Institute of Pharmacology and Toxicology

Jena, Germany

Institute of Pharmacology and Toxicology

Jena, Germany

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Queisser N.,University of Würzburg | Queisser N.,Institute of Pharmacology and Toxicology | Oteiza P.I.,University of California at Davis | Link S.,University of Würzburg | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2014

An increased kidney cancer risk was found in hypertensive patients, who frequently exhibit hyperaldosteronism, known to contribute to kidney injury, with oxidative stress playing an important role. The capacity of kidney cells to up-regulate transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2), a key regulator of the cellular antioxidative defense, as a prevention of aldosterone-induced oxidative damage was investigated both in vitro and in vivo. Results: Aldosterone activated Nrf2 and increased the expression of enzymes involved in glutathione (GSH) synthesis and detoxification. This activation depended on the mineralocorticoid receptor (MR) and oxidative stress. In vitro, Nrf2 activation, GSH amounts, and target gene levels decreased after 24ah, while oxidant levels remained high. Nrf2 activation could not protect cells against oxidative DNA damage, as aldosterone-induced double-strand breaks and 7,8-dihydro-8-oxo-guanine (8-oxodG) lesions steadily rose. The Nrf2 activator sulforaphane enhanced the Nrf2 response both in vitro and in vivo, thereby preventing aldosterone-induced DNA damage. In vivo, Nrf2 activation further had beneficial effects on the aldosterone-caused blood pressure increase and loss of kidney function. Innovation: This is the first study showing the activation of Nrf2 by aldosterone. Moreover, the results identify sulforaphane as a substance that is capable of preventing aldosterone-induced damage both in vivo and in vitro. Conclusion: Aldosterone-induced Nrf2 adaptive response cannot neutralize oxidative actions of chronically increased aldosterone, which, therefore could be causally involved in the increased cancer incidence of hypertensive individuals. Enhancing the cellular antioxidative defense with sulforaphane might exhibit beneficial effects. Antioxid. Redox Signal. 21, 2126-2142. © 2014 Mary Ann Liebert, Inc.


Wahl P.,German Sport University Cologne | Schmidt A.,Institute of Pharmacology and Toxicology | Demarees M.,German Sport University Cologne | Achtzehn S.,German Sport University Cologne | And 2 more authors.
International Journal of Sports Medicine | Year: 2013

The purpose of the present study was to compare the acute hormonal response of angiogenic regulators to a short-term hypoxic exposure at different altitudes with and without exercise. 7 subjects participated in 5 experimental trials. 2 times subjects stayed in a sedentary position for 90min at 2000m or 4000m, respectively. The same was carried out again in combination with exercise at the same relative intensity (2mmolL1 of lactate). The fifth trial consisted of 90min exercise at sea level. Venous blood samples were taken under resting conditions, 0 and 180min after each condition to determine VEGF, EPO, IL-6, IL-8 and IGF-1 serum concentrations. EPO, VEGF, and IL-8 showed increases only, when hypoxia was combined with exercise. IL-6 was increased after exercise, independent of altitude. IGF-1 showed no changes in any intervention. The present study suggests that short term hypoxic exposure combined with low intensity exercise is able to up-regulate angiogenic regulators, which might be beneficial to induce angiogenesis and to improve endurance performance. However, in some cases high altitudes are needed, or it can be speculated that exercise intensity needs to be increased. © Georg Thieme Verlag KG Stuttgart · New York.


Awad W.A.,University of Veterinary Medicine Vienna | Ghareeb K.,South Valley University | Dadak A.,Institute of Pharmacology and Toxicology | Gille L.,Institute of Pharmacology and Toxicology | And 3 more authors.
Poultry Science | Year: 2012

