16 results on '"Grazyna Domanska"'
Search Results
2. Increased mortality and altered local immune response in secondary peritonitis after previous visceral operations in mice
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Jonas Menz, Laura Hundt, Tobias Schulze, Katrin Schmoeckel, Pia Menges, and Grazyna Domanska
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Medicine ,Science - Abstract
Abstract Postoperative peritonitis is characterized by a more severe clinical course than other forms of secondary peritonitis. The pathophysiological mechanisms behind this phenomenon are incompletely understood. This study used an innovative model to investigate these mechanisms, combining the models of murine Colon Ascendens Stent Peritonitis (CASP) and Surgically induced Immune Dysfunction (SID). Moreover, the influence of the previously described anti-inflammatory reflex transmitted by the vagal nerve was characterized. SID alone, or 3 days before CASP were performed in female C57BL/6 N mice. Subdiaphragmatic vagotomy was performed six days before SID with following CASP. The immune status was assessed by FACS analysis and measurement of cytokines. Local intestinal inflammatory changes were characterized by immunohistochemistry. Mortality was increased in CASP animals previously subjected to SID. Subclinical bacteremia occurred after SID, and an immunosuppressive milieu occurred secondary to SID just before the induction of CASP. Previous SID modified the pattern of intestinal inflammation induced by CASP. Subdiaphragmatic vagotomy had no influence on sepsis mortality in our model of postoperative peritonitis. Our results indicate a surgery-induced inflammation of the small intestine and the peritoneal cavity with bacterial translocation, which led to immune dysfunction and consequently to a more severe peritonitis.
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- 2021
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3. Immune Polarization Potential of the S. aureus Virulence Factors SplB and GlpQ and Modulation by Adjuvants
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Daniel M. Mrochen, Patricia Trübe, Ilka Jorde, Grazyna Domanska, Cindy van den Brandt, and Barbara M. Bröker
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Staphylococcus aureus ,vaccine ,adjuvants ,SplB ,GlpQ ,immune polarization ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Protection against Staphylococcus aureus is determined by the polarization of the anti-bacterial immune effector mechanisms. Virulence factors of S. aureus can modulate these and induce differently polarized immune responses in a single individual. We proposed that this may be due to intrinsic properties of the bacterial proteins. To test this idea, we selected two virulence factors, the serine protease-like protein B (SplB) and the glycerophosphoryl diester phosphodiesterase (GlpQ). In humans naturally exposed to S. aureus, SplB induces a type 2-biased adaptive immune response, whereas GlpQ elicits type 1/type 3 immunity. We injected the recombinant bacterial antigens into the peritoneum of S. aureus-naïve C57BL/6N mice and analyzed the immune response. This was skewed by SplB toward a Th2 profile including specific IgE, whereas GlpQ was weakly immunogenic. To elucidate the influence of adjuvants on the proteins’ polarization potential, we studied Montanide ISA 71 VG and Imject™Alum, which promote a Th1 and Th2 response, respectively. Alum strongly increased antibody production to the Th2-polarizing protein SplB, but did not affect the response to GlpQ. Montanide enhanced the antibody production to both S. aureus virulence factors. Montanide also augmented the inflammation in general, whereas Alum had little effect on the cellular immune response. The adjuvants did not override the polarization potential of the S. aureus proteins on the adaptive immune response.
