Walther Straub Institute of Pharmacology and Toxicology

München, Germany

Walther Straub Institute of Pharmacology and Toxicology

München, Germany
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Chubanov V.,Walther Straub Institute of Pharmacology and Toxicology | Ferioli S.,Walther Straub Institute of Pharmacology and Toxicology | Gudermann T.,Walther Straub Institute of Pharmacology and Toxicology
Cell Calcium | Year: 2017

Transient receptor potential cation channel subfamily M member 7 (TRPM7) is a plasma membrane ion channel linked to a cytosolic protein kinase domain. Genetic inactivation of this bi-functional protein revealed its crucial role in Ca2+ signalling, Mg2+ metabolism, immune responses, cell motility, proliferation and differentiation. Malfunctions of TRPM7 are associated with anoxic neuronal death, cardiac fibrosis, tumour progression and macrothrombocytopenia. Recently, several groups have identified small organic compounds acting as inhibitors or activators of the TRPM7 channel. In follow-up studies, the identified TRPM7 modulators were successfully used to uncover new cellular functions of TRPM7 in situ including a crucial role of TRPM7 in Ca2+ signaling and Ca2+ dependent cellular processes. Hence, TRPM7 has been defined as a promising drug target. Here, we summarize the progress in this quickly developing field. © 2017 Elsevier Ltd.


Schafer M.,Johannes Gutenberg University Mainz | Koppe F.,Johannes Gutenberg University Mainz | Stenger B.,Johannes Gutenberg University Mainz | Stenger B.,Walther Straub Institute of Pharmacology and Toxicology | And 8 more authors.
Chemico-Biological Interactions | Year: 2013

Organophosphourus compounds (OPC, including nerve agents and pesticides) exhibit acute toxicity by inhibition of acetylcholinesterase. Lung affections are frequent complications and a risk factor for death. In addition, epidemiological studies reported immunological alterations after OPC exposure. In our experiments we investigated the effects of organophosphourus pesticides dimethoate and chlorpyrifos on dendritic cells (DC) that are essential for the initial immune response, especially in the pulmonary system. DC, differentiated from the monocyte cell line THP-1 by using various cytokines (IL-4, GM-CSF, TNF-α, Ionomycin), were exposed to organophosphourus compounds at different concentrations for a 24 h time period. DC were characterized by flow cytometry and immunofluorescence using typical dendritic cell markers (e.g., CD11c, CD209 and CD83). After OPC exposure we investigated cell death, the secretion profile of inflammatory mediators, changes of DC morphology, and the effect on protein kinase signalling pathways. Our results revealed a successful differentiation of THP-1 into DC. OPC exposure caused a significant concentration-dependent influence on DC: Dendrites of the DC were shortened and damaged, DC-specific cell surface markers (i.e., CD83and CD209) decreased dramatically after chlorpyrifos exposure. Interestingly, the effects caused by dimethoate were in general less pronounced. The organophosphourus compounds affected the release of inflammatory cytokines, such as IL-1ß and IL-8. The anti-inflammatory cytokine IL-10 was significantly down regulated. Protein kinases like the Akt family or ERK, which are essential for cell survival and proliferation, were inhibited by both OPC. These findings indicate that the tested organophosphourus compounds induced significant changes in cell morphology, inhibited anti-inflammatory cytokines and influenced important protein signalling pathways which are involved in regulation of apoptosis. Thus our results highlight novel aspects -apparently independent of AChE inhibition- of OPC poisoning with regard to lung toxicity. Our findings contribute to the basic understanding of pulmonary complications caused by OPC poisoning. © 2013 Elsevier B.V.


Dietrich A.,Walther Straub Institute of Pharmacology and Toxicology | Steinritz D.,Walther Straub Institute of Pharmacology and Toxicology | Steinritz D.,University of Federal Defense Munich | Gudermann T.,Walther Straub Institute of Pharmacology and Toxicology
Cell Calcium | Year: 2017

The lungs as the gateways of our body to the external environment are essential for gas exchange. They are also exposed to toxicants from two sides, the airways and the vasculature. Apart from naturally produced toxic agents, millions of human made chemicals were produced since the beginning of the industrial revolution whose toxicity still needs to be determined. While the knowledge about toxic substances is increasing only slowly, a paradigm shift regarding the proposed mechanisms of toxicity at the plasma membrane emerged. According to their broad-range chemical reactivity, the mechanism of lung injury evoked by these agents has long been described as rather unspecific. Consequently, therapeutic options are still restricted to symptomatic treatment. The identification of molecular down-stream effectors in cells was a major step forward in the mechanistic understanding of the action of toxic chemicals and will pave the way for more causal and specific toxicity testing as well as therapeutic options. In this context, the involvement of Transient Receptor Potential (TRP) channels as chemosensors involved in the detection and effectors of toxicant action is an attractive concept intensively discussed in the scientific community. In this review we will summarize recent evidence for an involvement of TRP channels (TRPA1, TRPC4, TRPC6, TRPV1, TRPV4, TRPM2 and TRPM8) expressed in the lung in pathways of toxin sensing and as mediators of lung inflammation and associated diseases like asthma, COPD, lung fibrosis and edema formation. Specific modulators of these channels may offer new therapeutic options in the future and will endorse strategies for a causal, specifically tailored treatment based on the mechanistic understanding of molecular events induced by lung-toxic agents. © 2017 Elsevier Ltd.


