Natural and Medical science Institute

Reutlingen, Germany

Natural and Medical science Institute

Reutlingen, Germany

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Dieckmann A.,Nycomed GmbH | Kriebel M.,Natural and Medical science Institute | Andriambeloson E.,Neurofit SAS | Ziegler D.,Heinrich Heine University Düsseldorf | Elmlinger M.,Nycomed International Management GmbH
Experimental and Clinical Endocrinology and Diabetes | Year: 2012

Background: Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of Actovegin®, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy. Methods: A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats. Actovegin® (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content. Results: A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of Actovegin®. Moreover, 600 mg/kg Actovegin® markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content. Conclusion: Actovegin® improved several parameters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for treatment of this disease in humans. © 2012 Georg Thieme Verlag KG Stuttgart New York.


Fuchsberger K.,Natural and Medical science Institute | Goff A.L.,University of Trieste | Gambazzi L.,Ecole Polytechnique Federale de Lausanne | Toma F.M.,University of Trieste | And 4 more authors.
Small | Year: 2011

A facile method is proposed for the deposition of multiwalled carbon nanotube (MWCNT) layers onto microelectrode arrays by means of a microcontact printing technique, leading to the fabrication of MEAs characterized by well defined electrical and morphological properties. Using polydimethyl siloxane stamps, produced from different mold designs, a flexibility of printing is achieved that provides access to microscale, nanostructured electrodes. The thickness of MWCNT layers can be exactly predetermined by evaluating the concentration of the MWCNT solution employed in the process. The electrode morphology is further characterized using laser scanning and scanning electron microscopy. Next, by means of impedance spectroscopy analysis, the MWCNT-electrode contact resistance and MWCNT film resistance is measured, while electrochemical impedance spectroscopy is used to estimate the obtained electrode-electrolyte interface. Structural and electrochemical properties make these electrodes suitable for electrical stimulation and recording of neurons and electrochemical detection of dopamine. MWCNT-functionalized electrodes show the ability to detect micromolar amounts of dopamine with a sensitivity of 19 nA μm-1. In combination with their biosensing properties, preliminary electrophysiological measurements show that MWCNT microelectrodes have recording properties superior to those of commercial TiN microelectrodes when detecting neuronal electrical activity under long-term cell-culture conditions. MWCNT-functionalized microelectrode arrays fabricated by microcontact printing represent a versatile and multipurpose platform for cell-culture monitoring. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Samba R.,Natural and Medical science Institute | Herrmann T.,Natural and Medical science Institute | Zeck G.,Natural and Medical science Institute
Journal of Neural Engineering | Year: 2015

Objective. The aim of this study was to compare two different microelectrode materials - the conductive polymer composite poly-3,4-ethylenedioxythiophene (PEDOT)-carbon nanotube (CNT) and titanium nitride (TiN) - at activating spikes in retinal ganglion cells in whole mount rat retina through stimulation of the local retinal network. Stimulation efficacy of the microelectrodes was analyzed by comparing voltage, current and transferred charge at stimulation threshold. Approach. Retinal ganglion cell spikes were recorded by a central electrode (30 μm diameter) in the planar grid of an electrode array. Extracellular stimulation (monophasic, cathodic, 0.1-1.0 ms) of the retinal network was performed using constant voltage pulses applied to the eight surrounding electrodes. The stimulation electrodes were equally spaced on the four sides of a square (400 x 400 μm). Threshold voltage was determined as the pulse amplitude required to evoke network-mediated ganglion cell spiking in a defined post stimulus time window in 50% of identical stimulus repetitions. For the two electrode materials threshold voltage, transferred charge at threshold, maximum current and the residual current at the end of the pulse were compared. Main results. Stimulation of retinal interneurons using PEDOT-CNT electrodes is achieved with lower stimulation voltage and requires lower charge transfer as compared to TiN. The key parameter for effective stimulation is a constant current over at least 0.5 ms, which is obtained by PEDOT-CNT electrodes at lower stimulation voltage due to its faradaic charge transfer mechanism. Significance. In neuroprosthetic implants, PEDOT-CNT may allow for smaller electrodes, effective stimulation in a safe voltage regime and lower energy-consumption. Our study also indicates, that the charge transferred at threshold or the charge injection capacity per se does not determine stimulation efficacy. © 2015 IOP Publishing Ltd.


