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Detailed Investigation of Human Galectins -1 and -3 by employing selectively deoxyfluorinated N-acetyllactosamines
Kurfiřt, Martin
This work is focused on a detailed investigation of supramolecular recognition events between human galectins -1 and -3 and monodeoxyfluorinated N-acetyllactosamine probes, which were previously prepared in our laboratory. The recognition was studied using a combination of X-ray crystallography, isothermal titration calorimetry and several advanced NMR techniques, such as 19F T2-filter, 1H–1H STD, 1H–15N CSP or 19F EXSY. These techniques provided insight into the thermodynamics and kinetics of recognition and enabled us to uncover of subtle differences between both investigated galectins. Such differences could be potentially exploited in the selective targeting of individual galectins with important implications for the galectins-focused\npharmaceutic industry.
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Polymeric nanomaterials for targeted inhibition of tumor growth
Šťastná, Katarína ; Etrych, Tomáš (advisor) ; Sedláček, Ondřej (referee)
Galectins are carbohydrate binding lectins which possess many biological activities related to the development and progression of cancer. The purpose of this bachelor's thesis is synthesis, physico- chemical and in vitro preliminary biological evaluation of novel glycopolymers with high affinity to galectin-3. Several biocompatible water-soluble linear and diblock N-(2- hydroxypropyl)methacrylamide (HPMA) copolymers bearing multivalently presented glycomimetic ligands, were synthesized and characterized by number of analytical methods, i.e. GPC, UV-VIS spectrometry, DLS and NMR. The polymer carriers were synthesized by the controlled RAFT polymerization, their molecular weight ranged from 25,000-33,000 g/mol and showed quite low dispersity. Glycopolymers containing about 4 mol% of glycomimetic ligands showed high ability to inhibit apoptosis of T lymphocytes in vitro. Nevertheless, the hypothesis consisting in the improvement of biological activity due to the denser ligand presentation on diblock copolymers was not proved. The thesis concludes that the prepared glycopolymers, linear as well as diblocks, could hypothetically be convenient tools for synergic therapy with polymer drug delivery systems in cancer treatment. Keywords: polymers, HPMA copolymers, drug-free macromolecular therapeutics,...
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Multivalent carbohydrate ligands of galectins
Hovorková, Michaela ; Křen, Vladimír (advisor) ; Kavan, Daniel (referee)
Galectins are proteins, wich belong to a group of lectins that are able to bind to saccharide units and they specifically recognize glycans exposed to the surface of the cells. Galectins participate in vivo, for example, in carcinogenesis, angiogenesis or fibrosis. Their occurrence increases significantly in connection with a number of pathogenic processes, therefore they can be used as markers for some types of cancer or cardiopathology and also for the targeted binding of therapeutics and/ or imaging agents in diagnosis and therapy. Galectin-3 has a specific structure known as chimeric and it is capable of forming multivalent oligomers. The natural ligands of galectins are glycans containing terminal β-galactosides, especially N-acetyllactosamine, but the binding of monovalent glycans is very weak. Glycoconjugates with high affinity to galectin receptors are optimally multivalent, biocompatible and stable in vivo. These criteria accomplish carbohydrate ligands conjugated to soluble and structurally flexible N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In this work two types of functionalized disaccharides based on N-acetyllactosamine (Galβ4GlcNAc) and its structural analogue of N,N'-diacetyllactosamine (GalNAcβ4GlcNAc) was prepared by enzymatic synthesis. For the synthesis were used...
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Genetical analysis of head and neck squamous cell carcinomas
Čapková, Markéta ; Plzák, Jan (advisor) ; Smilek, Pavel (referee) ; Čelakovský, Petr (referee)
Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. They are associated with high morbidity and mortality. Despite considerable advances in surgical and oncological treatment over the past two decades, overall treatment outcome has only slightly improved. In my thesis I focused on serum gene expression analysis of head and neck cancer patients, which followed the tissue gene expression analysis in same patients. Further we investigated gene expression analysis in tumour stroma, which is now considered as significant factor in cancer initiation and progression. We revealed several candidate genes, which are involved in signalling pathways connected with cell differentiation and proliferation and are involved in apoptotic pathway (BCl-2, BCl-XL a MAX). As well we detected down-regulation of the main tumour suppressor p 53 protein. In peritumoural tissue we detected overexpression of cytokines typical for embryonal development and ectoderm differentiation - IGF-2 and BMP-4, which significantly influence the phenotype of normal keratinocytes. Further we identified several candidate genes relating with overexpression of Gal-1 in stromal myofibroblasts rich tissue (SPIN1, FUSIP1, TRIM23, SLC25A40, PTPLAD1, MP3K2). HNSCC is a heterogeneous disease despite the presence of...