Durner J.,Walther Straub Institute of Pharmacology and Toxicology | Durner J.,Ludwig Maximilians University of Munich | Obermaier J.,Ludwig Maximilians University of Munich | Draenert M.,Ludwig Maximilians University of Munich | Ilie N.,Ludwig Maximilians University of Munich
Dental Materials | Year: 2012

Objectives: This study's purpose was to measure and compare the degree of conversion (DC) and the amount of elutable substances from modern resin-based composites (RBCs) as function of polymerization time. One nano-hybrid RBC based on tricyclodecane-(TCD)-urethane (Venus ® Diamond) and two conventionally formulated RBCs (TetricEvo Ceram ®, Filtek™ Supreme XTE) were considered. Method: DC (n = 5) was investigated in real time for 5 min by Fourier transform infrared spectroscopy (ATR-FTIR) in a filling depth of 2 mm at varied irradiation times (5, 10, 20, 40 s). After storing the specimens in ethanol/water for 7 d at 37 °C the eluates were analyzed by gas chromatography/mass spectrometry. Results were statistically analyzed using a multivariate analysis (α = 0.05) an independent t-test (p < 0.05) and a Pearson correlation analysis. Results: In all groups increasing curing time resulted in a significant increase in DC. For TetricEvo Ceram ® a high significant inverse correlation was found between DC and the amount of eluted camphorquinone (CQ, Pearson correlation coefficient = -0.88), ethylene glycol dimethacrylate (EGDMA, -0.73), 4-N,N-dimethylaminobenzoic acid ethylester (DMABEE, -0.87), triethylene glycol dimethacrylate (TEGDMA, -0.68), Tinuvin P (-0.71) and bisphenol-A-polyetheylene glycol dimethacrylate (BisEMA, -0.84). Unexpectedly DC and the amount of eluted methyl acrylate (MAA) correlated directly (0.72). In the specimens of Venus ® Diamond a significant inverse correlation was found between DC and the amount of eluted CQ (-0.69) and TEGDMA (-0.50), whereas in the specimen of Filtek™ Supreme XTE DC correlated with CQ (-0.96), EGDMA (-0.70), DMABEE (-0.87), TEGDMA (-0.92) and MAA (-0.92). Significance: This study demonstrated a strong inverse correlation between DC and elutable substances in RBCs. Both evaluation methods emphasis the importance of an adequate polymerization (20, 40 s), since short curing-times (5, 10 s) resulted in lower DC and higher amount of eluted substances with toxic potential. © 2012 Academy of Dental Materials.


Ilie N.,Ludwig Maximilians University of Munich | Kessler A.,Ludwig Maximilians University of Munich | Durner J.,Ludwig Maximilians University of Munich | Durner J.,Walther Straub Institute of Pharmacology and Toxicology
Journal of Dentistry | Year: 2013

Objectives To assess the effect of irradiation time and distance of the light tip on the micro-mechanical properties and polymerisation kinetics of two bulk-fill resin-based composites at simulated clinically relevant filling depth. Methods Micro-mechanical properties (Vickers hardness (HV), depth of cure (DOC) and indentation modulus (E)) and polymerisation kinetics (real-time increase of degree of cure (DC)) of two bulk-fill resin-based composites (Tetric EvoCeram® Bulk Fill, Ivoclar Vivadent and x-tra base, Voco) were assessed at varying depth (0.1-6 mm in 100 μm steps for E and HV and 0.1, 2, 4 and 6 mm for DC), irradiation time (10, 20 or 40 s, Elipar Freelight2) and distances from the light tip (0 and 7 mm). Curing unit's irradiance was monitored in 1 mm steps at distances up to 10 mm away from the light tip on a laboratory-grade spectrometer. Results Multivariate analysis (α = 0.05), Student's t-test and Pearson correlation analysis were considered. The influence of material on the measured mechanical properties was significant (η2 = 0.080 for E and 0.256 for HV), while the parameters irradiation time, distance from the light tip and depth emphasise a stronger influence on Tetric EvoCeram® Bulk Fill. The polymerisation kinetics could be described by an exponential sum function, distinguishing between the gel and the glass phase. The above mentioned parameters strongly influenced the start of polymerisation (gel phase), and were of less importance for the glass phase. Conclusions Both materials enable at least 4 mm thick increments to be cured in one step under clinically relevant curing conditions. Clinical significance The susceptibility to variation in irradiance was material dependent, thus properties measured under clinically simulated curing conditions might vary to a different extent from those measured under ideal curing conditions. © 2013 Elsevier Ltd.


