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1
Yang, Weidong. "Oxidative damage of endothelial cells". Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/29603.
Testo completoAbstract (sommario):
This study sought to investigate the consequences of different degrees of oxidative stress on endothelial cells, using a cultured endothelial cell model; principally bovine aortic endothelial cells, subjected to oxidative stress. High concentrations of H2O2 or a superoxide generating system caused rapid endothelial cell death, as evidenced by increased membrane permeability, which could be partially protected by myoglobin. Extracellular H2O2 caused a rapid increase in intracellular peroxidation but was also eliminated by endothelial cells. However, the anti-oxidant capacity of the bovine endothelial cells was very weak and could be overcome by as little as 5 femtomol hydrogen peroxide per cell. The effects were directly related to the amount of H2O2 available to each cell, rather than the concentration. Exposure to relatively low amounts of H2O2 (<0.5 picomol/cell) led to reduced endothelial cell function including prostacyclin production and mitochondrial dehydrogenase activity, and inhibited cell migration and proliferation. The cells showed gradual, partial recovery from these damaging effects. At low amounts (0.1 to 0.5 picomol/cell) H2O2 induced endothelial cell apoptosis within 48 hours of the exposure. After this time, some of the surviving cells showed evidence of senescence and could remain in culture for up to 30 days. Senescence was accompanied by an increase in cytoplasmic volume and accumulation of lipofusion. Investigation of -galactosidase activity suggested that the increased enzyme expression was linked to cell cycle rather than senescence. In conclusion, endothelial cells are very sensitive to oxidative damage but the nature of the damage is related to the degree of oxidative stress. The effects of oxidative stress may play an important role in atherosclerotic and cardiovascular diseases.
2
Soman, Sony. "OXIDATIVE DAMAGE TO DNA IN ALZHEIMER'S DISEASE". UKnowledge, 2013. http://uknowledge.uky.edu/chemistry_etds/28.
Testo completoAbstract (sommario):
Previous studies from our laboratory and others show a significant increase in levels of both nuclear and mitochondrial DNA and RNA oxidation in vulnerable brain regions in the progression of Alzheimer’s disease (AD). Although total DNA oxidation is increased in AD it remains unclear whether oxidative damage is widespread throughout the genome or is concentrated to specific genes. To test the hypothesis that specific genes are more highly oxidized in the progression of AD, we propose to quantify the percent oxidative damage in genes coding for proteins shown to be altered in the progression of AD using quantitative/real-time polymerase chain reaction (qPCR/ RT-PCR). To further test the hypothesis that diminished DNA repair capacity in the progression of AD contributes to increased DNA oxidation we will use custom PCR arrays and qPCR, Western blot analysis and activity assays to quantify changes in enzymes involved in base excision repair (BER).
In order to carry out these studies tissue specimens from superior and middle temporal gyri (SMTG) and inferior parietal lobe (IP), as well as, a non-vulnerable region, the cerebellum (CER) will be analyzed from normal control (NC) subjects and subjects throughout the progression of AD including those with preclinical AD (PCAD), mild cognitive impairment (MCI), and late stage AD (LAD). We will also analyze specimens from diseased control subjects (DC; Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB)) to determine if the changes we observe in AD are specific.
3
Farooq, Sabya. "Free radical induced oxidative DNA damage". Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/30749.
Testo completoAbstract (sommario):
Oxidative DNA damage has been implicated in processes such as carcinogenesis, mutagenesis, ageing and cell death. Reactive oxygen species (ROS) such as superoxide (O2), hydrogen peroxide (H2O 2) and hydroxyl radical (OH*) are produced in mammalian cells as a result of aerobic metabolism. However excess generation of these species by endogenous or exogenous sources can result in damage to DNA, producing a large number of sugar and base lesions. In order to understand the biological consequences of such free radical induced damage it is essential to characterise and quantitate this damage. This study describes the establishment of sensitive and specific techniques to chemically characterise and quantitate three markers of oxidative DNA damage, namely: cis-thymine glycol (Tg), 5-hydroxymethyluracil (5-OHMeU) and 8-hydroxyguanine (8-OHG). Techniques using gas chromatography/mass spectrometry (GC/MS) were established for Tg and 5-OHMeU, following their derivatisation with N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide (MTBSTFA). Standards of Tg and 5-OHMeU were synthesised, and stable isotopically labelled analogues were prepared as internal standards. Analysis of the DNA was carried out at the base level and therefore required acidic hydrolysis of the DNA in order to release the modified and intact bases. For the quantitation of 8-OHG a novel procedure using high performance liquid chromatography (HPLC) - electrochemical detection (ECD) with guanase incubation of DNA hydrolysates was established. The established assays were used to quantitate DNA lesions in vitro and in vivo. In vitro dose response curves were established for the three markers upon gamma-irradiation of DNA. In vivo results of an animal inhalation study indicated there was not a significant increase in oxidative damage upon exposure to crocidolite. An antioxidant supplementation study in humans placental DNA also did not show a significant reduction in levels of the three markers upon supplementation. Comparable background levels of Tg and 5-OHMeU were observed in human and calf thymus DNA, while 8-OHG levels were found to be significantly higher.
