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Study of exosomes as drug delivery system in therapy of glioblastoma
Tomášková, Lucia ; Šimůnek, Tomáš (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lucia Tomášková Supervisor: prof. PharmDr. Tomáš Šimůnek, Ph.D. Title of diploma thesis: Study of exosomes as a drug delivery system in the treatment of glioblastoma Central nervous system disorders are among the most serious diseases affecting humans. They affect not only the patient's life, but also his/her surroundings. Therefore, their therapy, whether at the level of complete cure or alleviation of accompanying symptoms, is a challenge for scientific research. In our research, we focused on glioblastoma multiforme, a brain cancer not yet treatable. The main drawback in therapy is overcoming the blood-brain barrier. Exosomes, such as the body's natural nano-vesicles, have been shown to be a suitable system for delivering drugs to brain tissue. Our research has shown that by a suitable method we are able to obtain sufficient quality exosomes from macrophage and fill them very efficiently with antitumor agents paclitaxel, doxorubicin and temozolomide, while the delivered substances show higher efficacy and fewer side effects than the free form.
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In vitro assessment of cytotoxic action of novel potential nitro group-containing potential antitubercular agents
Turoňová, Dorota ; Macháček, Miloslav (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Depatrment of Biochemical Sciences Candidate: Bc. Dorota Turoňová Supervisor: RNDr. Miloslav Macháček, Ph.D. Consultant: doc. PharmDr. Jaroslav Roh, Ph.D. Title of diploma thesis: In vitro assessment of cytotoxic action of novel potencial nitro group-containing antitubercular agents More than 10 million new cases of tuberculosis occur every year. Lack of efficient antituberculotic drugs and their unavailability, poor diagnostic and especially inappropriate treatment are drawbacks complicating and even precluding eradication of tuberculosis. An already serious disorder has become even more serious in the last years, especially because of the occurrence of drug-resistant tuberculosis, especially MDR-TB and XDR-TB. Due to chromosomal mutations that make bacteria resistant to drugs it is still necessary to develop new effective drugs to replace those in current use, which are often toxic and associated with the occurrence of side effects. The research group at the Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, which has been researching new antitubercular agents for many years, has created new structures of aromatic nitrocompounds with very high antimycobacterial effect. The aim of this...
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In vitro study of novel catalytic inhibitors of topoisomerase II.
Trnka, Tomáš ; Šimůnek, Tomáš (advisor) ; Macháček, Miloslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Tomáš Trnka Supervisor: Prof. PharmDr. Tomáš Šimůnek, PhD. Title of diploma thesis: In vitro study of new catalytic topoisomerase II inhibitors A wide range of drugs of different groups can be used for the pharmacotherapy of cancer. One of them are anthracycline antibiotics, which have been used in chemotherapy since the second half of the 20th century. Despite of their usage, there is still widespread concern about myocardial damage due to their cardiotoxic effect. The only cardioprotective agent, which is used is dexrazoxane (DEX). The mechanism of its effect has been traditionally supposed to consist on iron ion chelation, but recently, attention has shifted to its effects on topoisomerase II (TOP2), which could be the key element in the development of anthracycline cardiotoxicity. Apart from the positive effects on treatment, DEX has been also connected with its negative impact, due to the possible occurrence of acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome. The aim of our work was to assess the effects of other TOP2 catalytic inhibitors - novobiocin (NB), merbarone (MER), BNS-22, suramin (SUR) and also XK-469, for which was synthesized a series of analog substances...
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Novel phthalocyanine photosensitizers for photodynamic therapy of tumorous diseases
Zvolánková, Kateřina ; Macháček, Miloslav (advisor) ; Jirkovská, Anna (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Kateřina Zvolánková Supervisor: Mgr. Miloslav Macháček Title of diploma thesis: Novel phthalocyanine photosensitizers for photodynamic therapy of tumorous diseases Oncological diseases are considered to be a serious global problem for many years. One of the most significant factors of their expansion in human population is an increasing life expectancy. Higher incidence of physical and chemical carcinogens and better diagnostic methods of malignant neoplasms are farther possible factors. According to World Health Organisation (WHO) almost 8 million people in the world die from oncological disease every year, whereas 1.7 million of them are Europeans. Malign tumours in Czech Republic, as well as in the world, are the second most frequent causes of death right after cardiovascular diseases, in both genders. Despite increasing incidence of malign tumours in the world, the mortality rate is decreasing. This decline is connected especially with higher quality of medical care together with availability of new diagnostic and therapeutic means. Thus the therapy of cancer is an important subject of biomedical research. Scientists have been trying to discover an effective and highly selective...
