@article{KlotzMentrupRegensburgeretal.2012,
  author    = {Klotz, Barbara and Mentrup, Birgit and Regensburger, Martina and Zeck, Sabine and Schneidereit, Jutta and Schupp, Nicole and Linden, Christian and Merz, Cornelia and Ebert, Regina and Jakob, Franz},
  title     = {1,25-Dihydroxyvitamin D3 Treatment Delays Cellular Aging in Human Mesenchymal Stem Cells while Maintaining Their Multipotent Capacity},
  series = {PLoS ONE},
  volume    = {7},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0029959},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133392},
  pages     = {e29959},
  year      = {2012},
  abstract  = {1,25-dihydroxyvitamin D3 (1,25D3) was reported to induce premature organismal aging in fibroblast growth factor-23 (Fgf23) and klotho deficient mice, which is of main interest as 1,25D3 supplementation of its precursor cholecalciferol is used in basic osteoporosis treatment. We wanted to know if 1,25D3 is able to modulate aging processes on a cellular level in human mesenchymal stem cells (hMSC). Effects of 100 nM 1,25D3 on hMSC were analyzed by cell proliferation and apoptosis assay, beta-galactosidase staining, VDR and surface marker immunocytochemistry, RT-PCR of 1,25D3-responsive, quiescence-and replicative senescence-associated genes. 1,25D3 treatment significantly inhibited hMSC proliferation and apoptosis after 72 h and delayed the development of replicative senescence in long-term cultures according to beta-galactosidase staining and P16 expression. Cell morphology changed from a fibroblast like appearance to broad and rounded shapes. Long term treatment did not induce lineage commitment in terms of osteogenic pathways but maintained their clonogenic capacity, their surface marker characteristics (expression of CD73, CD90, CD105) and their multipotency to develop towards the chondrogenic, adipogenic and osteogenic pathways. In conclusion, 1,25D3 delays replicative senescence in primary hMSC while the pro-aging effects seen in mouse models might mainly be due to elevated systemic phosphate levels, which propagate organismal aging.},
  language  = {en}
}
@article{LohseKlotzDiekmannetal.1988,
  author    = {Lohse, M. J. and Klotz, Karl-Norbert and Diekmann, E. and Friedrich, K. and Schwabe, U.},
  title     = {2',3'-Dideoxy-N\(^6\)-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60282},
  year      = {1988},
  abstract  = {Tbe 2',3'-dideoxy analogue of the potent A\(_1\) receptor agonist, N\(^6\)-cyclohexyladenosine (CHA), was synthesized as a potential antagonist for the A\(_1\) adenosine receptor. In sturlies on adenylate cyclase 2',3'-dideoxy-N\(^6\)-cyclohexyladenosine (ddCHA) did not show agonist properties at A\(_1\) or at A\(_2\) receptors. However, it antagonized the inhibition by R-PIA of adenylate cyclase activity of fat cell membranes via A\(_1\) receptors with a K\(_i\) value of 13 \(\mu\)M. ddCHA competed for the binding of the selective A1 receptor antagonist, [\(^3\) HJ8-cyclopentyl-1,3-dipropylxantbine ([\(^3\)H]DPCPX), to rat brain membranes with a K\(_i\) value of 4.8 \(\mu\)M; GTP did not affect the competition curve. In contrast to the marked stereoselectivity of the A\(_1\) receptor for the cx- and the natural ß-anomer of adenosine, the cx-anomer of ddCHA showed a comparable affinity for the A\(_1\) receptor (K\(_i\) value 13.9 \8\mu\)M). These data indicate that the 2'- and 3'-hydroxy groups of adenosine and its derivatives are required foragonist activity at and high affinity binding to A\(_1\) adenosine receptors and for the distinction between the cx- and ß-forms.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CristalliEleuteriVittorietal.1992,
  author    = {Cristalli, G. and Eleuteri, A. and Vittori, S. and Volpini, R. and Lohse, M. J. and Klotz, Karl-Norbert},
  title     = {2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamides as selective agonists at A\(_2\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60412},
  year      = {1992},
  abstract  = {In the search for more selective A2-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A\(_2\) receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cycla.se, and platelet aggregation studies. Binding of [\(^3\)H]NECA to A\(_2\) receptors of rat striatal membranes was inhibited by compounds 2a-d with K\(_i\) values ranging from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affmity binding at solubilized A\(_2\) receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [\(^3\)H]DPCPX and for the agonist [\(^3\)H]CCPA gave K\(_i\) values in the nanomolar range, and the compounds showed moderate A\(_2\) selectivity. In order to improve this selectivity, the correaponding 2-alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. A\(_1\) expected, the 5'-N-ethyluronamide derivatives retained the A\(_2\) affinity whereas the A\(_1\) affinity was attenuated, resulting in an up to 10-fold increase in A\(_2\) selectivity. A similar patternwas observed in adenylate cyclase assays andin platelet aggregation studies. A 30- to 45-fold selectivity for platelet A\(_2\) receptors compared to A\(_1\) receptors was found for compounds 8a-c in adenylate cyclase studies.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzLohseSchwabeetal.1989,
  author    = {Klotz, Karl-Norbert and Lohse, M. J. and Schwabe, U. and Cristalli, G. and Vittori, S. and Grifantini, M.},
  title     = {2-Chloro-N\(^6\)-[\(^3\)H]cyclopentyladenosine ([\(^3\)H]CCPA) - a high affinity agonist radioligand for A\(_1\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60328},
  year      = {1989},
  abstract  = {The tritiated analogue of 2-chloro-N6-cyclopentyladenosine (CCPA), an adenosine derivative with subnanomolar affinity and a 10000-fold selectivity for A1 adenosine receptors, has been examined as a new agonist radioligand. [3H]CCP A was prepared with a specifi.c radioactivity of 1.58 TBqjmmol ( 43 Ci/mmol) and bound in a reversible manner to A1 receptors from rat brain membranes with a high affinity K0 -value of 0.2 nmol/1. In the presence of GTP a K0 -value of 13 nmol/1 was determined for the low affinity state for agonist binding. Competition of several adenosine receptor agonists and antagonists for [3H]CCPA binding to rat brain membranes confrrmed binding to an A1 receptor. Solubilized A1 receptors bound [3H]CCPA with similar affinity for the high affinity state. At solubilized receptors a reduced association rate was observed in the presence of MgC12, as has been shown for the agonist [ 3H]N6-phenylisopropyladenosine ([3H]PIA). [3H]CCPA was also used for detection of A1 receptors in rat cardio myocyte membranes, a tissue with a very low receptor density. A K0 -value of 0.4 nmol/1 and a Bmax-value of 16 fmol/ mg protein was determined in these membranes. In human platelet membranes no specific binding of [3H]CCPA was measured at concentrations up to 400 nmoljl, indicating that A2 receptors did not bind [3H]CCPA. Based on the subnanomolar affinity and the high selectivity for A1 receptors [ 3H]CCPA proved to be a useful agonist radioligand for characterization of A 1 adenosine receptors also in tissues with very low receptor density.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LohseKlotzSchwabeetal.1988,
  author    = {Lohse, M. J. and Klotz, Karl-Norbert and Schwabe, U. and Cristalli, G. and Vittori, S. and Grifantini, M.},
  title     = {2-Chloro-N\(^6\)-cyclopentyladenosine: a highly selective agonist at A\(_1\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60279},
  year      = {1988},
  abstract  = {2-Chloro-N\(^6\)-cyclopentyladenosine (CCPA) was synthesized as a potential high affinity ligand for At adenosine receptors. Binding of [\(^3\)H]PIA to A1 receptors of rat brain membranes was inhibited by CCP A with a Ki-value of 0.4 nM, compared to a Ki-value of 0.8 nM for the parent compound N\(^6\)-cyclopentyladenosine (CPA). Binding of [\(^3\)H]NECA to A\(_2\) receptors of rat striatal membranes was inhibited with a Ki-value of 3900 nM, demonstrating an almost 10,000-fold A\(_1\)-selectivity of CCPA. CCP A inhibited the activity of rat fat cell membrane adenylate cyclase, a model for the A\(_1\) receptor, with an IC\(_{50}\)-value of 33 nM, and it stimulated the adenylate cyclase activity of human platelet membranes with an EC\(_{50}\)-value of 3500 nM. The more than 100-fold A\(_1\)-selectivity compares favourably with a 38-fold selectivity of CPA. Thus, CCPA is an agonist at A\(_1\) adenosine receptors with a 4-fold higher selectivity and 2-fold higher affinity than CPA, and a considerably higher selectivity than the standard At receptor agonist R-N\(^6\) -phenylisopropyladenosine (R-PIA). CCP A represents the agonist with the highest selectivity for A\(_1\) receptors reported so far.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperPechanSchiffmann1992,
  author    = {Stopper, Helga and Pechan, R. and Schiffmann, D.},
  title     = {5-azacytidine induces micronuclei in and morphological transformation of Syrian hamster embryo fibroblasts in the absence of unscheduled DNA synthesis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63443},
  year      = {1992},
  abstract  = {lt is known that 5-azacytidine (5-AC) induces tumors in several organs of rats and mice. The mechanisms of these effects are still poorly understood although it is known that 5-AC can be incorporated into DNA. Furthermore, it can inhibit DNA methylation. The known data on its clastogenic andjor gene mutation-inducing potential are still controversial. Therefore, we have investigated the kinds of genotoxic effects caused by 5-AC in Syrian hamster embryo (SHE) fibroblasts. Three different endp6ints (micronucleus formation, unscheduled DNA synthesis (UDS) and cell transforrnation) were assayed under similar conditions of metabolism and dose at target in this cell system. 5-AC induces morphological transformation of SHE cells, but not UDS. Therefore, 5-AC does not seem to cause repairable DNA lesions. Furthermore, our studies revealed that 5-AC is a potent inducer of mkronuclei in the SHE system. Immunocytochemical analysis revealed that a certain percentage of these contain kinetochores indicating that 5-AC may induce both clastogenic events and numerical chromosome changes.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GrunickePyerinEisenbrandetal.1994,
  author    = {Grunicke, H. and Pyerin, W. and Eisenbrand, G. and Havemann, K. and Rabes, H. M. and Molling, K. and Schwab, M. and Lutz, Werner K. and Wahrendorf, J. and Schirrmacher, V.},
  title     = {7th International Symposium of the Division of Experimental Cancer Research (AEK) of the German Cancer Society : [Meeting report]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60651},
  year      = {1994},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LohseKlotzLindenbornFotinosetal.1987,
  author    = {Lohse, M. J. and Klotz, Karl-Norbert and Lindenborn Fotinos, J. and Reddington, M. and Schwabe, U. and Olsson, R. A.},
  title     = {8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) - a selective high affinity antagonist radioligand for A\(_1\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60246},
  year      = {1987},
  abstract  = {The properties of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as an antagonist ligand for A\(_1\) adenosirre receptors were examined and conipared with other radioligands for this receptor. DPCPX competitively antagonized both the inhibition of adenylate cyclase activity via A\(_1\) adenosirre receptors and the stimulationvia A\(_2\) adenosirre receptors. The K\(_i\)-values of this antagonism were 0.45 nM at the A\(_1\) receptor of rat fat cells, and 330 nM at the A\(_2\) receptor of human platelets, giving a more than 700-fold A\(_1\)-selectivity. A similar A\(_1\)-selectivity was determined in radioligand binding studies. Even at high concentrations, DPCPX did not significantly inhibit the soluble cAMPphosphodiesterase activity of human platelets. [\(^3\)H]DPCPX (105 Ci/mmol) bound in a saturable manner with high affinity to A\(_1\) receptors in membranes of bovine brain and heart, and rat brain and fat cells (K\(_D\) -values 50-190 pM). Its nonspecific binding was about 1\% of total at K\(_D\) , except in bovine myocardial membranes (about 10\%). Binding studies with bovine myocardial membranes allowed the analysis of both the high and low agonist affinity states of this receptor in a tissue with low receptor density. The binding properties of [\(^3\)H]DPCPX appear superior to those of other agonist and antagonist radioligands for the A\(_1\) receptor.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BommakantiKlotzDratzetal.1993,
  author    = {Bommakanti, R. K. and Klotz, Karl-Norbert and Dratz, E. A. and Jesaitis, A. J.},
  title     = {A carboxyl-terminal tail peptide of neutrophil chemotactic receptor disrupts its physical complex with G protein},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60456},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1978,
  author    = {Lutz, Werner K. and Schlatter, C.},
  title     = {A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80145},
  year      = {1978},
  abstract  = {In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected ~eparately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HollerFischerWeberetal.1987,
  author    = {Holler, E. and Fischer, H. and Weber, C. and Stopper, Helga and Steger, H. and Simek, H.},
  title     = {A DNA polymerase with unusual properties from the slime mold Physarum polycephalum},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63501},
  year      = {1987},
  abstract  = {Two forms of a DNA polymerase have been purified from microplasmodia of Physarum polycephalum by poly(ethyleneimine) precipitation and chromatography on DEAE-Sephacel, phosphocellulose, heparin Sepharose, hydroxyapatite, DNA-agarose, blue-Sepharose. They were separated from DNA polymerase cx on phosphocellulose and from each other on heparin-Sepharose. Form HS1 enzymewas 30-40\% pure and form HS2 enzyme 60\% with regard toprotein contents of the preparations. Form HS2 enzymewas generated from form HS1 enzyme on prolonged standing of enzyme preparations. The DNA polymerases were obtained as complexes of a 60-kDa protein associated with either a 135-kDa (HS1) or a 110-kDa (HS2) DNA-polymerizing polypeptidein a 1:1 molar stoichiometry. The biochemical function of the 60-kDa protein remained unknown. The complexes tended to dissociate during gradient centrifugation and during partition chromatography as weil as during polyacrylamide gradient gel electrophoresis under nondenaturing conditions at high dilutions of samples. Both forms existed in plasmodia extracts, their proportions depending on several factors including those which promoted proteolysis. The DNA polymerases resembled eucaryotic DNA polymerase ß by several criteria and were functionally indistinguishable from each other. It is suggested that lower eucaryotes contain repair DNA polymerases, which are similar to those of eubacteria on a molecular mass basis.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HommersRichterYangetal.2018,
  author    = {Hommers, L. G. and Richter, J. and Yang, Y. and Raab, A. and Baumann, C. and Lang, K. and Schiele, M. A. and Weber, H. and Wittmann, A. and Wolf, C. and Alpers, G. W. and Arolt, V. and Domschke, K. and Fehm, L. and Fydrich, T. and Gerlach, A. and Gloster, A. T. and Hamm, A. O. and Helbig-Lang, S. and Kircher, T. and Lang, T. and Pan{\´e}-Farr{\´e}, C. A. and Pauli, P. and Pfleiderer, B. and Reif, A. and Romanos, M. and Straube, B. and Str{\"o}hle, A. and Wittchen, H.-U. and Frantz, S. and Ertl, G. and Lohse, M. J. and Lueken, U. and Deckert, J.},
  title     = {A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety},
  series = {Translational Psychiatry},
  volume    = {8},
  journal   = {Translational Psychiatry},
  doi       = {10.1038/s41398-018-0278-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322497},
  year      = {2018},
  abstract  = {Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.},
  language  = {en}
}
@article{WinkelbeinerWandtEbertetal.2020,
  author    = {Winkelbeiner, Nicola and Wandt, Viktoria K. and Ebert, Franziska and Lossow, Kristina and Bankoglu, Ezgi E. and Martin, Maximilian and Mangerich, Aswin and Stopper, Helga and Bornhorst, Julia and Kipp, Anna P. and Schwerdtle, Tanja},
  title     = {A multi-endpoint approach to base excision repair incision activity augmented by PARylation and DNA damage levels in mice: impact of sex and age},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {18},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21186600},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285706},
  year      = {2020},
  abstract  = {Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2'-deoxyguanosine (8-oxodG), 5-hydroxy-2'-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.},
  language  = {en}
}
@article{SchihadaVandenabeeleZabeletal.2018,
