TY - JOUR A1 - Chen, Pan A1 - DeWitt, Margaret R. A1 - Bornhorst, Julia A1 - Soares, Felix A. A1 - Mukhopadhyay, Somshuvra A1 - Bowman, Aaron B. A1 - Aschner, Michael A. T1 - Age- and manganese-dependent modulation of dopaminergic phenotypes in a JF - Metallomics : integrated biometal science Y1 - 2015 U6 - https://doi.org/10.1039/c4mt00292j SN - 1756-5901 SN - 1756-591X VL - 7 IS - 2 SP - 289 EP - 298 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Henze, Andrea A1 - Homann, Thomas A1 - Rohn, Isabelle A1 - Aschner, Michael A. A1 - Link, Christopher D. A1 - Kleuser, Burkhard A1 - Schweigert, Florian J. A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin JF - Scientific reports N2 - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time-and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling. Y1 - 2016 U6 - https://doi.org/10.1038/srep37346 SN - 2045-2322 VL - 6 PB - Nature Publ. Group CY - London ER - TY - GEN A1 - Henze, Andrea A1 - Homann, Thomas A1 - Rohn, Isabelle A1 - Aschner, Michael A. A1 - Link, Christopher D. A1 - Kleuser, Burkhard A1 - Schweigert, Florian J. A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin N2 - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 312 KW - binding KW - c. elegans KW - cells KW - disease KW - force-field KW - life-span KW - menadione KW - n-acetyl-cysteine KW - protein KW - s-glutathionylation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-103674 ER - TY - JOUR A1 - Henze, Andrea A1 - Homann, Thomas A1 - Rohn, Isabelle A1 - Aschner, Michael A. A1 - Link, Christopher D. A1 - Kleuser, Burkhard A1 - Schweigert, Florian J. A1 - Schwerdtle, Tanja A1 - Bornhorst, Julia T1 - Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin JF - Scientific reports N2 - The visceral protein transthyretin (TTR) is frequently affected by oxidative post-translational protein modifications (PTPMs) in various diseases. Thus, better insight into structure-function relationships due to oxidative PTPMs of TTR should contribute to the understanding of pathophysiologic mechanisms. While the in vivo analysis of TTR in mammalian models is complex, time- and resource-consuming, transgenic Caenorhabditis elegans expressing hTTR provide an optimal model for the in vivo identification and characterization of drug-mediated oxidative PTPMs of hTTR by means of matrix assisted laser desorption/ionization – time of flight – mass spectrometry (MALDI-TOF-MS). Herein, we demonstrated that hTTR is expressed in all developmental stages of Caenorhabditis elegans, enabling the analysis of hTTR metabolism during the whole life-cycle. The suitability of the applied model was verified by exposing worms to D-penicillamine and menadione. Both drugs induced substantial changes in the oxidative PTPM pattern of hTTR. Additionally, for the first time a covalent binding of both drugs with hTTR was identified and verified by molecular modelling. KW - n-acetyl-cysteine KW - s-glutathionylation KW - force-field KW - c. elegans KW - life-span KW - protein KW - cells KW - menadione KW - disease KW - binding Y1 - 2016 U6 - https://doi.org/10.1038/srep37346 SN - 2045-2322 VL - 6 PB - Nature Publishing Group CY - London ER - TY - CHAP A1 - Tidball, Andrew M. A1 - Kumar, Kevin K. A1 - Bryan, Miles R. A1 - Bichell, Terry Jo A1 - Horning, Kyle A1 - Uhouse, Michael A. A1 - Goodwin, Cody R. A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Neely, Maja Diana A1 - McClean, John A. A1 - Aschner, Michael A. A1 - Bowman, Aaron B. T1 - Deficits in neural responses to manganese exposure in Huntington's disease models T2 - Neurotoxicology and teratology Y1 - 2015 U6 - https://doi.org/10.1016/j.ntt.2015.04.022 SN - 0892-0362 SN - 1872-9738 VL - 49 SP - 105 EP - 105 PB - Elsevier CY - Oxford ER - TY - JOUR A1 - Peres, Tanara V. A1 - Eyng, Helena A1 - Lopes, Samantha C. A1 - Colle, Dirleise A1 - Goncalves, Filipe M. A1 - Venske, Debora K. R. A1 - Lopes, Mark W. A1 - Ben, Juliana A1 - Bornhorst, Julia A1 - Schwerdtle, Tanja A1 - Aschner, Michael A. A1 - Farina, Marcelo A1 - Prediger, Rui D. A1 - Leal, Rodrigo B. T1 - Developmental exposure to manganese induces lasting motor and cognitive impairment in rats JF - Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system N2 - Exposure to high manganese (Mn) levels may damage the basal ganglia, leading to a syndrome analogous to Parkinson's disease, with motor and cognitive impairments. The molecular mechanisms underlying Mn neurotoxicity, particularly during development, still deserve further investigation. Herein, we addressed whether early-life Mn exposure affects motor coordination and cognitive function in adulthood and potential underlying mechanisms. Male Wistar rats were exposed intraperitoneally to saline (control) or MnCl2 (5, 10 or 20 mg/kg/day) from post-natal day (PND) 8-12. Behavioral tests were performed on PND 60-65 and biochemical analysis in the striatum and hippocampus were performed on PND14 or PND70. Rats exposed to Mn (10 and 20 