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Interactions of natural phenolic compounds with biogenic metals
Lomozová, Zuzana ; Mladěnka, Přemysl (advisor) ; Bittner Fialová, Silvia (referee) ; Patočka, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Zuzana Lomozová, MSc. Supervisor: Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: Interactions of natural phenolic compounds with biogenic metals Phenolic compounds are one of the most widely distributed groups of secondary plant metabolites. They are an integral part of the human diet and their consumption is associated with a number of positive effects. They include a wide range of substances, from simple molecules such as phenolic acids to large polymeric compounds such as tannins. Because of their structure, which includes, among others, free hydroxyl groups, they are able to interact with biogenic metals and form metal complexes with them. Under normal conditions, the homeostasis of these transition metals in the body is tightly regulated, but it can be disturbed in pathological conditions such as acute myocardial infarction, when the levels of free iron and copper increase as a result of a significant decrease in pH. Similar metal imbalance is observed as well as in inflammatory and neurodegenerative diseases, tumours, or diabetes mellitus. The aim of this dissertation was to find out how these substances react with biogenic metals using in vitro and ex...
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Interactions of natural phenolic compounds with biogenic metals
Lomozová, Zuzana ; Mladěnka, Přemysl (advisor) ; Bittner Fialová, Silvia (referee) ; Patočka, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Zuzana Lomozová, MSc. Supervisor: Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: Interactions of natural phenolic compounds with biogenic metals Phenolic compounds are one of the most widely distributed groups of secondary plant metabolites. They are an integral part of the human diet and their consumption is associated with a number of positive effects. They include a wide range of substances, from simple molecules such as phenolic acids to large polymeric compounds such as tannins. Because of their structure, which includes, among others, free hydroxyl groups, they are able to interact with biogenic metals and form metal complexes with them. Under normal conditions, the homeostasis of these transition metals in the body is tightly regulated, but it can be disturbed in pathological conditions such as acute myocardial infarction, when the levels of free iron and copper increase as a result of a significant decrease in pH. Similar metal imbalance is observed as well as in inflammatory and neurodegenerative diseases, tumours, or diabetes mellitus. The aim of this dissertation was to find out how these substances react with biogenic metals using in vitro and ex...
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Molecular biology investigation of somatostatin receptors in diagnostics of pituitary tumors
Drastíková, Monika ; Beránek, Martin (advisor) ; Fryšák, Zdeněk (referee) ; Patočka, Jiří (referee)
Molecular biology investigation of somatostatin receptors in diagnostics of pituitary tumors The overwhelming majority of pituitary tumors are benign, with 25-30% of them representing clinically non-functioning pituitary adenomas (NFA). The treatment of choice for NFA is transsphenoidal neurosurgery. However, the procedure is often not completely successful and frequently tumor remnants remain, resulting in regrow over the long-term follow-up period. This fact has led to the development of new therapy strategies using pharmacological treatment: somatostatin analogs (SA) and estrogen receptor modulators. SA are effectively used in the treatment of acromegaly, neuroendocrine tumors and Cushing's disease. In contrast, pharmacological treatment of NFA has for the most part been unsuccessful. Low SA effectiveness could be associated with the variable expression of target receptors on the adenomas. The aim of the study was to determine the somatostatin (SSTR subtypes 1-5) and estrogen receptor 1 (ER1) expression profile. To obtain more complex receptor profile expression in the pituitary, we also investigated dopamin receptor 2 (D2R). Methods The group of patients was made up of 105 men and 101 women (20-87 years old; median 61). 144 samples were NFA, 44 growth hormone secreting (GHomas), 9 corticotrophin...
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Preparation and evaluation of potential drugs inhibiting mitochondrial enzymes
Benek, Ondřej ; Musílek, Kamil (advisor) ; Patočka, Jiří (referee) ; Opletalová, Veronika (referee)
Preparation and evaluation of potential drugs inhibiting mitochondrial enzymes Summary in English Alzheimer's disease (AD) is the most common cause of senile dementia worldwide. Despite being subject to intensive research, the pathogenic mechanisms of AD are still not fully understood and consequently an effective treatment is yet to be developed. Although the aetiology of AD is still unknown, a build-up of amyloid-beta peptide (Aβ) is considered to play an important role in disease progression. The original amyloid cascade hypothesis proposed that insoluble extracellular plaques were responsible for the majority of Aβ toxicity. This hypothesis has since been refined, as recent data indicates that soluble intracellular oligomers are now responsible for the majority of Aβ induced toxic effects. The mitochondrial dysfunction also plays an important role in the pathophysiology of AD. Aβ was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aβ. Such interactions can affect a protein's function and cause damage to the mitochondria, which finally results in progression of AD. The background for the experimental part of this dissertation thesis was literature review summarizing current knowledge on mitochondrial proteins directly interacting with Aβ in order to...
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Influence of Polyphenolic Substances with Iron Chelating Activity in Model of Acute Myocardial Infarction and Oxidation Stress Induced by Catecholamines
Zatloukalová, Libuše ; Hrdina, Radomír (advisor) ; Tilšer, Ivan (referee) ; Patočka, Jiří (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Libuše Zatloukalová Supervisor Prof. MUDr. Radomír Hrdina, CSc. Title of Doctoral Thesis Influence of polyphenolic substances with iron chelating activity in model of acute myocardial infarction and oxidation stress induced by catecholamines Background and aim: Ischaemic heart disease (IHD) and particularly its most serious form - acute myocardial infarction (AMI) - represents significant health problem in the developed countries with relatively high mortality. Within multifactorial pathogenesis of AMI, reactive oxygen and nitrogen species (RONS) generated by free iron catalytic effect and increased activity of the sympathetic nervous system accompanied with a release of the catecholamines play a significant role. Large doses of the synthetic katecholamine isoprenaline has been used as a suitable experimental model of AMI. AIM is considered as typical form of ischaemic-reperfusion (I-R) injury. RONS, which are excessively released during the first minutes of reperfusion, play a significant role in the pathogenesis of myocardial I-R injury. Free iron significantly increases the process of RONS generation. Use of iron chelators could have protective influence in I-R injury and...