  author    = {Schihada, Hannes and Vandenabeele, Sylvie and Zabel, Ulrike and Frank, Monika and Lohse, Martin J. and Maiellaro, Isabella},
  title     = {A universal bioluminescence resonance energy transfer sensor design enables high-sensitivity screening of GPCR activation dynamics},
  series = {Communications Biology},
  volume    = {1},
  journal   = {Communications Biology},
  number    = {105},
  doi       = {10.1038/s42003-018-0072-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228592},
  pages     = {1-8},
  year      = {2018},
  abstract  = {G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the alpha(2 Lambda)-adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning beta(2)-adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands.},
  language  = {en}
}
@article{SpinaciLambertucciBuccionietal.2022,
  author    = {Spinaci, Andrea and Lambertucci, Catia and Buccioni, Michela and Dal Ben, Diego and Graiff, Claudia and Barbalace, Maria Cristina and Hrelia, Silvana and Angeloni, Cristina and Tayebati, Seyed Khosrow and Ubaldi, Massimo and Masi, Alessio and Klotz, Karl-Norbert and Volpini, Rosaria and Marucci, Gabriella},
  title     = {A\(_{2A}\) adenosine receptor antagonists: are triazolotriazine and purine scaffolds interchangeable?},
  series = {Molecules},
  volume    = {27},
  journal   = {Molecules},
  number    = {8},
  issn      = {1420-3049},
  doi       = {10.3390/molecules27082386},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270618},
  year      = {2022},
  abstract  = {The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.},
  language  = {en}
}
@article{CristalliFranchettiGrifantinietal.1988,
  author    = {Cristalli, G. and Franchetti, P. and Grifantini, M. and Vittori, S. and Klotz, Karl-Norbert and Lohse, M. J.},
  title     = {Adenosine receptor agonists: Synthesis and biological evaluation of 1-deaza analogues of adenosine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60262},
  year      = {1988},
  abstract  = {In a search for more selective A\(_1\) adenosine receptor agonists, N\(^6\)-[(R)-(-)-1-methyl-2-phenethyl]-1-deazaadenosine (1-deaza-R-PIA, 3a), N\(^6\)-cyclopentyl-1-deazaadenosine (1-deazaCPA, 3b), N\(^6\)-cyclohexyl-l-deazaadenosine (1-deazaCHA, Sc), and the corresponding 2-chloro derivatives 2a-c were synthesized from 5,7-dichloro-3-ß-D-ribofuranosyl-3Himidazo[ 4,5-b]pyridine (1). On the other band, N-ethyl-1'-deoxy-1'-(1-deaza-6-amino-9H-purin-9-yl)-ß-D-ribofuranuronamide (1-deazaNECA, 10) was prepared from 7-nitro-3-ß-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (4), in an attempt to find a more selective A\(_2\) agonist. The activity of all deaza analogues at adenosine receptors has been determined in adenylate cyclase andin radioligand binding studies. 1-DeazaNECA (10) proved tobe a nonselective agonist at both subtypes of the adenosine receptor. It is about 10-fold less active than NECA but clearly more active than the parent compound 1-deazaadenosine as an inhibitor of platelet aggregation and as a stimulator of cyclic AMP accumulation. The N\(^6\)-substituted 1-deazaadenosines largely retain the A\(_1\) agonist activity of their parent compounds, but lose some of their A\(_2\) agonist activity. This results in A\(_1\)-selective compounds, of which N\(^6\)cyclopentyl- 2-chloro-1-deazaadenosine (1-deaza-2-Cl-CPA, 2b) was identified as the most selective agonist at A\(_1\) adenosine receptors so far known. The activity of all 1-deaza analogues confirms that the presence of the nitrogen atom at position 1 of the purine ring is not critical for A\(_1\) receptor mediated adenosine actions.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{VazquezRodriguezVilarKachleretal.2020,
  author    = {Vazquez-Rodriguez, Saleta and Vilar, Santiago and Kachler, Sonja and Klotz, Karl-Norbert and Uriarte, Eugenio and Borges, Fernanda and Matos, Maria Jo{\~a}o},
  title     = {Adenosine receptor ligands: coumarin-chalcone hybrids as modulating agents on the activity of hARs},
  series = {Molecules},
  volume    = {25},
  journal   = {Molecules},
  number    = {18},
  issn      = {1420-3049},
  doi       = {10.3390/molecules25184306},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213165},
  year      = {2020},
  abstract  = {Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin-chalcone hybrids were synthesized (compounds 1-8) and screened in radioligand binding (hA\(_1\), hA\(_{2A}\) and hA\(_3\)) and adenylyl cyclase (hA\(_{2B}\)) assays in order to evaluate their affinity for the four human AR subtypes (hARs). Coumarin-chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for hA\(_1\) or hA\(_3\) subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA\(_1\), while the methoxy counterparts were selective for the hA\(_3\). The most potent hA\(_1\) ligand was compound 7 (K\(_i\) = 17.7 µM), whereas compound 4 was the most potent ligand for hA\(_3\) (K\(_i\) = 2.49 µM). In addition, docking studies with hA\(_1\) and hA\(_3\) homology models were established to analyze the structure-function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity.},
  language  = {en}
}
@article{LohseKlotzSalzeretal.1988,
  author    = {Lohse, Martin J. and Klotz, Karl-Norbert and Salzer, Manfred J. and Schwabe, Ulrich},
  title     = {Adenosine regulates the \(Ca^{2+} \) sensitivity of mast cell mediator release : (histamine secretion/inositol phosphates/calcium)},
  series = {Proceedings of the National Academy of Sciences of the United States of America},
  volume    = {85},
  journal   = {Proceedings of the National Academy of Sciences of the United States of America},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127883},
  pages     = {8875-8879},
  year      = {1988},
  abstract  = {Mast cells release histamine and other mediators of allergy in response to stimulation of their IgE receptors. This release is generally thought to be mediated by an elevation of cytosolic \(Ca^{2+}\). Recent evidence suggests that there might be factors that modulate the coupling between \(Ca^{2+}\) levels and mediator release. The present report identifies adenosine as one such modulator. Adenosine and several of its metabolically stable analogues were shown to enhance histamine release from rat peritoneal mast cells in response to stimuli such as concanavalin A. Metabolizing endogenous adenosine with adenosine deaminase dampened the response to stimuli, whereas trapping endogenous adenosine inside mast cells with nucleoside-transport inhibitors markedly enhanced stimulated histamine release. The metabolically stable adenosine analogue 5' -(N-ethylcarboxamido)adenosine (NECA) did not affect the initial steps in the sequence from IgE-receptor activation to mediator release, which are generation of inositol trisphosphate and increase of cytosolic \(Ca^{2+}\). However, NECA did enhance the release induced in ATP-permeabilized cells by exogenous \(Ca^{2+}\), but it had no effect on the release induced by phorbol esters. These data suggest that adenosine sensitizes mediator release by a mechanism regulating stimulus-secretion coupling at a step distal to receptor activation and second-messenger generation.},
  language  = {en}
}
@article{LohseBoeserKlotzetal.1987,
  author    = {Lohse, M. J. and B{\"o}ser, S. and Klotz, Karl-Norbert and Schwabe, U.},
  title     = {Affinities of barbiturates for the GABA-receptor complex and A\(_1\) adenosine receptors: A possible explanation of their excitatory effects},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60250},
  year      = {1987},
  abstract  = {The effects of barbiturates on the GABA·receptor complex and the A\(_1\) adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [\(^{35}\)S]t-butylbicyclophosphorothionate [\(^{35}\)S]TBPT) and enhanced the binding of [\(^3\)H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [\(^{35}\)S]TBPT binding, they showed varying degrees of maximal enhancement of [\(^3\)H]diazepam binding; (±)methohexital was idenafied as the most efficacious compound for this enhancement. At the A\(_1\) adenosine receptor all barbiturates inhibited the binding of [\(^3\)H]N\(^6\)-phenylisopropyladenosine (\(^3\)H]PIA) in a competitive manner. The comparison of the effects on [\(^3\)H]diazepam and [\(^3\)H]PIA binding showed that excitatory barbiturates interact preferentially with the A\(_1\) adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/ anaesthetic properties of barbiturates.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LohseKlotzSchwabe1986,
  author    = {Lohse, Martin J. and Klotz, Karl-Norbert and Schwabe, Ulrich},
  title     = {Agonist photoaffinity labeling of A1 adenosine receptors: Persistent activation reveals spare receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-87966},
  year      = {1986},
  abstract  = {No abstract available.},
  subject      = {Pharmazie},
  language  = {en}
}
@article{LutzWipfSimon1970,
  author    = {Lutz, Werner K. and Wipf, H. K. and Simon, W.},
  title     = {Alkalikationen-Spezifit{\"a}t und Tr{\"a}ger-Eigenschaftender Antibiotica Nigerfein und Monensin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61233},
  year      = {1970},
  abstract  = {It is shown by means of IR. spectroscopic methodsthat nigericin and monensin bave a cyclic conformation similar to that of their silver salts. Camplex fonnation constants with sodium and potassium ions follow the selectivity order determined by EMF. measurements on liquid membranes: nigericin: K\(^+\) >Rb\(^+\)> Na\(^+\)> Cs\(^+\) >Li\(^+\); monensin: Na\(^+\)> K\(^+\) >Li\(^+\)> Rb\(^+\)> Cs\(^+\). Transport experiments show that nigericin and monensin facilitate the diffusion of potassium ions across model membranes, although in electrolytic transport experiments the permeability is not affected.},
  subject      = {Toxikologie},
  language  = {de}
}
@article{SegererHadamekZundleretal.2016,
  author    = {Segerer, Gabriela and Hadamek, Kerstin and Zundler, Matthias and Fekete, Agnes and Seifried, Annegrit and Mueller, Martin J. and Koentgen, Frank and Gessler, Manfred and Jeanclos, Elisabeth and Gohla, Antje},
  title     = {An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation},
  series = {Scientific Reports},
  volume    = {6},
  journal   = {Scientific Reports},
  doi       = {10.1038/srep35160},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-181094},
  year      = {2016},
  abstract  = {Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp\(^{D34N}\) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.},
  language  = {en}
}
@article{StopperKoerberSpenceretal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Spencer, D. L. and Kirchner, S. and Caspary, W.J. and Schiffmann, D.},
  title     = {An investigation of micronucleus and mutation induction by oxazepam in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63404},
  year      = {1993},
  abstract  = {Tbe benzodiazepines are a class of d.rugs that are widely used in the treatment of various psychiatric disorders. One member of um ~' oxazepam, is also a common metabolite of sevmd other benzod.iazepines. Since the evidence for the genetic toxicity and carcinogenic properties of these compounds is incol:lsb1ent, we investigated the oxazepam-induced fonnation of micronuclei in Syrian Hamster embryo fibroblast (SHE) cells, human amniotic fluid fibroblast-like (AFFL) cells and LS178Y mouse cells. A dose-dependent increase in micronucleus fractions was found in all tbree ceU llnes. The time course of micronucleus induction in L5178Y cells showed a maximum at 5 h after treatment, suggesting that the micronuclei were fonned in the first mitosis after treatment. Kinetochore staining (CREST -antiserum) revealed the presence of kinetochores in -SO\% of the micronuclei in aU tbree ceU types. ThJs resu1t was further confinned by in situ bybridization in LS178Y cells and indicates tbe presence of wbole Chromosomes or centric fragments as weU as acentric fragments in the oxazepam-induced micronuclei. The LS178Y cells did not show a mutagenic response to oxazepam at any of the doses or expression times used.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KannenHintzscheZanetteetal.2012,
  author    = {Kannen, Vinicius and Hintzsche, Henning and Zanette, Dalila L. and Silva Jr., Wilson A. and Garcia, Sergio B. and Waaga-Gasser, Anna Maria and Stopper, Helga},
  title     = {Antiproliferative Effects of Fluoxetine on Colon Cancer Cells and in a Colonic Carcinogen Mouse Model},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75879},
  year      = {2012},
  abstract  = {The antidepressant fluoxetine has been under discussion because of its potential influence on cancer risk. It was found to inhibit the development of carcinogen-induced preneoplastic lesions in colon tissue, but the mechanisms of action are not well understood. Therefore, we investigated anti-proliferative effects, and used HT29 colon tumor cells in vitro, as well as C57BL/6 mice exposed to intra-rectal treatment with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as models. Fluoxetine increased the percentage of HT29 cells in the G0/G1 phase of cell-cycle, and the expression of p27 protein. This was not related to an induction of apoptosis, reactive oxygen species or DNA damage. In vivo, fluoxetine reduced the development of MNNG-induced dysplasia and vascularization-related dysplasia in colon tissue, which was analyzed by histopathological techniques. An anti-proliferative potential of fluoxetine was observed in epithelial and stromal areas. It was accompanied by a reduction of VEGF expression and of the number of cells with angiogenic potential, such as CD133, CD34, and CD31-positive cell clusters. Taken together, our findings suggest that fluoxetine treatment targets steps of early colon carcinogenesis. This confirms its protective potential, explaining at least partially the lower colon cancer risk under antidepressant therapy.},
  subject      = {Medizin},
  language  = {en}
}
@article{JarzinaDiFioreEllingeretal.2022,
  author    = {Jarzina, Sebastian and Di Fiore, Stefano and Ellinger, Bernhard and Reiser, Pia and Frank, Sabrina and Glaser, Markus and Wu, Jiaqing and Taverne, Femke J. and Kramer, Nynke I. and Mally, Angela},
  title     = {Application of the adverse outcome pathway concept to in vitro nephrotoxicity assessment: kidney injury due to receptor-mediated endocytosis and lysosomal overload as a case study},
  series = {Frontiers in Toxicology},
  volume    = {4},
  journal   = {Frontiers in Toxicology},
  issn      = {2673-3080},
  doi       = {10.3389/ftox.2022.864441},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284796},
  year      = {2022},
  abstract  = {Application of adverse outcome pathways (AOP) and integration of quantitative in vitro to in vivo extrapolation (QIVIVE) may support the paradigm shift in toxicity testing to move from apical endpoints in test animals to more mechanism-based in vitro assays. Here, we developed an AOP of proximal tubule injury linking a molecular initiating event (MIE) to a cascade of key events (KEs) leading to lysosomal overload and ultimately to cell death. This AOP was used as a case study to adopt the AOP concept for systemic toxicity testing and risk assessment based on in vitro data. In this AOP, nephrotoxicity is thought to result from receptor-mediated endocytosis (MIE) of the chemical stressor, disturbance of lysosomal function (KE1), and lysosomal disruption (KE2) associated with release of reactive oxygen species and cytotoxic lysosomal enzymes that induce cell death (KE3). Based on this mechanistic framework, in vitro readouts reflecting each KE were identified. Utilizing polymyxin antibiotics as chemical stressors for this AOP, the dose-response for each in vitro endpoint was recorded in proximal tubule cells from rat (NRK-52E) and human (RPTEC/TERT1) in order to (1) experimentally support the sequence of key events (KEs), to (2) establish quantitative relationships between KEs as a basis for prediction of downstream KEs based on in vitro data reflecting early KEs and to (3) derive suitable in vitro points of departure for human risk assessment. Time-resolved analysis was used to support the temporal sequence of events within this AOP. Quantitative response-response relationships between KEs established from in vitro data on polymyxin B were successfully used to predict in vitro toxicity of other polymyxin derivatives. Finally, a physiologically based kinetic (PBK) model was utilized to transform in vitro effect concentrations to a human equivalent dose for polymyxin B. The predicted in vivo effective doses were in the range of therapeutic doses known to be associated with a risk for nephrotoxicity. Taken together, these data provide proof-of-concept for the feasibility of in vitro based risk assessment through integration of mechanistic endpoints and reverse toxicokinetic modelling.},
  language  = {en}
}
@article{JochmannElkenaniMohamedetal.2019,
