@misc{NghinaunyeWaldeckJungetal., author = {Nghinaunye, Theopolina and Waldeck, Peter and Jung, C. G. H. and K{\"u}pper, Jan-Heiner and Jung, Friedrich and Braune, Steffen}, title = {Response of Arthrospira platensis to different temperatures regarding growth and biochemical composition}, series = {Clinical Hemorheology and Microcirculation}, journal = {Clinical Hemorheology and Microcirculation}, issn = {1386-0291}, doi = {10.3233/CH-238104}, pages = {1 -- 7}, abstract = {The growth of cyanobacteria can vary considerably depending on the ambient temperature. Since the optimal growth temperature for Arthrospira platensis (strain SAG21.99) is not yet known, this was investigated in the present study. The study revealed that a process temperature of 30°C seems to be optimal for the Arthrospira strain SAG21.99 cultivation in terms of a maximum biomass productivity. This was also true for the phycocyanin content which was at 30°C significantly higher than at 20 or 40°C.}, language = {en} } @misc{KruegerGengeKoehlerLaubeetal., author = {Kr{\"u}ger-Genge, Anne and K{\"o}hler, Susanne and Laube, Markus and Haileka, Vanessa and Lemm, Sandy and Majchrzak, Karolina and Kammerer, Sarah and Schulz, Christian and Storsberg, Joachim and Pietzsch, Jens and K{\"u}pper, Jan-Heiner and Jung, Friedrich}, title = {Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation—Relevance to Thrombosis}, series = {Cells}, volume = {12}, journal = {Cells}, number = {15}, issn = {2073-4409}, doi = {10.3390/cells12151965}, abstract = {Cancer patients are at a very high risk of serious thrombotic events, often fatal. The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.}, language = {en} } @misc{HaasWirachowskiThiboletal., author = {Haas, Manuel and Wirachowski, Karina and Thibol, Lea and K{\"u}pper, Jan-Heiner and Schrenk, Dieter and Fahrer, J{\"o}rg}, title = {Potency ranking of pyrrolizidine alkaloids in metabolically competent human liver cancer cells and primary human hepatocytes using a genotoxicity test battery}, series = {Archives of Toxicology}, volume = {97}, journal = {Archives of Toxicology}, number = {5}, issn = {0340-5761}, doi = {10.1007/s00204-023-03482-8}, pages = {1413 -- 1428}, abstract = {Pyrrolizidine alkaloids (PAs) occur as contaminants in plant-based foods and herbal medicines. Following metabolic activation by cytochrome P450 (CYP) enzymes, PAs induce DNA damage, hepatotoxicity and can cause liver cancer in rodents. There is ample evidence that the chemical structure of PAs determines their toxicity. However, more quantitative genotoxicity data are required, particularly in primary human hepatocytes (PHH). Here, the genotoxicity of eleven structurally different PAs was investigated in human HepG2 liver cells with CYP3A4 overexpression and PHH using an in vitro test battery. Furthermore, the data were subject to benchmark dose (BMD) modeling to derive the genotoxic potency of individual PAs. The cytotoxicity was initially determined in HepG2-CYP3A4 cells, revealing a clear structure-toxicity relationship for the PAs. Importantly, experiments in PHH confirmed the structure-dependent toxicity and cytotoxic potency ranking of the tested PAs. The genotoxicity markers γH2AX and p53 as well as the alkaline Comet assay consistently demonstrated a structure-dependent genotoxicity of PAs in HepG2-CYP3A4 cells, correlating well with their cytotoxic potency. BMD modeling yielded BMD values in the range of 0.1-10 µM for most cyclic and open diesters, followed by the monoesters. While retrorsine showed the highest genotoxic potency, monocrotaline and lycopsamine displayed the lowest genotoxicity. Finally, experiments in PHH corroborated the genotoxic potency ranking, and revealed genotoxic effects even in the absence of detectable cytotoxicity. In conclusion, our findings strongly support the concept of grouping PAs into potency classes and help to pave the way for a broader acceptance of relative potency factors in risk assessment.}, language = {en} } @misc{KruegerGengeJungHufertetal., author = {Kr{\"u}ger-Genge, Anne and Jung, Friedrich and Hufert, Frank and Jung, Ernst Michael and K{\"u}pper, Jan-Heiner and Storsberg, J.}, title = {Effects of gut microbial metabolite trimethylamine N-oxide (TMAO) on platelets and endothelial cells}, series = {Clinical Hemorheology and Microcirculation}, volume = {76}, journal = {Clinical Hemorheology and Microcirculation}, number = {2}, issn = {1875-8622}, doi = {10.3233/CH-209206}, pages = {309 -- 316}, abstract = {Thrombotic events result from different pathologies and are the underlying causes of severe diseases like stroke or myocardial infarction. Recent basic research now revealed a link between food uptake, food conversion and gut metabolism. Gut microbial production of trimethylamine N-oxide (TMAO) from dietary nutrients like choline, lecithin and L-carnitine was associated with the development of cardiovascular diseases. Within this review we give a systematic overview about the influence of TMAO on blood components like platelets and endothelial cells which both are involved as key players in thrombotic processes. In summary, a mechanistic correlation between the gut microbiome, TMAO and cardiovascular diseases becomes obvious and emphasizes to the significance of the intestinal microbiome.