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Nephrotoxicity testing in vitro
Handl, Jiří ; Roušar, Tomáš (advisor) ; Patočka, Jiří (referee) ; Andrýs, Rudolf (referee)
2020 UNIVERSITY OF PARDUBICE FACULTY OF CHEMICAL TECHNOLOGY Doctoral Thesis: NEPHROTOXICITY TESTING IN VITRO Author: Mgr. Jiří Handl, Ph.D. Supervisor: doc. RNDr. Tomáš Roušar, Ph.D. Abstract The doctoral thesis deals with in vitro testing of nephrotoxic effects of substances in immortalized human proximal tubular cells HK-2. The basic aim of the thesis was to introduce and optimize the cultivation of HK-2 cells under different culture conditions, to characterize the cultivation and growth stability of HK-2 cells and last but not least to characterize the nephrotoxic effect of cadmium in HK-2 cell line using bioanalytical and biochemical methods. The introduction summarizes the basic rules and conditions for long-term cultivation of cell lines. Furthermore, HK-2 cells and their importance in nephrotoxicity testing are characterized in detail. The thesis also mentions methods for monitoring toxic effects of substances with focus on measuring cell viability and oxidative stress. The outcomes of the thesis are characterizing nephrotoxic effects of CdCl2 in HK-2 cells. The results part describes obtained findings and the discussions follows. Keywords Nephrotoxicity; In vitro cultivation; HK-2 cell line; Cell viability; Cadmium.
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Screening of New Iron - and Copper - Chelating Substances - in vivo and in vitro Studies
Říha, Michal ; Mladěnka, Přemysl (advisor) ; Patočka, Jiří (referee) ; Tůmová, Lenka (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Michal Říha, MSc. First Supervisor: Assoc. Prof. Přemysl Mladěnka, Ph.D. Second Supervisor: Prof. Radomír Hrdina, M.D., Ph.D. Title of Doctoral Thesis: Screening of new iron- and copper-chelating substances - in vivo and in vitro studies Iron and copper are essential trace elements which play a role in a series of physiological processes in human organism. Homeostasis of these transition metals is meticulously regulated since free or loosely bound iron and copper can catalyse the production of free radicals. Hereditary hemochromatosis, transfusion hemosiderosis and Wilson's disease are associated with absolute iron and copper overload in the organism. Transition metal chelators have crucial significance for the treatment of these states. There are several other diseases with documented involvement of iron and/or copper in their pathophysiology. Examples are primarily neurodegenerative diseases, cardio- vascular diseases, tumours and diabetes mellitus. Various chelating compounds are examined in these possible indications. The aim of this doctoral thesis was to perform a screening of iron- and copper- chelating substances and to study their properties in detail using in vitro and...
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Interaction of Proteins with Low-molecular Substances in vitro. Effect of Glycation, Substances of Plant Origin, and Combination of these Factors on Function and Spectral Properties of Selected Proteins.
Trnková, Lucie ; Dršata, Jaroslav (advisor) ; Patočka, Jiří (referee) ; Mikšík, Ivan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate Ing. Lucie Trnková Supervisor Prof. MUDr. Jaroslav Dršata, CSc. Title of Doctoral Thesis Interaction of proteins with low-molecular substances in vitro. Effect of glycation, substances of plant origin, and combination of these factors on function and spectral properties of selected proteins. Plant polyphenolic compounds naturally occurring in human diet possess a wide range of biological and pharmacological properties. They can interact with various proteins including enzymes. Their interaction with serum albumin has a great significance because of its ability to bind, transport and store many endogenous and exogenous low-molecular compounds present in blood circulation. One of the objectives of this thesis was to study chemical structure-binding affinity relationships of two important groups of polyphenolic substances, namely hydroxycinnamic acids and catechins (flavanols), with the molecule of serum albumin in the in vitro models using spectroscopic (UV-Vis absorption spectroscopy, fluorescence quenching method) and electrophoretic (native and SDS PAGE) methods. Some polyphenols caused the changes in protein conformation and the relationships between their structures and obtained...
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Development of methods for testing drugs affecting the CNS
Hrabinová, Martina ; Jun, Daniel (advisor) ; Patočka, Jiří (referee)
1 Abstract and keywords The current thesis aims at the production of three enzymes, including beta-secretase 1 (BACE1; beta-site amyloid precursor protein cleaving enzyme 1), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). BACE1 is an integral membrane protein that plays a crucial role in the amyloid precursor protein's cleavage. The product is subsequently processed by y-secretase, producing amyloid-beta peptides and insoluble amyloid plaques in Alzheimer's patients (AD). According to the Annual Report of the Czech Alzheimer's Society, 158,000 patients were diagnosed in 2019. By 2050, this number is supposed to reach 300,000 patients. AChE inhibitors and N-methyl-D-aspartate receptor antagonists are currently the only alternatives for AD therapy. AChE is also a target enzyme in nerve agent (NA) poisoning (together with BChE). The Department of Toxicology and Military Pharmacy focuses on studying NA effects and medical protection against them. From this perspective, the production of AChE and BChE is essential for developing and evaluating newly synthesized cholinesterase (ChE) reactivators and inhibitors. The thesis focuses on introducing the expression system Expi293 to produce human recombinant enzymes BACE1, AChE, and BChE. For each enzyme, the individual steps required to obtain a...
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