4
Furness, Lindsay Jayne. "Energetics, oxidative damage and ageing in birds". Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25473.
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5
Jansson, Kristina. "Oxidative damage and the DNA glycosylase MutYH /". Göteborg : Department of Cell and Molecular Biology, University of Gothenburg, 2010. http://hdl.handle.net/2077/22092.
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6
Davies, John McCartan Caswell. "Oxidative damage in the colon and rectum". Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.493554.
Testo completoAbstract (sommario):
There is considerable supportive evidence to suggest that increased levels of DNA damage are associated with an increased risk of developing neoplastic lesions in the human colon and rectum. Within this thesis, several different topics related to DNA damage were explored in detail, principally using the single cell gel electrophoresis assay (the comet assay) to measure DNA damage both in cell line studies and in human colorectal mucosal biopsies from patients undergoing routine endoscopic examinations of the colon and rectum.
7
Konz, John O. (John Otto) 1971. "Oxidative damage to recombinant proteins during production". Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/17472.
Testo completoAbstract (sommario):
Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1998.Includes bibliographical references (p. 209-222).
Since the introduction of recombinant human insulin nearly two decades ago, recombinant proteins have increasingly been utilized as therapeutic agents. In addition, expression of recombinant proteins is now a common tool used in basic research. Recombinant proteins are subject to many subtle modifications that can affect their properties; among these modifications, oxidative damage is one of the most ubiquitous. Oxidative damage, however, is only occasionally considered as a "quality concern" since it rarely detectable using standard biochemical techniques. The production of an oxidatively-sensitive protein, a1-Antitrypsin, was investigated to ascertain the effect of fermentation parameters on the extent of oxidation. Oxidation of either of two methionine residues in the active site to methionine sulfoxide was sufficient for inactivation, and 50% of the antitrypsin produced under standard fermentation conditions was oxidized. Oxidative damage was linked to the dissolved oxygen concentration by experimentation and detailed modeling of the evolution and detoxification of reactive oxygen species. Under pseudo steady-state conditions, the fractional oxidation is near zero under anaerobic conditions and increases through the microaerobic regime. At dissolved oxygen concentrations greater than 10% of air saturation, the fractional oxidation did not vary. Step changes in the dissolved oxygen concentration, designed to emulate possible time variation resulting from poor mixing or changes in gas composition, caused transient increases in the fractional oxidation and enhanced proteolytic degradation. This may implicate oxidative stress in scale-up related protein quality and quantity limitations. In addition, oxidative damage to antitrypsin caused a 5-fold increase in the stepwise addition rate for in vitro aggregation, which suggests that oxidative damage will limit shelf stability. In addition, process simulation demonstrated that removal of oxidative variants caused a 100% increase in cost per unit when only 22% of the antitrypsin is oxidized during the fermentation step.
by John O. Konz.
Ph.D.
8
Renganathan, Kutralanathan. "Oxidative Damage and Age Related Macular Degeneration". Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1193002743.
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9
Carroll, Luke Dean. "Modulation of oxidative damage by selenium compounds". Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14124.
Testo completoAbstract (sommario):
Myeloperoxidase (MPO) is the primary enzyme responsible for the production of strong oxidants by neutrophils in response to pathogens. One of the major oxidants produced is hypochlorous acid (HOCl), which can react with amine groups to form the secondary oxidants N-chloramines. These oxidants play a role in the destruction of pathogens, however they also have the potential to damage host cells, and have been implicated in numerous inflammatory diseases. This Thesis explores the potential for selenium containing compounds and enzymes to act as catalytic oxidant scavengers. Reaction rates between MPO-derived oxidants and selenium compounds were determined product characterization of products performed. The reduction of the oxidised products, selenoxides, was examined and the rate constant for the thiol reduction of selenoxides determined. It is demonstrated that selenium and sulfur containing enzymes are capable of scavenging these oxidants, as well as reversing the formation of selenoxides. The ability of selenium compounds to protect against damage induced by treatment of cells with HOCl and N-chloramines was also assessed. Overall, selenium containing compounds and enzymes show potential in scavenging these oxidants with endogenous thiols capable of reversing the oxidised selenium products, making them a potential therapeutic intervention in inflammatory conditions.
