Schlotterbeck, Götz
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Götz
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Schlotterbeck, Götz
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- PublikationGABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding(Elsevier, 12/2017) Zabela, Volha; Hettich, Timm; Schlotterbeck, Götz; Wimmer, Laurin; Mihovilovic D., Marko; Guillet, Fabrice; Belkacem, Bouaita; Shevchenko, Bénédicte; Hamburger, Matthias; Oufir, Mouhssin [in: Journal of Chromatography B]In a screening of natural products for allosteric modulators of GABAA receptors (γ-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABAA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF-MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with Silensomes™. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationExtended and Fully Automated Newborn Screening Method for Mass Spectrometry Detection(MDPI, 12/2017) Gaugler, Stephan; Rykl, Jana; Wagner, Irene; von Däniken, Tamara; Fingerhut, Ralph; Schlotterbeck, Götz [in: International Journal of Neonatal Screening]A new and fully automated newborn screening method for mass spectrometry was introduced in this paper. Pathological relevant amino acids, acylcarnitines, and certain steroids are detected within 4 min per sample. Each sample is treated in an automated and standardized workflow, where a mixture of deuterated internal standards is sprayed onto the sample before extraction. All compounds showed good linearity, and intra- and inter-day variation lies within the acceptance criteria (except for aspartic acid). The described workflow decreases analysis cost and labor while improving the sample traceability towards good laboratory practice.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationAntimicrobial Polyethylene through Melt Compounding with Quaternary Ammonium Salts(Hindawi Publishing Corporation, 04/2017) Rossetti, Fernanda; Siegmann, Konstantin; Köser, Joachim; Wegner, Irene; Keskin, Ismail; Schlotterbeck, Götz; Winkler, Martin [in: International Journal of Polymer Science]Selected mono- and bicationic quats were compounded with polyethylene. The physicochemical surface properties, leaching behavior, and antibacterial activity of such modified samples were investigated. Contact angle measurements and fluorescein binding assays showed the presence of quaternary ammonium groups at the surface. After storing the samples in 50°C warm water for 30 days, several were still antimicrobially active. No correlation between the number of exposed N+ head groups after leaching and the antibacterial activity was observed. There is however a qualitative correlation of the antibacterial activity with the contact angles and surface concentrations of N+ before leaching/storing in warm water.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationAltered (neo-) lacto series glycolipid biosynthesis impairs α2-6 sialylation on N-glycoproteins in ovarian cancer cells(Nature, 30.03.2017) Alam, Shahidul; Anugraham, Merrina; Huang, Yen-Lin; Kohler, Reto; Hettich, Timm; Winkelbach, Katharina; Grether, Yasmin; Nunez Lopez, Monica; Khasbiullina, Nailia; Bovin, Nicolai V.; Schlotterbeck, Götz; Jacob, Francis [in: Scientific Reports]The (neo-) lacto series glycosphingolipids (nsGSLs) comprise of glycan epitopes that are present as blood group antigens, act as primary receptors for human pathogens and are also increasingly associated with malignant diseases. Beta-1, 3-N-acetyl-glucosaminyl-transferase 5 (B3GNT5) is suggested as the key glycosyltransferase for the biosynthesis of nsGSLs. In this study, we investigated the impact of CRISPR-Cas9 -mediated gene disruption of B3GNT5 (∆B3GNT5) on the expression of glycosphingolipids and N-glycoproteins by utilizing immunostaining and glycomics-based PGC-UHPLC-ESI-QTOF-MS/MS profiling. ∆B3GNT5 cells lost nsGSL expression coinciding with reduction of α2-6 sialylation on N-glycoproteins. In contrast, disruption of B4GALNT1, a glycosyltransferase for ganglio series GSLs did not affect α2-6 sialylation on N-glycoproteins. We further profiled all known α2-6 sialyltransferase-encoding genes and showed that the loss of α2-6 sialylation is due to silencing of ST6GAL1 expression in ∆B3GNT5 cells. These results demonstrate that nsGSLs are part of a complex network affecting N-glycosylation in ovarian cancer cells.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationA UHPLC–MS/MS method for the quantification of 7α-hydroxy-4-cholesten-3-one to assist in diagnosis of bile acid malabsorption(Elsevier, 01/2017) Prost, Jean-Christophe; Brunner, Félix; Grob, Christian; Berchtold, Christian; Schlotterbeck, Götz; Bovet, Cédric; Largiadèr, Carlo R.; Fiedler, Georg Martin; Juillerat, Pascal [in: Clinical Mass Spectrometry]Bile acids malabsorption (BAM) is encountered in numerous gastrointestinal pathologies and is a good example of a treatable cause of watery diarrhea after ileal resection. The gold standard for diagnosing BAM is the selenium homocholic acid taurine test (SeHCAT), an expensive and complex analysis. An alternative method is the quantification of 7α-hydroxy-4-cholesten-3-one (C4). Here, we present a simple, ultra high-performance liquid chromatography–tandem mass spectrometry method to measure C4 in human serum. To avoid time consuming sample preparation (e.g., derivatization, solid phase extraction), we used absorption chemistry-based extraction plates. This method demonstrates a lower limit of quantification of 5 ng/mL and is linear over a concentration range from 5 to 300 ng/mL (R2 = 0.9977). Inaccuracy and imprecision were less than 15%. The validated method is currently used for routine measurement of C4 from serum in patients to confirm BAM diagnosis.