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The effect of stress on regulation and regeneration of glucocorticoids in animal models differing in response of hypothalamo-pituitary-adrenal axis
Vodička, Martin ; Pácha, Jiří (advisor) ; Svoboda, Jan (referee) ; Bendová, Zdeňka (referee)
Stress reaction is usually activated by the brain, when homeostasis is or perceived to be threatened. The stress signals are transmitted from the brain by two main branches; the sympathoadrenomedullary and the hypothalamo-pituitary-adrenal (HPA) axes and employ neural, humoral and immune pathways to cope with the stressor. Because of its potency, the stress reaction has to be precisely regulated. The HPA axis is regulated by feedback loops where its end product, corticosterone in laboratory rat and mouse, inhibits its activity. The effect of corticosterone does not depend only on the concentration of corticosterone but also on local metabolism of glucocorticoids via oxo-reduction catalyzed by the enzyme 11β -hydroxysteroid dehydrogenase 1 (encoded by the Hsd11b1 gene), which intracellularly regenerates active corticosterone from inactive 11-dehydrocorticosterone, or by extra-adrenal de novo steroidogenesis of glucocorticoids. We focused on analysis of stress response in experimental animals differing in HPA axis responsivity (Fischer 344 rats (F344) vs. Lewis rats (LEW) and germ-free (GF) vs. specific pathogen free mice (SPF)) with special emphasis on regulation of stress response, glucocorticoid regeneration and influence of gut microbiota. We found that stress modulated local regeneration of...
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Molecular mechanisms of entrainment of the fetal circadian clocks
Lužná, Vendula ; Sumová, Alena (advisor) ; Šauman, Ivo (referee) ; Štaud, František (referee)
In order to adapt to changing external conditions, organisms developed the endogenous biological clock for predicting daily alterations. This so-called circadian system drives functions and processes in the whole body with an approximately 24h period. The central oscillator, located in hypothalamic suprachiasmatic nuclei (SCN), is synchronized by light and subsequently sends the information about the time of the day to the rest of the body. Even in the ontogenesis, the functional SCN clock is crucial for proper development as well as health later in life. Since the maturation of embryonic SCN is not completed before birth, maternal signals seem to play a fundamental role in setting and synchronizing the fetal clock. During my PhD studies, we focused on elucidating the nature of maternal signals and their diverse impact on fetal SCN of rat and mouse models. We have revealed that developing SCN is able to sense distinct signals related to various maternal behavioral regimes. Importantly, we have discovered eminent role of glucocorticoids in synchronizing the fetal SCN, along with their ability to accelerate SCN development. These observations point out the importance of regular daily routine and noxious effect of stress during pregnancy. Since the mother communicates with the fetus through placenta...
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Bacterial components in experimental intestinal inflammation prevention and therapy
Kverka, Miloslav ; Tlaskalová - Hogenová, Helena (advisor) ; Šedivá, Anna (referee) ; Stříž, Ilja (referee)
Although strong protective immune response is essential for preventing invasion by pathogens, equivalent responses against antigens originating from commensal bacteria can lead to chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Manipulating the mucosal immune responses with microbial antigens might be an excellent tool to IBD therapy or prevention. Our aim was to gain some insight into the regulation of the intestinal inflammation and to isolate bacterial immunomodulatory components that could be used in intestinal inflammation therapy and prevention. One particular mechanism of how healthy colon tissue regulates the inflammation during acute experimental colitis is through modulation of bioavailability of glucocorticoids (GCs) in gut mucosa. Here, we show that intestinal inflammation changes the local GC metabolism, which ultimately leads to decrease in inflammatory readiness of cells in the gut mucosa and in mesenteric lymph nodes. This pre-receptor regulation of GC function could represent an important homeostatic function of the gut mucosa. The actual triggers of intestinal inflammation in IBD seem to be either microbial dysbiosis or microbes with special "pathogenic" abilities, which both could be rectified by feeding with probiotics. Here, we report that oral feeding with live...
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Bone remodeling in rheumatic diseases: Bone loss in juvenile idiopathic arthritis
Brábníková Marešová, Kristýna ; Štěpán, Jan (advisor) ; Blahoš, Jaroslav (referee) ; Hrnčíř, Zbyněk (referee)
Introduction: The inflammation plays the essential role in the bone loss in juvenile idiopathic arthritis (JIA). Proinflammatory cytokines and also glucocorticoids (GCs) may activate bone resorption by osteoclasts. Simultaneously, bone formation can be attenuated, especially by inhibitors of proteins, which control the osteoblast differentiation. The aim was to verify the hypothesis that in patients with highly active JIA, reduction of bone formation via Wingless (Wnt) proteins inhibitors - Dickkopf 1 (Dkk-1) and sclerostin could be found. Except the densitometry measurements of bone and lean mass, we assessed markers of disease activity, bone metabolism and remodeling in young adult patients with JIA before and during 2 years of anti TNFα (tumour necrosis factor α) treatment, which decreases disease activity. Results: In patients with JIA before antiTNFα treatment, bone mineral density (BMD, g/cmš) was significantly reduced compared to controls. Values of BMD and body composition in JIA significantly depended on disease duration and GCs treatment. Serum concentration of sclerostin was significantly elevated in JIA compared to values in healthy controls. Values of the other monitored markers did not differ between JIA and controls. In patients with JIA, Dkk-1 correlated positively with C-reactive...