Akbani R.,University of Texas M. D. Anderson Cancer Center | Becker K.-F.,TU Munich | Carragher N.,University of Edinburgh | Goldstein T.,University of California at Santa Cruz | And 10 more authors.
Molecular and Cellular Proteomics | Year: 2014

Reverse phase protein array (RPPA) technology introduced a miniaturized "antigen-down" or "dot-blot" immunoassay suitable for quantifying the relative, semi-quantitative or quantitative (if a well-accepted reference standard exists) abundance of total protein levels and post-translational modifications across a variety of biological samples including cultured cells, tissues, and body fluids. The recent evolution of RPPA combined with more sophisticated sample handling, optical detection, quality control, and better quality affinity reagents provides exquisite sensitivity and high sample throughput at a reasonable cost per sample. This facilitates large-scale multiplex analysis of multiple post-translational markers across samples from in vitro, preclinical, or clinical samples. The technical power of RPPA is stimulating the application and widespread adoption of RPPA methods within academic, clinical, and industrial research laboratories. Advances in RPPA technology now offer scientists the opportunity to quantify protein analytes with high precision, sensitivity, throughput, and robustness. As a result, adopters of RPPA technology have recognized critical success factors for useful and maximum exploitation of RPPA technologies, including the following: • preservation and optimization of pre-analytical sample quality, • application of validated high-affinity and specific antibody (or other protein affinity) detection reagents, • dedicated informatics solutions to ensure accurate and robust quantification of protein analytes, and • quality-assured procedures and data analysis workflows compatible with application within regulated clinical environments. In 2011, 2012, and 2013, the first three Global RPPA workshops were held in the United States, Europe, and Japan, respectively. These workshops provided an opportunity for RPPA laboratories, vendors, and users to share and discuss results, the latest technology platforms, best practices, and future challenges and opportunities. The outcomes of the workshops included a number of key opportunities to advance the RPPA field and provide added benefit to existing and future participants in the RPPA research community. The purpose of this report is to share and disseminate, as a community, current knowledge and future directions of the RPPA technology. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Elmlinger M.W.,Nycomed International Management GmbH | Kriebel M.,Natural and Medical science Institute | Ziegler D.,Heinrich Heine University Düsseldorf | Ziegler D.,University Hospital
NeuroMolecular Medicine | Year: 2011

The recently described therapeutic benefits of the hemodialysate actovegin on neuropathic symptoms in diabetic patients with symptomatic polyneuropathy suggest a neuroprotective activity of the drug. To elucidate the possible cellular mechanism of the pharmacological effects of actovegin, we investigated its effects on cultured primary rat neurons in vitro. Primary neurons were cultured for up to 10 days in the presence of increasing doses of actovegin (0.3-1,000 mg/l). Total cell number, dendrite length and the number of excitatory synapses, i.e., the amount of the synaptic V-Glut1 protein, were measured by immunocytochemistry followed by fluorescence microscopy. The apoptotic level in neurons after induction of apoptosis by amyloid peptide Aβ 25-35 was assessed by the level of activated caspase-3. In addition, the capability of the neurons to diminish oxidative stress was assessed by measuring the cellular level of reactive oxygen species ROS in the presence of actovegin. Actovegin treatment yielded an increased maintenance of neuronal cells and total number of synapses and could lower the level of activated caspase-3 in a dose-dependent manner. Dendrite lengths were not significantly affected. In addition, actovegin reduced the cellular level of ROS in cultured neurons. The cellular effects observed suggest neuroprotective and anti-oxidative effects of the drug Actovegin®, which could at least partially explain its therapeutic benefits. © The Author(s) 2011.


Zeck G.,Natural and Medical science Institute | Herrmann T.,Natural and Medical science Institute
IFMBE Proceedings | Year: 2016

Electrostimulation of neurons is extensively used in different neuroprosthetic applications. In certain neuroprosthetic applications constant voltage pulses with stimulus amplitudes exceeding 1-2 Volts are used. Here we investigate which stimulus parameters of monophasic or biphasic constantvoltage pulses lead to cell electroporation in blind retinas. Towards this aim we interfaced ex vivo adult blind mouse retina to an electrode array comprising micron-sized iridium oxide electrodes. Our experiments demonstrate cell electroporation in retinal tissue in close vicinity (30μm) to the stimulation electrodes for monophasic voltage pulses of either polarity as low as 1.6 Volts and stimulus durations as short as 1 millisecond. These results will guide safe neuroprosthetic stimulation of blind retina. © Springer Science+Business Media Singapore 2016.


Radtke C.,Hannover Medical School | Sinis N.,Martin Luther Hospital | Sauter M.,University of Tübingen | Jahn S.,Hannover Medical School | And 4 more authors.
Journal of Burn Care and Research | Year: 2011