  author    = {Jochmann, Svenja and Elkenani, Manar and Mohamed, Belal A. and Buchholz, Eric and Lbik, Dawid and Binder, Lutz and Lorenz, Kristina and Shah, Ajay M. and Hasenfuß, Gerd and Toischer, Karl and Schnelle, Moritz},
  title     = {Assessing the role of extracellular signal-regulated kinases 1 and 2 in volume overload-induced cardiac remodelling},
  series = {ESC Heart Failure},
  volume    = {6},
  journal   = {ESC Heart Failure},
  number    = {5},
  doi       = {10.1002/ehf2.12497},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212735},
  pages     = {1015 -- 1026},
  year      = {2019},
  abstract  = {Aims Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen-activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown. Methods and results Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif (-28\% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. Conclusions VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte-specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.},
  language  = {en}
}
@article{BittnerBoonDelbancoetal.2022,
  author    = {Bittner, Nataly and Boon, Andy and Delbanco, Evert H. and Walter, Christof and Mally, Angela},
  title     = {Assessment of aromatic amides in printed food contact materials: analysis of potential cleavage to primary aromatic amines during simulated passage through the gastrointestinal tract},
  series = {Archives of Toxicology},
  volume    = {96},
  journal   = {Archives of Toxicology},
  number    = {5},
  doi       = {10.1007/s00204-022-03254-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324697},
  pages     = {1423-1435},
  year      = {2022},
  abstract  = {Recent analyses conducted by German official food control reported detection of the aromatic amides N-(2,4-dimethylphenyl)acetamide (NDPA), N-acetoacetyl-m-xylidine (NAAX) and 3-hydroxy-2-naphthanilide (Naphthol AS) in cold water extracts from certain food contact materials made from paper or cardboard, including paper straws, paper napkins, and cupcake liners. Because aromatic amides may be cleaved to potentially genotoxic primary amines upon oral intake, these findings raise concern that transfer of NDPA, NAAX and Naphthol AS from food contact materials into food may present a risk to human health. The aim of the present work was to assess the stability of NDPA, NAAX and Naphthol AS and potential cleavage to 2,4-dimethylaniline (2,4-DMA) and aniline during simulated passage through the gastrointestinal tract using static in vitro digestion models. Using the digestion model established by the National Institute for Public Health and the Environment (RIVM, Bilthoven, NL) and a protocol recommended by the European Food Safety Authority, potential hydrolysis of the aromatic amides to the respective aromatic amines was assessed by LC-MS/MS following incubation of the aromatic amides with digestive fluid simulants. Time-dependent hydrolysis of NDPA and NAAX resulting in formation of the primary aromatic amine 2,4-DMA was consistently observed in both models. The highest rate of cleavage of NDPA and NAAX was recorded following 4 h incubation with 0.07 M HCl as gastric-juice simulant, and amounted to 0.21\% and 0.053\%, respectively. Incubation of Naphthol AS with digestive fluid simulants did not give rise to an increase in the concentration of aniline above the background that resulted from the presence of aniline as an impurity of the test compound. Considering the lack of evidence for aniline formation from Naphthol AS and the extremely low rate of hydrolysis of the amide bonds of NDPA and NAAX during simulated passage through the gastrointestinal tract that gives rise to only very minor amounts of the potentially mutagenic and/or carcinogenic aromatic amine 2,4-DMA, risk assessment based on assumption of 100\% cleavage to the primary aromatic amines would appear to overestimate health risks related to the presence of aromatic amides in food contact materials.},
  language  = {en}
}
@article{DekantBridges2016,
  author    = {Dekant, Wolfgang and Bridges, James},
  title     = {Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence},
  series = {Regulatory Toxicology and Pharmacology},
  volume    = {81},
  journal   = {Regulatory Toxicology and Pharmacology},
  doi       = {10.1016/j.yrtph.2016.09.032},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186750},
  pages     = {397-406},
  year      = {2016},
  abstract  = {Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility.},
  language  = {en}
}
@article{ShephardSchlatterLutz1987,
  author    = {Shephard, S. E. and Schlatter, C. and Lutz, Werner K.},
  title     = {Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60925},
  year      = {1987},
  abstract  = {A literature review has shown that the daily intakes of various N -nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching Ievels of 100 g/day and 1 gjday, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this infonnation and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] x [gastric concentration of nitrite]\(^n\) x [nitrosatability rate constant} x [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligib1y small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and Ievels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power or genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SalingerHuLiuetal.2018,
  author    = {Salinger, Tim and Hu, Kai and Liu, Dan and Taleh, Scharoch and Herrmann, Sebastian and Oder, Daniel and Gensler, Daniel and M{\"u}ntze, Jonas and Ertl, Georg and Lorenz, Kristina and Frantz, Stefan and Weidemann, Frank and Nordbeck, Peter},
  title     = {Association between Comorbidities and Progression of Transvalvular Pressure Gradients in Patients with Moderate and Severe Aortic Valve Stenosis},
  series = {Cardiology Research and Practice},
  journal   = {Cardiology Research and Practice},
  doi       = {10.1155/2018/3713897},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227291},
  pages     = {3713897, 1-7},
  year      = {2018},
  abstract  = {Background. Fast progression of the transaortic mean gradient (P-mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. Methods. This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index >= 30 Kg/m(2), and history of smoking) were analyzed. Patients were divided into slow (P-mean < 5 mmHg/year) or fast (P-mean >= 5 mmHg/year) progression groups. Results. A total of 402 patients (mean age 78 +/- 9.4 years, 58\% males) were included in the study. Mean follow-up duration was 3.4 +/- 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 +/- 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 +/- 1.5 vs 2.9 +/- 1.7; P = 0.036). Patients in slow progression group had more often coronary heart disease (49.2\% vs 33.6\%; P = 0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 +/- 32.6 mg/dl vs 110.8 +/- 36.6 mg/dl; P = 0.005). Conclusion. These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.},
  language  = {en}
}
@article{ChenGassnerBoerneretal.2012,
  author    = {Chen, Wen and Gaßner, Birgit and B{\"o}rner, Sebastian and Nikolaev, Viacheslav O. and Schlegel, Nicolas and Waschke, Jens and Steinbronn, Nadine and Strasser, Ruth and Kuhn, Michaela},
  title     = {Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway},
  series = {Cardiovascular Research},
  volume    = {93},
  journal   = {Cardiovascular Research},
  number    = {1},
  doi       = {10.1093/cvr/cvr279},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126562},
  pages     = {141-151},
  year      = {2012},
  abstract  = {Aims Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP. Methods and results Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1-/- mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains. Conclusion ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume.},
  language  = {en}
}
@article{WippelMaurerFortschetal.2013,
  author    = {Wippel, Carolin and Maurer, Jana and Fortsch, Christina and Hupp, Sabrina and Bohl, Alexandra and Ma, Jiangtao and Mitchell, Timothy J. and Bunkowski, Stephanie and Br{\"u}ck, Wolfgang and Nau, Roland and Iliev, Asparouh I.},
  title     = {Bacterial Cytolysin during Meningitis Disrupts the Regulation of Glutamate in the Brain, Leading to Synaptic Damage},
  series = {PLoS Pathogens},
  volume    = {9},
  journal   = {PLoS Pathogens},
  number    = {6},
  doi       = {10.1371/journal.ppat.1003380},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130462},
  pages     = {e1003380},
  year      = {2013},
  abstract  = {Abstract Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage. Author Summary Bacterial meningitis is one of the most devastating brain diseases. Among the bacteria that cause meningitis, Streptococcus pneumoniae is the most common. Meningitis predominantly affects children, especially in the Third World, and most of them do not survive. Those that do survive often suffer permanent brain damage and hearing problems. The exact morphological substrates of brain damage in Streptococcus pneumoniae meningitis remain largely unknown. In our experiments, we found that the brain cortex of patients with meningitis demonstrated a loss of synapses (the contact points among neurons, responsible for the processes of learning and memory), and we identified the major pneumococcal neurotoxin pneumolysin as a sufficient cause of this loss. The effect was not direct but was mediated by the brain neurotransmitter glutamate, which was released upon toxin binding by one of the non-neuronal cell types of the brain - the astrocytes. Pneumolysin initiated calcium influx in astrocytes and subsequent glutamate release. Glutamate damaged the synapses via NMDA-receptors - a mechanism similar to the damage occurring in brain ischemia. Thus, we show that synaptic loss is present in pneumococcal meningitis, and we identify the toxic bacterial protein pneumolysin as the major factor in this process. These findings alter our understanding of bacterial meningitis and establish new therapeutic strategies for this fatal disease.},
  language  = {en}
}
@article{LohseKlotzJakobsetal.1985,
  author    = {Lohse, M. J. and Klotz, Karl-Norbert and Jakobs, K. H. and Schwabe, U.},
  title     = {Barbiturates are selective antagonists at A\(_1\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60187},
  year      = {1985},
  abstract  = {Barbiturates in pharmacologically relevant . concentrations inhibit binding of (R)-\(N^6\)-phenylisopropyl[\(^3\)H]adenosine ([\(^3\)H]PIA) to solubilized A\(_1\) adenosine receptors in a concentration-dependent, stereospecific, and competitive manner. K\(_i\) values are similar to those obtained for membrane-bound receptors and are 31 \(\mu\)M for ( ± )-5-(1 ,3-dimethyl)-5-ethylbarbituric acid [( ± )DMBB] and 89 \(\mu\)M for ( ± )-pentobarbital. Kinetic experiments demoostrate that barbiturates compete directly for the binding site of the receptor. The inhibition of rat striatal adenylate cyclase by unlabelled (R)-\(N^6\)-phenylisopropyladenosine [(R)-PIA] is antagonized by barbiturates in the same concentrations that inhibit radioligand binding. The Stimulation of adenylate cyclase via A\(_2\) adenosine receptors in membranes from NIE 115 neuroblastoma cells is antagonized only by 10-30 times higher concentrations of barbiturates. lt is concluded that barbiturates are selective antagonists at the A1 receptor subtype. In analogy to the excitatory effects of methylxanthines it is suggested that A\(_1\) adenosine receptor antagonism may convey excitatory properties to barbiturates. Key Words: Adenosine receptors-Barbiturates - Adenylate cyclase-Receptor solubilization-[3H]PIA binding-N1E 115 cells. Lohse M. J. et al. Barbiturates are selective antagonists at A1 adenosine receptors.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{ProppingLorenzMicheletal.2016,
  author    = {Propping, Stefan and Lorenz, Kristina and Michel, Martin C. and Wirth, Manfred P. and Ravens, Ursula},
  title     = {beta-Adrenoceptor-mediated Relaxation of Urinary Bladder Muscle in beta 2-Adrenoceptor Knockout Mice},
  series = {Frontiers in Pharmacology},
  volume    = {7},
  journal   = {Frontiers in Pharmacology},
  number    = {118},
  doi       = {10.3389/fphar.2016.00118},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165245},
  year      = {2016},
  abstract  = {Background and Objective: In order to characterize the β-adrenoceptor (AR) subtypes involved in agonist-stimulated relaxation of murine urinary bladder we studied the effects of (-)-isoprenaline and CL 316,243 on tonic contraction and spontaneous contractions in detrusor strips of wild-type (WT) and β2-AR knockout (β2-AR KO) mice. Materials and Methods: Urinary bladders were isolated from male WT and β2-AR KO mice. β-AR subtype expression was determined with quantitative real-time PCR. Intact muscle strips pre-contracted with KCl (40 mM) were exposed to cumulatively increasing concentrations of (-)-isoprenaline or β3-AR agonist CL 316,243 in the presence and absence of the subtype-selective β-AR blockers CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Results: Quantitative real-time PCR confirmed lack of β2-AR expression in bladder tissue from β2-AR KO mice. In isolated detrusor strips, pre-contraction with KCl increased basal tone and enhanced spontaneous activity significantly more in β2-AR KO than in WT. (-)-Isoprenaline relaxed tonic tension and attenuated spontaneous activity with similar potency, but the concentrations required were two orders of magnitude higher in β2-AR KO than WT. The concentration-response curves (CRCs) for relaxation were not affected by CGP 20712A (300 nM), but were shifted to the right by ICI 118,551 (50 nM) and L748,337 (10 μM). The -logEC50 values for (-)-isoprenaline in WT and β2-AR KO tissue were 7.98 and 6.00, respectively, suggesting a large receptor reserve of β2-AR. (-)-CL 316,243 relaxed detrusor and attenuated spontaneous contractions from WT and β2-AR KO mice with a potency corresponding to the drug's affinity for β3-AR. L743,337 shifted the CRCs to the right. Conclusion: Our findings in β2-AR KO mice suggest that there is a large receptor reserve for β2-AR in WT mice so that this β-AR subtype will mediate relaxation of tone and attenuation of spontaneous activity under physiological conditions. Nevertheless, upon removal of this reserve, β3-AR can also mediate murine detrusor relaxation.},
  language  = {en}
}
@article{KlaunigDekantPlotzkeetal.2016,
  author    = {Klaunig, James E. and Dekant, Wolfgang and Plotzke, Kathy and Scialli, Anthony R.},
  title     = {Biological relevance of decamethylcyclopentasiloxane (D5) induced rat uterine endometrial adenocarcinoma tumorigenesis: Mode of action and relevance to humans},
  series = {Regulatory Toxicology and Pharmacology},
  volume    = {74},
  journal   = {Regulatory Toxicology and Pharmacology},
  number    = {Supplement},
  doi       = {10.1016/j.yrtph.2015.06.021},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190952},
  pages     = {S44-S56},
  year      = {2016},
  abstract  = {Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the production and formulation of consumer products with potential exposure to manufacturing workers, consumer, and the general public. Following a combined 2-year inhalation chronic bioassay performed in Fischer 344 (F344) rats, an increase in uterine endometrial adenocarcinomas was noted at the highest concentration to which animals were exposed. No other neoplasms were detected. In this study, a dose of 160 ppm produced an incidence of 8\% endometrial adenocarcinomas. Based on a number of experimental studies with D5, the current manuscript examines the biological relevance and possible modes of action for the uterine endometrial adenocarcinomas observed in the rat following chronic exposure to D5. Variable rates of spontaneous uterine endometrial adenocarcinomas have been reported for untreated F344 CrIBr rats. As such, we concluded that the slight increase in uterine endometrial adenocarcinomas observed in the D5 chronic bioassay might not be the result of D5 exposure but may be related to variability of the spontaneous tumor incidence in this strain of rat. However, if the uterine endometrial adenocarcinomas are related to D5-exposure, alteration in the estrous cycle in the aging F344 rat is the most likely mode of action. D5 is not genotoxic or estrogenic. The alteration in the estrous cycle is caused by a decrease in progesterone with an increase in the estrogen:progesterone ratio most likely induced by a decrease in prolactin concentration. Available data support that exposure to D5 influences prolactin concentration. Although the effects on prolactin concentrations in a number of experiments were not always consistent, the available data support the conclusion that D5 is acting via a dopamine receptor agonist-like mechanism to alter the pituitary control of the estrous cycle. In further support of this mode of action, studies in F344 aged animals showed that the effects of D5 on estrous cyclicity produced a response consistent with a dopamine-like effect and further suggest that D5 is accelerating the aging of the reproductive endocrine system in the F344 rat utilized in this study. This mode of action for uterine endometrial adenocarcinoma tumorigenesis is not relevant for humans.},