Deoxynivalenol (DON) is one of the most abundant and important trichothecenes in food and feed, and it is a significant contaminant due to its frequent occurrence at toxicologically relevant concentrations worldwide. Deoxynivalenol has negative influences on the health and performance of chicks. However, there is little information available regarding the effect of DON on DNA fragmentation in blood lymphocytes. In addition, the effects of Mycofix select (Biomin GmbH, Herzogenburg, Austria) supplementation to DON-contaminated broiler diets on lymphocyte DNA have not yet been demonstrated. Therefore, the aim of the present study was to establish the effect of DON on lipid peroxidation and lymphocyte DNA fragmentation in broilers and to evaluate the potential of Mycofix select in the prevention of toxin-mediated changes. Thirty-two 1-d-old (Ross 308 male) broiler chicks were randomly divided into 4 groups. The control group was fed a noncontaminated diet, and a second group was fed the same diet but supplemented with Mycofix select (0.25%). A third group of broilers was fed a diet artificially contaminated with 10 mg of feed-grade DON/kg of diet, and a fourth group was fed a DON-contaminated diet supplemented with Mycofix select. At the end of the feeding trial, blood was collected and the degree of lymphocyte DNA damage was measured in the plasma by comet assay. Deoxynivalenol increased (P = 0.016) the amount of DNA damage in chicken lymphocytes by 46.8%. Mycofix select protected lymphocyte DNA from the DON effects. To our knowledge, these are the first data on genotoxic effects of a moderate dose of DON on chicken lymphocytes. However, the thiobarbituric acid reactive substances level in liver and liver enzyme activity did not differ among the groups. In conclusion, the present study demonstrated that the diets contaminated with the mycotoxin DON at moderate levels in combination with low-protein feed are able to induce lymphocyte DNA damage in chickens. Supplementation with Mycofix select protected lymphocyte DNA and it was beneficial for maintaining the lymphocyte DNA integrity. © 2012 Poultry Science Association Inc.


Home > Press > Using nanoparticles to combat arteriosclerosis: Researchers at the University of Bonn have developed a method for cell replacement in diseased vessels Abstract: In industrialized countries, a particularly high number of people suffer from arteriosclerosis -- with fatal consequences: Deposits in the arteries lead to strokes and heart attacks. A team of researchers under the leadership of the University of Bonn has now developed a method for guiding replacement cells to diseased vascular segments using nanoparticles. The scientists demonstrated in mice that the fresh cells actually exert their curative effect in these segments. However, much research remains to be done prior to use in humans. The results are now being published in the renowned journal ACS NANO. In arterial calcification (arteriosclerosis), pathological deposits form in the arteries and this leads to vascular stenosis. Strokes and heart attacks are a frequent outcome due to the resultant insufficient blood flow. Endothelial cells which line the blood vessels play an important role here. "They produce nitric oxide and also regulate the expansion of the vessels and the blood pressure," explains junior professor Dr. med. Daniela Wenzel from the Institute of Physiology I of the University of Bonn. Damage to the endothelial cells is generally the insidious onset of arteriosclerosis. A team of researchers working with Jun.-Prof. Wenzel, together with the Technische Universität München, the Institute of Pharmacology and Toxicology at the University of Bonn Hospital and the Physikalisch-Technische Bundesanstalt Berlin, developed a method with which damaged endothelial cells can regenerate and which they successfully tested in mice. The scientists transferred the gene for the enzyme eNOS into cultured cells with the aid of viruses. This enzyme stimulates nitic oxide production in the endothelium like a turboloader. "The enzyme is an essential precondition for the full restoration of the original function of the endothelial cells," reports Dr. Sarah Vosen from Jun.-Prof. Wenzel's team. A magnet delivers the nanoparticles to the desired site Together with the gene, the scientists also introduced tiny nanoparticles, measuring a few hundred nanometers (one-millionth of a millimeter), with an iron core. "The iron changes the properties of the endothelial cells: They become magnetic," explains Dr. Sarah Rieck from the Institute of Physiology I of the University of Bonn. The nanoparticles ensure that the endothelial cells equipped with the 'turbo' gene can be delivered to the desired site in the blood vessel using a magnet where they exert their curative effect. Researchers at the Technische Universität München have developed a special ring-shaped magnet configuration for this which ensures that the replacement cells equipped with nanoparticles line the blood vessel evenly. The researchers tested this combination method in mice whose carotid artery endothelial cells were injured. They injected the replacement cells into the artery and were able to position them at the correct site using the magnet. "After half an hour, the endothelial cells adhered so securely to the vascular wall that they could no longer be flushed away by the bloodstream," says Jun.-Prof. Wenzel. The scientists then removed the magnets and tested whether the fresh cells had fully regained their function. As desired, the new endothelial cells produced nitric oxide and thus expanded the vessel, as is usual in the case of healthy arteries. "The mouse woke up from the anesthesia and ate and drank normally," reported the physiologist. Transfer to humans requires additional research Normally, doctors surgically remove vascular deposits from the carotid artery and in some cases place a vascular support (stent) to correct the bottleneck in the crucial blood supply. "However, these areas frequently become blocked with deposits once again," reports Jun.-Prof. Wenzel. "In contrast, we are getting to the root of the problem and are restoring the original condition of healthy endothelial cells." The researchers hope that what works in mice is also possible in humans, in principle. However, there are still many challenges to overcome. Jun.-Prof. Wenzel: "There is still a considerable need for research." ### The study was supported by funding to the junior research group 'Magnetic nanoparticles (MNPs) -- endothelial cell replacement in injured vessels' by the State of North Rhine-Westphalia and to the DFG Research Unit FOR 917 'Nanoguide'. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


