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Native hyaluronan as a delivery system for hydrophobic drugs
Černá, Eva ; Mravec, Filip (referee) ; Pekař, Miloslav (advisor)
The aim of this paper is to discover whether it is possible to use the native form of hyaluronic acid as a hydrophobic drug carrier for a targeted distribution in the body. In its structure, hyaluronic acid is a linear high molecular weight biopolysaccharide which is found in most living organisms. Hyaluronan is involved in many physiological processes and therefore is essential for the functionality of the human body. It is in most tissues of the human body, high concentration is in the skin, the vitreous body and is also observed in cancer cells that contain several receptors for hyaluronan. These receptors include CD44 and RHAMM. The interaction of the hyaluronic acid delivery system and the hydrophobic medicinal with these receptors could ensure a free passage for drugs to the affected tissue, where the release of the drug would destroy the affected cells. The drug would directly target the damaged tissue and did not burden the rest of the body like the cytotoxic agents do. In this paper the native form of hyaluronic acid, which we normally find in the human organism, was chosen as the carrier. Its properties do not stand above other carrier systems, but its biocompatibility and biodegradability in the body greatly exceed them. High molecular weight hyaluronic acid was used as a carrier and the hydrophobic dye sudan red G, a substance of similar properties, was used instead of a hydrophobic drug.
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Cílený transport bioaktivních molekul pomocí ferritinových nanoklecí
Rogotovskaya, Alexandra
Abstract This bachelor's thesis deals with the topic of targeted transport of bioactive molecules using ferritin nanocages. Nanoparticles are widely tested for use in contemporary medicine, not only for their use in cancer management. The use of these materials is preferred due to their ability to decrease unwanted and toxic effects of conventional chemotherapy. The use of nanoparticles ensures targeted transport, which results in reduction of the toxic effect of drugs. Among the most promising nanomedicinal vehicles belong ferritins. Ferritin is a globular protein and the main natural intracellular iron storage molecule in almost all living organisms. Ferritin specifically recognizes transferrin receptor 1 (TfR1), which is usually highly expressed on various types of tumor cells. Ferritin exhibits unique ability of reversible self-assembly. Furthermore, the surface of ferritins can be chemically or genetically modified to bear variety of cancer targeting ligands. In addition, due to its origin, ferritins are biocompatible and do not induce unwanted immune reactions. Thus, ferritins are promising delivery vehicles for targeted cancer therapy.
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Strategies and results in the development of insulin derivatives for the treatment of diabetes
Pokorný, Štěpán ; Jiráček, Jiří (advisor) ; Hlouchová, Klára (referee)
The aim of this bachelor's thesis is to present insulin analogs and to analyse the direction of development of these organic compounds. The text contains basic information on this subject (e.g. the history of Diabetes Mellitus, the first treatment, the discovery of insulin (1921) and the experiments that preceded this discovery...). The thesis also explains the basic differences between type 1 and type 2 Diabetes Mellitus and the resulting differences in treatment. It mainly summarizes, the specific types of analogs, their chemical composition and the nature of their action. The main contribution of this work lies in the analysis of insulin analogs and the overview of the course in which the development of these analogues is proceeding or what innovations we can expect in diabetes therapy in the upcoming years. The thesis draws primarily from peer-reviewed scientific papers, articles and books (older as well as more recent ones) and from the expertise of the IOCB laboratory. All sources are well cited at the end of the work.
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In vitro models for studying Syncytin-1-induced fusion of trophoblast cells
Jech, Lukáš ; Trejbalová, Kateřina (advisor) ; Zíková, Martina (referee)
Trophoblast cell fusion is essential for human placenta development. Apart from initiating blastocyst implantation, syncytialization is critical for optimal nutrient and gas exchange between mother and fo- etus. Multicellular syncytia called syncytiotrophoblast covers the surface of the branched structure of chorionic villi, which is in direct contact with maternal blood. Impairment of the syncytialization process leads to insufficient fetal nutrition and severe pregnancy complications. Syncytia formation is induced by the interaction of the surface glycoprotein of retrovital origin, Syncytin-1, with its receptor. Despite the significance of these processes, the details of cell fusion and trophoblast differentiation remain unk- nown. Furthermore, because of its uniqueness, the human placenta cannot be covered by animal models. As a result, research into human placental development, especially Syncytin-1-induced trophoblast cell fusion, is limited to in vitro trophoblast models. These models include primary trophoblast cell cultures and trophoblast cell lines, which can be obtained by immortalizing cell cultures or extracted from trophoblast tumours. Dedifferentiated trophoblast stem cell cultures were also established. The most recent approach, however, involves the direct reprogramming of dermal...