  language  = {en}
}
@article{JeanclosKnoblochHoffmannetal.2020,
  author    = {Jeanclos, Elisabeth and Knobloch, Gunnar and Hoffmann, Axel and Fedorchenko, Oleg and Odersky, Andrea and Lamprecht, Anna-Karina and Schindelin, Hermann and Gohla, Antje},
  title     = {Ca\(^{2+}\) functions as a molecular switch that controls the mutually exclusive complex formation of pyridoxal phosphatase with CIB1 or calmodulin},
  series = {FEBS Letters},
  volume    = {594},
  journal   = {FEBS Letters},
  number    = {13},
  doi       = {10.1002/1873-3468.13795},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217963},
  pages     = {2099 -- 2115},
  year      = {2020},
  abstract  = {Pyridoxal 5′-phosphate (PLP) is an essential cofactor for neurotransmitter metabolism. Pyridoxal phosphatase (PDXP) deficiency in mice increases PLP and γ-aminobutyric acid levels in the brain, yet how PDXP is regulated is unclear. Here, we identify the Ca\(^{2+}\)- and integrin-binding protein 1 (CIB1) as a PDXP interactor by yeast two-hybrid screening and find a calmodulin (CaM)-binding motif that overlaps with the PDXP-CIB1 interaction site. Pulldown and crosslinking assays with purified proteins demonstrate that PDXP directly binds to CIB1 or CaM. CIB1 or CaM does not alter PDXP phosphatase activity. However, elevated Ca\(^{2+}\) concentrations promote CaM binding and, thereby, diminish CIB1 binding to PDXP, as both interactors bind in a mutually exclusive way. Hence, the PDXP-CIB1 complex may functionally differ from the PDXP-Ca\(^{2+}\)-CaM complex.},
  language  = {en}
}
@article{CalebiroMaiellaro2014,
  author    = {Calebiro, Davide and Maiellaro, Isabella},
  title     = {cAMP signaling microdomains and their observation by optical methods},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00350},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118252},
  pages     = {350},
  year      = {2014},
  abstract  = {The second messenger cyclic AMP (cAMP) is a major intracellular mediator of many hormones and neurotransmitters and regulates a myriad of cell functions, including synaptic plasticity in neurons. Whereas cAMP can freely diffuse in the cytosol, a growing body of evidence suggests the formation of cAMP gradients and microdomains near the sites of cAMP production, where cAMP signals remain apparently confined. The mechanisms responsible for the formation of such microdomains are subject of intensive investigation. The development of optical methods based on fluorescence resonance energy transfer (FRET), which allow a direct observation of cAMP signaling with high temporal and spatial resolution, is playing a fundamental role in elucidating the nature of such microdomains. Here, we will review the optical methods used for monitoring cAMP and protein kinase A (PKA) signaling in living cells, providing some examples of their application in neurons, and will discuss the major hypotheses on the formation of cAMP/PKA microdomains.},
  language  = {en}
}
@article{MaiellaroLohseKitteetal.2016,
  author    = {Maiellaro, Isabella and Lohse, Martin J. and Kitte, Robert J. and Calebiro, Davide},
  title     = {cAMP Signals in Drosophila Motor Neurons Are Confined to Single Synaptic Boutons},
  series = {Cell Reports},
  volume    = {17},
  journal   = {Cell Reports},
  number    = {5},
  doi       = {10.1016/j.celrep.2016.09.090},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162324},
  pages     = {1238-1246},
  year      = {2016},
  abstract  = {The second messenger cyclic AMP (cAMP) plays an important role in synaptic plasticity. Although there is evidence for local control of synaptic transmission and plasticity, it is less clear whether a similar spatial confinement of cAMP signaling exists. Here, we suggest a possible biophysical basis for the site-specific regulation of synaptic plasticity by cAMP, a highly diffusible small molecule that transforms the physiology of synapses in a local and specific manner. By exploiting the octopaminergic system of Drosophila, which mediates structural synaptic plasticity via a cAMP-dependent pathway, we demonstrate the existence of local cAMP signaling compartments of micrometer dimensions within single motor neurons. In addition, we provide evidence that heterogeneous octopamine receptor localization, coupled with local differences in phosphodiesterase activity, underlies the observed differences in cAMP signaling in the axon, cell body, and boutons.},
  language  = {en}
}
@article{GunzShephardLutz1993,
  author    = {Gunz, D. and Shephard, S. E. and Lutz, Werner K.},
  title     = {Can nongenotoxic carcinogens be detected with the lacI transgenic mouse mutation assay?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60707},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{vanCalkerSteberKlotzetal.1991,
  author    = {van Calker, D. and Steber, R. and Klotz, Karl-Norbert and Greil, W.},
  title     = {Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60392},
  year      = {1991},
  abstract  = {The mechanism of the therapeutic and prophylactic effects of carbamazepine (CBZ) in affective psychoses is unknown but may in part be related to the potent competitive interaction of CBZ with adenosine-binding sites in the brain. The antioonvulsant and sedative properties of CBZ are reminiscent of the effects evoked by adenosine-agonists and contrast sharply with the opposite aclions of adenosine-antagonists like caffeine. However. indirect evidence suggests an antagonist- rather than an agonist-like activity of CBZ at adenosi11e-receptors. We have used various model systems, in which adenosine receptor subtypes mediate different second messenger-responses, to investigate this apparent paradox. CBZ was found to antagonize the A\(_1\) receptor-mediated inhibition of cydic AMP accumulation in cultured astroblasts and in GH3-cells. Furthermore, CBZ also inhibits the adenosine-induced increase in the level of cyclic AMP in cultured astroblasts, which is mediated by low-affinity A\(_{2b}\)-receptors. ln contrast, CBZ does not block the inhibition elicited by adenosine-agonists of the agonist-induced increased formation of inositolphosphates in human neutrophils, which is mediated by high-affinity A\(_{2a}\)-receptors. The specific antagonism by CBZ of A\(_1\)- but not of high-affinity A\(_{2a}\)-receptors was further supported by binding experiments using rat brain membranes. These results suggest tbat the paradox of CBZ's antagonistic effects at adenosine-receptors might be at least partially reconciled by a selective antagonistic action of CBZ at A\(_1\)recertors but not at high-affinity A\(_{2a}\)-receptors.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{StopperMetzler1991,
  author    = {Stopper, Helga and Metzler, M.},
  title     = {Carcinogenic oestrogens induce respiration deficiency mutation in yeast},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63466},
  year      = {1991},
  abstract  = {In addition to hormonal activity, genetic darnage has been proposed as an important factor in oestrogen-mediated carcinogenesis. However, as short-term tests for oestrogens usually fail to show DNA mutations, lesions other than dassie nuclear DNA mutation have to be considered. Oestrogeninduced mitochondrial darnage was studied in the yeast Saccharomyces cerevisiae. Stilbene-type, but not steroidal, oestrogens were found to induce respiration-dcficient petite mutation. The effect was inversely correlated with cytotoxicity and required aromatic hydroxyl groups at the stilbene molecule. It only occurred under growth conditions and apparently was not due to the A TPase inhibitory qualities of stilbene oestrogens. Other studies have shown that petite mutation clones, which can be induced by a variety of substances, contain altered mitochondrial DNA. The mechanism of petite mutation induction might be important in tumorigenesis by also acting on nuclear DNA or facilitating carcinogenesis by disturbance of mitochondrial function.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{TolstikAliGuoetal.2022,
  author    = {Tolstik, Elen and Ali, Nairveen and Guo, Shuxia and Ebersbach, Paul and M{\"o}llmann, Dorothe and Arias-Loza, Paula and Dierks, Johann and Schuler, Irina and Freier, Erik and Debus, J{\"o}rg and Baba, Hideo A. and Nordbeck, Peter and Bocklitz, Thomas and Lorenz, Kristina},
  title     = {CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {10},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23105345},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284427},
  year      = {2022},
  abstract  = {Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient's prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90-96\%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.},
  language  = {en}
}
@article{StopperKirchnerSchiffmannetal.1994,
  author    = {Stopper, Helga and Kirchner, S. and Schiffmann, D. and Poot, M.},
  title     = {Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-82250},
  year      = {1994},
  abstract  = {In addition to its tumor-promoting activity in honnone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were fonned during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus fonnation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the GO/G 1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of Sand G2 transit may involve a process ultimately leading to micronucleus formation.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BankogluSchueleStopper2021,
  author    = {Bankoglu, Ezgi Eyluel and Schuele, Carolin and Stopper, Helga},
  title     = {Cell survival after DNA damage in the comet assay},
  series = {Archives of Toxicology},
  volume    = {95},
  journal   = {Archives of Toxicology},
  number    = {12},
  doi       = {10.1007/s00204-021-03164-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265339},
  pages     = {3803-3813},
  year      = {2021},
  abstract  = {The comet assay is widely used in basic research, genotoxicity testing, and human biomonitoring. However, interpretation of the comet assay data might benefit from a better understanding of the future fate of a cell with DNA damage. DNA damage is in principle repairable, or if extensive, can lead to cell death. Here, we have correlated the maximally induced DNA damage with three test substances in TK6 cells with the survival of the cells. For this, we selected hydrogen peroxide (H\(_{2}\)O\(_{2}\)) as an oxidizing agent, methyl methanesulfonate (MMS) as an alkylating agent and etoposide as a topoisomerase II inhibitor. We measured cell viability, cell proliferation, apoptosis, and micronucleus frequency on the following day, in the same cell culture, which had been analyzed in the comet assay. After treatment, a concentration dependent increase in DNA damage and in the percentage of non-vital and apoptotic cells was found for each substance. Values greater than 20-30\% DNA in tail caused the death of more than 50\% of the cells, with etoposide causing slightly more cell death than H\(_{2}\)O\(_{2}\) or MMS. Despite that, cells seemed to repair of at least some DNA damage within few hours after substance removal. Overall, the reduction of DNA damage over time is due to both DNA repair and death of heavily damaged cells. We recommend that in experiments with induction of DNA damage of more than 20\% DNA in tail, survival data for the cells are provided.},
  language  = {en}
}
@article{StopperKoerberSchiffmannetal.1993,
  author    = {Stopper, Helga and K{\"o}rber, C. and Schiffmann, D. and Caspary, W. J.},
  title     = {Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63411},
  year      = {1993},
  abstract  = {5-Azacytidine was originally developed to treat human myelogenous leukemia. However, interest in this compound has expanded because of reports of its ability to affect cell differentiation and to alter eukaryotic gene expression. In an ongoing attempt to understand the biochemical effects of this compound, we examined the effects of 5-azacytidine on mitosis and on micronucleus formation in mammalian cells. In L5178Y mouse cells, 5-azacytidine induced micronuclei at concentrations at which we and others have already reported its mutagenicity at the tk locus. Using CREST staining and C-banding studies, we showed that the induced micronuclei contained mostly chromosomal fragments although some may have contained whole chromosomes. By incorporating BrdU into the DNA of SHE cells, we determined that micronuclei were induced only when the compound was added while the cells were in S phase. Microscopically visible effects due to 5-azacytidine treatment were not observed until anaphase of the mitosis following treatment or thereafter. 5-Azacytidine did not induce micronuclei via interference with formation of the metaphase chromosome arrangement in mitosis, a common mechanism leading to aneuploidy. SupravitalUV microscopy revealed that chromatid bridges were observed in anaphase and, in some cases, were sustained into interphase. In the first mitosis after 5-azacytidine treatment we observed that many cells were unable to perform anaphase separation. All of these observations indicate that 5-azacytidine is predominantly a clastogen through its incorporation into DNA.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{WagnerSadekDybkovaetal.2021,
  author    = {Wagner, Michael and Sadek, Mirna S. and Dybkova, Nataliya and Mason, Fleur E. and Klehr, Johann and Firneburg, Rebecca and Cachorro, Eleder and Richter, Kurt and Klapproth, Erik and Kuenzel, Stephan R. and Lorenz, Kristina and Heijman, Jordi and Dobrev, Dobromir and El-Armouche, Ali and Sossalla, Samuel and K{\"a}mmerer, Susanne},
  title     = {Cellular mechanisms of the anti-arrhythmic effect of cardiac PDE2 overexpression},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22094816},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285888},
  year      = {2021},
  abstract  = {Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca\(^{2+}\)-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in I\(_{CaL}\) seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in I\(_{NaL}\) and Ca\(^{2+}\)-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF.},
  language  = {en}
}
@article{FoertschHuppMaetal.2011,
  author    = {F{\"o}rtsch, Christina and Hupp, Sabrina and Ma, Jiangtao and Mitchell, Timothy J. and Maier, Elke and Benz, Roland and Iliev, Asparouh I.},
  title     = {Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69084},
  year      = {2011},
  abstract  = {Streptococcus pneumoniae is a common pathogen that causes various infections, such as sepsis and meningitis. A major pathogenic factor of S. pneumoniae is the cholesterol-dependent cytolysin, pneumolysin. It produces cell lysis at high concentrations and apoptosis at lower concentrations. We have shown that sublytic amounts of pneumolysin induce small GTPase-dependent actin cytoskeleton reorganization and microtubule stabilization in human neuroblastoma cells that are manifested by cell retraction and changes in cell shape. In this study, we utilized a live imaging approach to analyze the role of pneumolysin's pore-forming capacity in the actin-dependent cell shape changes in primary astrocytes. After the initial challenge with the wild-type toxin, a permeabilized cell population was rapidly established within 20-40 minutes. After the initial rapid permeabilization, the size of the permeabilized population remained unchanged and reached a plateau. Thus, we analyzed the non-permeabilized (non-lytic) population, which demonstrated retraction and shape changes that were inhibited by actin depolymerization. Despite the non-lytic nature of pneumolysin treatment, the toxin's lytic capacity remained critical for the initiation of cell shape changes. The non-lytic pneumolysin mutants W433F-pneumolysin and delta6-pneumolysin, which bind the cell membrane with affinities similar to that of the wild-type toxin, were not able to induce shape changes. The initiation of cell shape changes and cell retraction by the wild-type toxin were independent of calcium and sodium influx and membrane depolarization, which are known to occur following cellular challenge and suggested to result from the ion channel-like properties of the pneumolysin pores. Excluding the major pore-related phenomena as the initiation mechanism of cell shape changes, the existence of a more complex relationship between the pore-forming capacity of pneumolysin and the actin cytoskeleton reorganization is suggested.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GonzalezCaleroCuberoKlotz1991,