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- 2021
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4. The Immunomodulator 1-Methyltryptophan Drives Tryptophan Catabolism Toward the Kynurenic Acid Branch
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Elisa Wirthgen, Anne K. Leonard, Christian Scharf, and Grazyna Domanska
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1-MT ,IDO ,KYNA ,kynurenine pathway ,tryptophan ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Animal model studies revealed that the application of 1-methyltryptophan (1-MT), a tryptophan (TRP) analog, surprisingly increased plasma levels of the TRP metabolite, kynurenic acid (KYNA). Under inflammatory conditions, KYNA has been shown to mediate various immunomodulatory effects. Therefore, the present study aims to confirm and clarify the effects of 1-MT on TRP metabolism in mice as well as in humans.Methods: Splenocytes from Balb/C or indoleamine 2,3-dioxygenase knockout (IDO1−/−) mice or whole human blood were stimulated with 1-MT for 6, 24, or 36 h. C57BL/6 mice received 1-MT in drinking water for 5 days. Cell-free supernatants and plasma were analyzed for TRP and its metabolites by tandem mass spectrometry (MS/MS).Results: 1-MT treatment induced an increase in TRP and its metabolite, KYNA in Balb/C, IDO−/− mice, and in human blood. Concurrently, the intermediate metabolite kynurenine (KYN), as well as the KYN/TRP ratio, were reduced after 1-MT treatment. The effects of 1-MT on TRP metabolites were similar after the in vivo application of 1-MT to C57BL/6 mice.Conclusions: The data indicate that 1-MT induced an increase of KYNA ex vivo and in vivo confirming previously described results. Furthermore, the results of IDO−/− mice indicate that this effect seems not to be mediated by IDO1. Due to the proven immunomodulatory properties of KYNA, a shift toward this branch of the kynurenine pathway (KP) may be one potential mode of action by 1-MT and should be considered for further applications.
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- 2020
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5. Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib
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Christin Riess, Björn Schneider, Hanna Kehnscherper, Julia Gesche, Nina Irmscher, Fatemeh Shokraie, Carl Friedrich Classen, Elisa Wirthgen, Grazyna Domanska, Annette Zimpfer, Daniel Strüder, Christian Junghanss, and Claudia Maletzki
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targeted therapy ,solid tumor models ,tryptophan metabolites ,IDO1 ,chemotherapy ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.
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- 2020
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6. Obesity Impairs Mobility and Adult Hippocampal Neurogenesis
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Alexander Bracke, Grazyna Domanska, Katharina Bracke, Steffen Harzsch, Jens van den Brandt, Barbara Bröker, and Oliver von Bohlen und Halbach
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Currently, it is controversially discussed whether a relationship between obesity and cognition exists. We here analyzed a mouse model of obesity (leptin-deficient mice) to study the effects of obesity on the morphology of the hippocampus (a brain structure involved in mechanisms related to learning and memory) and on behavior. Mice aged 4 to 6 months were analyzed. At this age, the obese mice have nearly double the body weight as controls, but display smaller brains (brain volume is about 10% smaller) as control animals of the same age. Adult hippocampal neurogenesis, a process that is linked to learning and memory, might be disturbed in the obese mice and contribute to the smaller brain volume. Adult hippocampal neurogenesis was examined using specific markers for cell proliferation (phosphohistone H3), neuronal differentiation (doublecortin), and apoptosis (caspase 3). The number of phosphohistone H3 and doublecortin-positive cells was markedly reduced in leptin-deficient mice, but not the number of apoptotic cells, indicating that adult hippocampal neurogenesis on the level of cell proliferation was affected. In addition, dendritic spine densities of pyramidal neurons in the hippocampal area CA1 were analyzed using Golgi impregnation. However, no significant change in dendritic spine densities was noted in the obese mice. Moreover, the performance of the mice was analyzed in the open field as well as in the Morris water maze. In the open field test, obese mice showed reduced locomotor activity, but in the Morris water maze they showed similar performance compared with control animals.
