17 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
- Full Text
- View/download PDF
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
- Full Text
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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. Association between waist circumference and gray matter volume in 2344 individuals from two adult community-based samples.
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Deborah Janowitz, Katharina Wittfeld, Jan Terock, Harald Jürgen Freyberger, Katrin Hegenscheid, Henry Völzke, Mohamad Habes, Norbert Hosten, Nele Friedrich, Matthias Nauck, Grazyna Domanska, and Hans Jörgen Grabe
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- 2015
- Full Text
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10. Increased mortality and altered local immune response in secondary peritonitis after previous visceral operations in mice
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Grazyna Domanska, P. Menges, Katrin Schmoeckel, Jonas Menz, Laura Hundt, and Tobias Schulze
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medicine.medical_specialty ,Science ,Immunology ,Peritonitis ,Inflammation ,Pathogenesis ,Gastroenterology ,Article ,Mice ,Peritoneal cavity ,Postoperative Complications ,Immune system ,Internal medicine ,medicine ,Animals ,CASP ,Peritoneal Cavity ,Subclinical infection ,Multidisciplinary ,business.industry ,Immunity ,medicine.disease ,humanities ,Pathophysiology ,Experimental models of disease ,Disease Models, Animal ,medicine.anatomical_structure ,Bacteremia ,Medicine ,medicine.symptom ,business - 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.
- Published
- 2021
11. Siponimod (BAF312) Treatment Reduces Brain Infiltration but Not Lesion Volume in Middle-Aged Mice in Experimental Stroke
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Grazyna Domanska, Michael Kirsch, Juliane Schulze, Johanna Ruhnau, Antje Vogelgesang, and Alexander Dressel
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Male ,Sphingosine 1 Phosphate Receptor Modulators ,Pathology ,medicine.medical_specialty ,T-Lymphocytes ,Central nervous system ,Ischemia ,Brain Ischemia ,Lesion ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Benzyl Compounds ,medicine ,Animals ,Neuroinflammation ,030304 developmental biology ,Advanced and Specialized Nursing ,0303 health sciences ,business.industry ,Multiple sclerosis ,Age Factors ,Brain ,medicine.disease ,Pathophysiology ,Mice, Inbred C57BL ,Stroke ,Disease Models, Animal ,Treatment Outcome ,Lymphatic system ,medicine.anatomical_structure ,Siponimod ,chemistry ,Azetidines ,Neurology (clinical) ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery - Abstract
Background and Purpose— The contribution of neuroinflammation and, in particular, the infiltration of the brain by lymphocytes is increasingly recognized as a substantial pathophysiological mechanism after stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thromboinflammation, fosters microvascular dysfunction and secondary infarct growth. Siponimod is an S1PR (sphingosine-1-phosphate receptor) modulator, which blocks the egress of lymphocytes from lymphoid organs and has demonstrated beneficial effects in multiple sclerosis treatment. We investigated the effect of treatment with siponimod on stroke outcome in a mouse model of cerebral ischemia. Methods— Transient middle cerebral artery occlusion was induced in middle-aged wild-type mice. Animals were either treated with siponimod (3 mg/kg; intraperitoneal) or vehicle for 6 days. Stroke outcome was assessed by magnetic resonance imaging (spleen volume: prestroke, day 3, and day 7; infarct volume: days 1, 3, and 7) and behavioral tests (prestroke, day 2, and day 6). Immune cells of the peripheral blood and brain-infiltrating cells ipsilateral and contralateral were analyzed by VETScan and by flow cytometry. Results— Siponimod significantly induced lymphopenia on day 7 after transient middle cerebral artery occlusion and reduced T-lymphocyte accumulation in the central nervous system. No effect was detected for lesion size. Conclusions— For siponimod administered at 3 mg/kg in transient middle cerebral artery occlusion mouse model, our findings do not provide preclinical evidence for the use of S1PR1/5 modulators as neuroprotectant in stroke therapy.
