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Investigation of compouds affecting the neoplastic cell changes
Andrš, Martin ; Jun, Daniel (advisor) ; Šinkorová, Zuzana (referee) ; Vávrová, Jiřina (referee)
Radiation and genotoxic drugs after more than 70 years since their discovery still belong to the cornerstones of cancer treatment. However, these types of therapy often suffer from severe adverse effects and resistance caused by DNA repair mechanisms. The basic feature of cancer cells is genome instability, leading to various mutations and upregulated or otherwise defective DNA repair, making the cancer cells vulnerable to additional interference with the DNA damage response (DDR) mechanisms. This is the fundamental idea behind the DDR targeted therapy, which has been thoroughly studied for almost two decades. The main goals of this therapy is an improvement of the efficacy of DNA damaging treatments leading to lesser doses and adverse effects but also enabling selective targeting of defective cancer cells. The development of this area of research was very slow at the onset, but last few years it finally brought the first compound into therapy and several others into clinical trials. Among the plethora of signal and effector proteins involved in DDR, three related kinases ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related) and DNA-PK (DNA- dependent protein kinase) play the principal roles in initiation and regulation of signaling pathways in response to DNA double and single strand...
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Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol 3-kinases and related protein kinases I.
Poledníková, Michaela ; Opletalová, Veronika (advisor) ; Jun, Daniel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Michaela Poledníková Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Consultant: Mgr. Martin Andrš Title of diploma thesis: Synthesis and biological evaluation of purine inhibitors of phosphatidylinositol 3-kinases and related protein kinases I. Cancer is a group of diseases characterized by the uncontrolled, abnormal growth of cells. Anticancer chemotherapy is one of the basic methods for treatment, but its mechanism of action is not specific and targets rapidly dividing cells, including cancer cells as well as certain normal tissues. In recent years one of the most studied ways to improve cancer treatment is inhibition of DNA repair mechanisms. This process can lead to potentially higher efficacy of cytotoxic therapy and thus lower doses of cytostatic agents with benefit of less adverse side effects for the patient. Suitable candidate for this purpose is family of phosphatidylinositol 3-kinase- related protein kinases (PIKK). In this diploma thesis, sixteen purine analogs of nonselective inhibitor PIKK LY294002 were prepared. We also analyzed chemo-sensitizing properties of these newly synthesized inhibitors in combination with a chemotherapeutic agent doxorubicin in...
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STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS
Jansová, Hana ; Šimůnek, Tomáš (advisor) ; Hrdina, Radomír (referee) ; Jun, Daniel (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF BIOCHEMICAL SCIENCES Candidate: Mgr. Hana Jansová Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of Doctoral Thesis: STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS Development of cardiovascular disorders is associated with various risk factors and oxidative stress plays an important role in many of them. Iron-catalysed production of highly toxic and reactive hydroxyl radicals may contribute to oxidative stress. Chelation of free iron seems to be a promising strategy to prevent the propagation of oxidative stress. However, the use of classic iron chelators in pathological conditions without iron overload is associated with the risk of toxicity due to the iron depletion. Hence, this study deals with cardioprotective properties of iron chelators as well as prochelators derived from them. We focused on prochelators with almost no affinity for iron ions until they are activated under disease-specific oxidative stress conditions. For a long time, it has been assumed that oxidative stress is also the main denominator in an anthracycline-induced cardiotoxicity. However, the previous studies suggested alternative mechanism(s). Therefore in the...
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Muskarinové receptory v regulaci mechanizmů vaskulární perfúze u potkanů
Soukup, Ondřej ; Tilšer, Ivan (advisor) ; Jun, Daniel (referee)
Muscarinic receptors in the regulation of vascular perfusion mechanisms in the rat and sheep salivary glands Author: Ondřej Soukup Supervisor: Gunnar Tobin, Sahgrenska Academy,Goteborg University, Sweden Formal supervisor: Ivan Tilšer, Faculty of Pharmacy, Charles University, Czech Republic This study constists of the functional experiments, the assesment of VIP in plasma and the immunohistochemistry. Functional experiments include investigation of muscarinic receptors subtypes, their occurence and function in the rat carotid artery and jugular vein using tissue bath and muscarinic receptors agonist (carbachol) and antagonists ( pirenzepine, methoctramine, 4-DAMP). Assesment of VIP was done in the sheep plasma samples collected during 8 Hz stimulation of chorda lingual using ELISA. Immunohistochemistry of rat carotid artery and jugular vein was done using specific muscarinic antibodies and evaluated udner the fluorescence microscope. Statistical significance was determined by Student's t-test for paired data. ANOVA test in cases of multiple comparisons and post-hoc test according to Bonferoni were applied. P-values of 0.05 or less were regarded as statistically significant. The results show that muscarinic receptors have direct and indirect effect on vessels affecting the blood flow over the...