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- 2019
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7. The Impact of Lidocaine on Adipose-Derived Stem Cells in Human Adipose Tissue Harvested by Liposuction and Used for Lipotransfer
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Felix Grambow, Rico Rutkowski, Fred Podmelle, Katrin Schmoeckel, Florian Siegerist, Grzegorz Domanski, Matthias W. Schuster, and Grazyna Domanska
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lipofilling ,autologous lipotransfer ,adipose-derived stem cells ,lidocaine ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The local anesthetic lidocaine, which has been used extensively during liposuction, has been reported to have cytotoxic effects and therefore would be unsuitable for use in autologous lipotransfer. We evaluated the effect of lidocaine on the distribution, number, and viability of adipose-derived stem cells (ASCs), preadipocytes, mature adipocytes, and leukocytes in the fatty and fluid portion of the lipoaspirate using antibody staining and flow cytometry analyses. Adipose tissue was harvested from 11 female patients who underwent liposuction. Abdominal subcutaneous fat tissue was infiltrated with tumescent local anesthesia, containing lidocaine on the left and lacking lidocaine on the right side of the abdomen, and harvested subsequently. Lidocaine had no influence on the relative distribution, cell number, or viability of ASCs, preadipocytes, mature adipocytes, or leukocytes in the stromal-vascular fraction. Assessing the fatty and fluid portions of the lipoaspirate, the fatty portions contained significantly more ASCs (p < 0.05), stem cells expressing the preadipocyte marker Pref-1 (p < 0.01 w/lidocaine, p < 0.05 w/o lidocaine), and mature adipocytes (p < 0.05 w/lidocaine, p < 0.01 w/o lidocaine) than the fluid portions. Only the fatty portion should be used for transplantation. This study found no evidence that would contraindicate the use of lidocaine in lipotransfer. Limitations of the study include the small sample size and the inclusion of only female patients.
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- 2020
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8. Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs
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Elisa Wirthgen, Winfried Otten, Margret Tuchscherer, Armin Tuchscherer, Grazyna Domanska, Julia Brenmoehl, Juliane Günther, Daniela Ohde, Werner Weitschies, Anne Seidlitz, Eberhard Scheuch, and Ellen Kanitz
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indoleamine 2,3-dioxygenase ,kynurenine pathway ,methyltryptophan ,LPS ,pig ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT) is currently in the interest of research due to its potential inhibitory effects on IDO1 and immunomodulatory properties. The present study aims to investigate the protective and immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan (TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be considered for therapeutic applications of 1-MT.
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- 2018
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9. Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on immunosuppression in mice and humans.
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Cornelia Kiank, Jan-Philip Zeden, Solveig Drude, Grazyna Domanska, Gerhard Fusch, Winfried Otten, and Christine Schuett
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Medicine ,Science - Abstract
It is increasingly recognized that psychological stress influences inflammatory responses and mood. Here, we investigated whether psychological stress (combined acoustic and restraint stress) activates the tryptophan (Trp) catabolizing enzyme indoleamine 2,3-dioxygenase 1(IDO1) and thereby alters the immune homeostasis and behavior in mice. We measured IDO1 mRNA expression and plasma levels of Trp catabolites after a single 2-h stress session and in repeatedly stressed (4.5-days stress, 2-h twice a day) naïve BALB/c mice. A role of cytokines in acute stress-induced IDO1 activation was studied after IFNgamma and TNFalpha blockade and in IDO1(-/-) mice. RU486 and 1-Methyl-L-tryptophan (1-MT) were used to study role of glucocorticoids and IDO1 on Trp depletion in altering the immune and behavioral response in repeatedly stressed animals. Clinical relevance was addressed by analyzing IDO1 activity in patients expecting abdominal surgery. Acute stress increased the IDO1 mRNA expression in brain, lung, spleen and Peyer's patches (max. 14.1+/-4.9-fold in brain 6-h after stress) and resulted in a transient depletion of Trp (-25.2+/-6.6%) and serotonin (-27.3+/-4.6%) from the plasma measured 6-h after stress while kynurenine levels increased 6-h later (11.2+/-9.3%). IDO1 mRNA up-regulation was blocked by anti-TNFalpha and anti-IFNgamma treatment. Continuous IDO1 blockade by 1-MT but not RU486 treatment normalized the anti-bacterial defense and attenuated increased IL-10 inducibility in splenocytes after repeated stress as it reduced the loss of body weight and behavioral alterations. Moreover, kynurenic acid which remained increased in 1-MT treated repeatedly stressed mice was identified to reduce the TNFalpha inducibility of splenocytes in vitro and in vivo. Thus, psychological stress stimulates cytokine-driven IDO1 activation and Trp depletion which seems to have a central role for developing stress-induced immunosuppression and behavioral alteration. Since patients showed Trp catabolism already prior to surgery, IDO is also a possible target enzyme for humans modulating immune homeostasis and mood.