  author    = {Gonzalez-Calero, G. and Cubero, A. and Klotz, Karl-Norbert},
  title     = {Characterization and photoaffinity labeling of A1 adenosine receptors in coated visicles form bovine brain},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86004},
  year      = {1991},
  abstract  = {The antagonist (3 II ) DPCPX exhi bitcd a Kd of 0. 4 nM at coalcd vcsicles from bovine brain. Agonist compelition for ( 3 11) DPCPX bind in~ revcaled two affini ty slales for gonists. The pholoaffinity probe I25 I -AHPIA specifically labelled a band with a molecular weight of 35 Kd.},
  subject      = {Pharmakologie},
  language  = {en}
}
@article{LohseKlotzUkenaetal.1984,
  author    = {Lohse, M. J. and Klotz, K.-N. and Ukena, D. and Schwabe, U.},
  title     = {Characterization of \([^3H]\)Phenobarbital Binding to Rat Brain Membranes},
  series = {Neuroscience Letters},
  volume    = {52},
  journal   = {Neuroscience Letters},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127894},
  pages     = {97-101},
  year      = {1984},
  abstract  = {The binding of \([^3H]\)phenobarbital to rat brain membranes was studied in order to determine its characteristics and specificity. The binding reaction was rapid and occurred at sites of low affinity. \((K_d = 700 μM)\) and very high density \((B_{max} = 2.7 nmoll/mg protein)\). It was unaffected by temperature changes from O°C to 95°C and was maximal at pH 5. Detergents in low concentrations markedly decreased the binding, apparently without solubilizing the binding sites. It is concluded that the binding of \([^3H]\) phenobarbital is a rather non-specific interaction with the plasma membrane.},
  language  = {en}
}
@article{SpielmanKlotzArendetal.1992,
  author    = {Spielman, William S. and Klotz, Karl-Norbert and Arend, Lois J. and Olson, Barbara A. and LeVier, David G. and Schwabe, Ulrich},
  title     = {Characterization of adenosine A1 receptor in a cell line (28A) derived from the rabbit collecting tubule},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86083},
  year      = {1992},
  abstract  = {We have previously reported that in several renal cell types, adenosine receptor agonists inhibit adenylyl cyclase and activate phospholipase C via a pertussis toxin-sensitive G protein. In the present study, in 28A cells, both uf these adenosine receptor-mediated responses were inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). a highly selective A1 adenosine receptor antagonist. The binding characteristics of the adenosine A 1 receptor in the 28A renal cell line were studied using the radiolabeled antagonist f:1H]DPCPX to determine whether two separate binding sites could account for these responses. Saturation binding of [: 1H]DPCPX to 28A cell membranes revealed a single class of A1 binding sites with an apparent Kd value of 1.4 nM and maximal binding capacity of 64 fmol/mg protein. Competition experiments with a variety of adenosine agonists gave biphasic displacement curves with a pharmacological profile characteristic of A1 receptors. Comparison of [: 1H]DPCPX competition binding data from 28A cell membranes with rabbit brain membranes, a tissue with well-characterized A1 receptors, reveals that the A 1 receptor population in 28A cells has similar agonist binding affinities to the receptor population in brain but has a considerably lower density. Addition of guanosine ;)' -triphosphate ( 100 ,uM) to 28A cell membranes caused the competition curves to shift from biphasic to monophasic. indicating that the A1 receptors exist in two interconvertible affinity states because of their coupling to G proteins. In the absence of evidence for subpopulations of the A1 receptor, it appears that in 28A cells. A single A1 receptor population. As defined by ligand binding characteristics, couples via one or more pertussis toxin-sensitive guanine nucleotide binding proteins to two different biological signaling mechanisms.},
  language  = {en}
}
@article{KochDegerKlotzetal.1986,
  author    = {Koch, R. and Deger, A. and Klotz, Karl-Norbert and Schenzle, D. and Kr{\"a}mer, H. and Kelm, S. and M{\"u}ller, G. and Rapp, R. and Weber, U.},
  title     = {Characterization of solubilized insulin receptors from rat liver microsomes. Existence of two receptor species with different binding properties},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60215},
  year      = {1986},
  abstract  = {Insulin receptors were solubilized from rat liver microsomes by the nonionic detergent Triton X-100. After gel filtration of the extract on Sepharose CL-6B, two insulin-binding species (peak I and peak li) were obtained. The structure and binding properties of both peaks were characterized. Gel filtration yielded Stokes radii of 9.2 nm (peak I) and 8.0 nm (peak Il). Both peaks were glycoproteins. At 4°C peak 1 showed optimal insulin binding at pH 8.0 and high ionic strength. In contrast, peak li bad its binding optimum at pH 7.0 and low ionic strength, where peak I bindingwas minimal. For peak I the change in insulin binding under different conditions of pH and ionic strength was due to a change in receptor affinity only. For peak 11 an additional change in receptor number was found. Both peaks yielded non-linear Scatchard plots under most of the buffer conditions examined. At their binding optima at 4 oc the high affinity dissociation constants were 0.50 nM (peak I) and 0.55 nM (peak II). Sodium dodecyl sulfatejpolyacrylamide gel electrophoresis of peak I revealed five receptor bands with Mr 400000, 365000, 320000, 290000, and 245000 under non-reducing conditions. For peak II two major receptor bands with M\(_r\) 210000 and 115000 were found. The peak II receptor bands were also obtained aftermild reduction of peak I. After complete reduction both peaks showed one major receptor band with M\(_r\) 130000. The reductive generation of the peak II receptor together with molecular mass estimations suggest that the peak I receptor is the disulfide-linked dimer of the peak II receptor. Thus, Triton extracts from rat liver microsomes contain two receptor species, which are related, but differ considerably in their size and insulin-binding properties.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{TawfikSchlieperKlotzKreyeetal.1989,
  author    = {Tawfik-Schlieper, H. and Klotz, Karl-Norbert and Kreye, V. A. W. and Schwabe, U.},
  title     = {Characterization of the K\(^+\)-channel-coupled adenosine receptor in guinea pig atria},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60333},
  year      = {1989},
  abstract  = {In the present work we studied the pharmacological profile of adenosine receptors in guinea pig atria by investigating the effect of different adenosine analogues on 86Rb + -efflux from isolated left atria and on binding of the antagonist radioligand 8-cyclopentyl-1 ,3-[\(^3\)H]dipropylxanthine ([\(^3\)H]DPCPX) to atrial membrane preparations. The rate of \8^{86}\)Rb\(^+\) -effiux was increased twofold by the maximally effective concentrations of adenosine receptor agonists. The EC50-values for 2-chloro-N\(^6\)-cyclopentyladenosine (CCPA), R-N\(^6\)-phenylisopropyladenosine (R-PIA), 5'-Nethylcarboxamidoadenosine (NECA), and S-N\(^6\)-phenylisopropyladenosine (S-PIA) were 0.10, 0.14, 0.24 and 12.9 \(\mu\)M, respectively. DPCPX shifted the R-PIA concentration-response curve to the right in a concentration-dependent manner with a K\(_B\)-value of 8.1 nM, indicating competitive antagonism. [\(^3\)H]DPCPX showed a saturable binding to atrial membranes with a Bmax·value of 227 fmol/mg protein and a K\(_D\)-value of 1.3 nM. Competition experiments showed a similar potency for the three agonists CCPA, R-PIA and NECA. S-PIA is 200 times less potent than R-PIA. Our results suggest that the K\(^+\) channel-coupled adenosine receptor in guinea pig atria is of an A\(_1\) subtype.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzLohseSchwabe1986,
  author    = {Klotz, Karl-Norbert and Lohse, M. J. and Schwabe, U.},
  title     = {Characterization of the solubilized A\(_1\) adenosine receptor from rat brain membranes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60222},
  year      = {1986},
  abstract  = {A\(_1\) adenosine receptors from rat brain membranes were solubilized with the zwitterionic detergent 3-[3-( cholamidopropyl)dimethylammonio]-1-propanesulfonate. The solubilized receptors retained all the characteristics of membrane-bound A\(_1\) adenosine receptors. A high and a low agonist affinity state for the radiolabelled agonist (R)-\(N^6\)-[\(^3\)H]phenylisopropyladenosine([\(^3\)H]PJA) with K\(_D\) values of 0.3 and 12 nM, respectively, were detected. High-affinity agonist binding was regulated by guanine nucleotides. In addition agonist binding was still modulated by divalent cations. The solubilized A\(_1\) adenosine receptors could be labelled not only with the agonist [\(^3\)H]PIA but also with the antagonist I ,3-diethyi-8-[\(^3\)H]phenylxanthine. Guanine nucleotides did not affect antagonist binding as reported for membrane-bound receptors. These results suggest that the solubilized receptors are still coupled to the guanine nucleotide binding protein N; and that all regulatory functions are retained on solubilization. Key Words: A1 adenosine receptors - Solubilization- Rat brain membranes. Klotz K.-N. et al. Characterization of the solubilized A1 adenosine receptor from rat brain membranes. J. Neurochem. 46, 1528-1534 (1986).},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzSchlatter1992,
  author    = {Lutz, Werner K. and Schlatter, J.},
  title     = {Chemical carcinogens and overnutrition in diet-related cancer [commentary]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60712},
  year      = {1992},
  abstract  = {The intake of known dietary carclnogens was compiled and the cancer risk was estlmated on the basis of carcinogenic potencies in animals as derived from the Carcinogenic Potency Database by Gold and co-workers. The total cancer risk was compared with the number of cancer cases attributed by epidemiologists to dietary factors (one-third of all cancer cases, i.e. -80 000 per one million Jives). Except for alcohol, the known dietary carcinogens could not account for more than a few bundred cancer cases. Tbis was seen both with tbe DNA-reactive carcinogens (beterocyclic aromatic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, estragole, aflatoxin B., ethyl carbamate, to name the most important factors) as wen as with those carclnogens wbich have not been shown to react with DNA (e.g. caffelc acid and the carcinogeruc metals arsenic and cadmium). Residues and contaminants turned out to be negligible. Among the various pmsibilities to explain the discrepancy we investigated the roJe of ovemutritlon. Dietary restriction in animals is weil known for its strong reducing effect on spontaneous tumor formation. These data can be used to derive a carcinogenic potency for excess macronutrients: tbe tumor incidence seen with the restrlcted animals is taken as a control value and the increased tumor incidence in the animals fed ad libitum is attributed to the additional feed iotake. For excess standard diet in rats, a carcinogenic potency TD50 of 16 glkg/day was deduced from a recent study. Ovemutrition in Switzerland, estimated to be 5.5 kcallkg/day, was converted to excess food (1.9 g/kg/day) and tbe cancer incidence was calculated. The result, 60 000 cancer cases per one million Jives, is provocatively close to the number of cases not explained by the known dietary chemical carcinogens. Mechanistic studies will be required to test our hypothesis and investigate the role of different types of macronutrients in ovemutrition.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzLohseSchwabe1988,
  author    = {Klotz, Karl-Norbert and Lohse, M. J. and Schwabe, U.},
  title     = {Chemical modification of A\(_1\) adenosine receptors in rat brain membranes - evidence for histidine in different domains of the ligand binding site},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60295},
  year      = {1988},
  abstract  = {Chemical modification of amino acid residues was used to probe the ligand recognition site of A\(_1\) adenosine receptors from rat brain membranes. The effect of treatment with group·specific reagents on agonist and antagonist radioligand binding was investigated. The histidine-specific reagent diethylpyrocarbonate (DEP) induced a loss of binding of the agonist R-N\(^6\)-[\(^3\)H]phenylisopropyladenosine ([\(^3\)H]PIA), which could be prevented in part by agonists, but not by antagonists. DEP treatment induced also a loss of binding of the antagonist [\(^3\)H]8- cyclopentyl-1 ,3-dipropylxanthine ([\(^3\)H]DPCPX). Antagonists protected A\(_1\) receptors from this inactivation while agonists did not. This result provided evidence for the existence of at least 2 different histidine residues involved in ligand binding. Consistent with a modification of the binding site, DEP did not alter the affinity of [\(^3\)H]DPCPX, but reduced receptor number. From the selective protection of [\(^3\)H] PIA and [\(^3\)H]DPCPX binding from inactivation, it is concluded that agonists and antagonists oocupy different domains at the binding site. Sulfhydryl modifying reagents did not influence antagonist binding, but inhibited agonist binding. This effect is explained by modification of tbe inhibitory guanine nucleotide binding protein. Pyridoxal 5-phosphate inactivated both [\(^3\)H]PIA and [\(^3\)H]DPCPX binding, but the receptors could not be protected from inactivation by ligands. Therefore, no amino group seems to be located at the Iigand binding site. In addition, it was shown that no further amino acids witb polar side chains are present. The absence of bydrophilic amino acids frout the recognition site of the receptor apart from histidine suggests an explanation for the lack of hydrophilic ligands with high affinity for A\(_1\) receptors.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{FreyGassenmaierHofmannetal.2020,
  author    = {Frey, Anna and Gassenmaier, Tobias and Hofmann, Ulrich and Schmitt, Dominik and Fette, Georg and Marx, Almuth and Heterich, Sabine and Boivin-Jahns, Val{\´e}rie and Ertl, Georg and Bley, Thorsten and Frantz, Stefan and Jahns, Roland and St{\"o}rk, Stefan},
  title     = {Coagulation factor XIII activity predicts left ventricular remodelling after acute myocardial infarction},
  series = {ESC Heart Failure},
  volume    = {7},
  journal   = {ESC Heart Failure},
  number    = {5},
  doi       = {10.1002/ehf2.12774},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236013},
  pages     = {2354-2364},
  year      = {2020},
  abstract  = {Aims Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing. Methods and results This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13\% women). Median FXIIIa was 118 \% (quartiles, 102-132\%) and dropped to a trough on the second day after MI: 109\%(98-109\%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124 \% (110-142\%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman's ρ = -0.31; P = 0.01) and Scan 3 (ρ = -0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively. Conclusions FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial.},
  language  = {en}
}
@article{StopperKuehnelPodschun1994,
  author    = {Stopper, Helga and K{\"u}hnel, A. and Podschun, B.},
  title     = {Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63383},
  year      = {1994},
  abstract  = {The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor. 2,6-Dihydroxypyridine alone and the naturally occuring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JaggiLutzSchlatter1979,
  author    = {Jaggi, W. and Lutz, Werner K. and Schlatter, C.},
  title     = {Comparative studies on the covalent binding of the carcinogen benzo(a)pyrene to DNA in various model systems},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61131},
  year      = {1979},
  abstract  = {The covalent binding of tritiated benzo(a)pyrene (BP) to DNA has been determined in rat liver in vivo, in rat liver perfused in situ, after incubation of BP with liver single cells, with liver homogenate, with liver microsomes and DNA, with fibroblasts from a rat granulorna pouch, and with · 2 cell lines. Li ver single cells were found to be a valuable compromise between the rnost sensitive system (microsomal incubation of BP with DNA) and the biologically most relevant system (in vivo ).},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzVogtTawfikSchlieper1991,
  author    = {Klotz, Karl-Norbert and Vogt, H. and Tawfik-Schlieper, H.},
  title     = {Comparison of A\(_1\) adenosine receptors in brain from different species by radioligand binding and photoaffinity labelling},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60388},
  year      = {1991},