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New insulin-like growth factor 1 (IGF-1) analogs for receptor studies and therapeutic applications
Lin, Jingjing ; Jiráček, Jiří (advisor) ; Hodek, Petr (referee) ; Lapčík, Oldřich (referee)
The insulin/IGF system is an evolutionary conserved network that includes three closely related peptide hormones (insulin, IGF-1 and IGF-2), three homologous tyrosine kinase receptors (IR-A, IR-B and IGF-1R), a distinct IGF-2 receptor (IGF-2R), and six IGF-binding proteins. While insulin signals mainly via IR, playing a key role in glucose homeostasis, IGFs mainly signal via IGF-1R to mediate normal human growth. A tight control of ligands and receptors expression is crucial for the proper functioning of the organism. Aberrant signaling by these receptors is manifested in many pathological conditions, including cancer, growth disorders, neurodegenerative diseases and diabetes. Hence, the insulin/IGF axis represents a promising therapeutic target. In view of the multiple unsuccessful clinical anticancer trials performed either with tyrosine kinase inhibitors or antibodies targeted against IGF-1R, the development of novel selective and receptor-specific insulin and IGF analogs with minimized side effects would be of interest. Our study began with the recombinant preparation of IGF-1 dimers in which IGF-1 monomers are interlinked between their C- and N-termini with Ser-Gly linkers (length of 8, 15 or 25 residues). The goal was to investigate whether the binding of two covalently linked IGF-1 molecules...
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Consequences of perinatal insult on brain excitability in immature and adult rats
Fábera, Petr ; Mareš, Pavel (advisor) ; Pokorný, Jaroslav (referee) ; Ošlejšková, Hana (referee)
Perinatal insult may lead to a permanent impairment of brain function resulting in the development of epilepsy. Status epilepticus (SE) in immature rats leads to hippocampal hyperexcitability. The functional and morphological changes of the hippocampus are similar to those seen in human temporal lobe epilepsy. The excitability may be influenced by adenosine. Adenosine acts its anticonvulsant effect by activation of A1 receptors (A1R). The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms - ADK-L and -S. The main goal of the thesis is to elucidate the changes in A1R and ADK isoforms expression during intact brain development and after SE. A1R agonist 2-chloro-N6- cyclopentyladenosine (CCPA), as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may bolster the anticonvulsant effect, but their action may correspond with the level of A1R and ADK. Hippocampal excitability in immature rats after LiCl-pilocarpine SE was studied by the model of hippocampal afterdischarges (ADs) and correlated with changes of A1R and ADK in the hippocampus. ADs demonstrated significantly decreased hippocampal excitability shortly after SE induction, whereas significant hyperexcitability accompanied by spontaneous seizures in older rats was shown. Increasing ADK-S expression...
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Structure and function of RTX toxins of Gram-negative bacteria
Zhuk, Karyna ; Osička, Radim (advisor) ; Šulc, Miroslav (referee)
RTX toxins (Repeats in ToXin) are produced by Gram-negative bacteria, most of which are important human or animal pathogens. The polypeptide chain of each RTX toxin consists of four conserved regions. An N-terminal hydrophobic domain, which is important for insertion of the RTX toxin into the host cell membrane and pore formation. The hydrophobic domain is followed by an acylated segment containing conserved lysine residues, at which the toxin is acylated and thus activated. The C-terminal portion of each RTX toxin contains a repeat domain to which calcium ions bind. The C-terminus of the toxin contains a secretion signal that is recognized by the type I secretion system, which transports the toxin from the bacterial cytosol to the external environment. After secretion, RTX toxins interact with the cell surface via specific β2 integrins and/or glycosylated structures such as glycoproteins and gangliosides or membrane components such as sphingomyelins and cholesterol. Once bound to the cell, RTX toxin monomers insert into the membrane and oligomerize to form pores. The uncontrolled flow of ions through these pores can lead to disruption of bactericidal functions of myeloid phagocytes, stimulation or suppression of the release of pro-inflammatory cytokines, modulation of various signaling and...
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Opioid receptors and their signaling system in the myocardium
Ladislav, Marek ; Novotný, Jiří (advisor) ; Neckář, Jan (referee)
The main objective of this bachelor thesis is to systematically collect and sort information about opioid receptors and their signaling system in the myocardium. Heart activity is controlled mainly by adrenergic signaling, and this work therefore contains also some data concerning the characteristic and significance of other relevant receptors. For better understanding, general basic information about opioid system, especially about the receptors and their signaling, is also provided. Relatively little is known about opioid receptors in the myocardium even though these receptors may have an important role especially in various pathophysiological conditions. There can be several reasons for this. The possibility of further characterization of opioid receptors in the myocardium is rather difficult due to the relatively small number of these receptors in heart tissue. The situation is somewhat complicated also by some differences in the modulation of cardiac function among different species. The complete molecular mechanism by which opioid receptors act on the myocardium has not yet been fully uncovered. Especially in the case of humans this knowledge can be crucial, because these receptors and their ligands could be used for medical purposes.
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Role of DD- and DED-containing adaptor proteins in apoptotic signaling
Čaja, Fabián ; Anděra, Ladislav (advisor) ; Janštová, Vanda (referee)
Proteins containing a bundle of six anti-paralel α-helices in so-called "death domain" (DD) and similar structures (DED, CARD) represent important players in apoptotic signaling. To DD/DED/CARD domains-containing proteins belong pro- apoptotic membrane receptors from the TNFR superfamily, then adaptor proteins and enzymes as proteases or kinases. These pro-apoptotic "death receptors" interact with adaptor proteins and initiator caspases containing DDs or DEDs and activate apoptotic signaling cascade. DEDs and DDs are in addition found in many proteins participating in activation of caspases or other non-apoptotic signaling. Many experimental models document that defects in and deregulations of proteins containing DDs and DEDs can have severe if not lethal consequences for an organism. Abberations in these proteins in many cases could lead to cancerogenesis, immunodeficiencies or developmental defects.
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