News Article | January 6, 2016
Site: phys.org

On the left are fluorescence-labeled cells with nanoparticles: The cellular nuclei are shown in blue, the fluorescence labeling is shown in green and the nanoparticles in the cells are identified by arrows. The middle photo shows a blood vessel populated with these cells (green). On the right is a detailed image of a vascular wall with the eNOS protein identified (red). Credit: Dr. Sarah Rieck/Dr. Sarah Vosen/University of Bonn In industrialized countries, a particularly high number of people suffer from arteriosclerosis—with fatal consequences: Deposits in the arteries lead to strokes and heart attacks. A team of researchers under the leadership of the University of Bonn has now developed a method for guiding replacement cells to diseased vascular segments using nanoparticles. The scientists demonstrated in mice that the fresh cells actually exert their curative effect in these segments. However, much research remains to be done prior to use in humans. The results are now being published in the renowned journal ACS Nano. In arterial calcification (arteriosclerosis), pathological deposits form in the arteries and this leads to vascular stenosis. Strokes and heart attacks are a frequent outcome due to the resultant insufficient blood flow. Endothelial cells which line the blood vessels play an important role here. "They produce nitric oxide and also regulate the expansion of the vessels and the blood pressure," explains junior professor Dr. med. Daniela Wenzel from the Institute of Physiology I of the University of Bonn. Damage to the endothelial cells is generally the insidious onset of arteriosclerosis. A team of researchers working with Jun.-Prof. Wenzel, together with the Technische Universität München, the Institute of Pharmacology and Toxicology at the University of Bonn Hospital and the Physikalisch-Technische Bundesanstalt Berlin, developed a method with which damaged endothelial cells can regenerate and which they successfully tested in mice. The scientists transferred the gene for the enzyme eNOS into cultured cells with the aid of viruses. This enzyme stimulates nitic oxide production in the endothelium like a turboloader. "The enzyme is an essential precondition for the full restoration of the original function of the endothelial cells," reports Dr. Sarah Vosen from Jun.-Prof. Wenzel's team. A magnet delivers the nanoparticles to the desired site Together with the gene, the scientists also introduced tiny nanoparticles, measuring a few hundred nanometers (one-millionth of a millimeter), with an iron core. "The iron changes the properties of the endothelial cells: They become magnetic," explains Dr. Sarah Rieck from the Institute of Physiology I of the University of Bonn. The nanoparticles ensure that the endothelial cells equipped with the 'turbo' gene can be delivered to the desired site in the blood vessel using a magnet where they exert their curative effect. Researchers at the Technische Universität München have developed a special ring-shaped magnet configuration for this which ensures that the replacement cells equipped with nanoparticles line the blood vessel evenly. The researchers tested this combination method in mice whose carotid artery endothelial cells were injured. They injected the replacement cells into the artery and were able to position them at the correct site using the magnet. "After half an hour, the endothelial cells adhered so securely to the vascular wall that they could no longer be flushed away by the bloodstream," says Jun.-Prof. Wenzel. The scientists then removed the magnets and tested whether the fresh cells had fully regained their function. As desired, the new endothelial cells produced nitric oxide and thus expanded the vessel, as is usual in the case of healthy arteries. "The mouse woke up from the anesthesia and ate and drank normally," reported the physiologist. Normally, doctors surgically remove vascular deposits from the carotid artery and in some cases place a vascular support (stent) to correct the bottleneck in the crucial blood supply. "However, these areas frequently become blocked with deposits once again," reports Jun.-Prof. Wenzel. "In contrast, we are getting to the root of the problem and are restoring the original condition of healthy endothelial cells." The researchers hope that what works in mice is also possible in humans, in principle. However, there are still many challenges to overcome. Jun.-Prof. Wenzel: "There is still a considerable need for research." Explore further: Researcher pinpoints the cellular mechanism responsible for modulating the permeability of blood vessels More information: Sarah Vosen et al. Vascular Repair by Circumferential Cell Therapy Using Magnetic Nanoparticles and Tailored Magnets, ACS Nano (2016). DOI: 10.1021/acsnano.5b04996