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- 2019
12. Immune Polarization Potential of the S. aureus Virulence Factors SplB and GlpQ and Modulation by Adjuvants
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Ilka Jorde, Daniel M. Mrochen, Grazyna Domanska, Barbara M. Bröker, Cindy van den Brandt, and Patricia Trübe
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Staphylococcus aureus ,Virulence Factors ,030106 microbiology ,Immunology ,Antigen-Presenting Cells ,Virulence ,chemical and pharmacologic phenomena ,Inflammation ,medicine.disease_cause ,Immunoglobulin E ,Microbiology ,Th2 ,Mice ,03 medical and health sciences ,Th2 Cells ,Immune system ,Adjuvants, Immunologic ,Bacterial Proteins ,Immunity ,vaccine ,medicine ,Animals ,Immunology and Allergy ,mouse models ,GlpQ ,Original Research ,Antigens, Bacterial ,biology ,Phosphoric Diester Hydrolases ,Chemistry ,SplB ,Th1 Cells ,Acquired immune system ,Antibodies, Bacterial ,Mice, Inbred C57BL ,030104 developmental biology ,adjuvants ,biology.protein ,Cytokines ,immune polarization ,Female ,Immunization ,Bacterial antigen ,medicine.symptom ,lcsh: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.
- Published
- 2021
13. Vitamin B6 deficiency in new born rats affects hepatic cardiolipin composition and oxidative phosphorylation
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Uwe Lendeckel, Grazyna Domanska, Daniela Peter, Lorenz Schild, Jens Weingärtner, Sarah Gürtler, and Carmen Wolke
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0301 basic medicine ,Male ,medicine.medical_specialty ,Cardiolipins ,Mitochondria, Liver ,Oxidative phosphorylation ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,Oxidative Phosphorylation ,03 medical and health sciences ,chemistry.chemical_compound ,Oxygen Consumption ,Pregnancy ,Internal medicine ,Cardiolipin ,medicine ,Animals ,Original Research ,010401 analytical chemistry ,Plasma levels ,medicine.disease ,Vitamin D Deficiency ,Mitochondrial respiration ,0104 chemical sciences ,Rats ,030104 developmental biology ,Endocrinology ,chemistry ,Animals, Newborn ,Liver ,Rats, Inbred Lew ,Composition (visual arts) ,Female ,Vitamin b6 - Abstract
Vitamin B6 deficiency during pregnancy translates into a severe vitamin B6 deficiency (plasma levels decreased by 97%) in new-born rats. Further, hallmarks are increased (+89%) concentrations of homocysteine, gross changes in gene methylation and expression, and metabolic alterations including lipid metabolism. This study focuses on determining the effects of vitamin B6-deficiency on cardiolipin composition and oxidative phosphorylation in liver. For this purpose, hepatic cardiolipin composition was analyzed by means of LC/MS/MS, and mitochondrial oxygen consumption was determined by using a Clark-type electrode in a rat model of vitamin B6 deficiency. Liver mitochondria from new-born rats with pre-term vitamin B6 deficiency responded with substantial alterations in cardiolipin composition that include the following changes in the amounts of cardiolipin incorporated fatty acids: increase in C16, decrease in C18, decrease in saturated fatty acid, as well as increase in amount of oxidized cardiolipin species. These changes were accompanied by significantly decreased capacity of oxidative phosphorylation. In conclusion, vitamin B6 deficiency in new born rats induces massive alterations of cardiolipin composition and function of liver mitochondria. These findings support the importance of sufficient periconceptional supply of vitamin B6 to prevent vitamin B6 deficiency.Impact statementVitamin B6 (VitB6) is an active co-enzyme for more than 150 enzymes and is required for a great diversity of biosynthesis and metabolic reactions. There is an increased need for VitB6 during pregnancy and sufficient supply of VitB6 is crucial for the prevention of cleft palate and neural tube defects. We show that liver mitochondria from new-born rats with pre-term VitB6 deficiency respond with substantial alterations in cardiolipin (CL) composition and in the amount of oxidized CL species. These changes are associated with a decrease in the efficiency of oxidative phosphorylation. The results of this study support the significance of sufficient supply of VitB6 during pregnancy (and periconceptional) for diminishing the number of early abortions and minimizing malformation. The established link between VitB6 deficiency, CL composition, and mitochondrial respiration/energy production provides mechanistic insight as to how the VitB6 deficiency translates into the known pathophysiological and clinically relevant conditions.
- Published
- 2019
14. 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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15. 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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16. 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.
- Published
- 2015
17. 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
- Subjects
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.
- Published
- 2015
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