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Modulace exprese alfa-synukleinu pomocí působení 5-S-cysteinyldopaminu na buňky lidského neuroblastonu SH-SY5Y: možná úloha katecholthioetherů při neurodegeneraci
Hrabáková, Rita ; Štaud, František (advisor) ; Mladěnka, Přemysl (referee)
-Synuclein is a presynaptic protein which has been demonstrated to be involved in PD etiopathogenesis.It can regulate DA homeostasis by inhibition of TH activity, by regulation of the DAT activity and finally by potential role in vesicular storage. - Synuclein is a natively unfolded protein, which can undergo overexpression and aggregation due to toxic insults or oxidative stress. The aggregation of α-synuclein leads to a loss of function, which in PD neurons may determine a dysregulation of the DA pathways with subsequent excess of cytosolic DA, that can enhance the neurotoxic effect of α-synuclein aggregates. In recent years, a catecholthioether metabolite of DA, 5-S-cysteinyl-dopamine, has been identified in certain dopaminergic regions of the brain, notably the Substantia nigra. Cys-DA seems to have a possible significance as an index of oxidative stress in aging and in neurodegenerative processes and it was recently hypothesized that this substance or its metabolites may be the endogenous neurotoxins responsible for neurodegeneration in PD. Hence, the aim of this experimental work was to determine whether Cys-DA is able to cause overexpression of -synuclein both at transcriptional and translational levels in a cellular model of PD, the human neuroblastoma dopaminergic cell line SH-SY5Y....
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Proteome analysis of anti-cancer drug effects and characterisation of drug resistance
Hrabáková, Rita
Despite significant progress in the development of anti-cancer drugs, there is still a need for novel therapeutic strategies that would improve the outcome of cancer patients. Using proteomic technologies and cell lines with different phenotype of p53 tumour suppressor, we monitored cancer cell response to anti-cancer treatment with focus on the development of drug resistance. The different levels of metabolic proteins were identified in our study which may help to explain different anti-cancer activity of drugs with only a subtle difference in structure. More importantly, proteins associated with the development of drug resistance were identified and such expression changes have become a focus of interest. Our findings demonstrate a higher protein level of serine hydroxymethyltransferase, serpin B5 and calretinin in cancer cells resistant to Aurora kinase inhibitors. Such proteins promote the tumour growth with no apparent impact of p53 phenotype whilst voltage-dependent anion-selective channel protein 2 contributes to the development of resistance only in cells with functional p53 which is accompanied by the decreased level of elongation factor 2. On the other hand, cancer cells with loss of p53 appear to amplify alternative mechanisms such as protection against oxidative stress. The results...
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Proteome analysis of anti-cancer drug effects and characterisation of drug resistance
Hrabáková, Rita ; Kovářová, Hana (advisor) ; Hernychová, Lenka (referee) ; Šulc, Miroslav (referee)
Despite significant progress in the development of anti-cancer drugs, there is still a need for novel therapeutic strategies that would improve the outcome of cancer patients. Using proteomic technologies and cell lines with different phenotype of p53 tumour suppressor, we monitored cancer cell response to anti-cancer treatment with focus on the development of drug resistance. The different levels of metabolic proteins were identified in our study which may help to explain different anti-cancer activity of drugs with only a subtle difference in structure. More importantly, proteins associated with the development of drug resistance were identified and such expression changes have become a focus of interest. Our findings demonstrate a higher protein level of serine hydroxymethyltransferase, serpin B5 and calretinin in cancer cells resistant to Aurora kinase inhibitors. Such proteins promote the tumour growth with no apparent impact of p53 phenotype whilst voltage-dependent anion-selective channel protein 2 contributes to the development of resistance only in cells with functional p53 which is accompanied by the decreased level of elongation factor 2. On the other hand, cancer cells with loss of p53 appear to amplify alternative mechanisms such as protection against oxidative stress. The results...
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Proteome analysis of anti-cancer drug effects and characterisation of drug resistance
Hrabáková, Rita
Despite significant progress in the development of anti-cancer drugs, there is still a need for novel therapeutic strategies that would improve the outcome of cancer patients. Using proteomic technologies and cell lines with different phenotype of p53 tumour suppressor, we monitored cancer cell response to anti-cancer treatment with focus on the development of drug resistance. The different levels of metabolic proteins were identified in our study which may help to explain different anti-cancer activity of drugs with only a subtle difference in structure. More importantly, proteins associated with the development of drug resistance were identified and such expression changes have become a focus of interest. Our findings demonstrate a higher protein level of serine hydroxymethyltransferase, serpin B5 and calretinin in cancer cells resistant to Aurora kinase inhibitors. Such proteins promote the tumour growth with no apparent impact of p53 phenotype whilst voltage-dependent anion-selective channel protein 2 contributes to the development of resistance only in cells with functional p53 which is accompanied by the decreased level of elongation factor 2. On the other hand, cancer cells with loss of p53 appear to amplify alternative mechanisms such as protection against oxidative stress. The results...
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Modulace exprese alfa-synukleinu pomocí působení 5-S-cysteinyldopaminu na buňky lidského neuroblastonu SH-SY5Y: možná úloha katecholthioetherů při neurodegeneraci
Hrabáková, Rita ; Štaud, František (advisor) ; Mladěnka, Přemysl (referee)
-Synuclein is a presynaptic protein which has been demonstrated to be involved in PD etiopathogenesis.It can regulate DA homeostasis by inhibition of TH activity, by regulation of the DAT activity and finally by potential role in vesicular storage. - Synuclein is a natively unfolded protein, which can undergo overexpression and aggregation due to toxic insults or oxidative stress. The aggregation of α-synuclein leads to a loss of function, which in PD neurons may determine a dysregulation of the DA pathways with subsequent excess of cytosolic DA, that can enhance the neurotoxic effect of α-synuclein aggregates. In recent years, a catecholthioether metabolite of DA, 5-S-cysteinyl-dopamine, has been identified in certain dopaminergic regions of the brain, notably the Substantia nigra. Cys-DA seems to have a possible significance as an index of oxidative stress in aging and in neurodegenerative processes and it was recently hypothesized that this substance or its metabolites may be the endogenous neurotoxins responsible for neurodegeneration in PD. Hence, the aim of this experimental work was to determine whether Cys-DA is able to cause overexpression of -synuclein both at transcriptional and translational levels in a cellular model of PD, the human neuroblastoma dopaminergic cell line SH-SY5Y....
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