Prut L.,University of Zürich | Prut L.,Novartis | Prenosil G.,University of Basel | Willadt S.,University of Basel | And 4 more authors.
Genes, Brain and Behavior | Year: 2010

The memory for location of objects, which binds information about objects to discrete positions or spatial contexts of occurrence, is a form of episodic memory particularly sensitive to hippocampal damage. Its early decline is symptomatic for elderly dementia. Substances that selectively reduce α5-GABAA receptor function are currently developed as potential cognition enhancers for Alzheimer's syndrome and other dementia, consistent with genetic studies implicating these receptors that are highly expressed in hippocampus in learning performance. Here we explored the consequences of reduced GABAA α5-subunit contents, as occurring in α5(H105R) knock-in mice, on the memory for location of objects. This required the behavioral characterization of α5(H105R) and wild-type animals in various tasks examining learning and memory retrieval strategies for objects, locations, contexts and their combinations. In mutants, decreased amounts of α5-subunits and retained long-term potentiation in hippocampus were confirmed. They exhibited hyperactivity with conserved circadian rhythm in familiar actimeters, and normal exploration and emotional reactivity in novel places, allocentric spatial guidance, and motor pattern learning acquisition, inhibition and flexibility in T- and eight-arm mazes. Processing of object, position and context memories and object-guided response learning were spared. Genotype difference in object-in-place memory retrieval and in encoding and response learning strategies for object-location combinations manifested as a bias favoring object-based recognition and guidance strategies over spatial processing of objects in the mutants. These findings identify in α5(H105R) mice a behavioral-cognitive phenotype affecting basal locomotion and the memory for location of objects indicative of hippocampal dysfunction resulting from moderately decreased α5-subunit contents. © 2010 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society.


Reiner S.,Institute of Pharmacology and Toxicology | Ambrosio M.,Institute of Pharmacology and Toxicology | Ambrosio M.,University of Milan | Hoffmann C.,Institute of Pharmacology and Toxicology | Lohse M.J.,Institute of Pharmacology and Toxicology
Journal of Biological Chemistry | Year: 2010

The concept of "functional selectivity" or "biased signaling" suggests that a ligand can have distinct efficacies with regard to different signaling pathways. We have investigated the question of whether biased signaling may be related to distinct agonist-induced conformational changes in receptors using the β2-adrenergic receptor (β2AR) and its two endogenous ligands epinephrine and norepinephrine as a model system. Agonist-induced conformational changes were determined in a fluorescently tagged β2ARFRET sensor. In this β2AR sensor, norepinephrine caused signals that amounted to only ≈50% of those induced by epinephrine and the standard "full" agonist isoproterenol. Furthermore, norepinephrine-induced changes in the β2AR FRET sensor were slower than those induced by epinephrine (rate constants, 47 versus 128 ms). A similar partial β2AR activation signal was revealed for the synthetic agonists fenoterol and terbutaline. However, norepinephrine was almost as efficient as epinephrine (and isoproterenol) in causing activation of Gs and adenylyl cyclase. In contrast, fenoterol was quite efficient in triggering β-arrestin2 recruitment to the cell surface and its interaction with β2AR, as well as internalization of the receptors, whereas norepinephrine caused partial and slow changes in these assays. We conclude that partial agonism of norepinephrine at the β2AR is related to the induction of a different active conformation and that this conformation is efficient in signaling to Gs and less efficient in signaling to β-arrestin2. These observations extend the concept of biased signaling to the endogenous agonists of the β2AR and link it to distinct conformational changes in the receptor. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Soloviev A.I.,Institute of Pharmacology and Toxicology | Bondarenko A.I.,Aa Bogomoletz Institute Of Physiology | Kizub I.V.,Institute of Pharmacology and Toxicology
Vascular Pharmacology | Year: 2012