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- 2010
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10. Obesity alters mobility and adult neurogenesis, but not hippocampal dependent learning in ob/ob mice
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Katharina Bracke, von Bohlen und Halbach O, van den Brandt J, Barbara M. Bröker, Alexander Bracke, Steffen Harzsch, and Grazyna Domanska
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medicine.medical_specialty ,education.field_of_study ,Dentate gyrus ,Population ,Neurogenesis ,Morris water navigation task ,Hippocampus ,Hippocampal formation ,Biology ,Cell morphology ,Doublecortin ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,education - Abstract
sBackgroundObesity has become a severe problem among the world’s population with clearly increasing prevalence over the last decades. Because obesity is associated with several comorbidities (e.g. hypertension or cancer) it constitutes an increasing burden for the health care system. Correlations between obesity and cognition have been studied in humans with ambivalent results. Here, we studied the effects of obesity on hippocampus dependent learning and memory and cell morphology in a mouse model of obesity.MethodsThe body mass of male and female Lep+/+(wt) and Lepob/ob(ob/ob) animals with access to food and water ad libitum was measured between postnatal day 60-200 and animals with clear adiposity (4-6 months) were further analyzed. Adult hippocampal neurogenesis in the dentate gyrus was examined using phosphohistone H3 as a marker for proliferation, doublecortin as a marker for differentiation and caspase3 as a marker for apoptosis. Moreover, the density of dendritic spines on apical and basal dendrites of pyramidal neurons of the cornu ammonis 1 (CA1) were analyzed using Golgi impregnation. In addition, mice were subjected to the open field and Morris water maze test in order to analyze locomotor activity and spatial learning.ResultsThe body weight of ob/ob mice nearly doubled during the first 120 postnatal days. Adult hippocampal neurogenesis was reduced in ob/ob mice due to reduced cell proliferation. Dendritic spine densities in the hippocampal area CA1 were not altered in ob/ob mice. Four to six months old ob/ob mice showed reduced locomotor activity in the open field test but similar performance in the Morris water maze compared to control mice.ConclusionOur data show that alterations in adult neurogenesis in leptin-deficient mice are not associated with an impairment in spatial learning abilities. Moreover, ob/ob mice are inconspicuous in the Morris water maze and do not display altered spine densities in the hippocampus, suggesting that obesity does not have a severe impact upon hippocampal neuronal plasticity and spatial learning.
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- 2019
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11. Simulation of the Measured Reactivity Distributions in the Subcritical MYRRHA Reactor
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Jerzy Janczyszyn, Grażyna Domańska, and Mikołaj Oettingen
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ADS ,MYRRHA ,reactivity ,detectors ,spatial effect ,area method ,Technology - Abstract
The designed MYRRHA reactor, in its subcritical version, will be equipped with a set of detectors monitoring its condition by measuring the current value of negative reactivity, which is a crucial parameter for its safe operation. In subcritical systems, accurate and precise measurement of negative reactivity is disturbed by the so-called spatial effect, i.e., the response of detectors depends on their placement in the reactor core. This paper focuses on the Monte Carlo simulations of reactivity measurements using the area method for natU, 238U, 241Am, 239Pu, and 232Th detectors. The simulations were performed in six positions with increasing distance from the center of the core and at three axial levels. The obtained results allow for selecting optimum locations for detectors and detector nuclides in terms of the accuracy of reactivity measurement and illustrate the dependence of the reactivity on the distance. Additionally, the possibility of using 103Rh in self-powered neutron detectors was investigated. The influence of spatial effect in calculations using the area method was directly indicated in the MYRRHA reactor core for chosen isotopes and in-core positions. The results closest to true values were obtained for the second fuel assembly for 239Pu, and the third fuel assembly for natU, 238U, 232Th, and 241Am; thus, these nuclides and positions should be preferred when selecting detectors for MYRRHA.