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Determination of oxidative stress biomarkers by HPLC
Váňová, Nela ; Jun, Daniel (advisor) ; Doležal, Rafael (referee) ; Hroch, Miloš (referee)
and keywords Although reactive oxygen and nitrogen species have a fundamental role in physiological processes occurring in living organisms, their overproduction induced by endogenous and/or exogenous sources may lead to serious imbalance in redox homeostasis, damage to intracellular components and thus, dramatically alter their function or even trigger cell death. Oxidative stress is believed to be very important mechanism of toxicity of xenobiotics, including drugs, and may be responsible for the development of their unwanted side effects. Considering a very low number of studies evaluating oxidative stress after the treatment with oxime reactivators of acetylcholinesterase (AChE) in vivo and in vitro, the relationship between their toxicity and generation of specific biomarkers of oxidative damage is not still fully understood. In order to monitor antioxidant/prooxidant properties of drugs, high performance liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS) for simultaneous determination of two biomarkers of oxidative stress, malondialdehyde (MDA) and 3-nitrotyrosine (3-NT), in biological matrices was developed. Validation of this LC-MS/MS method demonstrated the acceptable appreciable selectivity, accuracy, intra- and interday precission, and recovery of sample...
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Detergents based on quarternized nitrogenous heterocycles.
Marek, Jan ; Hrabálek, Alexandr (advisor) ; Jun, Daniel (referee)
This thesis is divided into three subsections. In the first part, there is described synthesis of seven already known benzalkonium homologues (C8-C20), which were used as a standard compounds for synthesis and analyzes of amphiphilic substances. The second part deals with preparation for other series of quartenary detergents having heteroaromatic rings (pyridine, isoquinoline, quinoline, acridine) in their structures. According to the analysis of the newly prepared compounds, we have prepared all pyridinium, quinolinium, isoquinolinium homoloques only. Our future forts will by focus on acridinium salts, which we were not able to prepare. Moreover, further biological activity evaluation was managed and its results will be obtained within several month. In the third part, the measurement of inhibition activity compared with acetylcholinesterase and critical micellar concentration was realized.
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Study of potential pharmacological protection of cardiac cells against oxidative stress and antracycline anticancer drugs
Jansová, Hana ; Šimůnek, Tomáš (advisor) ; Hrdina, Radomír (referee) ; Jun, Daniel (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF BIOCHEMICAL SCIENCES Candidate: Mgr. Hana Jansová Supervisor: Doc. PharmDr. Tomáš Šimůnek, Ph.D. Title of Doctoral Thesis: STUDY OF POTENTIAL PHARMACOLOGICAL PROTECTION OF CARDIAC CELLS AGAINST OXIDATIVE STRESS AND ANTRACYCLINE ANTICANCER DRUGS Development of cardiovascular disorders is associated with various risk factors and oxidative stress plays an important role in many of them. Iron-catalysed production of highly toxic and reactive hydroxyl radicals may contribute to oxidative stress. Chelation of free iron seems to be a promising strategy to prevent the propagation of oxidative stress. However, the use of classic iron chelators in pathological conditions without iron overload is associated with the risk of toxicity due to the iron depletion. Hence, this study deals with cardioprotective properties of iron chelators as well as prochelators derived from them. We focused on prochelators with almost no affinity for iron ions until they are activated under disease-specific oxidative stress conditions. For a long time, it has been assumed that oxidative stress is also the main denominator in an anthracycline-induced cardiotoxicity. However, the previous studies suggested alternative mechanism(s). Therefore in the...
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