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Multiple sclerosis: correlation of gene expression and response to immunomodulatory therapy
Kleinová, Pavlína ; Kubala Havrdová, Eva (advisor) ; Taláb, Radomír (referee) ; Musil, Zdeněk (referee)
KLEINOVÁ, Pavlína. Roztroušená skleróza mozkomíšní: korelace genové exprese a odpovědi na imunomodulační léčbu [Multiple sclerosis: correlation of gene expression and response to immunomodulatory therapy]. Praha, 2023. 107 s., 3 přílohy. Disertační práce. 1. lékařská fakulta Univerzity Karlovy v Praze. Vedoucí práce Eva Kubala Havrdová. Abstract Multiple sclerosis is a chronic autoimmune disease of the central nervous system with a genetic component, modifiable with immunomodulatory therapy. It is assumed that genetic factors influence the course of the disease and the therapeutic response. The thesis presents the results of two studies investigating the genetic background of multiple sclerosis. In the first study, the influence of the (GT)n polymorphism of the promoter of the HMOX1 gene for heme oxygenase 1 affecting its expression was investigated in people with multiple sclerosis. No effect of this polymorphism on the course of the disease was observed. We confirmed the effect of immunomodulatory therapy on delaying disease progression. The second study, called the Genotype/Phenotype Project, is a multicentre international genome-wide association study aimed at detecting single nucleotide polymorphisms associated with severity of multiple sclerosis. It has been shown that common genetic variants with...
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Some aspects of molecular mechanisms of xenobiotics' hepatotoxicity and hepatoprotection : Modulatory roles of natural polyphenols
Lekic, Nataša ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Brůha, Radan (referee)
Background & Aims: Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. The aim of this work is to find early signal markers of drug-induced injury of the liver by focusing on select antioxidant/oxidant and apoptotic genes. As well, to address the relationship between conventional liver dysfunction markers and the measured mRNA and protein expressions in the D-galactosamine/lipopolysaccharide and tert-butylhydroperoxide hepatotoxicity models. Furthermore, potential hepatoprotective capabilities of antioxidant polyphenols quercetin and curcumin were evaluated in relation to its modulation of the oxidative stress and apoptotic parameters in the given xenobiotic hepatotoxicity models. Methods: Biochemical markers testing the hepatic function included aminotransferases (ALT, AST) and bilirubin. Measurements of TBARS and conjugated dienes were used to assess lipoperoxidation. Plasma levels of catalase and reduced glutathione were used as indicators of the oxidative status of the cell. Real time PCR was used to analyse the mRNA expressions of the inducible nitric oxide synthase (NOS-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD-1), glutathione peroxidase (Gpx-1), caspase 3 (Casp3), BH3 interacting domain death agonist (Bid) and Bcl-2...
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Molecular basis of endothelial sysfunction: endothelial nitric oxide synthase and heme oxygenase 1 genetic variations
Král, Aleš ; Martásek, Pavel (advisor) ; Baxová, Alice (referee) ; Schneider, Bohdan (referee)
Endothelial dysfunction is a pathologic state characterized by an altered equilibrium among vasodilatory and antithrombotic mediators and vasoconstrictive and prothrombotic mediators produced by the vascular endothelium. Multiple factors induce impaired production or increased consumption nitric oxide (NO), the key mediator of vascular homeostasis, produced by the nitric oxide synthase enzymes (NOS). Endothelial dysfunction represents one of the initial steps in the development of atherosclerosis, a chronic inflammatory disease of the vascular wall. The inducible enzyme heme oxygenase 1 (HO-1) represents one of the main cellular defense mechanisms against increased oxidative stress and decreased NO bioavailability accompanying endothelial dysfunction and atherosclerosis. We studied the genetic determinants of endothelial dysfunction and atherosclerosis by evaluating the association of the G894T endothelial NOS (eNOS) polymorphism and the HO-1 (GT)n promoter polymorphism with coronary artery atherosclerosis severity and risk profile and their evolution during hypolipidaemic treatment. In addition, we searched for genetic variations in exons 25 and 26 of eNOS gene, encoding the C-terminal part of the protein, deemed crucial for proper enzyme function and the 3'- untranslated region crucial for eNOS...
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Molecular basis of endothelial sysfunction: endothelial nitric oxide synthase and heme oxygenase 1 genetic variations
Král, Aleš ; Martásek, Pavel (advisor) ; Baxová, Alice (referee) ; Schneider, Bohdan (referee)
Endothelial dysfunction is a pathologic state characterized by an altered equilibrium among vasodilatory and antithrombotic mediators and vasoconstrictive and prothrombotic mediators produced by the vascular endothelium. Multiple factors induce impaired production or increased consumption nitric oxide (NO), the key mediator of vascular homeostasis, produced by the nitric oxide synthase enzymes (NOS). Endothelial dysfunction represents one of the initial steps in the development of atherosclerosis, a chronic inflammatory disease of the vascular wall. The inducible enzyme heme oxygenase 1 (HO-1) represents one of the main cellular defense mechanisms against increased oxidative stress and decreased NO bioavailability accompanying endothelial dysfunction and atherosclerosis. We studied the genetic determinants of endothelial dysfunction and atherosclerosis by evaluating the association of the G894T endothelial NOS (eNOS) polymorphism and the HO-1 (GT)n promoter polymorphism with coronary artery atherosclerosis severity and risk profile and their evolution during hypolipidaemic treatment. In addition, we searched for genetic variations in exons 25 and 26 of eNOS gene, encoding the C-terminal part of the protein, deemed crucial for proper enzyme function and the 3'- untranslated region crucial for eNOS...
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Some aspects of molecular mechanisms of xenobiotics' hepatotoxicity and hepatoprotection : Modulatory roles of natural polyphenols
Lekic, Nataša ; Farghali, Hassan (advisor) ; Kršiak, Miloslav (referee) ; Brůha, Radan (referee)
Background & Aims: Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. The aim of this work is to find early signal markers of drug-induced injury of the liver by focusing on select antioxidant/oxidant and apoptotic genes. As well, to address the relationship between conventional liver dysfunction markers and the measured mRNA and protein expressions in the D-galactosamine/lipopolysaccharide and tert-butylhydroperoxide hepatotoxicity models. Furthermore, potential hepatoprotective capabilities of antioxidant polyphenols quercetin and curcumin were evaluated in relation to its modulation of the oxidative stress and apoptotic parameters in the given xenobiotic hepatotoxicity models. Methods: Biochemical markers testing the hepatic function included aminotransferases (ALT, AST) and bilirubin. Measurements of TBARS and conjugated dienes were used to assess lipoperoxidation. Plasma levels of catalase and reduced glutathione were used as indicators of the oxidative status of the cell. Real time PCR was used to analyse the mRNA expressions of the inducible nitric oxide synthase (NOS-2), heme oxygenase-1 (HO-1), superoxide dismutase (SOD-1), glutathione peroxidase (Gpx-1), caspase 3 (Casp3), BH3 interacting domain death agonist (Bid) and Bcl-2...
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