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Biomedical applications of cationic gold nanoparticles
Žárská, Monika ; Hodný, Zdeněk (advisor) ; Králová, Jarmila (referee) ; Bačáková, Lucie (referee)
Cationic gold nanoparticles (GNPs) represent innovative materials promising for treating severe diseases, including cancer. Due to the unique physical properties of colloidal gold, GNPs have been shown to function as theranostics agents, allowing the diagnosis and treatment of the pathological area simulataneously. In addition, a cationic surface charge of GNPs provides extensive nanoparticle-cell interactions. However, despite the great potential in clinical medicine, various types of GNPs have contradictory results, and the studies dealing with the biological and therapeutic properties of cationic GNPs are inconsistent. This doctoral thesis summarizes the current state of knowledge about the biological properties and medical applications of GNPs focusing specifically on positively charged GNPs. A overview of plasmonic photothermal therapy (PPTT) as a cancer treatment strategy is included. Using a step-by-step research approach, our results then characterize the therapeutic potential of GNPs with a specific shape of nanorods (GNRs) and surface modification with quaternary ammonium salt (QAS). At first, the elementary factors participating in the interaction of cationic GNRs with cells, their transmembrane and intracellular transport, and long-term persistence in cells were described. Subsequently,...
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The Role of Cytokines in Support of Malignant Properties of Glioblastomas
Fortelková, Nikol ; Hodný, Zdeněk (advisor) ; Nováková, Zora (referee)
The tumor microenvironment of Glioblastomas (GB) is very complex and transforms throughout radiotherapy and chemotherapy, posing a favourable environment for the malignant properties of GB including invasivity, which promotes aggressive recurrency of the tumor. These changes in the tumor microenvironment are partly induced by cellular senescence and cellular response to stress, accompanied by a specific secretome, so called senescence-associated secretory phenotype (SASP). The SASP is distinct in its secretion of growth factors, components of the extracellular matrix and remodelling enzymes, but above all proinflammatory cytokines, which may contribute to the malignant properties of GB. This thesis reviews the current state of knowledge of the potential role of selected cytokines of the SASP (IL-6, IL-1β, IL-8, IL-1α, TGF-β, CCL2, TNF-α) in support of the malignant properties of GB. Key words: glioblastoma (GB), senescence, SASP, malignant properties, cytokines
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Cell response to genotoxic stress-based anti-cancer therapies
Imrichová, Terezie ; Hodný, Zdeněk (advisor) ; Rossmeislová, Lenka (referee) ; Rotrekl, Vladimír (referee)
The dissertation deals with a cell response to genotoxic stress, specifically to anti-cancer treatments with a genotoxic mechanism of action. In principle, cells can respond to these perturbing stimuli in several ways: in case of severe DNA damage, they usually undergo apoptosis or enter senescence. In case of minor DNA damage, or upon defective checkpoint mechanisms, they may continue the cell cycle, either with successfully repaired DNA or with mutations of various kind. Thanks to selection pressure, the mutations that provide cells with a certain growth advantage under conditions of continuing genotoxic stress, gradually accumulate and render the tumor treatment-resistant. In my thesis, I focus on several aspects of this whole process. First, I participated in a characterization of a radioresistant and anoikis-resistant population of prostate cancer cells. This population was generated by irradiating cells 35 times by 2 Gy, a regime used in clinics. After this treatment, a population of low-adherent cells emerged that demonstrated increased expression of EMT- and stem cell markers. The low-adherent state of these cells was maintained by Snail signaling and their anoikis resistance by ERK1/2 signaling. Interestingly, after a protracted period of time, these cells were able to re-adhere and...
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Posttranlational protein modifications in response to DNA damage
Kroupa, Michal ; Hodný, Zdeněk (advisor) ; Novotný, Marian (referee)
- 5 - Abstract Thousands of DNA lessions occur in each cell every day of which the most toxic are double-strand breaks (DSBs). Signaling of their presence and subsequent repair are mediated by so-called DNA-damage response mechanism (DDR), which involves accumulation of many effector proteins into DSBs sites. These molecular accumulation at DSBs are termed DNA damage foci. Depending on presence of sister chromatid, DSBs are repaired by two major mechanisms: by homologous recombination and by non-homologous end joining. Both pathways lead to activation of checkpoint kinases (Chk1 or Chk2) which iniciate checkpoints in cell cycle and allow repair of damaged DNA. Signaling of DNA damage and activation of these pathways are regulated by posttranslational protein modifications. These enzymatic reactions involve mainly phosphorylation, ubiquitination and sumoylation. Recently it was shown that ubiquitination of damaged chromatin is a prerequisite for sumoylation of tumor supressors BRCA1 and 53BP1. Failure in DNA damage recognizing mechanisms caused by disorders such as modifications or mutations of 53BP1 and BRCA1 genes can lead to subsequent disruption of genomic integrity and then a high risk for selection of cell clones with tumorigenic potencial. Current research is focused on regulation of posttranslational...
