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Alemat s.r.o. headquarters and warehouse
Petr, Lukáš ; Neužil, Jiří (referee) ; Müller, Jan (advisor)
This diploma thesis deals with design of office building with warehouse. The buildings are situated on slightly sloping terrain in cadastre unit of Sudoměřice u Tábora. Both buildings have rectangular shape and are connected with two sides. The Alemat s.r.o. company is internet shop, predominately with electronics. In the office building is also showroom where are some products will be shown. The warehouse will serve for receipt and issue of goods and to store them. The perimeter walls of office building is designed from ceramic block thickness of 250mm, for example Heluz Family 25. The walls will be insulated with 200mm of expanded polystyrene. The foundation construction is designed as foundation strips from plain concrete and permanent formwork brick filled with concrete and reinforced with steel. The ceiling construction is designed as prestressed panels thickness of 250mm. The roof is flat with main hydro isolation made of plasticized PVC foil loaded with pea gravel. The main construction of warehouse will be made of steel frames. The exterior skin of the warehouse will form panels Kingspan thickness of 140mm. The foundation construction is designed as monolithic foundation pads. Between the pads will be monolith grade beams. The roof is designed also from Kingspan panels. To the panel will be mechanically fastened plasticized PVC foil. Roof drainage is designed to rain gutters.
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Induction of heme oxygenase and biological role of its metabolic products.
Šuk, Jakub ; Muchová, Lucie (advisor) ; Jirsa, Milan (referee) ; Neužil, Jiří (referee)
Heme oxygenase (HMOX) catalyzes first and rate-limiting step in heme degradation. By its action, carbon monoxide (CO), ferrous iron and biliverdin which is subsequently reduced to bilirubin are produced. Before discovery of HMOX reaction mechanism, CO was considered only a toxic waste product without any significant importance for human organism. Bilirubin, marker of liver dysfunction, has been also exposed to similar perception. But results from past decades show that HMOX and its metabolic products play an important role in number of physiological as well as defense against pathophysiological processes. The aim of this thesis was to clarify the role of HMOX and its metabolic products, presumably CO and bilirubin, in vivo and in vitro. We focused on the role of CO in a rat model of lipopolysaccharide-induced cholestasis. We were first to describe tissue distribution and pharmacokinetics of inhaled CO in this animal model and found out that CO inhalation is associated with anti-inflammatory and hepatoprotective effects. In a rat model of ethinylestradiol-induced cholestasis, we demonstrated the anticholestatic effect of HMOX. The induction of HMOX by its substrate heme increased the expression of liver transporters thereby increasing bile flow and simultaneously facilitated effective clearance of...
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Horizontal transfer of mitochondria and its role in carcinogenesis
Nováková, Anna ; Neužil, Jiří (advisor) ; Rösel, Daniel (referee)
Mitochondria are essential organelles as they produce most ATP to support cellular activities, synthesize critical metabolic factors and are involved in lipid and phospholipid metabolism as well as calcium signalling. The oxidative phosphorylation (OXPHOS) system, present at the inner mitochondrial membrane, plays role in regulation of cellular metabolism and survival of cancer cells. Recent studies show importance of OXPHOS in growth of cancer cells via regulation of the de novo pyrimidine synthesis pathway. Dihydroorotate dehydrogenase (DHODH), a flavoprotein localized in the inner mitochondrial membrane, converts dihydroorotate (DHO) to orotate within the de novo pyrimidine synthesis pathway, generating electrons that are transferred, via redox- cycling of ubiquinone, to complex III (CIII) of respiratory chain. Since DHODH is functionally linked to CIII activity, impairment of respiration results in reduced activity of DHODH and pyrimidine synthesis. Therefore, mitochondrial damage or mutation in mitochondrial DNA (mtDNA) leads to decreased respiration, cancer cell proliferation and delay of tumour growth. As a compensation for damaged mitochondria, horizontal transfer of functional mitochondria from donor somatic cells to the mitochondria-damaged tumour cells was demonstrated. This...
