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Evaluation of the pharmacological properties of new potential drugs for Alzheimer's disease
Čechová, Pavlína ; Šorf, Aleš (advisor) ; Urbánková Rathouská, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Social and Clinical Pharmacy Student: Pavlína Čechová Supervisor: PharmDr. Aleš Šorf, Ph.D. Consultant: mjr. PharmDr. Vendula Hepnarová, Ph.D. Title of diploma thesis: Assessment of pharmacological properties of new potencial drugs for Alzheimer's disease treatment Alzheimer's disease is a neurodegenerative disease with a progressive and irreversible course. The cause of AD is still not exactly known. There are currently four drugs available that have been approved by the State Institute for Drug Control. Three of them act as cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the fourth one as a N-methyl-D-aspartate (NMDA) receptor antagonist (memantine). Unfortunately, these drugs do not affect the course of the disease and provide only temporary symptomatic relief. An important area of current research is MTDLs (Multi-Target Directed Ligands), which act on multiple target structures related to the pathophysiology of the disease. These agents represent a promising therapeutic strategy. The aim of the study was to measure the ability to inhibit human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of 58 new potential MTDLs derived from biphenyl and benzhydryl using Ellman's method, as well as...
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Role of cAMP signaling in phagocyte migration
Dáňová, Klára ; Kamanová, Jana (advisor) ; Paňková, Daniela (referee)
Cell migration plays a key role in a wide diversity of biological processes. Migration enables phagocytic cells to localize into the site of inflammation and to lymph nodes, thereby leading to initiation of innate and adaptive immune responses, respectively. The signal transduction that coordinates phagocyte migration consist of diverse signaling proteins, being often under control of 3'-5'-cyclic adenosine monophosphate (cAMP) and its two effectors, protein kinase A (PKA) and Epac (exchange protein activated by cAMP). Small GTPase Rap is activated by Epac and controls phagocyte migration via activation of RAPL and RIAM proteins. On the other hand, PKA regulates cell migration via modulation of activity of other proteins, which comprise actin, integrins, small GTPases Rho, Rac, Cdc42 as well as protein VASP. A prominent feature of cAMP signalization is its spatio-temporal organization. Therefore, besides description of cAMP-regulated signaling cascades in cell migration, this bachelor thesis also depicts how changes of activity of cAMP effectors in time and place are involved in regulation of cell movement.
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Mechanisms of regulation of inhibitory factor IF1
Sklenář, Filip ; Dlasková, Andrea (advisor) ; Zelenka, Jaroslav (referee)
Inhibitory factor 1 (IF1) is one of the major regulators of mitochondrial ATP synthase activity, a key enzyme of energy metabolism. Its inhibitory effects are known in conditions such as hypoxia or starvation, but the hypothesis that IF1 inhibits ATP synthase activity even under physiological conditions is still not entirely accepted. Disorders of ATP synthase regulation can be fatal to the cell and have been described, for example, in carcinogenesis and ischemia. It has also been found that silencing of the IF1 gene in pancreatic β-cells increases insulin secretion, and thus, IF1 may be important in the pathogenesis of type 2 diabetes. The goal of this work is to summarize the current knowledge about the IF1 protein and to obtain new results that will help elucidate the mechanism by which this protein regulates mitochondrial ATP synthase. Specifically, this work deals with the ratio of IF1 protein to ATP synthase in pancreatic β-cells, depending on different culture conditions. It further investigates the occurrence of post-translational modifications of the IF1 protein in pancreatic β-cells (INS- 1E model cells), which may play a role in the regulation of IF1 activity. It also deals with the cellular ATP/ADP ratio, which is one of the key factors for insulin secretion by pancreatic β-cells. An...
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Zero Ionic Strength Corrections of pKA Constants and Electrophoretic Mobilities of Weak Electrolytes
Lorinčíková, Kateřina ; Gaš, Bohuslav (advisor) ; Sobotníková, Jana (referee)
The dependencies of the electrophoretic mobility of histidine on pH were measured in two sets of buffers at 20mM ionic strength. The parameters, which were obtained from these curves, were subsequently corrected to zero ionic strength using an older approach, as well as using the newly developed program AnglerFish. The effect of the ionic atmosphere on the pKA and mobility is shown, as well as the shape of the relevant corrections, which allow the determination of the pKA and mobility at infinite dilution. A new compound, imatinib, which is a quadruple positively charged nitrogenous heterocyclic compound, was also measured, and its pKA constants and mobilities were likewise determined. Key Words capillary zone electrophoresis, ionic strength, limiting mobility, pKA, zero ionic strength corrections
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Role of cAMP signaling in phagocyte migration
Dáňová, Klára ; Paňková, Daniela (referee) ; Kamanová, Jana (advisor)
Cell migration plays a key role in a wide diversity of biological processes. Migration enables phagocytic cells to localize into the site of inflammation and to lymph nodes, thereby leading to initiation of innate and adaptive immune responses, respectively. The signal transduction that coordinates phagocyte migration consist of diverse signaling proteins, being often under control of 3'-5'-cyclic adenosine monophosphate (cAMP) and its two effectors, protein kinase A (PKA) and Epac (exchange protein activated by cAMP). Small GTPase Rap is activated by Epac and controls phagocyte migration via activation of RAPL and RIAM proteins. On the other hand, PKA regulates cell migration via modulation of activity of other proteins, which comprise actin, integrins, small GTPases Rho, Rac, Cdc42 as well as protein VASP. A prominent feature of cAMP signalization is its spatio-temporal organization. Therefore, besides description of cAMP-regulated signaling cascades in cell migration, this bachelor thesis also depicts how changes of activity of cAMP effectors in time and place are involved in regulation of cell movement.
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