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- 2024
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12. Pharmacokinetics of 1-methyl-L-tryptophan after single and repeated subcutaneous application in a porcine model
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Margret Tuchscherer, Ellen Kanitz, Grazyna Domanska, Anne Seidlitz, Elisa Wirthgen, Winfried Otten, Werner Weitschies, Armin Tuchscherer, and Eberhard Scheuch
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0301 basic medicine ,Single administration ,pig ,medicine.medical_specialty ,Time Factors ,Original ,Swine ,Injections, Subcutaneous ,methyltryptophan ,General Biochemistry, Genetics and Molecular Biology ,Subcutaneous application ,03 medical and health sciences ,Pharmacokinetics ,Internal medicine ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Tissue Distribution ,Enzyme Inhibitors ,Indoleamine 2,3-dioxygenase ,chemistry.chemical_classification ,General Veterinary ,biology ,Tryptophan ,General Medicine ,pharmacokinetics ,indoleamine 2,3-dioxygenase ,tryptophan ,Enzyme assay ,Sus scrofa domestica ,030104 developmental biology ,Endocrinology ,Enzyme ,3-dioxygenase ,chemistry ,Models, Animal ,biology.protein ,indoleamine 2 ,Animal Science and Zoology - Abstract
Increased activity of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is associated with immunological and neurological disorders, and inhibition of its enzyme activity could be a therapeutic approach for treatment of these disorders. The aim of the present study was to establish a large animal model to study the accumulation of the potential IDO inhibitor 1-methyltryptophan (1-MT) in blood and different organs of domestic pigs (Sus scrofa domestica). Because 1-MT has not been previously evaluated in pigs, the pharmacokinetics of a single subcutaneous 1-MT application was investigated. Based on this kinetic study, a profile for repeated 1-MT applications over a period of five days was simulated and tested. The results show that a single administration of 1-MT increases its concentrations in blood, with the maximum concentration being obtained at 12 h. Repeated daily injections of 1‑MT generated increasing plasma concentrations followed by a steady-state after two days. Twelve hours after the final application, accumulation of 1-MT was observed in the brain and other organs, with a substantial variability among various tissues. The concentrations of 1-MT measured in plasma and tissues were similar to, or even higher, than those of tryptophan. Our data indicate that repeated subcutaneous injections of 1-MT provide a suitable model for accumulation of 1-MT in plasma and tissues of domestic pigs. These findings provide a basis for further research on the immunoregulatory functions of IDO in a large animal model.
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- 2015
13. Association between waist circumference and gray matter volume in 2344 individuals from two adult community-based samples
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Harald J. Freyberger, Jan Terock, Grazyna Domanska, Katrin Hegenscheid, Nele Friedrich, Mohamad Habes, Deborah Janowitz, Hans Jörgen Grabe, Matthias Nauck, Katharina Wittfeld, Norbert Hosten, and Henry Völzke
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Adult ,Male ,Waist ,pathology [Obesity] ,Cognitive Neuroscience ,Olfactory sulcus ,Cuneus ,Lingual gyrus ,Sex Factors ,Supramarginal gyrus ,Gyrus ,pathology [Brain] ,pathology [Gray Matter] ,medicine ,Humans ,Obesity ,ddc:610 ,Gray Matter ,Postcentral gyrus ,Age Factors ,Brain ,Anatomy ,Middle Aged ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Cross-Sectional Studies ,nervous system ,Neurology ,Frontal lobe ,Female ,Waist Circumference ,Psychology ,Neuroscience - Abstract