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Development of 3D spheroid cell culture derived from tumor cell lines suitable for photodynamic therapy research
Brieslingerová, Lenka ; Macháček, Miloslav (advisor) ; Boušová, Iva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Lenka Brieslingerová Supervisor: RNDr. Miloslav Macháček, Ph.D. Title od diploma thesis: Development of 3D spheroid cell culture derived from tumor cell lines suitable for photodynamic therapy research Growing number of tumorous diseases worldwide is urging great effort to make anticancer treatment more effective. Conventional testing of newly developed drugs is performed on tumor cell cultures growing in a monolayer. However, the use of 3D spheroid models provides a more appropriate method of testing, as these models are able to better mimic the in vivo properties of tumors and thus provide a more realistic response to administered drugs. In addition to testing new cytostatics, 3D spheroid models can also be used as tumor models to study the effect of photodynamic therapy (PDT), although this model is still not widely utilized in the field of PDT research. PDT is an alternative and minimally invasive treatment method used not only to treat tumors. It utilises a photosensitizer (PS), molecular oxygen (3O2) and light to form reactive oxygen species (ROS), consequently damaging tumor tissue. This diploma thesis deals with the production of 3D spheroid cell cultures from the HeLa cell line, which...
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Effect of evobrutinib on cancer cell resistance to daunorubicin caused by carbonyl reducing enzymes
Zenkerová, Katharina ; Wsól, Vladimír (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Katharina Zenkerová Supervisor: Prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: Effect of evobrutinib on cancer cell resistance to daunorubicin caused by carbonyl reducing enzymes Anthracyclines (ANT) have been among the first line treatments for many types of cancer, including acute myeloid leukemia, for decades. These chemotherapeutic agents target topoisomerase II, interfere with DNA and RNA synthesis by intercalation, and induce apoptosis by forming reactive oxygen species. As with many other chemotherapeutics, administration of ANT is associated with a range of adverse effects, particularly cardiotoxicity and resistance. The culprit responsible for this cardiotoxicity is the hydroxy metabolite of ANT, formed by reduction of the carbonyl group at position 13. This metabolite is also considerably less cytotoxic; cancer cells excessively metabolize ANT, thus developing resistance to their effects. Enzymes involved in the ANT reductions are NADPH dependant carbonyl reducing enzymes, primarily from aldo-keto reductase and short-chain dehydrogenase/reductase superfamilies. These enzymes are frequently over-expressed in cancer cells and they might be an attractive target of novel...
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Photodynamic inactivation of microorganisms using (aza)phthalocyanine photosensitisers
Holmanová, Pavlína ; Macháček, Miloslav (advisor) ; Kollár, Jan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Author: Bc. Pavlína Holmanová Supervisor: RNDr. Miloslav Macháček, Ph.D. Consultant: RNDr. Klára Konečná, Ph.D. Title of diploma thesis: Photodynamic inactivation of microorganisms using (aza)phthalocyanine photosensitisers Background: This work is aimed to optimize methodological approaches for the evaluation of the antimicrobial activity of selected representative (aza)phthalocyanine photosensitizers (PSs) in vitro. In addition, the in vitro antimicrobial activity of candidate PSs was evaluated against three clinically important pathogens. Namely, gram positive methicillin resistant bacterium Staphylococcus aureus (MRSA), gram negative bacterium Pseudomonas aeruginosa (PA), and yeast Candida albicans (CA) were included in the study. Methods: Microorganisms were incubated with the selected PSs, which were subsequently washed away, and microorganisms with bound PSs were irradiated for 15 or 30 min. At the same time, the intrinsic antimicrobial activities of the studied compounds without irradiation were determined as well. Three different methodological approaches were used to evaluate the minimum bactericidal concentration (MBC)/minimum fungicidal concentration (MFC). The Bioscreen C instrument was used for...