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Oxidative phosphorylation addiciton as a new approach to the therapy of neoplastic diseases
Růžičková, Anna ; Neužil, Jiří (advisor) ; Merta, Ladislav (referee)
Neoplastic diseases belong at present time among the most frequent causes of premature death in industrialized countries. Discovery of novel approaches to their therapy is highly warranted. Recent results point to the requirement of mitochondrial respiration for tumor progression. This is linked primarily to recent discovery of horizontal transfer of mitochondrial transfer from the host to cancer cells with damaged mitochondrial DNA. This is a needed for the recovery of mitochondrial respiration, a prerequisite for tumor progression. It has appeared that the rate of respiration necessary for tumor progression differs in individual types of tumors. This hypothesis, which is refer to as 'oxidative phosphorylation addiction', however, needs to be verified. It could serve as the basis for proposing of novel therapic strategy for neoplastic diseases, using compounds that directly affect mitochondrial respiratory complexes. Key words: mitochondria, oxidative phosphorylation, horizontal transfer of mitochondrial DNA, neoplastic pathologies, mitochondrially targeted anti-cancer agents
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Targeting mitochondria to overcome resistance of breast cancer to therapy
Rohlenová, Kateřina ; Neužil, Jiří (advisor) ; Špíšek, Radek (referee) ; Vítek, Libor (referee)
(EN) Tumours are heterogeneous and consist of multiple populations of cells. The population of cells with tumour-initiating capability is known as cancer stem cells (CSC). Cells with increased stemness properties and elevated resistance to anti-cancer treatment have been shown to be highly affected upon decline of mitochondrial respiration, linking the concept of CSCs to deregulated bioenergetics. Consistently, functional electron transport chain (ETC) is crucial in tumorigenesis. Expression of HER2 oncogene, associated with resistance to treatment in breast cancer, has been connected with regulation of mitochondrial function. We therefore investigated the possibility that manipulation of mitochondrial bioenergetics via disruption of ETC eliminates the conventional therapy-resistant populations of tumour, such as CSCs and HER2high cells. We demonstrate that HER2high cells and tumours have increased complex I-driven respiration and increased assembly of respiratory supercomplexes (SC). These cells are highly sensitive to MitoTam, a novel mitochondria-targeted derivative of tamoxifen, acting as a CI inhibitor and SC disruptor. MitoTam was able to overcome resistance to tamoxifen, and to reduce the metastatic potential of HER2high cells. Higher sensitivity of HER2high cells to MitoTam is dependent on...
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Molecular mechanisms of cell death induction in pancreatic cancer cells
Ezrová, Zuzana ; Neužil, Jiří (advisor) ; Hyršlová Vaculová, Alena (referee)
Pancreatic adenocarcinoma is one of the most challenging types of tumours to treat; furthermore, standard therapies used so far turn out to be highly inadequate in its treatment. There has been no significant progress in the introduction of new therapeutic approaches to date, and so this disease remains one of the most common causes of death from cancer. Currently, many scientific papers refer to the potential use of metformin, the substance of the biguanide class most commonly used to treat diabetes mellitus type 2. Metformin, according to retrospective studies, reduces the risk of pancreatic cancer in diabetics, possibly by interacting with the complex I of electron transport chain. However, laboratory research registered neoplastic activity of this compound at super-physiological concentrations that are very difficult to achieve in patients. Due to the growing body of evidence of indispensability of functional mitochondria in the initiation and development of malignant neoplasms, we have, in collaboration with other researchers, modified metformin to strengthen its accumulation in mitochondria. We expected that mitochondrially targeted metformin, norMitoMet, will be considerably more efficiency in comparison with the parental compound. The main focus of this study is to shed light on the...
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Heme catabolic pathway in pathogenesis of liver diseases
Váňová, Kateřina ; Muchová, Lucie (advisor) ; Brůha, Radan (referee) ; Neužil, Jiří (referee)
This thesis focuses on the role of heme catabolic pathway in the pathogenesis of selected liver diseases. The aim was to clarify if the modulation of heme oxygenase (Hmox) and its catabolic products - especially carbon monoxide (CO) and bilirubin - affected the development and progression of liver diseases, focusing on inflammatory and cholestatic pathways. Firstly, we discovered that the induction of hmox1 prevented hepatocellular damage in endotoxin-induced inflammation. Furthermore, administration of CO in vivo in early-phase of endotoxin-induced cholestasis decreased the inflammatory cytokine production in the liver and simultaneously prevented downregulatory effect of cytokines on hepatocyte transporters resulting in hepatoprotection. For the first time, we characterized in vivo tissue distribution and elimination of inhaled CO in rats. In vitro experiments and the model of extrahepatic cholestasis revealed the significant role of intracellular bilirubin in hepatocellular protection against oxidative damage which accompanies cholestatic disorders. Last but not least, hmox1 induction by heme increased hepatocyte transporters expression and subsequently stimulated bile flow participating in conferring protection against estrogen-induced cholestasis. Presented results demonstrate that the heme...