We analyzed the putative association between abdominal obesity (measured in waist circumference) and gray matter volume (Study of Health in Pomerania: SHIP-2, N=758) adjusted for age and gender by applying volumetric analysis and voxel-based morphometry (VBM) with VBM8 to brain magnetic resonance (MR) imaging. We sought replication in a second, independent population sample (SHIP-TREND, N=1586). In a combined analysis (SHIP-2 and SHIP-TREND) we investigated the impact of hypertension, type II diabetes and blood lipids on the association between waist circumference and gray matter. Volumetric analysis revealed a significant inverse association between waist circumference and gray matter volume. VBM in SHIP-2 indicated distinct inverse associations in the following structures for both hemispheres: frontal lobe, temporal lobes, pre- and postcentral gyrus, supplementary motor area, supramarginal gyrus, insula, cingulate gyrus, caudate nucleus, olfactory sulcus, para-/hippocampus, gyrus rectus, amygdala, globus pallidus, putamen, cerebellum, fusiform and lingual gyrus, (pre-) cuneus and thalamus. These areas were replicated in SHIP-TREND. More than 76% of the voxels with significant gray matter volume reduction in SHIP-2 were also distinct in TREND. These brain areas are involved in cognition, attention to interoceptive signals as satiety or reward and control food intake. Due to our cross-sectional design we cannot clarify the causal direction of the association. However, previous studies described an association between subjects with higher waist circumference and future cognitive decline suggesting a progressive brain alteration in obese subjects. Pathomechanisms may involve chronic inflammation, increased oxidative stress or cellular autophagy associated with obesity.
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- 2015
14. Different stress-related phenotypes of BALB/c mice from in-house or vendor: alterations of the sympathetic and HPA axis responsiveness
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Christine Schuett, Cornelia Kiank, Grazyna Domanska, and Jakob Olfe
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medicine.medical_specialty ,Hypothalamo-Hypophyseal System ,Time Factors ,Physiology ,Pituitary-Adrenal System ,Breeding ,lcsh:Physiology ,BALB/c ,chemistry.chemical_compound ,Mice ,Norepinephrine ,Adrenocorticotropic Hormone ,Corticosterone ,Stress, Physiological ,Physiology (medical) ,Internal medicine ,Monoaminergic ,Research article ,medicine ,Animals ,Analysis of Variance ,Mice, Inbred BALB C ,biology ,lcsh:QP1-981 ,Body Weight ,General Medicine ,Reserpine ,biology.organism_classification ,Phenotype ,Housing, Animal ,Monoamine neurotransmitter ,Endocrinology ,chemistry ,Female ,Analysis of variance ,Glucocorticoid ,Stress, Psychological ,medicine.drug - Abstract
Background Laboratory routine procedures such as handling, injection, gavage or transportation are stressful events which may influence physiological parameters of laboratory animals and may interfere with the interpretation of the experimental results. Here, we investigated if female BALB/c mice derived from in-house breeding and BALB/c mice from a vendor which were shipped during their juvenile life differ in their HPA axis activity and stress responsiveness in adulthood. Results We show that already transferring the home cage to another room is a stressful event which causes an increased HPA axis activation for at least 24 hours as well as a loss of circulating lymphocytes which normalizes during a few days after transportation. However and important for the interpretation of experimental data, commercially available strain-, age- and gender-matched animals that were shipped over-night showed elevated glucocorticoid levels for up to three weeks after shipment, indicating a heightened HPA axis activation and they gained less body weight during adolescence. Four weeks after shipment, these vendor-derived mice showed increased corticosterone levels at 45-min after intraperitoneal ACTH challenge but, unexpectedly, no acute stress-induced glucocorticoid release. Surprisingly, activation of monoaminergic pathways were identified to inhibit the central nervous HPA axis activation in the vendor-derived, shipped animals since depletion of monoamines by reserpine treatment could restore the stress-induced HPA axis response during acute stress. Conclusions In-house bred and vendor-derived BALB/c mice show a different stress-induced HPA axis response in adulthood which seems to be associated with different central monoaminergic pathway activity. The stress of shipment itself and/or differences in raising conditions, therefore, can cause the development of different stress response phenotypes which needs to be taken into account when interpreting experimental data.