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The effect of olaparib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes.
Lekešová, Alžběta ; Wsól, Vladimír (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Alžběta Lekešová Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Title of diploma thesis: The effect of olaparib on tumor cell resistance to daunorubicin due to carbonyl reducing enzymes Daunorubicin (DAUN) belongs to the group of anthracycline antibiotics, belonging to the group of cytostatics used in a wide range of different carcinomas. However, even with this group of drugs, the resistance to chemotherapy, followed by treatment failure is becoming more and more common. This problem of resistance is often dealt with by combination therapy, which uses the addition of drugs that affect the cytostatic by different mechanisms. One possibility is to keep the cytostatic in tumor cells in their active form for as long as possible. This may be affected by the blockade of efflux transporters or inhibition of enzymes responsible for the inactivation of cytostatics. The possible inhibition of enzymes by the low molecular weight drug olaparib (OLA) was studied in this diploma thesis. OLA is a drug with a cytostatic effect on its own and has been used in certain cancer therapies for several years. We tested its inhibitory potential to selected carbonyl reducing enzymes, which are involved in the metabolism of...
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In vitro effects of 3-hydroxytyrosol on renal hypoxia and inflammation
Kamasová, Terézia ; Boušová, Iva (advisor) ; Macháček, Miloslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Terézia Kamasová Supervisor: Asst. Prof. PharmDr. Iva Boušová, Ph.D. Prof. Alice Santos-Silva Maria João Valente, Ph.D. Title of diploma thesis: In vitro effects of 3-hydroxytyrosol on renal hypoxia and inflammation Chronic kidney disease (CKD) results from a group of heterogeneous disorders affecting the kidneys. The renal hypoxia and hypoxia-derived oxidative stress, renal fibrosis, and inflammation are highly prevailing conditions appearing in the diseased kidney, contributing to the progression of CKD. Phytochemicals are an essential part of contemporary therapeutic strategies for the treatment of various diseases. 3-Hydroxytyrosol (HT), a phenolic compound extracted from olives and olive-derived products (e.g. olive oil), is believed to carry a potent antioxidant, anti-inflammatory, antithrombotic, bactericidal and bacteriostatic activity. The aim of this work was to determine the preventive effect of HT in hypoxic renal cells and evaluate the effect of HT on hypoxia-related inflammation, fibrosis, and oxidative stress, in order to summarize the value of this phenolic compound as a promising novel remedy in the treatment of CKD. A cell line of human renal proximal tubular cells (HK-2) was...
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Activity of novel acridine dyes - in vitro study
Pavlová, Dominika ; Macháček, Miloslav (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Dominika Pavlová Supervisor: RNDr. Miloslav Macháček, PhD. Title of diploma thesis: Activity of novel acridine dyes - in vitro study Acridine derivatives are being investigated for their potential in the treatment of many diseases, such as cancer, bacterial infections, and malaria. For example, amsakrin, acting as a topoisomerase poison that interacts with both DNA and human topoisomerase II, is used in clinical practice in conventional antitumor chemotherapy. Derivatives of 9-aminoacridine-4- carboxidoamide act similarly. The master's thesis investigates the in vitro activity of the newly synthesized 9-aminoacridine-4-carboxidoamide derivatives and other derivatives of acridine. The purpose of the thesis was to determine whether the studied compounds FK-8-HCl, FK-20-HCl, FK-27-HCl, FK-36-HCl, FK-42-HCl, FK-46-HCl, FK-48, FK-78-HCl, FK-97- HCl and FK-106 are cytotoxic, what concentration induce inhibition of proliferation, what type of cell death is triggered and whether they inhibit the human topoisomerase II. The human epithelial cell line HeLa was used for cytotoxicity experiments. The neutral red uptake assay was used to determine the cell viability. Cells were exposed to different...
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