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The role of cellular senescence in carcinogenesis and aging of the brain
Paroubková, Michaela ; Hodný, Zdeněk (advisor) ; Horníková, Daniela (referee)
The risk of developing many pathological conditions and ageing-releated diseases increases persistently throughout a lifetime. A dramatic increase in the number of people suffering from one of these diseases, such as atherosclerosis, Alzheimer's disease or Parkinson's disease, is caused by constant elevation of human life's length due to advancements in modern medicine and changes in life style. Several recent studies have demonstrated that senescent cells accumulate in aged and ill tissues. Senescent cells are metabolically active, but unable of proliferation and unlike the terminally differented cells, they secrete many factors that contribute to the transformation of the tissue microenviroment. The role of senescence as anticancer barier is known for a long time, but its importance in physiological processes and aging is mainly a matter of a recent time. While there is also a lot of studies focusing on cellular senescence in peripheral tissues, their involvement in or contribution to cognitive decline with aging of the central nervous system (CNS) remains relatively unknown. Recent data of many laboratories suggest that senescence-associated secretory phenotype of the non-neuronal senescent cells in brain can cause chronic level of inflammation and thus accompany aging and ageing-related...
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Cellular senescence and ageing-associated diseases
Antoš, Šimon ; Hodný, Zdeněk (advisor) ; Horníková, Daniela (referee)
In the last years more evidence supports the role of cellular senescence in ageing-associated diseases. Cellular senescence plays a role in these diseases on multiple levels and often directly supports their pathogenesis. The goal of this bachelor thesis is to summarize latest knowledge regarding the mechanism and the efect cellular senescence has in ageing-associated diseases, namely cancer, atherosclerosis, osteoarthritis, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, obesity and diabetes mellitus type two.
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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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Senolytics - current state
Sekáč, Dávid ; Hodný, Zdeněk (advisor) ; Zima, Michal (referee)
Cellular senescence is a state of the permanent cell cycle arrest caused by different stresses or cell to cell fusion. Senescent cells, unlike naturally aged cells, exhibit a specific phenotype, referred to as senescence associated phenotype (SASP). It is characterized by the production of biologically active substances such as interleukins, chemoattractants or proteases that affect their surroundings. Long-term survival of these cells in the body is the cause of age-related diseases. Under normal circumstances, number of senescent cells is maintained in the body by the immune system. However, the age-related abrogation of immune system function per se (immunosenescence) contributes to accumulation of senescent cells in tissues and aging of organism. This work describes origin, positive and negative effects of cell senescence, elimination of senescent cells by the immune system and current state of development of new substances causing specific lysis (killing) of senescent cells (senolytics).
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Signaling mechanism in nuclear reorientation and its functional singnificance in cell migration.
Maninová, Miloslava ; Vomastek, Tomáš (advisor) ; Hodný, Zdeněk (referee) ; Jaroš, Josef (referee)
The establishment of cellular polarity is first critical step of directional cell migration. The process of cellular polarization requires many signaling pathways that are differently regulated at the cell front and at the rear side and enables creation of typical asymmetrical profile of migrating cell. During the polarization cell forms the leading edge and trailing rear and relocalizes the intracellular organelles to such a position that is optimal for directional movement. In many migrating cells cell nucleus is usually located at the cell rear and microtubule organizing center localizes between the nucleus and the leading edge of the cell. This cellular arrangement is prerequisite for directional cell migration. We have shown that during cell polarization cell also reorients the nucleus to the direction of migration. The nuclear reorientation is temporally restricted rotation of the cell nucleus that aligns the longer nuclear axis with the axis of migration. Nuclear reorientation promotes the establishment of cellular polarity and facilitates the movement of the cell. The nuclear reorientation requires the physical linkage of the nucleus to cell cytoskeleton mediated by LINC (Linker of Nucleoskeleton and Cytoskeleton) complex. We have shown that LINC complex anchors the nucleus to actin stress...
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Radiation-induced plasticity of prostate cancer cells
Kyjacová, Lenka ; Hodný, Zdeněk (advisor) ; Bouchal, Jan (referee) ; Vomastek, Tomáš (referee)
Resistance of various cancers to conventional therapies including radio- and chemo- therapy is one of the most investigated phenomena in the molecular and clinical oncology. Recurrent disease is characterized by the presence of metastases, which are responsible for 90% of cancer-related mortality. Fractionated ionizing radiation (fIR) combined with surgery or hormone therapy represent the first-choice treatment for medium to high risk localized prostate carcinoma (PCa). In PCa, the failure of radiotherapy (RT) is often caused by radioresistance and further dissemination of escaping (surviving) cells. To investigate the radioresistance-associated phenotype, we exposed four metastasis- derived human PCa cell lines (DU145, PC-3, LNCaP, and 22RV1) to clinically relevant daily fractions of ionizing radiation (fIR; 35 doses of 2 Gy) resulting in generation of two surviving populations: adherent senescent-like cells expressing common senescence-associated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2, and Nanog. While the radioresistant adherent cells were capable to resume proliferation shortly after the end of irradiation, the non- adherent cells started to proliferate only after their reattachment...
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Role of transcription factor Snail in mechanism of development of radiorezistence in prostate carcinoma cell lines
Davidová, Eliška ; Hodný, Zdeněk (advisor) ; Benada, Jan (referee)
The frequent cause of failure of prostate carcinoma radiotherapy and chemotherapy is the emergence of resistance and a progress into the essentially incurable metastatic form of disease. Although the mechanisms of the radioresistance and chemoresistance are still not well understood, recent studies indicate that transcription factor Snail, a key mediator of the epithelial-mesenchymal transition and subsequent metastasis formation, plays a critical role in the development of the chemoresistance and radioresistance in the tumor cells. As the activation of the optimal DNA damage response pathway is the determining factor for the cell survival after chemotherapy and radiotherapy, we hypothesized the role of Snail in the transcription regulation of these processes. In this study, we first analyzed the relationship between Snail and ATM kinase, as the ATM was recently reported to regulate stability of Snail by its phosphorylation. Although, we observed a modest effect of ATM inhibition on Snail levels after cancer cells exposure to ionizing radiation, we did not fully reproduced the recently published findings. Furthermore, we evaluated the role of Snail in transcription regulation of cyclin-dependent kinase inhibitor p21waf1/cip1 . Our data point towards the suppressive role of Snail in p21waf1/cip1...
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Changes in oxidative phosphorylation during development of cellular senescence
Zima, Michal ; Hodný, Zdeněk (advisor) ; Kašparová, Dita (referee)
Cellular senescence represents a state of permanent cell cycle arrest. It is considered to be an active response of the cell to various extrinsic and intrinsic types of stress, which are damaged and/or uncapped telomeres, activation of certain oncogenes, DNA damage and effects of several cytokines. This thesis describes current mechanisms which may result in establishment of senescence phenotype, putting those facts in association with changes in oxidative phosphorylation. In thesis are also mentioned features of senescence cells and their impact on the neighborhood. Special attention is focused on the role of reactive oxygen species in promotion of cellular senescence, mechanisms of their elevation, the role of NADPH oxidases and the inhibition of mitochondrial oxidative phosphorylation complexes by activity of cytokine signaling pathways STAT3 and TGFbeta. Key words: cellular senescence, reactive oxygen species, cytokines, mitochondria, oxidative phosphorylation chain, NADPH oxidases, Signal Transducer and Activator of Transcription 3 (STAT3), TGF-β, DNA damage response (DDR)
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