Debiak M.,University of Konstanz | Lex K.,University of Konstanz | Ponath V.,University of Konstanz | Burckhardt-Boer W.,University of Konstanz | And 6 more authors.
Toxicology Letters | Year: 2016

Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard-induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy.PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP-ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2-chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence-based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose- and time-dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES-induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES-induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the molecular mechanism of PARP1 activation and its functional consequences after mustard treatment in general. Such a study is presented in an accompanying article (. Mangerich et al., 2016). © 2015.


Ilie N.,Ludwig Maximilians University of Munich | Obermaier J.,Ludwig Maximilians University of Munich | Durner J.,Ludwig Maximilians University of Munich | Durner J.,Walther Straub Institute of Pharmacology and Toxicology
Clinical Oral Investigations | Year: 2014

Objectives: The aim of our study was to analyse whether the irradiation time and/or the modulation of irradiation time influence the degree of conversion (DC) and the amount of elutable substances from modern nano-hybrid resin-based composites (RBCs). Materials and methods: The DC was recorded in real time for 5 min by means of attenuated total reflectance-Fourier transform infrared spectroscopy (n = 5) on the lower surface of 2-mm-thick samples irradiated with continuous and modulated irradiation times for 20 s and 40 s. The modulated times comprise a short polymerisation (2 s or 5 s) followed by a rest period of 1 min and an additional polymerisation to complete 20 s and 40 s of polymerisation (2 s + 18 s, 5 s + 15 s, 2 s + 38 s and 5 s + 35 s). After storing the specimens in ethanol/water for 7 days at 37 °C, the eluates were analysed by gas chromatography-mass spectrometry. Results were statistically analyzed using a one-way ANOVA analysis (α = 0.05). Results: The effect of irradiation time on DC is similar in all three analyzed materials, showing a significant increase in DC by increasing irradiation time from 20 s to 40 s, while the DC is not influenced within one irradiation time (20 s or 40 s) by the modulation of time. Conclusions: The type and amount of eluates are strongly dependent from the material and the irradiation protocol. Clinical relevance: An interrupt irradiation of RBCs is clinically feasible, reducing in general the amount of elutable substances at similar DC as the corresponding continuous polymerisation. © 2013 Springer-Verlag Berlin Heidelberg.


Durner J.,Walther Straub Institute of Pharmacology and Toxicology
Dental materials : official publication of the Academy of Dental Materials | Year: 2012

This study's purpose was to measure and compare the degree of conversion (DC) and the amount of elutable substances from modern resin-based composites (RBCs) as function of polymerization time. One nano-hybrid RBC based on tricyclodecane-(TCD)-urethane (Venus(®) Diamond) and two conventionally formulated RBCs (TetricEvo Ceram(®), Filtek™ Supreme XTE) were considered. DC (n=5) was investigated in real time for 5min by Fourier transform infrared spectroscopy (ATR-FTIR) in a filling depth of 2mm at varied irradiation times (5, 10, 20, 40s). After storing the specimens in ethanol/water for 7 d at 37°C the eluates were analyzed by gas chromatography/mass spectrometry. Results were statistically analyzed using a multivariate analysis (α=0.05) an independent t-test (p<0.05) and a Pearson correlation analysis. In all groups increasing curing time resulted in a significant increase in DC. For TetricEvo Ceram(®) a high significant inverse correlation was found between DC and the amount of eluted camphorquinone (CQ, Pearson correlation coefficient=-0.88), ethylene glycol dimethacrylate (EGDMA, -0.73), 4-N,N-dimethylaminobenzoic acid ethylester (DMABEE, -0.87), triethylene glycol dimethacrylate (TEGDMA, -0.68), Tinuvin P (-0.71) and bisphenol-A-polyetheylene glycol dimethacrylate (BisEMA, -0.84). Unexpectedly DC and the amount of eluted methyl acrylate (MAA) correlated directly (0.72). In the specimens of Venus(®) Diamond a significant inverse correlation was found between DC and the amount of eluted CQ (-0.69) and TEGDMA (-0.50), whereas in the specimen of Filtek™ Supreme XTE DC correlated with CQ (-0.96), EGDMA (-0.70), DMABEE (-0.87), TEGDMA (-0.92) and MAA (-0.92). This study demonstrated a strong inverse correlation between DC and elutable substances in RBCs. Both evaluation methods emphasis the importance of an adequate polymerization (20, 40s), since short curing-times (5, 10s) resulted in lower DC and higher amount of eluted substances with toxic potential. Copyright © 2012 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.