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- 2010
15. Hypermetabolic syndrome as a consequence of repeated psychological stress in mice
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Robert Geffers, Cornelia Kiank, Christine Schuett, Uwe Völker, Grazyna Domanska, Gerhard Fusch, Maren Depke, and Ernst-Moritz-Arndt-University, Interfaculty Institute of Genetics and Functional Genomics, 17487 Greifswald, Germany.
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medicine.medical_specialty ,Ratón ,Drinking Behavior ,Biology ,Polymerase Chain Reaction ,Mice ,Endocrinology ,Insulin resistance ,In vivo ,Internal medicine ,medicine ,Animals ,Acidosis ,Oligonucleotide Array Sequence Analysis ,Metabolic Syndrome ,Mice, Inbred BALB C ,Metabolic Syndrome X ,Stressor ,Water ,medicine.disease ,Disease Models, Animal ,Kinetics ,Gluconeogenesis ,Acoustic Stimulation ,Acute Disease ,Lean body mass ,Female ,medicine.symptom ,Energy Intake ,Energy Metabolism ,Dyslipidemia ,Stress, Psychological - Abstract
Stress is a powerful modulator of neuroendocrine, behavioral, and immunological functions. After 4.5-d repeated combined acoustic and restraint stress as a murine model of chronic psychological stress, severe metabolic dysregulations became detectable in female BALB/c mice. Stress-induced alterations of metabolic processes that were found in a hepatic mRNA expression profiling were verified by in vivo analyses. Repeatedly stressed mice developed a hypermetabolic syndrome with the severe loss of lean body mass, hyperglycemia, dyslipidemia, increased amino acid turnover, and acidosis. This was associated with hypercortisolism, hyperleptinemia, insulin resistance, and hypothyroidism. In contrast, after a single acute stress exposure, changes in expression of metabolic genes were much less pronounced and predominantly confined to gluconeogenesis, probably indicating that metabolic disturbances might be initiated already early but will only manifest in repeatedly stressed mice. Thus, in our murine model, repeated stress caused severe metabolic dysregulations, leading to a drastic reduction of the individual’s energy reserves. Under such circumstances stress may further reduce the ability to cope with new stressors such as infection or cancer.
- Published
- 2008
16. Helicobacter pylori VacA toxin/subunit p34: targeting of an anion channel to the inner mitochondrial membrane.
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Grazyna Domańska, Christian Motz, Michael Meinecke, Anke Harsman, Panagiotis Papatheodorou, Boris Reljic, Elke A Dian-Lothrop, Antoine Galmiche, Oliver Kepp, Lars Becker, Kathrin Günnewig, Richard Wagner, and Joachim Rassow
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The vacuolating toxin VacA, released by Helicobacter pylori, is an important virulence factor in the pathogenesis of gastritis and gastroduodenal ulcers. VacA contains two subunits: The p58 subunit mediates entry into target cells, and the p34 subunit mediates targeting to mitochondria and is essential for toxicity. In this study we found that targeting to mitochondria is dependent on a unique signal sequence of 32 uncharged amino acid residues at the p34 N-terminus. Mitochondrial import of p34 is mediated by the import receptor Tom20 and the import channel of the outer membrane TOM complex, leading to insertion of p34 into the mitochondrial inner membrane. p34 assembles in homo-hexamers of extraordinary high stability. CD spectra of the purified protein indicate a content of >40% beta-strands, similar to pore-forming beta-barrel proteins. p34 forms an anion channel with a conductivity of about 12 pS in 1.5 M KCl buffer. Oligomerization and channel formation are independent both of the 32 uncharged N-terminal residues and of the p58 subunit of the toxin. The conductivity is efficiently blocked by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), a reagent known to inhibit VacA-mediated apoptosis. We conclude that p34 essentially acts as a small pore-forming toxin, targeted to the mitochondrial inner membrane by a special hydrophobic N-terminal signal.
- Published
- 2010
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