  abstract  = {Radioligand binding to A\(_1\) adenosine receptors at brain membranes from seven species was investigated. The antagonist 8-cyclopentyl-1 ,3-[\(^3\)H]dipropylxanthine ([\(^3\)H]DPCPX) bound with affinities between 0.17 nM in sheep brain and 2.1 nM in guinea pig brain. Competition of several antagonists for [\(^3\)H]DPCPX binding showed that the most potent compounds were DPCPX with K\(_i\) values of 0.05 nM in bovine brain and 1.1 nM in guinea pig brain and xanthine amine congener (XAC) with K\(_i\) values of 0.03 nM in bovine brain and 5.5 nM in guinea pig brain. The differences in affinity of the agonist radio Iigand 2-chloro-N\(^6\) -[\(^3\)H]cyclopen tyladenosine ([\(^3\)H]CCP A) were less pronounced, rauging from a K\(_D\) value of 0.12 nM (hamster brain) to 0.42 nM (guinea pig brain). Agonist competition for [\(^3\)H]DPCPX binding of photoaffinity labelling, however, exhibited marked species differences. N-Ethylcarboxamidoadenosine (NECA) and S-N\(^6\)-phenylisopropyladenosine (S-PIA) showed 20 to 25-fold different K\(_D\) values in different species. NECA had a particularly high affinity in guinea pig brain and was only two-fold less potent than R-PIA. Thus, the difference from the "classical" A\(_1\) receptor profile (R-PIA > -NECA > S-PIA) is not sufficient to speculate that A\(_1\) receptor subtypes may exist that are coupled to different effector systems. Our data show that these difference can easily be explained by species differences.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SchanbacherHermannsLorenzetal.2023,
  author    = {Schanbacher, Constanze and Hermanns, Heike M. and Lorenz, Kristina and Wajant, Harald and Lang, Isabell},
  title     = {Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling},
  series = {Biomedicines},
  volume    = {11},
  journal   = {Biomedicines},
  number    = {2},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines11020559},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304136},
  year      = {2023},
  abstract  = {Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.},
  language  = {en}
}
@article{GuthHueserRothetal.2021,
  author    = {Guth, Sabine and H{\"u}ser, Stephanie and Roth, Angelika and Degen, Gisela and Diel, Patrick and Edlund, Karolina and Eisenbrand, Gerhard and Engel, Karl-Heinz and Epe, Bernd and Grune, Tilman and Heinz, Volker and Henle, Thomas and Humpf, Hans-Ulrich and J{\"a}ger, Henry and Joost, Hans-Georg and Kulling, Sabine E. and Lampen, Alfonso and Mally, Angela and Marchan, Rosemarie and Marko, Doris and M{\"u}hle, Eva and Nitsche, Michael A. and R{\"o}hrdanz, Elke and Stadler, Richard and van Thriel, Christoph and Vieths, Stefan and Vogel, Rudi F. and Wascher, Edmund and Watzl, Carsten and N{\"o}thlings, Ute and Hengstler, Jan G.},
  title     = {Contribution to the ongoing discussion on fluoride toxicity},
  series = {Archives of Toxicology},
  volume    = {95},
  journal   = {Archives of Toxicology},
  number    = {7},
  issn      = {0340-5761},
  doi       = {10.1007/s00204-021-03072-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307161},
  pages     = {2571-2587},
  year      = {2021},
  abstract  = {Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.},
  language  = {en}
}
@article{AlldrickLutz1989,
  author    = {Alldrick, A. J. and Lutz, Werner K.},
  title     = {Covalent binding of [2-\(^{14}\)C]2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) to mouse DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60832},
  year      = {1989},
  abstract  = {Fernale BALB/c mice were administered intragastrically with equimolar amounts of either [2-\(^{14}\)C]2-amino-3,8-dimethyi[ 4,5-J]qulnoxaline (MeiQx) or 2-acetylamino[9-\(^{14}\)C]fluorene (2AAF). DNA was isolated from tissues of mice killed either 6 or 24 h after administration. Analysis of liver DNA nucleotide digests by HPLC analysis revealed that all of the radioactivity was attributable to adduct formation. Tbe specific activities of DNA samples were converted to covalent bindlog indices (CBI, J.LIDOI adduct per mol DNA nucleotides/mmol chemical app6ed per kg animal body weight). CBI values of 25 and 9 were detennined for 2AAF and MeiQx in tbe llvers of mice killed 6 h after dosing. The values were in general agreement with the moderate carcinogenic potency of these compounds. The specific activities of DNA preparations obtained from the lddneys, spleens, stomachs, small intestines and large intestlnes of mice treated witb MeiQx and killed 6 h after doslng were S- to 35-times less tban those obtained witb the llver. DNA isolated from tbe lungs (a target organ for MeiQx tumorigenicity) of MeiQx-treated mice was not radiolabeUed at tbe limit of detection (CBI <0.3). With tbe exception of tbe gastrolntestinal tract, the specific activities of DNA samples isolated from mice killed 6 h after administration were higher than those from mice killed after 24 h.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{MarinovichLutz1985,
  author    = {Marinovich, M. and Lutz, Werner K.},
  title     = {Covalent binding of aflatoxin B\(_1\) to liver DNA in rats pretreated with ethanol},
  series = {Experientia},
  volume    = {41},
  journal   = {Experientia},
  number    = {10},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-55237},
  pages     = {1338 -- 1340},
  year      = {1985},
  abstract  = {Male Fischer F-344 rats were given ethanol in the drinking water and/or by single oral administration. Following this, the animals received p.o. 100 ng/kg of the hepatocarcinogen eHJaflatoxin BI (AFBI)' 24 h later, the level of DNA-bound AFBI was determined in the liver and was found not to be affected by any type of ethanol pretreatment. A cocarcinogenic effect of ethanol in the liver is therefore unlikely to be due to an effect on the metabolic activation and inactivation processes governing the formation of DNA-binding AFBI metabolites.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzJaggiSchlatter1982,
  author    = {Lutz, Werner K. and Jaggi, W. and Schlatter, C.},
  title     = {Covalent binding of diethylstilbestrol to DNA in rat and hamster liver and kidney [Short Communication]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61066},
  year      = {1982},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JaggiLutzSchlatter1978,
  author    = {Jaggi, W. and Lutz, Werner K. and Schlatter, C.},
  title     = {Covalent binding of ethinylestradiol and estrone to rat liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61162},
  year      = {1978},
  abstract  = {Thecovalent bindingof [6,7-\(^3\)H]ethinylestradiol (EE)and [6,7-\(^3\)H]estrone (E) to liver DNA of 200 g female ratswas measured 8 h after the administration of 80 \(\mu\)g (9.2 mCi) estrogen by gavage. The binding is 1.5 for EE and 1.1 for E, expressedas binding to DNA/dose, in units of \(\mu\)mol hormonefmol DNA phosphate/mmole honnone/kg body wt. It is in the same order of magnitude as for benzene and about 10 000 tim es below the binding of typical liver carcinogens, such as aflatoxin B\(_1\) or N,N-dimethylnitrosamine.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{EpeHarttigStopperetal.1990,
  author    = {Epe, B. and Harttig, U. and Stopper, Helga and Metzler, M.},
  title     = {Covalent binding of reactive estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63478},
  year      = {1990},
  abstract  = {Neoplastic cell transfonnation induced by estrogens and some other carcinogen\& such as benzene appears to involve the induction of mitotic aneuploidy rather than DNA damage and point mutations. As metabolic activation may also play an important roJe in the mechanism of carcinogenesis of these nongenotoxic compounds, we have studied the Interaction of reactive quinone metabolites of various estrogens and of benzene with the major microtubular protein, tubulin, in a cell-free system. Covalent binding of the radioactively labeled metabolites to the a- and 13-subunit of tubulin was found to depend on the structure of the metabolite. When the adducted tubulins were tested in vitro for their ability to polymerize to microtubules, Inhibition of microtubule assembly was obsened in every case, although to varying extents. It is proposed that the fonnation of covalent tubulin adducts may impair the formation of mitotic spindies and thus contribute to chromosomal nondisjunction and aneuploidy induction.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CantoreggiLutz1993,
  author    = {Cantoreggi, S. and Lutz, Werner K.},
  title     = {Covalent binding of styrene to DNA in rat and mouse},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60693},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LutzWinklerDunitz1971,
  author    = {Lutz, Werner K. and Winkler, F. K. and Dunitz, J. D.},
  title     = {Crystal structure of the antibiotic monensin similarities and differences betweeen free acid and metal complex},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61228},
  year      = {1971},
  abstract  = {The structure of monensin, C36H620 11 , has been deterrnined by X-ray analysis of its crystalline monohydrate (orthorhombic, a = 15.15, b = 23.61, c = 10.65 A, Z = 4, space group P212121). Phases were assigned by direct methods, malring use of the 'tangent formula'. Although the conformation of the free acid resembles that of the silver salt in being cyclic, there are differences in the hydrogen bonding pattern. These featurcs are discussed in relation to the cornplexation of metal ions by m.onensin.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{VoglLutzSchoenfelderetal.2015,
  author    = {Vogl, Silvia and Lutz, Roman W. and Sch{\"o}nfelder, Gilbert and Lutz, Werner K.},
  title     = {CYP2C9 genotype vs. metabolic phenotype for individual drug dosing - a correlation analysis using flurbiprofen as probe drug},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0120403},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148783},
  pages     = {e0120403},
  year      = {2015},
  abstract  = {Currently, genotyping of patients for polymorphic enzymes responsible for metabolic elimination is considered a possibility to adjust drug dose levels. For a patient to profit from this procedure, the interindividual differences in drug metabolism within one genotype should be smaller than those between different genotypes. We studied a large cohort of healthy young adults (283 subjects), correlating their CYP2C9 genotype to a simple phenotyping metric, using flurbiprofen as probe drug. Genotyping was conducted for CYP2C9*1, *2, *3. The urinary metabolic ratio MR (concentration of CYP2C9-dependent metabolite divided by concentration of flurbiprofen) determined two hours after flurbiprofen (8.75 mg) administration served as phenotyping metric. Linear statistical models correlating genotype and phenotype provided highly significant allele-specific MR estimates of 0.596 for the wild type allele CYP2C9*1, 0.405 for CYP2C9*2 (68 \% of wild type), and 0.113 for CYP2C9*3 (19 \% of wild type). If these estimates were used for flurbiprofen dose adjustment, taking 100 \% for genotype *1/*1, an average reduction to 84 \%, 60 \%, 68 \%, 43 \%, and 19\% would result for genotype *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Due to the large individual variation within genotypes with coefficients of variation >= 20\% and supposing the normal distribution, one in three individuals would be out of the average optimum dose by more than 20 \%, one in 20 would be 40\% off. Whether this problem also applies to other CYPs and other drugs has to be investigated case by case. Our data for the given example, however, puts the benefit of individual drug dosing to question, if it is exclusively based on genotype.},
  language  = {en}
}
@article{KirchnerStopperPappetal.1993,
  author    = {Kirchner, S. and Stopper, Helga and Papp, T. and Eckert, I. and Yoo, H. J. and Vig, B. K. and Schiffmann, D.},
  title     = {Cytogenetic changes in primary, immortalized and malignant mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63439},
  year      = {1993},
  abstract  = {Some chromosomes in transformed rat cells and somatic cell hybrids fail to display the presence of kinetochore proteins as detected by antikinetochore antibodies. Suchchromosomes (K- Chromosomes) may constitute a novel mechanism for the genesis of aneuploidy. Wehave analyzed primary~ immortalized and malignant marnmalian cells for the presence of kinetochore proteins and micronuclei. Our resuJts suggest a correlation of the K- chromosome and micronucleus frequency with the variability in chromosome number. Upon in situ hybridization with the minor satellite and alpha satellite sequences some Kchromosomes showed a signal. This indicates that the observed lack of kinetocbores is not necessarily due to a lack of centromeric DNA. We conclude that dislocated K- chromosomes may become incorporated into micronuclei which are prone to loss. Such events would be associated with the generation of aneuploidy.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JesaitisKlotz1993,
  author    = {Jesaitis, A. J. and Klotz, Karl-Norbert},
  title     = {Cytoskeletal regulation of chemotactic receptors: Molecular complexation of N-formyl peptide receptors with G proteins and actin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-79673},
  year      = {1993},
  abstract  = {Signal transduction via receptors for N-formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process. It involves direct interaction of receptors with heterotrimeric G-proteins and may be under thc control of cytoskeletal clemcnts. Evidencc exists suggesting that thc cytoskeleton and/or the membrane ske1eton determines the distribution of FPR in the plane of the plasma membrane, thus controlling FPR accessibility to different protcins in functionally distinct membrane domains. In desensitized cells, FPR are restricted to domains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inacccssible to the agonist-occupied receptor, preventing cell activation. We are investigating the molecular basis for the interaction of FPR with the membrane skeleton, and our results suggest that FPR, and possibly other receptors, may directly bind to cytoskeletal proteins such as actin.},
  subject      = {Immunologie},
  language  = {en}
}
@article{BankogluArnoldHeringetal.2018,
  author    = {Bankoglu, Ezgi Eyluel and Arnold, Charlotte and Hering, Ilona and Hankir, Mohammed and Seyfried, Florian and Stopper, Helga},
  title     = {Decreased chromosomal damage in lymphocytes of obese patients after bariatric surgery},
  series = {Scientific Reports},
  volume    = {8},
  journal   = {Scientific Reports},
  number    = {11195},
  doi       = {10.1038/s41598-018-29581-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177090},
  year      = {2018},
  abstract  = {The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.},
  language  = {en}
}
@article{TanBabakVenkatesanetal.2019,
  author    = {Tan, Aaron and Babak, Maria V. and Venkatesan, Gopalakrishnan and Lim, Clarissa and Klotz, Karl-Norbert and Herr, Deron Raymond and Cheong, Siew Lee and Federico, Stephanie and Spalluto, Giampiero and Ong, Wei-Yi and Chen, Yu Zong and Loo, Jason Siau Ee and Pastorin, Giorgia},
  title     = {Design, Synthesis and Evaluation of New Indolylpyrimidylpiperazines for Gastrointestinal Cancer Therapy},
  series = {Molecules},
  volume    = {24},
  journal   = {Molecules},
  number    = {20},
  issn      = {1420-3049},
  doi       = {10.3390/molecules24203661},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193271},
  pages     = {3661},
  year      = {2019},
  abstract  = {Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30\% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.},
  language  = {en}
}
@article{HegiSagelsdorffLutz1989,
  author    = {Hegi, M.E. and Sagelsdorff, P. and Lutz, Werner K.},
  title     = {Detection by \(^{32}\)P-postlabeling of thymidine glycol in gamma-irradiated DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60863},
  year      = {1989},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JanevskiChohStopperetal.1993,
  author    = {Janevski, J. and Choh, V. and Stopper, Helga and Schiffmann, D. and De Boni, U.},
  title     = {Diethylstilbestrol alters the morphology and calcium levels of growth cones of PC12 cells in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86858},
  year      = {1993},