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Mitochondria as a target for anti-cancer therapy by vitamin E analogues.
Kľučková, Katarína ; Neužil, Jiří (advisor) ; Hyršlová Vaculová, Alena (referee) ; Pecina, Petr (referee)
(EN) Based on the promising results concerning the anti-cancer properties of redox-silent analogue vitamin E α-tocopheryl succinate (α-TOS), we prepared its mitochondrially targeted derivative MitoVES by attaching the positively charged triphenylphosphonium (TPP+ ) tag to α-TOS molecule. We tested the hypothesis that 'sending' the drug directly to its cellular site of action, mitochondria, should enhance its anti-cancer properties, which would result in more effective anti-cancer agent while making it possible to reduce the effective concentration. We provide evidence that, indeed, MitoVES is a highly effective anti-cancer compound, superior to untargeted α-TOS both in vitro and in vivo. We show that MitoVES exerts its anti-cancer effects by interfering with complex II (CII) activity specifically at the ubiquinone binding site (Qp), where it blocks further electron transfer resulting in increased reactive oxygen species (ROS) production, which then leads to apoptosis induction via the intrinsic mitochondrial pathway, preferentially engaging the pro-apoptotic Bak protein causing mitochondrial membrane permeabilisation. We further show that mitochondrial targeting on the basis of higher mitochondrial membrane potential (ΔΨ) is important for MitoVES pro-apoptotic activity. This feature endows the...
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The study of the influence of vitamin E analogues on malignant mesothelioma
Kovářová, Jaromíra ; Neužil, Jiří (advisor) ; Kozubík, Alois (referee) ; Vítek, Libor (referee)
Cancer is a leading cause of death in the western world and is increasing in frequency world-wide. Although diagnosis, treatment and therapeutic approaches to cancer have improved, many types of cancer are still lethal due to the lack of radical treatment. One of the fatal neoplastic disease types with poor prognosis is represented by malignant mesothelioma (MM). MM is characterised by very high mortality rate and limited therapeutic options. The etiology of the disease is mainly associated with exposure to asbestos fibres. The incidence of MM is increasing in many countries. The search for novel molecular targets, anti-cancer strategies and drugs, which would considerably improve the treatment is of great importance. Certain new drugs, especially those with specific molecular targets, show high selectivity in their action to cancer cells, and have considerably increased the cure rate in some types of cancer. Mitochondria have recently emerged as a very promising target for anti-cancer agents. A group of compounds with anti-cancer activity that induce apoptosis by way of mitochondrial destabilisation, termed 'mitocans', have been a recent focus of research. Several mitocans have been shown to selectively induce apoptosis in cancer cells and suppress the growth of many types of carcinomas in...
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The role of erbB-2 oncogene in the biology of cancer stem-like cells
Prokopová, Kateřina ; Neužil, Jiří (advisor) ; Anděra, Ladislav (referee)
Recent studies indicate the existence of a subpopulation of cells within tumours with stem cell-like characteristics. These "cancer stem-like cells" (CSCs) are relatively resistant to established therapies, usually targeting differentiated and fast proliferating cells. Therefore, CSCs may be a reason for the relapse of neoplastic diseases. CSCs can be characterised by a specific gene expression profile and deregulated signalling pathways. Of these, upregulation of the erbB-2 (HER2) receptor, a hallmark of ~25-30% breast cancer patients, is related to dismal prognosis, elevated proliferation potential and resistance to chemotherapy. Recent evidence has suggested that upregulation of erbB-2 leads to increase in the pool of CSCs. In our study we used mammospheres, cells grown in the absence of serum, an in vitro model of breast CSCs, which were prepared by "weaning" breast cancer MCF7 cells to a special medium. These cells were CD44high and showed increased expression of ABCG-2, Sox-2, Vimentin as well as high levels of erbB-2. Next, we prepared a stable line of MCF7 cells with low levels of erbB-2 by shRNA. ErbB-2low cells were characterised for expression of set of CSCs markers and tested for tumour forming efficacy in nude mice using ultrasound imaging. Keywords Cancer stem-like cells, erbB-2,...
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