Cell death via necrosis and apoptosis is a hallmark of deep dermal to full-thickness cutaneous burn injuries. Keratinocytes might act as thermosensory cells that transmit information regarding ambient temperature via heat-gated transient receptor potential vanilloid (TRPV) ion channels. The aim of this study was to investigate the distribution of TRPV1, 2, 3, and 4 in uninjured and thermally burned skin. The authors investigated warmth-evoked currents in keratinocytes and cell kinetics of thermally injured keratinocytes in culture with agonists and antagonists of TRPV channels. Specimens of uninjured normal skin and discarded tissue of thermally injured skin were stained for TRPV1, 2, 3, and 4. Cultured primary human keratinocytes were heated for 5 minutes at the following temperatures: 37°C (control), 42°C, and 60°C and thereafter cultured for 24 or 48 hours at 37°C. Thermally stressed cells were treated with TRPV antagonists capsazepine or ruthenium red, and cell viability capacity was determined. TRPV1, TRPV2, TRPV3, and TRPV4 immunoreactivity was differentially identified on basal and suprabasal keratinocytes of healthy human skin. Patch clamp analysis showed a functional response of human keratinocytes at temperatures >40°C. Cell death of keratinocytes after heating at 42°C was reduced by 15 and 5% with ruthenium red and by 20 and 30% by capsazepine at 24 and 48 hours, respectively. Cell death after treatment at 60°C was significantly reduced at 24 hours with capsazepine (22%) or ruthenium red (18%) but only minimally affected after 48 hours postinjury. Interaction with TRPV channels on keratinocytes may offer a new strategy to counteract cell death after thermal injury. Copyright © 2011 by the American Burn Association.


Zeitler R.,Max Planck Institute of Biochemistry | Fromherz P.,Max Planck Institute of Biochemistry | Zeck G.,Natural and Medical science Institute
Applied Physics Letters | Year: 2011

Neuroprosthetic devices rely on a tight contact between electrodes and neurons in the interfaced tissue. A simple method to probe the contact properties in a non-invasive way would be highly attractive. Here we show for retinal tissue that crucial electrical properties of the interface can be extracted from the voltage noise that is recorded with an array of capacitive sensors. The monitoring of the interface properties, which are either interpreted as variable local conductivities or as a cleft of varying distance, allows assessment of the long-term efficiency of neuroprosthetic devices. © 2011 American Institute of Physics.


Gerwig R.,Natural and Medical science Institute | Fuchsberger K.,Natural and Medical science Institute | Schroeppel B.,Natural and Medical science Institute | Link G.S.,Natural and Medical science Institute | And 5 more authors.
Frontiers in Neuroengineering | Year: 2012

Composites of carbon nanotubes and poly(3,4-ethylenedioxythiophene, PEDOT) and layers of PEDOT are deposited onto microelectrodes by electropolymerization of ethylene-dioxythiophene in the presence of a suspension of carbon nanotubes and polystyrene sulfonate. Analysis by FIB and SEM demonstrates that CNT-PEDOT composites exhibit a porous morphology whereas PEDOT layers are more compact. Accordingly, capacitance and charge injection capacity of the composite material exceed those of pure PEDOT layers. In vitro cell culture experiments reveal excellent biocompatibility and adhesion of both PEDOT and PEDOT-CNT electrodes. Signals recorded from heart muscle cells demonstrate the high S/N ratio achievable with these electrodes. Long-term pulsing experiments confirm stability of charge injection capacity. In conclusion, a robust fabrication procedure for composite PEDOT-CNT electrodesisdemonstrated and results show that these electrodes are well suited for stimulation and recording in cardiac and neurophysiological research. Copyright © 2012 Gerwig, Fuchsberger, Schroeppel, Link, Heusel, Kraushaar, Schuhmann, Stett and Stelzle.


PubMed | German Federal Institute for Risk Assessment, University of Tübingen, Natural and Medical science Institute and French Institute of Health and Medical Research
Type: Journal Article | Journal: Archives of toxicology | Year: 2016

Activation of Wnt/-catenin signaling is important for human and rodent hepatocarcinogenesis. In mice, the tumor promoter phenobarbital (PB) selects for hepatocellular tumors with activating -catenin mutations via constitutive androstane receptor activation. PB-dependent tumor promotion was studied in mice with genetic inactivation of Apc, a negative regulator of -catenin, to circumvent the problem of randomly induced mutations by chemical initiators and to allow monitoring of PB- and Wnt/-catenin-dependent tumorigenesis in the absence of unknown genomic alterations. Moreover, the study was designed to investigate PB-induced proliferation of liver cells with activated -catenin. PB treatment provided Apc-deficient hepatocytes with only a minor proliferative advantage, and additional connexin 32 deficiency did not affect the proliferative response. PB significantly promoted the outgrowth of Apc-deficient hepatocellular adenoma (HCA), but simultaneously inhibited the formation of Apc-deficient hepatocellular carcinoma (HCC). The probability of tumor promotion by PB was calculated to be much lower for hepatocytes with loss of Apc, as compared to mutational -catenin activation. Comprehensive transcriptomic and phosphoproteomic characterization of HCA and HCC revealed molecular details of the two tumor types. HCC were characterized by a loss of differentiated hepatocellular gene expression, enhanced proliferative signaling, and massive over-activation of Wnt/-catenin signaling. In conclusion, PB exerts a dual role in liver tumor formation by promoting the growth of HCA but inhibiting the growth of HCC. Data demonstrate that one and the same compound can produce opposite effects on hepatocarcinogenesis, depending on context, highlighting the necessity to develop a more differentiated view on the tumorigenicity of this model compound.

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