  abstract  = {Diethylstilbestrol (DES) is a synthetic estrogen with carcinogenic properties. DES is known to alter cytoskeletal components, including the organization of actin stress fibres in C6 rat glioma cells. ln a test of the hypothesis that DES disrupts actin Filaments of growth cones in neuron-like cells, DES-induced changes in filopodial lengths were quantified in rat pheochromocytoma (PC12) cells in vitro. DES significantly altered growth cone morphology, with collapse of growth cone filopodia and neurite retraction invariably occurring at a concentration of 10 MikroM. At 5 MikroM DES, transient reductions in total filopodiallengths occurred. At DES concentrations of 0.1 nM and 1 nM, reductions in total filopodiallengths occurred in a fraction of growth cones. Evidence exists which shows that growth cone activity and morphology are intimately linked to Ieveis of intracellular, free calcium and that DES increases such levels. Measurements of free intracellular calcium levels by fluorescence microscopy, at times concurrent with the DES-induced reduction in total filopodial lengths, showed that calcium levels were indeed significantly increased by 10 MirkoM DES. Labelling of filamentaus actin (f-actin) with FITC-phalloidin showed that the f-actin distribution in growth cones exposed to DES could not be differentiated from the distribution found in spontaneously retracting growth cones. Tagether with evidence which showed that growth cone motility was not affected, the results are taken to indicate that DES, rather than acting directly on the cytoskeleton, exerts its effects indirectly, by a calcium-induced destabilization of actin filaments in the growth cone.},
  subject      = {Calcium},
  language  = {en}
}
@article{WeigandRonchiRizkRabinetal.2017,
  author    = {Weigand, Isabel and Ronchi, Cristina L. and Rizk-Rabin, Marthe and Dalmazi, Guido Di and Wild, Vanessa and Bathon, Kerstin and Rubin, Beatrice and Calebiro, Davide and Beuschlein, Felix and Bertherat, J{\´e}r{\^o}me and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {49},
  doi       = {10.1038/s41598-017-00125-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157952},
  year      = {2017},
  abstract  = {Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40\% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.},
  language  = {en}
}
@article{PaisdziorDimitriouSchoepeetal.2020,
  author    = {Paisdzior, Sarah and Dimitriou, Ioanna Maria and Sch{\"o}pe, Paul Curtis and Annibale, Paolo and Scheerer, Patrick and Krude, Heiko and Lohse, Martin J. and Biebermann, Heike and K{\"u}hnen, Peter},
  title     = {Differential signaling profiles of MC4R mutations with three different ligands},
  series = {International Journal of Molecular Sciences},
  volume    = {21},
  journal   = {International Journal of Molecular Sciences},
  number    = {4},
  issn      = {1422-0067},
  doi       = {10.3390/ijms21041224},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285108},
  year      = {2020},
  abstract  = {The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin-melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via G\(_S\)-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a G\(_S\) loss-of-function (S127L) and a G\(_S\) gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the G\(_{q/11}\) pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.},
  language  = {en}
}
@article{HuppFoertschWippeletal.2013,
  author    = {Hupp, Sabrina and F{\"o}rtsch, Christina and Wippel, Carolin and Ma, Jiangtao and Mitchell, Timothy J. and Iliev, Asparouh I.},
  title     = {Direct Transmembrane Interaction between Actin and the Pore-Competent, Cholesterol-Dependent Cytolysin Pneumolysin},
  series = {Journal of Molecular Biology},
  volume    = {425},
  journal   = {Journal of Molecular Biology},
  number    = {3},
  doi       = {10.1016/j.jmb.2012.11.034},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132297},
  pages     = {636-646},
  year      = {2013},
  abstract  = {The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by F{\"o}rster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170-190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought.},
  language  = {en}
}
@article{HarnošCanizalJuraseketal.2019,
  author    = {Harnoš, Jakub and Ca{\~n}izal, Maria Consuelo Alonso and Jur{\´a}sek, Miroslav and Kumar, Jitender and Holler, Cornelia and Schambony, Alexandra and Han{\´a}kov{\´a}, Kateřina and Bernat{\´i}k, Ondřej and Zdr{\´a}hal, Zbyn{\^e}k and G{\"o}m{\"o}ryov{\´a}, Krist{\´i}na and Gybeľ, Tom{\´a}š and Radaszkiewicz, Tomasz Witold and Kravec, Marek and Trant{\´i}rek, Luk{\´a}š and Ryneš, Jan and Dave, Zankruti and Fern{\´a}ndez-Llamazares, Ana Iris and V{\´a}cha, Robert and Tripsianes, Konstantinos and Hoffmann, Carsten and Bryja, V{\´i}tězslav},
  title     = {Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1},
  series = {Nature Communications},
  volume    = {10},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-019-09651-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227837},
  year      = {2019},
  abstract  = {Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.},
  language  = {en}
}
@article{MaurerHuppBischoffetal.2017,
  author    = {Maurer, Jana and Hupp, Sabrina and Bischoff, Carolin and Foertsch, Christina and Mitchell, Timothy J. and Chakraborty, Trinad and Iliev, Asparouh I.},
  title     = {Distinct neurotoxicity profile of listeriolysin O from \(Listeria\) \(monocytogenes\)},
  series = {Toxins},
  volume    = {9},
  journal   = {Toxins},
  number    = {1},
  doi       = {10.3390/toxins9010034},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172130},
  year      = {2017},
  abstract  = {Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, \(Streptococcus\) \(pneumoniae\) and \(Listeria\) \(monocytogenes\), cause fatal bacterial meningitis, and both produce toxins of the CDC family—pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA-dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology.},
  language  = {en}
}
@article{FischerBelandLutz1993,
  author    = {Fischer, W. H. and Beland, P. E. and Lutz, Werner K.},
  title     = {DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60673},
  year      = {1993},
  abstract  = {'lbe mouse skin tumor model was used to investigate whether the Ievel of DNA 8dducts and/or the rate of cell division in the epidermis are indicators of the risk of cancer formation for an individual in an outbred animal popul8tion. A high risk was considered to be reftected by 8 short latency period for the 8ppearance of 8 papilloma. Fernale NMRI mice were treated twice weekly with 2.5 nmol 7 ,12-dimethylbenz[a]antbracene (DMBA) and 3 nmoi12-0-tetradecanoylphorbol-13- 8cetate (TPA) and the appearance of papillomas was registered. The first papilloma 8ppeared after 7.5 weeks. After 17 weeks, when 12 of 14 mice bad 8t least one papilloma, an osmotic minipump deliverlog 5-bromo-2'deoxyuridine (BrdU) was implanted into eacb mouse for 24 h. The mice were killed after 24 h ~d the epidermis was analyzed for D:MBA-nucleotide 8dducts by 32p.postlabeling, for the cell number per unit skin length, and for the labeling index for DNA synthesls. Unexpectedly, D:MBA-nucleotide 8dduct Ievels were highest in those anima1s wbich showed the Iongest latency periods. Adduct Ievels were negatively correlated with the 18beling index, indicating that dilution of adducts by cell division was a predominant factor in determining average adduct concentrations. Individual tumor-latency time was not corTelated with either cell ntunber or labeling index. This could be due to the fact that the measurements only provided 8veraged data and gave no infonnation on the specific situation in clones of premalignant cells. Under the conditions of tbis assay, therefore, neither DNA adduct Ievels nor information on the average kinetics of cell division bad a predidive value for the individual amcer risk withln a group of outbred animals receiving the same treatment},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SchuppStopperHeidland2016,
  author    = {Schupp, Nicole and Stopper, Helga and Heidland, August},
  title     = {DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers},
  series = {Oxidative Medicine and Cellular Longevity},
  volume    = {2016},
  journal   = {Oxidative Medicine and Cellular Longevity},
  number    = {3592042},
  doi       = {10.1155/2016/3592042},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166569},
  year      = {2016},
  abstract  = {Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients' burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker's potential to predict clinical outcomes.},
  language  = {en}
}
@article{EpeHaeringRamaiahetal.1993,
  author    = {Epe, Bernd and H{\"a}ring, Martin and Ramaiah, Danaboyina and Stopper, Helga and Abou-Elzahab, Mohamed M. and Adam, Waldemar and Saha-M{\"o}ller, Chantu R.},
  title     = {DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86870},
  year      = {1993},
  abstract  = {Wben irradiated at 360 nm, furocoumarins with a hydroperoxide group in a side chain effciently give rise to a type of DNA damage that can best be explained by a photoinduced generation of hydroxyl radicals from the excited pbotosensitizers. The observed DNA damage profiles, i.e. the ratios of single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to fonnamidopyrimidine-DNA glycosylase (FPG protein) and endonuclease m, are similar to the DNA damage profile produced by hydroxyl radicals generated by lonizing radiation or by xanthine and xanthine oxidase in the presence of Fe(III)-EDTA. No such damage is observed with the corresponding furocoumarin alcohols or in the absence of near-UV radiation. The damage caused by the photo-excited hydroperoxides is not influenced by superoxide dismutase (SOD) or catalase or by D2O as solvent. The presence of t-butanol, however, reduces both the formation of single-strand breaks and of base odifications sensitive to FPG protein. The cytotoxicity caused by one of the hydroperoxides in L5178Y mome lymphoma cells is found to be dependent on the near-UV irradiation and to be much higher than that of the corresponding alcohol. Therefore the new type of photoinduced damage occurs inside cells. Intercalating photosensitizers with an attached hydroperoxide group might represent a novel and versatile class of DNA damaging agents, e.g. for phototherapy.},
  subject      = {DNS-Sch{\"a}digung},
  language  = {en}
}
@article{SagelsdorffLutzSchlatter1988,
  author    = {Sagelsdorff, P. and Lutz, Werner K. and Schlatter, C.},
  title     = {DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60875},
  year      = {1988},
  abstract  = {DNA Methylation in Rat Li ver by Daminozide, 1, 1-Dimethylhydrazine, and Dimethylnitrosamine. SAGELSDORFF, P., LUTZ, W. K., AND ScHLAITER C. (1988). Fundam. Appl. Toxico/. 11, 723-730. [methyP4C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mgjkg), l,l( 14C]dimethylhydrazine (UDMH; 19 mgtkg), and (14C]dimethylnitrosamine (DMNA; 0.1 mg/ kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the Ievel of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis ofpurines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyPH]UDMH, the formation of7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mgj kg. The methylation ofDNA was strictly proportional to the dose. The data were used to compare the Ievel of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could Iead to a DNA methylation in the Ii ver of about 6\% of an average exposure to DMNA},
  subject      = {Toxikologie},
  language  = {en}
}
@article{OhgakiLudekeMeieretal.1991,
  author    = {Ohgaki, H. and Ludeke, B. I. and Meier, I. and Kleihues, P. and Lutz, Werner K. and Schlatter, C.},
  title     = {DNA methylation in the digestive tract of F344 rats during chronic exposure to N-methyl-N-nitrosourea},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60759},
  year      = {1991},
  abstract  = {The formation of \(O^6\)-methyldeoxyguanosine (\(O^6\)-MedGuo) was determined by an immuno-slot-blot assay in DNA of various tissues of F344 rats exposed to N-methyl-N-nitrosourea (MNU) in the drinking waterat 400 ppm for 2 weeks. Although the pyloric region of the glandular stomach is a target organ under these experimental conditions, the extent of DNA methylation was highest in the forestomach (185 \(\mu\)mol \(O^6\)-MedGuojmol guanine). Fundus (91 J.!moljmol guanine) and pylorus (105 J.!moljmol guanine) of the glandular stomach, oesophagus (124 \(\mu\)mol/mol guanine) and duodenum (109 )lmoljmol guanine) showed lower Ievels of \(O^6\) - MedGuo but differed little between each other. Thus, no correlation was observed between target organ specificity and the extent of DNA methylation. This is in contrast to the gastric carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which preferentially alkylates DNA of the pylorus, the main site of induction of gastric carcinomas by this chemical. In contrast to MNU, the nonenzymic decomposition of MNNG is accelerated by thiol compounds (reduced glutathione, L-cysteine), which are present at much higher concentrations in the glandular stomach than in the forestomach and oesophagus. During chronic exposure to MNNG (80 ppm), mucosal cells immunoreactive to 0 6-MedGuo are limited to the luminal surface [Kobori et al. (1988) Carcinogenesis 9:2271-2274]. Although MNU (400 ppm) produced similar Ievels of \(O^6\)-MedGuo in the pylorus, no cells containing methylpurines were detectable by immunohistochemistry, suggesting a more uniform methylation of mucosal cells by MNU than by MNNG. After a single oral dose of MNU (90 mg/kg) cells containing methylpurines were unequivocally identified using antibodies to \(O^6\)-MedGuo and the imidazole-ring-opened product of 7-methyldeoxyguanosine. In the gastric fundus, their distribution was similar to those methylated by exposure to MNNG, whereas the pyloric region contained immunoreactive cells also in the deeper mucosallayers. After a 2-week MNU treatment, the rate of cell proliferation, as determined by bromodeoxyuridine immunoreactivity, was only slightly enhanced in the oesophagus andin the fundus, but markedly in the forestomach and the pyloric region of the glandular stomach. lt is concluded that the overall extent of DNA methylation, the distribution of alkylated cells within the mucosa and the proliferative response all contribute to the organ-specific carcinogenicity of MNU.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1990,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationship and low dose extrapolation in chemical carcinogenesis [commentary]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60789},
  year      = {1990},
  abstract  = {Data supporting various dose-respome relationships in chemical carcinogenesis are summarized. General principles are derived to explain the relationships between exposure dose, JI>NA adduct Ievel, induction of genetic changes, and tumor incidence. Some mechanistic aspects of epigenetic carcinogens (stimulation of ceU division and maldlfl'erentlation) are analyzed in a similar way. In a bomogeneous pnpulation, non-linearities are frequent. They are due to pbenomena of induction or saturation of enzymatic activities and to the multi-step nature of carcinog~: if a carcinogen acce1erates more than one step, the SUperposition of the dose- response curves for the indJvidual steps can result in an exponential relationship. A fourth power of the dose was the maximum seen in animals (fonnaldehyde). At the lowest dose Ievels, a proportionality between dose and tumor induction is postulated independent of the mechanism of action if the carcinogen aceeierotes the endogenous proass responsible for spootaneous tumor formation. Low-dose thresholds are expected only for situations where the carcinogen acts in a way that has no endogenous counterpart. Epidemiologfcal studies in humans show linear dose- response curves in all but two investigations. The difference from the strongly nonlinear slopes ·seen in animal studies could be due to the heterogeneity of the human population: if the individual sensitivity to a carcinogen is governed by a large number of genetic and Iife-style factors, the non-linea.rities will tend to cancel each other out and the dose- response curve becomes 'quasi-linear'.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1991,
  author    = {Lutz, Werner K.},
  title     = {Dose-response relationship for chemical carcinogenesis by genotoxic agents},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60766},
  year      = {1991},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1990,
  author    = {Lutz, Werner K.},
  title     = {Dosis-Wirkungs-Beziehungen in der chemischen Kanzerogenese},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-80046},
  year      = {1990},
  abstract  = {Ich habe versucht darzulegen, daß mechanistische {\"U}berlegungen zur Extrapolation der Dosis-WirkungsBeziehung herangezogen werden k{\"o}nnen. Ein nichtlinearer Verlauf ist nicht nur bei den epigenetischen Kanzerogenen wahrscheinlich, sondern auch bei den DNA-bindenden. Echte Schwellen sind aber nur in solchen F{\"a}llen zu erwarten, wo kein endogenes Korrelat besteht. Immerhin k{\"o}nnen auch steile Nichtlinearit{\"a}ten zu einer drastischen Risikoreduktion f{\"u}hren, so daß die Anstrengungen dahin gehen sollten, die Steigung und den Bereich des {\"u}berproportionalen Abfalls experimentell zu zeigen. In einer heterogenen Population kann die 0 0- sis-Wirkungs-Kurve zus{\"a}tzliche "Wellen" bekommen und wird dadurch grunds{\"a}tzlich flacher. Im Extremfall ergibt sich eine lineare Dosis-Wirkungs-Beziehung unabh{\"a}ngig vom Wirkmechanismus des Kanzerogens. Diese Proportionalit{\"a}t zwischen tiefster Dosis und Effekt wird bei genotoxischen Kanzerogenen aus mechanistischen Gr{\"u}nden schon f{\"u}r eine homogene Population postuliert, doch kann dies in einer heterogenen Population auch bei epigenetischen Kanzerogenen in Frage kommen.},