The goal of this study was to clarify the mechanisms of hypoxic pulmonary vasoconstriction (HPV) reversal following selective glycolysis blockade and to assess possible contribution of endothelial electrogenesis to this phenomenon as a trigger mechanism.We compared smooth muscle (SM) contractility and endothelial cell (EC) membrane potential (MP) during acute hypoxia before and after glycolysis blockade. MPs were recorded from the endothelium of guinea pig pulmonary artery (GPPA) and thoracic aorta (GPTA) using the patch-clamp technique. Acute hypoxia caused hyperpolarization in GPTA EC, while EC from GPPA were depolarized. Also, acute hypoxia elicited constriction in isolated GPPA and dilatation in GPTA. Selective glycolysis inhibition always reversed both electrical and contractile responses in GPPA to hypoxia, but in GPTA this only occurred in 30% of experiments. It is likely that an unknown glycolysis-driven mechanism in EC mediates vascular tone regulation under hypoxia and underlies the paradoxical difference in the response of pulmonary and systemic arterial SM to hypoxia. Our data suggest that HPV development in GPPA might, at least partially, be driven by EC depolarization spreading to the underlying SM cells. © 2012 Elsevier Inc..


Otte M.,Institute of Pharmacology and Toxicology | Kliewer A.,Institute of Pharmacology and Toxicology | Schutz D.,Institute of Pharmacology and Toxicology | Reimann C.,Institute of Pharmacology and Toxicology | And 2 more authors.
FEBS Letters | Year: 2014

C-X-C motif chemokine 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) signaling is involved in ontogenesis, hematopoiesis, immune function and cancer. Recently, the orphan chemokine CXCL14 was reported to inhibit CXCL12-induced chemotaxis - probably by allosteric modulation of CXCR4. We thus examined the effects of CXCL14 on CXCR4 regulation and function using CXCR4-transfected human embryonic kidney (HEK293) cells and Jurkat T cells. CXCL14 did not affect dose-response profiles of CXCL12-induced CXCR4 phosphorylation, G protein-mediated calcium mobilization, dynamic mass redistribution, kinetics of extracellular signal-regulated kinase 1 (ERK1) and ERK2 phosphorylation or CXCR4 internalization. Hence, essential CXCL12-operated functions of CXCR4 are insensitive to CXCL14, suggesting that interactions of CXCL12 and CXCL14 pathways depend on a yet to be identified CXCL14 receptor. © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Brown S.A.,Institute of Pharmacology and Toxicology | Azzi A.,Institute of Pharmacology and Toxicology
Handbook of Experimental Pharmacology | Year: 2013

Although circadian rhythms in mammalian physiology and behavior are dependent upon a biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus, the molecular mechanism of this clock is in fact cell autonomous and conserved in nearly all cells of the body. Thus, the SCN serves in part as a "master clock," synchronizing "slave" clocks in peripheral tissues, and in part directly orchestrates circadian physiology. In this chapter, we first consider the detailed mechanism of peripheral clocks as compared to clocks in the SCN and how mechanistic differences facilitate their functions. Next, we discuss the different mechanisms by which peripheral tissues can be entrained to the SCN and to the environment. Finally, we look directly at how peripheral oscillators control circadian physiology in cells and tissues. © 2013 Springer-Verlag Berlin Heidelberg.

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