Sevkusic M.,Walther Straub Institute of Pharmacology and Toxicology | Schuster L.,Walther Straub Institute of Pharmacology and Toxicology | Rothmund L.,Walther Straub Institute of Pharmacology and Toxicology | Dettinger K.,Walther Straub Institute of Pharmacology and Toxicology | And 7 more authors.
Dental Materials | Year: 2014

Objectives Constituents of dental composites can be released from dental fillings after polymerization. The aim of this study was to examine the time-related elution and breakdown of separable constituents of polymerized composites using deuterated solvents. Method Elution and breakdown of constituents were investigated with deuterated solvents methanol and water by gas chromatography/mass spectrometry of following composites for 180 days: Filtek™ Supreme XT, Filtek™ Supreme XT Flow, Tetric Ceram®, Tetric Flow®, Grandio®, Grandio® Flow. Results Within 180 days no compounds were formed as the products of breakdown. 19 compounds were identified as elution products: Bis-EMA, TEGDMA, DDDMA, EGDMA, MAA, BPA, CQ, HQME, DMABEE, CSA, BL, TEG, BHT, TINP, TPP, TPSB, DEDHTP, DCHP, ß-PHEA. The highest concentration of Bis-EMA was measured for Tetric Flow® in deuterated methanol on day 90 at 36.993 mmol/l and in deuterated water also on day 90 at 0.031 mmol/l. The highest TEGDMA concentrations were measured for Grandio® Flow in deuterated methanol on day 60 at 1.322 mmol/l and for Filtek™ Supreme XT Flow in deuterated water on day 3 at 0.689 mmol/l. The highest BPA concentration was measured for Tetric Flow® in deuterated methanol on day 90 at 1.469 mmol/l. The highest BPA concentration was measured for Grandio® in deuterated water on day 180 at 0.007 mmol/l. Significance Examination of time-related elution indicates that various elution products (e.g. Bis-EMA, BPA) were only released in small quantities during the first 90 days, but in high quantities between day 90 and day 180. © 2014 Academy of Dental Materials.


PubMed | Walther Straub Institute of Pharmacology and Toxicology
Type: Comparative Study | Journal: Dental materials : official publication of the Academy of Dental Materials | Year: 2012

This studys purpose was to measure and compare the degree of conversion (DC) and the amount of elutable substances from modern resin-based composites (RBCs) as function of polymerization time. One nano-hybrid RBC based on tricyclodecane-(TCD)-urethane (Venus() Diamond) and two conventionally formulated RBCs (TetricEvo Ceram(), Filtek Supreme XTE) were considered.DC (n=5) was investigated in real time for 5min by Fourier transform infrared spectroscopy (ATR-FTIR) in a filling depth of 2mm at varied irradiation times (5, 10, 20, 40s). After storing the specimens in ethanol/water for 7 d at 37C the eluates were analyzed by gas chromatography/mass spectrometry. Results were statistically analyzed using a multivariate analysis (=0.05) an independent t-test (p<0.05) and a Pearson correlation analysis.In all groups increasing curing time resulted in a significant increase in DC. For TetricEvo Ceram() a high significant inverse correlation was found between DC and the amount of eluted camphorquinone (CQ, Pearson correlation coefficient=-0.88), ethylene glycol dimethacrylate (EGDMA, -0.73), 4-N,N-dimethylaminobenzoic acid ethylester (DMABEE, -0.87), triethylene glycol dimethacrylate (TEGDMA, -0.68), Tinuvin P (-0.71) and bisphenol-A-polyetheylene glycol dimethacrylate (BisEMA, -0.84). Unexpectedly DC and the amount of eluted methyl acrylate (MAA) correlated directly (0.72). In the specimens of Venus() Diamond a significant inverse correlation was found between DC and the amount of eluted CQ (-0.69) and TEGDMA (-0.50), whereas in the specimen of Filtek Supreme XTE DC correlated with CQ (-0.96), EGDMA (-0.70), DMABEE (-0.87), TEGDMA (-0.92) and MAA (-0.92).This study demonstrated a strong inverse correlation between DC and elutable substances in RBCs. Both evaluation methods emphasis the importance of an adequate polymerization (20, 40s), since short curing-times (5, 10s) resulted in lower DC and higher amount of eluted substances with toxic potential.

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