  subject      = {Toxikologie},
  language  = {de}
}
@article{JoosSaadatmandSchnabeletal.2018,
  author    = {Joos, J. P. and Saadatmand, A. R. and Schnabel, C. and Viktorinov{\´a}, I. and Brand, T. and Kramer, M. and Nattel, S. and Dobrev, D. and Tomancak, P. and Backs, J. and Kleinbongard, P. and Heusch, G. and Lorenz, K. and Koch, E. and Weber, S. and El-Armouche, A.},
  title     = {Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila},
  series = {Scientific Reports},
  volume    = {8},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-018-21372-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323637},
  year      = {2018},
  abstract  = {Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.},
  language  = {en}
}
@article{BankogluStippGerberetal.2021,
  author    = {Bankoglu, Ezgi Eyluel and Stipp, Franzisca and Gerber, Johanna and Seyfried, Florian and Heidland, August and Bahner, Udo and Stopper, Helga},
  title     = {Effect of cryopreservation on DNA damage and DNA repair activity in human blood samples in the comet assay},
  series = {Archives of Toxicology},
  volume    = {95},
  journal   = {Archives of Toxicology},
  number    = {5},
  doi       = {10.1007/s00204-021-03012-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265326},
  pages     = {1831-1841},
  year      = {2021},
  abstract  = {The comet assay is a commonly used method to determine DNA damage and repair activity in many types of samples. In recent years, the use of the comet assay in human biomonitoring became highly attractive due to its various modified versions, which may be useful to determine individual susceptibility in blood samples. However, in human biomonitoring studies, working with large sample numbers that are acquired over an extended time period requires some additional considerations. One of the most important issues is the storage of samples and its effect on the outcome of the comet assay. Another important question is the suitability of different blood preparations. In this study, we analysed the effect of cryopreservation on DNA damage and repair activity in human blood samples. In addition, we investigated the suitability of different blood preparations. The alkaline and FPG as well as two different types of repair comet assay and an in vitro hydrogen peroxide challenge were applied. Our results confirmed that cryopreserved blood preparations are suitable for investigating DNA damage in the alkaline and FPG comet assay in whole blood, buffy coat and PBMCs. Ex vivo hydrogen peroxide challenge yielded its optimal effect in isolated PBMCs. The utilised repair comet assay with either UVC or hydrogen peroxide-induced lesions and an aphidicolin block worked well in fresh PBMCs. Cryopreserved PBMCs could not be used immediately after thawing. However, a 16-h recovery with or without mitotic stimulation enabled the application of the repair comet assay, albeit only in a surviving cell fraction.},
  language  = {en}
}
@article{LutzBraendleZbinden1978,
  author    = {Lutz, Werner K. and Br{\"a}ndle, E. and Zbinden, G.},
  title     = {Effect of gum Arabic on aminopyrine demethylation in rats},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61146},
  year      = {1978},
  abstract  = {Stimulation of aminopyrine demethylation induced in rats by oral or i.p. administration of phenobarbital was partially inhibited in animals receiving daily treatments of 2 x 200 mg/kg gum Arabic p.o.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{SchuppAliBeegametal.2013,
  author    = {Schupp, Nicole and Ali, Badreldin H. and Beegam, Sumyia and Al-Husseni, Isehaq and Al-Shukaili, Ahmed and Nemmar, Abderrahim and Schierling, Simone and Queisser, Nina},
  title     = {Effect of gum arabic on oxidative stress and inflammation in adenine-induced chronic renal failure in rats},
  series = {PLoS One},
  journal   = {PLoS One},
  doi       = {10.1371/journal.pone.0055242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-95787},
  year      = {2013},
  abstract  = {Inflammation and oxidative stress are known to be involved in the pathogenesis of chronic kidney disease in humans, and in chronic renal failure (CRF) in rats. The aim of this work was to study the role of inflammation and oxidative stress in adenine-induced CRF and the effect thereon of the purported nephroprotective agent gum arabic (GA). Rats were divided into four groups and treated for 4 weeks as follows: control, adenine in feed (0.75\%, w/w), GA in drinking water (15\%, w/v) and adenine+GA, as before. Urine, blood and kidneys were collected from the rats at the end of the treatment for analysis of conventional renal function tests (plasma creatinine and urea concentration). In addition, the concentrations of the pro-inflammatory cytokine TNF-a and the oxidative stress markers glutathione and superoxide dismutase, renal apoptosis, superoxide formation and DNA double strand break frequency, detected by immunohistochemistry for c-H2AX, were measured. Adenine significantly increased the concentrations of urea and creatinine in plasma, significantly decreased the creatinine clearance and induced significant increases in the concentration of the measured inflammatory mediators. Further, it caused oxidative stress and DNA damage. Treatment with GA significantly ameliorated these actions. The mechanism of the reported salutary effect of GA in adenine-induced CRF is associated with mitigation of the adenine-induced inflammation and generation of free radicals.},
  language  = {en}
}
@article{BaertschLutzSchlatter1991,
  author    = {Baertsch, A. and Lutz, Werner K. and Schlatter, C.},
  title     = {Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60743},
  year      = {1991},
  abstract  = {1 ,2-Dichloroethane (DCE) was reported to be carcinogenic in rats in a long-tenn bioassay using gavage in com oil (24 and 48 mg/kg/day), but not by inhalation (up to 150-250 ppm, 7 h/day, 5 days/week). The daily dose metabolized was similar in the two experiments. In order to address this discrepancy, the genotoxicity of DCE was investigated in vivo under different exposure conditions. Fernale F-344 rats (183-188 g) were exposed to [1,2-14C]DCE in a closed inhalation chamber to either a low, constant concentration (0.3 mg/l = 80 ppm for 4 h) or to a peak concentration (up to 18 mg/1 = 4400 ppm) for a few minutes. After 12 h in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/k:g. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymaticaBy hydrolyzed to the 3' -nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density' indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. The Ievel of DNA adducts was expressed in the dose-nonnalized units ofthe Covalent Binding Index, CBI = f.Lmol adduct per mol DNA nucleotide/ mmol DCE per kg body wt. In liver DNA, the different exposure regimens resulted in markedly different CBI values of 1.8 and 69, for "constant-low" and ''peak" DCE exposure Ievels. In the Jung, the respective values were 0.9 and 31. It is concluded that the DNA darnage by DCE depends upon the concentration-time profile and that the carcinogenic potency determined in the gavage study should not be used for low-Ievel inhalation exposure.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{VivianiDaenikenSchlatteretal.1980,
  author    = {Viviani, A. and D{\"a}niken, A. von and Schlatter, C. and Lutz, Werner K.},
  title     = {Effect of selected induction of microsomal and nuclear aryl hydrocarbon monooxygenase and epoxide hydrolase as well as cytoplasmic glutathione S-epoxide transferase on the covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61114},
  year      = {1980},
  abstract  = {Groups of four adult male rats [ZUR:SIV -Z] were pretreated with corn oil (control; 2 ml/kg/day i. p. for 3 days), trans-stilbene-oxide (SO; 200 mg/kg/day i. p. for 2 days), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 \(\mu\)g/kg i. p. once, 4 days before killing), phenobarbital (PB; 1 gjliter in the drinking water for 8 days), and dieldrin (20 mg/kg/day i. p. for 3 or 9 days). They received an injection of [G-\(^3\)H]benzo(a)pyrene (BaP, 31 \(\mu\)g/kg, 7.4. 10\(^9\) dpm/kg; i. v.) 16 h before killing. In the liver of each rat, five enzymatic activities and the covalent binding of BaP to DNA have been determined. The rnicrosomal aryl hydrocarbon monooxygenase activity (AHM) ranged frorn 75\% of control (SO) to 356\% (TCDD), the nuclear AHM from 63\% (SO) to 333\% (TCDD). Microsomal epoxide hydrolase activity (EH) was induced up to 238\% (PB), nuclear EH ranged from 86\% (TCDD) to 218\% (PB). A different extent of induction was observed in the two compartments. Highest induction of glutathione S-epoxide transferase activity (GST) was found with PB (202\%). The DNA binding of BaP was modulated within 79\% (dieldrin, 9 days) and 238\% of control (TCDD). An enzyme digest of control DNA was analysed by Sephadex LH-20 chromatography. Multiple linear regression analysis with all data expressedas o/o of control yielded the following equation: DNA Binding = 1.49 · Microsomal AHM- 1.07 · Nuclear AHM+ 0.33 · Microsomal EH- 0.52 · N uclear EH+ 0.11 · Cytoplasmic GST + 58.2. From this analysis it is concluded that (1) AHM located in the endoplasmic reticulum is most important in the formation of DNA-binding metabolites, (2) EH in the same compar.tment is not determinative in thls respect nor has it a protective effect, (3) both membrane-bound enzyme activities located in the nucleus may inactivate potential ultimate carcinogens, and ( 4) cytoplasmic GST probably cannot reduce DNA binding due to its subcellular localization.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{LohseKlotzSchwabe1986,
  author    = {Lohse, Martin J. and Klotz, Karl-Norbert and Schwabe, Ulrich},
  title     = {Effectes of temperature and membrane phase transitions on ligand binding to a2-receptors of human platelets},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86023},
  year      = {1986},
  abstract  = {The binding of agonists and antagonists to a2-adrenergic receptors of human platelets was studied. The receptors showed homogeneaus affinities for antagonists but two affinity states for the agonist (-)-epinephrine, which were modulated by guanine nucleotides. Van't Hoffplots of antagonist binding had a break point at about 18° and considerable diversity between 18° and 0°. Agonist binding to both affinity states showed a similar break point; agonist binding to the high affinity state was characterized by a large entropy component compared to the low affinity state. This entropy component was reduced at higher concentrations of sodium, indicating that it may be due to Iiberation of sodium ions. Measurements of the fluorescence of 1-anilin-8-naphthalenesulfonate showed thermotropic phase transitions of theplatelet membranes at about 17°. The transition temperature was decreased to about 12° by addition of 1 0 mM octanoic acid. Octanoic acidalso shifted the break points of the van't Hoffplot of antagonist and low affinity agonist binding from 18° to 12°. High affinity agonist binding, however, remained unchanged. It is concluded that agonist-specific thennodynamic characteristics of ligand binding to a2-receptors of human platelets can only be investigated by regarding differences between high and low affinity agonist binding. These differences include an entropy increase upon Iigand binding, which is in part due to enhanced liberation of sodium ions, and a loss of sensitivity to fluidity changes in the outer layer of the plasma membrane.},
  subject      = {Molekularpharmakologie},
  language  = {en}
}
@article{OttLohseKlotzetal.1982,
  author    = {Ott, Ilka and Lohse, Martin J. and Klotz, Karl-Norbert and Vogt-Moykopf, Ingolf and Schwabe, Ulrich},
  title     = {Effects of Adenosine on Histamine Release from Human Lung Fragments},
  series = {International Archives of Allergy and Immunology},
  volume    = {98},
  journal   = {International Archives of Allergy and Immunology},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127877},
  pages     = {50-56},
  year      = {1982},
  abstract  = {The actions of adenosine on histamine release of human lung fragments were investigated. Histamine release was stimulated either with the calcium ionophore A 23187 orwith concanavalin A. Adenosine and its analogue 5'-N-ethylcarboxamidoadenosine alone had no significant effect on basal release or on the release elicited by A 23187 or concanavalin A. However, in the presence of the adenosine receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]-carbonyl] methyloxy]-phenyl]-1,3-dipropylaxanthine (XAC), which itself did not affect the release, adenosine increased the stimulated histamine release. On the other hand, in the presence of the nucleoside transport inhibitor S-(p-nitrobenzyl)-6-thioninosine (NBTI), adenosine caused a reduction in stimulated histamine release. NBTI itself caused a stimulation of release. Thus, a stimulatory effect of adenosine was seen in the presence ofXAC, whereas an inhibitory effect was unmasked by NBTI. From these data it is concluded that adenosine exerts two opposing effects on histamine release in the human lung which neutralize each other: it inhibits release via a si te antagonized by XAC, which presumably represents an A2 adenosine receptor, and it stimulates release via a mechanism that is blocked by NBTI, suggesting that adenosine needs to reach the interior of cells to exert this effect. The slight stimulatory effect of NBTI alone demonstrates that trapping intracellularly formed adenosine inside mast cells leads to sufficient concentrations of adenosine to stimulate histamine release. These findings suggest an important bimodal role of adenosine in regulating histamine release in the human lung.},
  language  = {en}
}
@article{AwadOthmanStopper2017,
  author    = {Awad, Eman and Othman, Eman M. and Stopper, Helga},
  title     = {Effects of resveratrol, lovastatin and the mTOR-inhibitor RAD-001 on insulin-induced genomic damage in vitro},
  series = {Molecules},
  volume    = {22},
  journal   = {Molecules},
  number    = {12},
  doi       = {10.3390/molecules22122207},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159260},
  pages     = {2207},
  year      = {2017},
  abstract  = {Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy.},
  language  = {en}
}
@article{ZimmermannStopper1986,
  author    = {Zimmermann, U. and Stopper, Helga},
  title     = {Elektrofusion und Elektropermeabilisierung von Zellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86865},
  year      = {1986},
  abstract  = {No abstract available.},
  subject      = {Elektrofusion},
  language  = {de}
}
@article{ZimmermannStopper1987,
  author    = {Zimmermann, U. and Stopper, Helga},
  title     = {Elektrofusion und Elektropermeabilisierung von Zellen : Eine neuartige Methode der Biotechnologie zur gezieltenVer{\"a}nderung der genetischen Eigenschaften von Zellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63514},
  year      = {1987},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{Lutz1986,
  author    = {Lutz, Werner K.},
  title     = {Endogenous formaldehyde does not produce detectable DNA-protein crosslinks in rat liver},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60972},
  year      = {1986},
  abstract  = {Formaldehydeis an electrophilic molecule able to crosslink DNA and protein. It has been found to induce tumors in the nasal epithelium in rodents. The safety margin between the maximum tolerated FA concentration in the work place and the concentration found to be tumorigenic in animal studies is very small. Because FA is produced endogenously as a result of a variety of oxidative demethylations, the assessment of the tumor risk from exogenaus FA exposure has tobe related quantitatively to the level of DNA-protein crosslinks induced by endogenaus FA generation. It is reported here that the high level of endogenaus FA formed in the liver after a large dose of methanol or of aminopyrine did not lead to any observable increase in DNA-protein crosslinks. Using positive and negative control data from in vitro incubations of liver homogenate with FA or methanol it is estimated that the endogenous level of DNA damage in the liver must be more than three orders of magnitude below the damage observed at tumorigenic concentrations for the rat nose. The fact that FA is formed endogenously cannot, therefore, be used to claim that exogenous FA merely leads to a negligible increase in DNA damage.},
  subject      = {Toxikologie},
  language  = {en}
}