mg/kg) performed significantly worse on the rotarod test than controls indicating motor coordination and balance impairments. The object and social recognition tasks were used to evaluate short-term memory. Rats exposed to the highest Mn dose failed to recognize a familiar object when replaced by a novel object as well as to recognize a familiar juvenile rat after a short period of time. However, Mn did not alter olfactory discrimination ability. In addition, Mn-treated rats displayed decreased levels of non-protein thiols (e.g. glutathione) and increased levels of glial fibrillary acidic protein (GFAP) in the striatum. Moreover, Mn significantly increased hippocampal glutathione peroxidase (GPx) activity. These findings demonstrate that acute low-level exposure to Mn during a critical neurodevelopmental period causes cognitive and motor dysfunctions that last into adulthood, that are accompanied by alterations in antioxidant defense system in both the hippocampus and striatum. (C) 2015 Elsevier Inc. All rights reserved. KW - Manganese KW - Neurotoxicity KW - Development KW - Motor coordination KW - Cognition Y1 - 2015 U6 - https://doi.org/10.1016/j.neuro.2015.07.005 SN - 0161-813X SN - 1872-9711 VL - 50 SP - 28 EP - 37 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Crone, Barbara A1 - Aschner, Michael A. A1 - Schwerdtle, Tanja A1 - Karst, Uwe A1 - Bornhorst, Julia T1 - Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS JF - Metallomics : integrated biometal science N2 - cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 mm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose) metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00096c SN - 1756-5901 SN - 1756-591X VL - 7 IS - 7 SP - 1189 EP - 1195 PB - Royal Society of Chemistry CY - Cambridge ER - TY - GEN A1 - Crone, Barbara A1 - Aschner, Michael A. A1 - Schwerdtle, Tanja A1 - Karst, Uwe A1 - Bornhorst, Julia T1 - Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS N2 - cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 μm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 192 Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-80031 SP - 1189 EP - 1195 ER - TY - JOUR A1 - Crone, Barbara A1 - Aschner, Michael A. A1 - Schwerdtle, Tanja A1 - Karst, Uwe A1 - Bornhorst, Julia T1 - Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS JF - Metallomics N2 - cis-Diamminedichloroplatinum(II) (Cisplatin) is one of the most important and frequently used cytostatic drugs for the treatment of various solid tumors. Herein, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method incorporating a fast and simple sample preparation protocol was developed for the elemental mapping of Cisplatin in the model organism Caenorhabditis elegans (C. elegans). The method allows imaging of the spatially-resolved elemental distribution of platinum in the whole organism with respect to the anatomic structure in L4 stage worms at a lateral resolution of 5 μm. In addition, a dose- and time-dependent Cisplatin uptake was corroborated quantitatively by a total reflection X-ray fluorescence spectroscopy (TXRF) method, and the elemental mapping indicated that Cisplatin is located in the intestine and in the head of the worms. Better understanding of the distribution of Cisplatin in this well-established model organism will be instrumental in deciphering Cisplatin toxicity and pharmacokinetics. Since the cytostatic effect of Cisplatin is based on binding the DNA by forming intra- and interstrand crosslinks, the response of poly(ADP-ribose)metabolism enzyme 1 (pme-1) deletion mutants to Cisplatin was also examined. Loss of pme-1, which is the C. elegans ortholog of human poly(ADP-ribose) polymerase 1 (PARP-1) led to disturbed DNA damage response. With respect to survival and brood size, pme-1 deletion mutants were more sensitive to Cisplatin as compared to wildtype worms, while Cisplatin uptake was indistinguishable. Y1 - 2015 U6 - https://doi.org/10.1039/c5mt00096c SN - 1756-591X SN - 1756-5901 VL - 2015 IS - 7 SP - 1189 EP - 1195 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Schumacher, Fabian A1 - Chakraborty, Sudipta A1 - Kleuser, Burkhard A1 - Gulbins, Erich A1 - Schwerdtle, Tanja A1 - Aschner, Michael A. A1 - Bornhorst, Julia T1 - Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans JF - Talanta : the international journal of pure and applied analytical chemistry N2 - Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C elegans to the monoamine oxidase B (MAOB) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and SRT system in order to identify compounds with neuroprotective or regenerative properties. (C) 2015 Elsevier B.V. All rights reserved. KW - Caenorhabditis elegans KW - Dopamine KW - Serotonin KW - Liquid chromatography-tandem mass spectrometry KW - Isotope-dilution analysis Y1 - 2015 U6 - https://doi.org/10.1016/j.talanta.2015.05.057 SN - 0039-9140 SN - 1873-3573 VL - 144 SP - 71 EP - 79 PB - Elsevier CY - Amsterdam ER -