Article
Biochemical Research Methods
Marianne Koller, Horst Thiermann, Franz Worek, Timo Wille
Summary: A method for regenerating BChE inhibited by nerve agents in whole blood samples has been developed and validated for selectivity, linearity, and stability. The method showed high selectivity, good linearity up to saturation concentration, and reproducibility for GB and GF. The detection limits were found to be 0.5 ng/mL for GB and 0.3 ng/mL for GF, confirming its effectiveness.
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
(2021)
Article
Toxicology
Anja Kohler, Benjamin Escher, Laura Job, Marianne Koller, Horst Thiermann, Arne Skerra, Franz Worek
Summary: The study investigated the catalytic efficacies of five BdPTE mutants and modified versions with delayed plasma clearance, as well as a bispecific BdPTE with broadened substrate spectrum. The newly developed enzymes BdPTE-4 and BdPTE-7 exhibited high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(-) VX enantiomer in vitro.
ARCHIVES OF TOXICOLOGY
(2021)
Article
Physiology
Jonas Tigges, Florian Eggerbauer, Franz Worek, Horst Thiermann, Ursula Rauen, Timo Wille
Summary: Utilizing optimized preservation solutions can prolong the viability of rat PCLS during cold storage, preserving cell populations and enabling a longer response to inflammatory stimulation. An improved base solution with a high potassium chloride concentration optimizes cold storage of PCLS, enhancing efficiency in transportation and stockpiling.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2021)
Article
Toxicology
Jonas Tigges, Franz Worek, Horst Thiermann, Timo Wille
Summary: Organophosphorus compound pesticides have the potential to induce pneumonia and lung edema after poisoning, leading to life-threatening complications. Experimental data shows that different organophosphorus compounds have varying toxic effects on lung tissues, contributing to a better understanding of their cellular targets and clinical outcomes.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Toxicology
Lisa Stigler, Anja Koehler, Marianne Koller, Laura Job, Benjamin Escher, Heidrun Potschka, Horst Thiermann, Arne Skerra, Franz Worek, Timo Wille
Summary: Two engineered mutants of Brevundimonas diminuta phosphotriesterase showed enhanced catalytic efficiency in detoxifying the highly toxic organophosphorus nerve agent VX, demonstrating their potential for the development of effective catalytic scavengers against VX.
ARCHIVES OF TOXICOLOGY
(2022)
Article
Pharmacology & Pharmacy
Horst Thiermann, Franz Worek
Summary: In the treatment of poisoning with organophosphorus compounds, drug-induced reactivation of acetylcholinesterase is essential for timely termination of the cholinergic crisis. Obidoxime and pralidoxime have been proven to reactivate inhibited cholinesterase and save the lives of poisoned animals.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)
Article
Toxicology
Anja Koehler, Laura Job, Franz Worek, Arne Skerra
Summary: The phosphotriesterase BdTPE is inhibited by human plasma components, particularly serum albumin, which depletes crucial zinc ions from the enzyme's active site. The concentration of available zinc ions in blood plays a significant role in BdTPE activity in vivo.
TOXICOLOGY LETTERS
(2021)
Article
Toxicology
N. Amend, F. Worek, H. Thiermann, T. Wille
Summary: The study evaluated the cardiac effects of compounds from the oleander plant using human induced pluripotent stem cells derived cardiomyocytes in a microelectrode array system. It was found that neriifolin, oleandrin, digitoxigenin, peruvoside had dose-dependent pro-arrhythmic potential, while thevetin A did not cause arrhythmia. A cardiac effect rank order was established as neriifolin > oleandrin > digitoxigenin = peruvoside > digoxin > thevetin A.