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The influence of pulse glucocorticoid therapy on ECG
Bosaková, Nikola ; Vlček, Jiří (advisor) ; Rozsívalová, Petra (referee)
Candidate: Nikola Juríková1 Supervisor: prof. RNDr. Jiří Vlček, CSc.1 Consultant: doc. MUDr. Tomáš Soukup, PhD.2 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University 2 2nd Department of Internal Medicine - Gastroenterology, University Hospital in Hradec Králové Title of the master thesis: Effect of pulse glucocorticoid therapy on ECG Glucocorticoid pulse therapy (PT) is used to terminate acute exacerbations of immunologically mediated diseases. The aim of this thesis was to analyze the influence of methylprednisolone (MP) PT on ECG changes, mainly on QT interval, as prolonged QT interval may induce ventricular arrhythmias and to identify other risk factors (RF) for QT prolongation. Data were gained retrospectively from medical records of patients hospitalized at II. Internal Gastroenterology Clinic of University Hospital Hradec Králové. QT was corrected to QTc using Bazzet (QTcB) and Fridericia (QTcF) formula, QTc >450 ms (men) and QTc >460 ms (women) was considered prolonged. QTc changes before and after pulse therapy were determined as ∆QTc. 325 pulses of MP were administered to 277 patients (66,0 % women), ECG was available in 94,2 % (n=306 from 325). After PT there was significant ∆QTcF 14,6 ms (p <0,001) and ∆QTcB 5,6 ms (p <0,001)....
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The influence of pulse glucocorticoid therapy on ECG
Juríková, Nikola ; Vlček, Jiří (advisor) ; Rozsívalová, Petra (referee)
Candidate: Nikola Juríková1 Supervisor: prof. RNDr. Jiří Vlček, CSc.1 Consultant: doc. MUDr. Tomáš Soukup, PhD.2 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University 2 2nd Department of Internal Medicine - Gastroenterology, University Hospital in Hradec Králové Title of the master thesis: Effect of pulse glucocorticoid therapy on ECG Glucocorticoid pulse therapy (PT) is used to terminate acute exacerbations of immunologically mediated diseases. The aim of this thesis was to analyze the influence of methylprednisolone (MP) PT on ECG changes, mainly on QT interval, as prolonged QT interval may induce ventricular arrhythmias and to identify other risk factors (RF) for QT prolongation. Data were gained retrospectively from medical records of patients hospitalized at II. Internal Gastroenterology Clinic of University Hospital Hradec Králové. QT was corrected to QTc using Bazzet (QTcB) and Fridericia (QTcF) formula, QTc >450 ms (men) and QTc >460 ms (women) was considered prolonged. QTc changes before and after pulse therapy were determined as ∆QTc. 325 pulses of MP were administered to 277 patients (66,0 % women), ECG was available in 94,2 % (n=306 from 325). After PT there was significant ∆QTcF 14,6 ms (p <0,001) and ∆QTcB 5,6 ms (p <0,001)....
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miRNAs as diagnostic markers after treatment with glucocorticoids in rheumatology
Tripská, Katarína ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Katarína Tripská Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: miRNAs as diagnostic markers after treatment with glucocorticoids in rheumatology MicroRNAs are important class of non-coding RNAs that play important role in modulation of expression of multiple genes at a post-transcriptional level. Their deregulation contributes to many immune disorders including rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. This thesis represents the most recent knowledge about functions of microRNAs in pathogenesis of these disorders and results were obtained by review of scientific literature published on PubMed database. The most perspective microRNAs in rheumatoid arthritis seem to be miR-16, miR-21, miR- 146a, miR-150 a miR-223. In lupus miR-148, miR-126, miR-21, miR-155, miR-125a a miR- 146 will probably find their useage as biomarkers. Systemic sclerosis is less examined diseases and we know most about miR-29 in the disease. Since the research of microRNA as diagnostic biomarkers is only at the beginning, it is most likely, that with the time there will be more and more of new microRNAs helping us clarify pathogenesis of each disorder. We can suppose...
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Local steroidogenesis in peripheral tissues and its regulation
Langová, Veronika ; Ergang, Peter (advisor) ; Hudcovic, Tomáš (referee)
The innate and adaptive immune processes are modulated by hormones including glucocorticoids and by microbiota. The exact mechanisms underlying the microbial and hormonal contributions to this control are not completely clear. Present study is therefore focused to crosstalk between microbiota and de novo biogenesis or local regeneration of glucocorticoids. In particular, the study analysed the effect of commensal microbiota on expression of genes encoding steroidogenic enzymes (Star, Cyp11a1, Hsd3b1, Cyp21a1, Cyp11b1) and regeneration of glucocorticoids (Hsd11b1) in adrenal glands, colon, spleen and mesenteric lymph nodes using conventional and germ-free mice. The expression of all 5 components of steroidogenesis was identified only in the adrenal gland and colon, whereas the lymphoid organs expressed predominantly Star, Cyp11a1 and Hsd3b1 indicating the ability to produce only progesterone but not corticosterone. Microbiota decreased the expression of Star in all studied tissues but the expression of other genes was insensitive to microbiota or did not respond homogenously depending on the tissue and gene. Hsd11b1 expression was upregulated by microbiota in the spleen but not in other tissues. Similarly, the in vitro treatment of immune cells isolated from mesenteric lymph nodes by microbial...
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