoacylase (EC 3.5.1.14), designated SgAA, and an ε-lysine acylase (EC 3.5.1.17), designated SgELA, in S. lividans TK23. The purified aminoacylase SgAA was biochemically characterized, focusing on its hydrolytic activity to determine temperature- and pH optima and stabilities. The aminoacylase could hydrolyze various acetyl-amino acids at the Nα -position with a broad specificity regarding the sidechain. Substrates with longer acyl chains, like lauroyl-amino acids, were hydrolyzed to a lesser extent. Purified aminoacylase SgELA specific for the hydrolysis of Nε -acetyl-L-lysine was unstable and lost its enzymatic activity upon storage for a longer period but could initially be characterized. The pH optimum of SgELA was pH 8.0. While synthesis of acyl-amino acids was not observed with SgELA, SgAA catalyzed the synthesis of lauroyl-methionine.
KW  - Streptomyces lividans
KW  - recombinant expression
KW  - Streptomyces griseus
KW  - ε-lysine acylase
KW  - α-aminoacylase
Y1  - 2023
U6  - https://doi.org/10.1002/2211-5463.13723
SN  - 2211-5463
N1  - Corresponding author: Petra Siegert
VL  - 13
IS  - 12
SP  - 2224
EP  - 2238
PB  - Wiley
CY  - Hoboken, NJ
ER  - 
TY  - JOUR
A1  - Mues genannt Koers, Lucas
A1  - McNeil, S. W.
A1  - Radchenko, V.
A1  - Paulßen, Elisabeth
A1  - Hoehr, Cornelia
T1  - Production of Co-58m in a siphon-style liquid target on a medical cyclotron
N2  - We present the production of 58mCo on a small, 13 MeV medical cyclotron utilizing a siphon style liquid target system. Different concentrated iron(III)-nitrate solutions of natural isotopic distribution were irradiated at varying initial pressures and subsequently separated by solid phase extraction chromatography. The radio cobalt (58m/gCo and 56Co) was successfully produced with saturation activities of (0.35 ± 0.03) MBq μA−1 for 58mCo with a separation recovery of (75 ± 2) % of cobalt after one separation step utilizing LN-resin.
Y1  - 2023
U6  - https://doi.org/10.1016/j.apradiso.2023.110734
SN  - 0969-8043
VL  - 195
IS  - Art. 110734
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Hafidi, Youssef
A1  - El Hatka, Hicham
A1  - Schmitz, Dominik
A1  - Krauss, Manuel
A1  - Pettrak, Jürgen
A1  - Biel, Markus
A1  - Ittobane, Najim
T1  - Sustainable soil additives for water and micronutrient supply: swelling and chelating properties of polyaspartic acid hydrogels utilizing newly developed crosslinkers
JF  - Gels
N2  - Drought and water shortage are serious problems in many arid and semi-arid regions. This problem is getting worse and even continues in temperate climatic regions due to climate change. To address this problem, the use of biodegradable hydrogels is increasingly important for the application as water-retaining additives in soil. Furthermore, efficient (micro-)nutrient supply can be provided by the use of tailored hydrogels. Biodegradable polyaspartic acid (PASP) hydrogels with different available (1,6-hexamethylene diamine (HMD) and L-lysine (LYS)) and newly developed crosslinkers based on diesters of glycine (GLY) and (di-)ethylene glycol (DEG and EG, respectively) were synthesized and characterized using Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) and regarding their swelling properties (kinetic, absorbency under load (AUL)) as well as biodegradability of PASP hydrogel. Copper (II) and zinc (II), respectively, were loaded as micronutrients in two different approaches: in situ with crosslinking and subsequent loading of prepared hydrogels. The results showed successful syntheses of di-glycine-ester-based crosslinkers. Hydrogels with good water-absorbing properties were formed. Moreover, the developed crosslinking agents in combination with the specific reaction conditions resulted in higher water absorbency with increased crosslinker content used in synthesis (10% vs. 20%). The prepared hydrogels are candidates for water-storing soil additives due to the biodegradability of PASP, which is shown in an exemple. The incorporation of Cu(II) and Zn(II) ions can provide these micronutrients for plant growth.
KW  - micronutrients
KW  - swelling properties
KW  - biodegradable polymers
KW  - hydrogels
KW  - superabsorbent polymers
KW  - glycine
KW  - polyaspartic acid
Y1  - 2024
U6  - https://doi.org/10.3390/gels10030170
SN  - 2310-2861
VL  - 10
IS  - 3
SP  - Artikel 170
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Berndt, Heinz
A1  - Zahn, Helmut
T1  - Peptide, 99 : Monomere cyclische Cystinpeptidderivate, III ; Synthese der Schafinsulin-A-Kettensequenzen A2–21 und A1–21 als monomere cyclische Dicystinpeptidderivate
JF  - Justus Liebigs Annalen der Chemie
N2  - Die Synthese der Sequenzen A2—21 (13) und A1—21 (15) der Schafinsulin-A-Kette als monomere cyclische Dicystinpeptidderivate wird beschrieben. Die intrachenaren Cystinbrücken A6—7 und A 11 —20 vermitteln die Löslichkeit dieser Derivate in Dimethylformamid und ermöglichen erstmalig die Reindarstellung vollgeschützter Insulin-A-Kettenderivate. Die während der Synthese eingesetzten Schutzgruppen lassen sich mittels Trifluoressigsäure und 2-Mercaptoäthanol quantitativ entfernen.
Y1  - 1975
U6  - https://doi.org/10.1002/jlac.197519750908
SN  - 1099-0690
VL  - 1975
IS  - 9
SP  - 1601
EP  - 1612
PB  - Wiley-VCH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Berndt, Heinz
A1  - Gattner, Hans-Gregor
A1  - Zahn, Helmut
T1  - Semisynthetisches Des-A1-glycin-Schafinsulin
JF  - Biological Chemistry
Y1  - 1975
U6  - https://doi.org/10.1515/bchm2.1975.356.2.1455
SN  - 1437-4315
VL  - 356
IS  - 2
SP  - 1469
EP  - 1472
PB  - De Gruyter
CY  - Berlin
ER  -