Institute of Pharmacology and Toxicology

Jena, Germany

Institute of Pharmacology and Toxicology

Jena, Germany
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Tarokh L.,E P Bradley Sleep Research Laboratory | Tarokh L.,Brown University | Tarokh L.,Institute of Pharmacology and Toxicology | Carskadon M.A.,E P Bradley Sleep Research Laboratory | And 4 more authors.
Journal of Neuroscience | Year: 2011

Waking and sleep data in adults show high heritability and trait-like characteristics in EEG spectra. This phenomenon has not been examined in children and adolescents where brain development influences the EEG. The present study examines whether a trait-like sleep EEG pattern is detectable across adolescent development. Two consecutive nights of standard sleep recordings were performed in 19 9-10-year-old children and 26 15-16-year-old teens, and were repeated 1.5-3 years later. EEG spectra averaged across the night for non-rapid eye movement and rapid eye movement sleep separately were classified using hierarchical cluster analysis, which showed that all 4 nights of a participant clustered together for a majority of participants. Intraclass correlation coefficients were also very high (>0.7) across nights separated by several years, indicating a trait-like feature of the sleep EEG. In summary, our results, using two measures of stability, indicate that a "trait-like" aspect can be detected in the sleep EEG across adolescent development despite considerable neuro-developmental changes. This finding indicates that the brain oscillators responsible for generating the sleep EEG signal remain relatively stable across adolescent development.


Lohse M.J.,Institute of Pharmacology and Toxicology | Lohse M.J.,University of Würzburg
Current Opinion in Pharmacology | Year: 2010

Many types of cell surface as well as intracellular DNA-binding receptors exist and function as dimers; formation of homodimers or heterodimers appears to not only provide molecular mechanisms for agonist-induced activation but also increase specificity of ligand recognition and versatility of downstream signaling. G-protein-coupled receptors (GPCRs) were long thought to be an exception, but in recent years a lot of evidence has accumulated that GPCRs also can form dimers, even though it is far from certain when and where they actually do so under physiological conditions. Dimerization of GPCRs does not generally seem to be required for ligand recognition or signaling. However, dimerization may serve to affect receptor mobility at the cell surface and in intracellular trafficking, and may be involved in and affect their signaling functions. © 2009 Elsevier Ltd. All rights reserved.


Chourbaji S.,University of Heidelberg | Hortnagl H.,Institute of Pharmacology and Toxicology | Molteni R.,University of Milan | Riva M.A.,University of Milan | And 2 more authors.
Neuroscience | Year: 2012

Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF+/-) and wild-types. Notably, in enriched-reared BDNF+/- mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF+/- mice is directed by distinct mechanisms in males and females. Only in male BDNF+/- mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner. © 2012.


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.


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


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.


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.


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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