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Cellular senescence escape mechanisms - anti-cancer barrier
Davidová, Eliška ; Hodný, Zdeněk (advisor) ; Horníková, Daniela (referee)
Cancer is one of the most dangerous diseases of the modern world. Therefore, many world laboratories engaged in research into the causes leading to the outbreak of this insidious disease. In this context, it has already been found that the normal animal cells do not divide indefinitely, but have a finite replicative life span. After this period, cells undergo either apoptotic processes or enter into so-called senescence, typical for proliferation arrest, but preserved metabolic processes. Further research has revealed that senescence serves as an effective anticancer program and currently is shed light on its significance in relation to various physiological or pathological processes associated with aging. In this work, the focus is on the role of senescence as a barrier for cancer development, and effectiveness. It can be assumed, that if the senescent cycle arrest functioned perfectly, the incidence of cancer among people would be recorded in much lower extent. The aim of this thesis is the current knowledge about the physiological and pathological roles of senescence and possible causes of overcoming this barrier, the result may be the uncontrolled cell division and tumorigenicity.
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The role of JAK-STAT signalling pathway in cellular senescence
Černohorská, Markéta ; Hodný, Zdeněk (advisor) ; Schierová, Michaela (referee)
Proliferating human cells cultivated in vitro after certain number of population doublings withdraw from the cell cycle and enter a specific state termed replicative cellular senescence. Lately, several other forms of senescence independent of the proliferative history and telomere shortening were described. This is called premature senescence, and can be elicited by exposure of cells to aberrant mitogenic or oncogenic signals, to oxidative stress or to variety of chemically and functionally unrelated DNA damaging agents. Senescent cells alter their morphology and expression pattern. This complex phenotype is characterized by enlarged cytoplasm, activation of cell cycle inhibitors, expression of tumor supressors and profound changes in cell secretory phenotype. These cytokines/chemokines induce many different cascades, for example Jak/STAT signaling pathway, that are activated in response to viral infection or inflammation. Senescent cells were found also in vivo in the tumor tissue that produces altered cytokines itself. This diploma thesis inquires into the role of interferon-Jak/STAT signaling pathway in premature cellular senescence induced by genotoxic agents that are often used in chemotherapy. Obtained results might help to understand the complexity of tumorogenesis and senescence. Powered by TCPDF...
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Gold nanoparticles as a tool of targeted therapy of cancer
Knoblochová, Lucie ; Hodný, Zdeněk (advisor) ; Brábek, Jan (referee)
Nanomaterials have caught the interest of biomedical science because of their size (which enables them to interact with cellular structures), high surface area, and unique physical properties. Gold nanoparticles (GNPs) can be synthesised in various shapes. Their common property is surface plasmon resonance, which makes it possible to detect these particles with high resolution using dark field microscopy. GNPs can be efficiently modified with various ligands such as drugs, antibodies, or aptamers; this can be utilized to selectively bind GNPs to tissues, e.g. for drug delivery. Conjugated GNPs can also be used in diagnostics of tumor cells as well. Photothermal therapy consists of GNPs selectively binding to the tumor tissue, where they transform light into heat upon irradiation by near-infrared (NIR) light, thereby damaging nearby cells. The toxicity of GNPs is currently unclear. Research into modified gold nanoparticles is of great interest for targeted tumor therapy, as it may yield a tool for the selective destruction of tumor cells.
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Role of STAT3 signalling in oncogenesis and cancer therapy
Machalová, Veronika ; Hodný, Zdeněk (advisor) ; Brábek, Jan (referee)
STAT3 (Signal Transducer and Activator of Transcription 3) is considered to be one of the possible targets of cancer treatment. The ability of STAT3 constitutive activation to form tumors is a foundation of such theories. Additionally, constitutively activated STAT3 is present in many types of cancer with high occurrence, such as breast and prostate carcinoma. This protein is required in normal body cells as well. STAT3 is a transcription factor targeting many genes that are essential for the cell. STAT3 is activated by phosphorylation of its tyrosine residue and homodimerization. Proteins transcribed with help of STAT3 function in cell cycle progression, cell growth, replication, negative regulation of apoptosis, and other roles, typical for cancer. Moreover, STAT3 is modulating mitochondrial function and maintaining ROS production in mitochondria, but in form of transcriptionally inactive monomers. The purpose of this Thesis is to review known data about STAT3 in oncogenesis and by that, to show STAT3 has great potential to become the target of cancer treatment. This Thesis contains a short overview of known STAT3 inhibitors as well. Key words: Signal Transducer and Activator of Transcription 3 (STAT3), JAK/STAT3 pathway, constitutive activation, cancer, tumor, inhibitor, mitochondria, apoptosis
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L1CAM and its role in cellular senescence
Mrázková, Blanka ; Hodný, Zdeněk (advisor) ; Hubálek Kalbáčová, Marie (referee) ; Rohlena, Jakub (referee)
Cellular senescence, originally defined as irreversible cell cycle arrest, was shown to act in organism as a double-edged sword. On the one hand, cellular senescence is considered an anti-cancer barrier and it beneficially contributes to processes such as wound healing and tissue regeneration. On the other hand, its longer persistence in the organism, usually when not eliminated by the immune system in elder age, cellular senescence contributes to age-related diseases and ageing itself. Moreover, senescent cells emerge as a result of radio- and chemo- therapy and can lead to detrimental effects when not eliminated. There is also accumulated evidence that senescent cells can overcome the proliferation barrier and become malignant (often after a cancer therapy) rendering senescence original definition invalid. In effort to improve the quality of health and life and to minimize the cancer risk after therapies, senescent cells have become one of the most interesting subjects for a targeted therapy. There is a promising potential in developing effective tools, namely drugs specifically killing senescent cells or reducing their detrimental effect (senolytics) that focus on senescent cells elimination in order to rejuvenate the organism, to extend a life span, and to prevent ageing-associated diseases and...
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