}, language = {en} } @misc{RahmanMoolaKuepper, author = {Rahman, Ateeq and Moola, Nyambe and K{\"u}pper, Jan-Heiner}, title = {Namibian algae species: A review of their distribution, medicinal uses and chemical constituents}, series = {Journal of Cellular Biotechnology}, volume = {6}, journal = {Journal of Cellular Biotechnology}, number = {2}, doi = {10.3233/JCB-209010}, pages = {139 -- 159}, abstract = {The use of indigenous or remote popular knowledge to identify new drugs against diseases or infections is a well-known approach in medicine. The inhabitants of coastal regions in Namibia and other African countries are known to prepare algae extracts for the treatment of disorders and ailments such as wounds, fever and stomach aches, as well as for the prevention of arrhythmia, cancer, and many other diseases. Algae survive in a competitive environment and, therefore, developed defense strategies that have resulted in a significant level of chemical structural diversity in various metabolic pathways. The exploration of these organisms for pharmaceutical, nutritional and medical purposes has provided important chemical candidates for the discovery of new agents against neglected tropical diseases and stimulated the use of sophisticated physical techniques. This current review provides a broad picture on the taxonomy, various medical and nutritional uses of algae, which thus should be of relevance for the African continent and underdeveloped countries in the Global South.}, language = {en} } @misc{GehreFlechnerKammereretal., author = {Gehre, Christian P. and Flechner, Marie and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Coleman, Charles Dominic and P{\"u}schel, Gerhard Paul and Uhlig, Katja and Duschl, Claus}, title = {Real time monitoring of oxygen uptake of hepatocytes in a microreactor using optical microsensors}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, issn = {2045-2322}, doi = {10.1038/s41598-020-70785-6}, abstract = {Most in vitro test systems for the assessment of toxicity are based on endpoint measurements and cannot contribute much to the establishment of mechanistic models, which are crucially important for further progress in this field. Hence, in recent years, much effort has been put into the development of methods that generate kinetic data. Real time measurements of the metabolic activity of cells based on the use of oxygen sensitive microsensor beads have been shown to provide access to the mode of action of compounds in hepatocytes. However, for fully exploiting this approach a detailed knowledge of the microenvironment of the cells is required. In this work, we investigate the cellular behaviour of three types of hepatocytes, HepG2 cells, HepG2-3A4 cells and primary mouse hepatocytes, towards their exposure to acetaminophen when the availability of oxygen for the cell is systematically varied. We show that the relative emergence of two modes of action, one NAPQI dependent and the other one transient and NAPQI independent, scale with expression level of CYP3A4. The transient cellular response associated to mitochondrial respiration is used to characterise the influence of the initial oxygen concentration in the wells before exposure to acetaminophen on the cell behaviour. A simple model is presented to describe the behaviour of the cells in this scenario. It demonstrates the level of control over the role of oxygen supply in these experiments. This is crucial for establishing this approach into a reliable and powerful method for the assessment of toxicity.}, language = {en} } @misc{SteinbrechtKammererKuepper, author = {Steinbrecht, Susanne and Kammerer, Sarah and K{\"u}pper, Jan-Heiner}, title = {HepG2 cells with recombinant cytochrome P450 enzyme overexpression: Their use and limitation as in vitro liver model}, series = {Journal of Cellular Biotechnology}, volume = {5}, journal = {Journal of Cellular Biotechnology}, number = {1}, issn = {2352-3697}, doi = {10.3233/JCB-189013}, pages = {55 -- 64}, language = {en} } @misc{SchulzKammererKuepper, author = {Schulz, Christian and Kammerer, Sarah and K{\"u}pper, Jan-Heiner}, title = {NADPH-cytochrome P450 reductase expression and enzymatic activity in primary-like human hepatocytes and HepG2 cells for in vitro biotransformation studies}, series = {Clinical Hemorheology and Microcirculation}, volume = {73}, journal = {Clinical Hemorheology and Microcirculation}, number = {1}, issn = {1386-0291}, doi = {10.3233/CH-199226}, pages = {249 -- 260}, language = {en} } @misc{HofmanSorfVagiannisetal., author = {Hofman, Jakub and Sorf, Ales and Vagiannis, Dimitrios and Sucha, Simona and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Chen, Si and Guo, Lei and Ceckova, Martina and Staud, Frantisek}, title = {Brivanib Exhibits Potential for Pharmacokinetic Drug-Drug Interactions and the Modulation of Multidrug Resistance through the Inhibition of Human ABCG2 Drug Efflux Transporter and CYP450 Biotransformation Enzymes}, series = {Molecular Pharmaceutics}, volume = {16}, journal = {Molecular Pharmaceutics}, number = {11}, doi = {10.1021/acs.molpharmaceut.9b00361}, pages = {4436 -- 4450}, language = {en} } @misc{HofmanSorfVagiannisetal., author = {Hofman, Jakub and Sorf, Ales and Vagiannis, Dimitrios and Sucha, Simona and Novotna, Eva and Kammerer, Sarah and K{\"u}pper, Jan-Heiner and Ceckova, Martina and Staud, Frantisek}, title = {Interactions of Alectinib with Human ATP-Binding Cassette Drug Efflux Transporters and Cytochrome P450 Biotransformation Enzymes: Effect on Pharmacokinetic Multidrug Resistance}, series = {Drug Metabolism and Disposition}, volume = {47}, journal = {Drug Metabolism and Disposition}, number = {7}, issn = {1521-009X}, doi = {10.1124/dmd.119.086975}, pages = {699 -- 709}, language = {en} }