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationEpigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients(Impact Journals LLC, 12.07.2016) Kohler, Reto; Anugraham, Merrina; Nunez Lopez, Monica; Xiao, Christina; Schoetzau, Andreas; Hettich, Timm; Schlotterbeck, Götz; Fedier, André; Jacob, Francis; Heinzelmann-Schwarz, Viola [in: Oncotarget]Bisecting GlcNAc on N-glycoproteins is described in E-cadherin-, EGF-, Wnt- and integrin- cancer-associated signaling pathways. However, the mechanisms regulating bisecting GlcNAc expression are not clear. Bisecting GlcNAc is attached to N-glycans through beta 1-4 N-acetylglucosaminyl transferase III (MGAT3), which is encoded by two exons flanked by high-density CpG islands. Despite a recently described correlation of MGAT3 and bisecting GlcNAc in ovarian cancer cells, it remains unknown whether DNA methylation is causative for the presence of bisecting GlcNAc. Here, we narrow down the regulatory genomic region and show that reconstitution of MGAT3 expression with 5-Aza coincides with reduced DNA methylation at the MGAT3 transcription start site. The presence of bisecting GlcNAc on released N-glycans was detected by mass spectrometry (LC-ESI-qTOF-MS/MS) in serous ovarian cancer cells upon DNA methyltransferase inhibition. The regulatory impact of DNA methylation on MGAT3 was further evaluated in 18 TCGA cancer types (n = 6118 samples) and the results indicate an improved overall survival in patients with reduced MGAT3 expression, thereby identifying long-term survivors of high-grade serous ovarian cancers (HGSOC). Epigenetic activation of MGAT3 was also confirmed in basal-like breast cancers sharing similar molecular and genetic features with HGSOC. These results provide novel insights into the epigenetic regulation of MGAT3/bisecting01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationCaco-2 Permeability Studies and In Vitro hERG Liability Assessment of Tryptanthrin and Indolinone(Thieme, 2016) Jähne, Evelyn A.; Eigenmann, Daniela E.; Moradi-Afrapoli, Fahimeh; Verjee, Sheela; Butterweck, Veronika; Hebeisen, Simon; Hettich, Timm; Schlotterbeck, Götz; Smiesko, Martin; Hamburger, Matthias; Oufir, Mouhssin [in: Planta Medica]Tryptanthrin and (E,Z)-3-(4-hydroxy-3,5-dimethoxybenzylidene)indolinone (indolinone) were recently isolated from Isatis tinctoria as potent anti-inflammatory and antiallergic alkaloids, and shown to inhibit COX-2, 5-LOX catalyzed leukotriene synthesis, and mast cell degranulation at low μM to nM concns. To assess their suitability for oral administration, we screened the compds. in an in vitro intestinal permeability assay using human colonic adenocarcinoma cells. For exact quantification of the compds., validated UPLC-MS/MS methods were used. Tryptanthrin displayed high permeability (apparent permeability coeff. > 32.0 × 10-6 cm/s) across the cell monolayer. The efflux ratio below 2 (< 1.12) and unchanged apparent permeability coeff. values in the presence of the P-glycoprotein inhibitor verapamil (50 μM) indicated that tryptanthrin was not involved in P-glycoprotein interactions. For indolinone, a low recovery was found in the human colon adenocarcinoma cell assay. High-resoln. mass spectrometry pointed to extensive phase II metab. of indolinone (sulfation and glucuronidation). Possible cardiotoxic liability of the compds. was assessed in vitro by measurement of an inhibitory effect on human ether-a-go-go-related gene tail currents in stably transfected HEK 293 cells using the patch clamp technique. Low human ether-a-go-go-related gene inhibition was found for tryptanthrin (IC50 > 10 μM) and indolinone (IC50 of 24.96 μM). The anal. of compds. using various in silico methods confirmed favorable pharmacokinetic properties, as well as a slight inhibition of the human ether-a-go-go-related gene potassium channel at micromolar concns.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationAn Acute Ocfentanil Fatality: A Case Report with Postmortem Concentrations(Oxford University Press, 2016) Dussy, Franz; Hangartner, Sarah; Hamberg, Cornelia; Berchtold, Christoph; Scherer, Ulrich; Schlotterbeck, Götz; Wyler, David; Briellmann, Thomas [in: Journal of Analytical Toxicology]A 24-year-old man known to consume illegal drugs was found dead in his apartment. A reclosable plastic zipper bag containing several hundred milligrams of a brown powder was found close to the dead body and the first assumption of the investigators was death due to heroin intoxication. Therefore, a legal autopsy was ordered. The following toxicological analysis revealed ocfentanil in urine and in the brown powder. Four different approaches for the determination of the ocfentanil concentrations in peripheral whole blood are described. Enrichment of ocfentanil from the powder was realized. With this reference, it was possible to determine the ocfentanil concentration in the seized powder to be 0.91%. Concentrations of ocfentanil were also determined in the sampled body fluids using the standard addition procedure. In peripheral blood 9.1 µg/L, in heart blood 27.9 µg/L and in urine 480 µg/L were measured. In addition, the antidepressant citalopram, the neuroleptic quetiapine and cannabinoids were found in urine and subsequently quantified in peripheral blood.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationMethod Development For High-Throughput LC/MS With Minimized Carry Over(2015) Schlotterbeck, Götz06 - Präsentation
- PublikationMetabolic Profiling(2015) Berchtold, Christian; Hettich, Timm; Schlotterbeck, Götz; Senner, Frank [in: GIT: Labor-Fachzeitschrift]01 - Zeitschriftenartikel, Journalartikel oder Magazin