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Apoptosis of pancreatic β-cells induced by endoplasmic reticulum stress and its mechanisms in type 2 diabetes
Glatzová, Daniela ; Němcová, Vlasta (advisor) ; Libusová, Lenka (referee)
Increasing incidence of type 2 diabetes represents one of the principal threats to human health in the 21st century. Strong evidence indicates that the rise in incidence of type 2 diabetes is correlated with increasing levels of obesity and that important factor playing role in the development of this disease is an elevation in circulating glucose and fatty acids. Chronically increased concentration of these nutrients was shown to induce apoptosis of pancreatic beta-cells that subsequently contributes to diabetes progression. Despite intensive research, molecular mechanisms underlying this beta-cells loss are still unclear. However, there is increasing evidence that one of the key processes involved in glucose and fatty acid-induced beta-cell death is induction of endoplasmic reticulum stress. The aim of this work is to summarize the recent knowledge about induction of apoptosis by endoplasmic reticulum stress in pancreatic beta-cells in relation to type 2 diabetes.
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Molecular mechanisms of apoptosis induced by photodynamic activation in cancer cells
Moserová, Irena ; Králová, Jarmila (advisor) ; Kuželová, Kateřina (referee) ; Kovář, Jan (referee)
Photodynamic therapy (PDT) is a treatment modality for cancer. It combines selective accumulation of chemical compounds, called photosensitizers (PS), with light to irreversibly damage cancer cells via oxidative stress. The main goal of this thesis was to study photosensitizers represented by a unique group of newly synthesized porphyrin derivatives with glycol chain substitution. Glycol-functionalized porphyrins containing one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin (mTPP(EG)1-4) were compared with fluorinated (pTPPF(EG)4) and nonfluorinated (TPP(EG)4) derivatives having glycol chains in para-phenyl positions. The cellular uptake and photodynamic activity was significantly dependent on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, exhibited efficient intracellular transport and high induction of apoptosis in tumor cell lines in vitro. After initial testing effective prototype hydroxy ethylene glycol derivatives were selected and analyzed in detail. Para derivatives pTPP(EG)4 and pTPPF(EG)4 accumulated mainly in lysosomes whereas meta derivatives mTPP(EG)1-4 in the endoplasmic reticulum (ER). Position of ethylene glycol chain on the...
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Molecular mechanisms of apoptosis induced by photodynamic activation in cancer cells
Moserová, Irena ; Králová, Jarmila (advisor) ; Kuželová, Kateřina (referee) ; Kovář, Jan (referee)
Photodynamic therapy (PDT) is a treatment modality for cancer. It combines selective accumulation of chemical compounds, called photosensitizers (PS), with light to irreversibly damage cancer cells via oxidative stress. The main goal of this thesis was to study photosensitizers represented by a unique group of newly synthesized porphyrin derivatives with glycol chain substitution. Glycol-functionalized porphyrins containing one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin (mTPP(EG)1-4) were compared with fluorinated (pTPPF(EG)4) and nonfluorinated (TPP(EG)4) derivatives having glycol chains in para-phenyl positions. The cellular uptake and photodynamic activity was significantly dependent on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, exhibited efficient intracellular transport and high induction of apoptosis in tumor cell lines in vitro. After initial testing effective prototype hydroxy ethylene glycol derivatives were selected and analyzed in detail. Para derivatives pTPP(EG)4 and pTPPF(EG)4 accumulated mainly in lysosomes whereas meta derivatives mTPP(EG)1-4 in the endoplasmic reticulum (ER). Position of ethylene glycol chain on the...
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Apoptosis of pancreatic β-cells induced by endoplasmic reticulum stress and its mechanisms in type 2 diabetes
Glatzová, Daniela ; Němcová, Vlasta (advisor) ; Libusová, Lenka (referee)
Increasing incidence of type 2 diabetes represents one of the principal threats to human health in the 21st century. Strong evidence indicates that the rise in incidence of type 2 diabetes is correlated with increasing levels of obesity and that important factor playing role in the development of this disease is an elevation in circulating glucose and fatty acids. Chronically increased concentration of these nutrients was shown to induce apoptosis of pancreatic beta-cells that subsequently contributes to diabetes progression. Despite intensive research, molecular mechanisms underlying this beta-cells loss are still unclear. However, there is increasing evidence that one of the key processes involved in glucose and fatty acid-induced beta-cell death is induction of endoplasmic reticulum stress. The aim of this work is to summarize the recent knowledge about induction of apoptosis by endoplasmic reticulum stress in pancreatic beta-cells in relation to type 2 diabetes.
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Stress of endoplasmic reticulum and its role for the development of adipose tissue inflammation
Zemánková, Kateřina ; Rossmeislová, Lenka (advisor) ; Janovská, Petra (referee)
Endoplasmic reticulum (ER) is a cellular organelle responsible for folding of proteins that are then transported to the various places in the cell or secreted. It is also crucial for the synthesis of triglycerides. Metabolic imbalance leads to ER stress and consequently triggers signaling pathway, which is called unfolded-protein response (UPR). The aim of this pathway is to alleviate ER stress, restore natural homeostasis and prevent death of cell. At the same time however, it activates stress kinases and other factors that may perturb insulin signaling and increase expression of proinflammatory cytokines. These signs are characteristic for human obesity, which is associated with reduced tissue's sensitivity to insulin and is considered as a disease with low level of inflammation. Recent studies have suggested that the source of proinflammatory cytokines in obesity are stressed adipocytes and macrophage infiltrated into adipose tissue. Indeed, it has been demonstrated that stress of endoplasmic reticulum is significantly increased in adipose tissue of obese individuals. Weight loss associated with reduction of adipose tissue mass decreases stress while lowers both, the production of proinflammatory cytokines and insulin resistence. This work aims to collect and discuss these new findings, which...
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