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Study of Epithelial Mesenchymal Interactions in Squamous Epithelium Derived Tumors
Kodet, Ondřej ; Lacina, Lukáš (advisor) ; Borovanský, Jan (referee) ; Ehrmann, Jiří (referee)
This thesis is focused on the epithelial mesenchymal interactions in tumors derived from squamous epithelium including tumors arising from minor cell population (melanocytes). This study is also reflecting aspects of epithelial glycobiology resp. the study of endogenous lectins, the galectins, in head and neck squamous carcinomas. Galectins represent, in the current concepts of cell and tumor biology molecules with a remarkable potential. Galectins participate, besides in regulation of pre- and postnatal homeostasis in normal tissues, also in many pathological processes such as autoimmune reactions or malignancies. In this thesis, we demonstrated the presence of galectin-1 and -2 and their glycoligands in interphasic and mitotic nuclei, which may contribute to regulation of the cell cycle. Furthermore, we demonstrated galectin-9 as a sensitive marker of transformation normal to the dysplastic squamous epithelium in head and neck. The epithelial mesenchymal interactions represent mechanisms, which are responsible for dynamic maintenance of the homeostasis of the organism during prenatal development, postnatal growth and during cyclic renewal of certain tissues. These interactions also participate in wound healing. On the other hand they play a crucial role in the process of tumor transformation,...
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Multivalent carbohydrate ligands of galectins
Hovorková, Michaela ; Křen, Vladimír (advisor) ; Kavan, Daniel (referee)
Galectins are proteins, wich belong to a group of lectins that are able to bind to saccharide units and they specifically recognize glycans exposed to the surface of the cells. Galectins participate in vivo, for example, in carcinogenesis, angiogenesis or fibrosis. Their occurrence increases significantly in connection with a number of pathogenic processes, therefore they can be used as markers for some types of cancer or cardiopathology and also for the targeted binding of therapeutics and/ or imaging agents in diagnosis and therapy. Galectin-3 has a specific structure known as chimeric and it is capable of forming multivalent oligomers. The natural ligands of galectins are glycans containing terminal β-galactosides, especially N-acetyllactosamine, but the binding of monovalent glycans is very weak. Glycoconjugates with high affinity to galectin receptors are optimally multivalent, biocompatible and stable in vivo. These criteria accomplish carbohydrate ligands conjugated to soluble and structurally flexible N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In this work two types of functionalized disaccharides based on N-acetyllactosamine (Galβ4GlcNAc) and its structural analogue of N,N'-diacetyllactosamine (GalNAcβ4GlcNAc) was prepared by enzymatic synthesis. For the synthesis were used...
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The role of galectins in cancer cell invasiveness
Remišová, Michaela ; Brábek, Jan (advisor) ; Kovář, Marek (referee)
Galectins are family of β-galactosidase binding proteins that serve many functions in all kind of mammalian cells. In the past years galectins, namely galectin-1 and galectin-3, have been revealed to play a major role in various cancer processes including cancer cell invasiveness, a process indispensable for the formation of metastasis. Both extracellular and intracellular forms of galectins modify the process of invasiveness in various ways, through interacting with different components of the cell or of the cell signalling pathways. The aim of this bachelor's thesis is to summarize mechanisms by which galectins promote cancer cell invasiveness. Keywords: galectins, galectin-1, galectin-3, invasiveness, cancer, metastasis
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Study of Epithelial Mesenchymal Interactions in Squamous Epithelium Derived Tumors
Kodet, Ondřej ; Lacina, Lukáš (advisor) ; Borovanský, Jan (referee) ; Ehrmann, Jiří (referee)
This thesis is focused on the epithelial mesenchymal interactions in tumors derived from squamous epithelium including tumors arising from minor cell population (melanocytes). This study is also reflecting aspects of epithelial glycobiology resp. the study of endogenous lectins, the galectins, in head and neck squamous carcinomas. Galectins represent, in the current concepts of cell and tumor biology molecules with a remarkable potential. Galectins participate, besides in regulation of pre- and postnatal homeostasis in normal tissues, also in many pathological processes such as autoimmune reactions or malignancies. In this thesis, we demonstrated the presence of galectin-1 and -2 and their glycoligands in interphasic and mitotic nuclei, which may contribute to regulation of the cell cycle. Furthermore, we demonstrated galectin-9 as a sensitive marker of transformation normal to the dysplastic squamous epithelium in head and neck. The epithelial mesenchymal interactions represent mechanisms, which are responsible for dynamic maintenance of the homeostasis of the organism during prenatal development, postnatal growth and during cyclic renewal of certain tissues. These interactions also participate in wound healing. On the other hand they play a crucial role in the process of tumor transformation,...
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Genetical analysis of head and neck squamous cell carcinomas
Čapková, Markéta ; Plzák, Jan (advisor) ; Smilek, Pavel (referee) ; Čelakovský, Petr (referee)
Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. They are associated with high morbidity and mortality. Despite considerable advances in surgical and oncological treatment over the past two decades, overall treatment outcome has only slightly improved. In my thesis I focused on serum gene expression analysis of head and neck cancer patients, which followed the tissue gene expression analysis in same patients. Further we investigated gene expression analysis in tumour stroma, which is now considered as significant factor in cancer initiation and progression. We revealed several candidate genes, which are involved in signalling pathways connected with cell differentiation and proliferation and are involved in apoptotic pathway (BCl-2, BCl-XL a MAX). As well we detected down-regulation of the main tumour suppressor p 53 protein. In peritumoural tissue we detected overexpression of cytokines typical for embryonal development and ectoderm differentiation - IGF-2 and BMP-4, which significantly influence the phenotype of normal keratinocytes. Further we identified several candidate genes relating with overexpression of Gal-1 in stromal myofibroblasts rich tissue (SPIN1, FUSIP1, TRIM23, SLC25A40, PTPLAD1, MP3K2). HNSCC is a heterogeneous disease despite the presence of...
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