TOXICOLOGY LETTERS
(2021)
Article
Chemistry, Multidisciplinary
Cecilia Lindgren, Nina Forsgren, Norman Hoster, Christine Akfur, Elisabet Artursson, Lotta Edvinsson, Richard Svensson, Franz Worek, Fredrik Ekstrom, Anna Linusson
Summary: This article introduces new strategies and tools for developing reactivators. By studying the non-covalent interactions with OPNA-AChEs, suitable inhibitor scaffolds are converted into broad-spectrum reactivators. Determinants of reactivation efficiency are identified through analysis of reactivation and pre-reactivation kinetics and structural data.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Gabriele Horn, Tamara Kranawetvogl, Harald John, Carlotta Weigel, Ursula Rauen, Franz Worek, Timo Wille
Summary: Oximes-induced liver toxicity was examined using human three-dimensional HepaRG spheroids as a complex in vitro model. The results showed that cold storage at 4 degrees C preserved the viability of the liver spheroids in optimized tissue preservation solutions, but resulted in complete loss of viability in standard culture medium. In addition, it was found that there is a potential risk of liver injury when oxime antidotes are strongly overdosed.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Toxicology
Jesko Kaiser, Christoph G. W. Gertzen, Tamara Bernauer, Georg Hoefner, Karin Niessen, Thomas Seeger, Franz F. Paintner, Klaus T. Wanner, Franz Worek, Horst Thiermann, Holger Gohlke
Summary: Organophosphorus compounds (OPCs) are highly toxic and can block acetylcholine esterase (AChE), leading to overstimulation of acetylcholine receptors (nAChRs). Current treatment options are insufficient, necessitating the development of new therapeutic approaches. The bispyridinium non-oxime MB327 has been found to interact directly with nAChRs, potentially through allosteric mechanisms. In this study, a new allosteric binding pocket (MB327-PAM-1) for MB327 was identified at the transition of the extracellular to the transmembrane region. The interaction of MB327 at this site suggests its potential as a novel treatment target, as it can interact with multiple nAChR subtypes from different species. Furthermore, modifications of MB327 resulted in more potent resensitizers PTM0062 and PTM0063.
TOXICOLOGY LETTERS
(2023)
Article
Pharmacology & Pharmacy
Tobias Zellner, Christian Rabe, Jens von der Wellen-Pawlowski, Dagmar Hansen, Harald John, Franz Worek, Florian Eyer
Summary: A 63-year-old male was admitted to the hospital after ingesting ethanol and pirimiphos-methyl with suicidal intentions. The patient had a complex medical history and received medical treatment and monitoring. He eventually recovered and was transferred to a neurological rehabilitation facility for further treatment.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Toxicology
Tamara Kranawetvogl, Andreas Kranawetvogl, Lisa Scheidegger, Timo Wille, Dirk Steinritz, Franz Worek, Horst Thiermann, Harald John
Summary: A microbore liquid chromatography-electrospray ionization high-resolution tandem mass spectrometry method was developed to detect three albumin-derived biomarkers for the analysis of VX nerve agent exposure. The stability and identification limit of the biomarkers were evaluated, and a dipeptide disulfide biomarker (Cys(34)(-DPAET)Pro) showed the highest performance. In vivo experiments confirmed the time-dependent concentration increase of Cys(34)(-DPAET)Pro after subcutaneous exposure in rats.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Laura Job, Anja Kohler, Andreas Eichinger, Mauricio Testanera, Benjamin Escher, Franz Worek, Arne Skerra
Summary: Neurotoxic organophosphorus compounds (OPs) can be extremely dangerous when misused. A potential treatment involves using an enzyme to break down the nerve agent into harmless substances. The bacterium Brevundimonas diminuta (BdPTE) has been studied for its potential in this area. Engineering studies have led to improved versions of BdPTE with high catalytic efficiency. Unexpectedly, the crystal structure of a highly active variant revealed a new conformation in the active site region, leading to further amino acid exchanges and optimization of the enzyme for OP nerve agent detoxification.
Article
Toxicology
Niko Amend, Horst Thiermann, Franz Worek, Timo Wille
Summary: Isolated organ models are valuable for studying the effects of opioids, and in this study, a rat small bowel model was established to evaluate the effects of carfentanil, remifentanil, and U-48800. The IC50 values of these opioids were determined, and the administration of antagonist drugs shifted the dose-response curves. This model provides a robust alternative to electrical stimulation for studying opioid effects in the small bowel.
TOXICOLOGY LETTERS
(2023)