10
Cao, Huachuan. "Probe Oxidative Damage in DNA Charge Transfer Process". Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/6983.
Testo completoAbstract (sommario):
As a hydrophilic biopolymer, a DNA molecule is surrounded by water molecules in aqueous solution. The charge hopping mechanism indicates the competition between radical cation quenching by water molecules and migration along DNA partially determines the distance and efficiency of charge transport in DNA. Lipid can effectively bind DNA to induce hydrophobic environment around the DNA helix and reduce the water contact with bases in the DNA duplex. Therefore, the effect of water molecules on charge transport can be studied by comparison between nature DNA and DNA-lipid complexes. We synthesized several cationic lipids with various lengths of dialkyl chain (2, 8, 18) and spermine (Sp4+) binding core in this research, which posses strong DNA binding affinity due to their multi-charged spermine head-groups. Among those, C8GlySp4+ and C2GlySp4+ can form stable complex with DNA oligomer in aqueous solution, characterized by time dependent UV and CD spectrometry. C2GlySp4+ showed the similar inhibition on oxidative damage in GG steps as spermine while C8GlySp4+ demonstrated much more significant prohibitive effect at the same concentration. Since all the lipids bear the same binding core, they should afford the similar binding affinity towards DNA duplexes. we attributed the observation to the longer length of dialkyl group in C8GlySp4+, which can more effectively shield the DNA duplex from the water molecules than either spermine or C2GlySp4+. A kinetic model based on phonon-assist polaron hopping mechanism was proposed to rationalize the experimental results. The finding may give insight on the protection of DNA oxidative damage by reducing the access of the water molecule to DNA duplex and may have potential impact on the application of DNA as conducting biopolymer and protection of DNA in biological system.
11
Karihtala, P. (Peeter). "Oxidative damage and counteracting mechanisms in breast carcinoma". Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514279530.
Testo completoAbstract (sommario):
Abstract
Breast cancer is the leading cause of death from cancer among Finnish women, but the ultimate causation of carcinogenesis still remains unclear. Reactive oxygen species (ROS) is a collective term for several types of reactive oxygen metabolites that are continuously generated in human cells mainly as by-products of aerobic respiration. ROS, including nitric oxide and its derivatives, play highly important roles in cell physiology. If ROS production exceeds the capacity of detoxification systems, principally antioxidant enzymes, oxidative stress is said to occur. This state is known to contribute to all stages of carcinogenesis.
To explore the widely unstudied role of ROS and cell redox state modulating enzymes in breast carcinomas, the extent of ROS-derived macromolecule damage and the expression of the vast majority of known antioxidant enzymes were assessed in a large series of breast carcinomas, and the results were compared to the patients' clinicopathological parameters. The results were also compared to angiogenesis, DNA repair enzymes, cell proliferation, NF-κB, p53 expression, and survival. Immunohistochemistry was the main method applied, but western blotting and immunoelectron microscopy were also used.
There is extensive oxidative damage in breast carcinomas, which seems to associate with tumor development. Oxidative macromolecule damage is notable even in stage I tumors. Cell redox state regulating enzymes, such as peroxiredoxin V, thioredoxin, thioredoxin reductase, and glutamate-cysteine ligase, associate with more aggressive phenotypes of tumors, including larger primary tumors, growth of metastases, increased cell proliferation, and poor differentiation. This indirectly suggests that cell redox state modulating enzymes may be inductive of tumor promotion in an oxidated environment. The results of this thesis support the importance of ROS in all stages of carcinogenesis. These observations are largely in line with the previous studies on different carcinomas, but there seem to be certain carcinoma type specific differences in the expression of these enzymes. Since the expression of given cell redox state modulating enzymes distinctly associates with clinicopathological parameters, these enzymes may be useful as prognostic indicators and facilitate the choice of appropriate treatment in the future.
12
Davies, Stefan M. K., e n/a. "Oxidative damage to mitochondria on ageing in rats". University of Otago. Department of Biochemistry, 2007. http://adt.otago.ac.nz./public/adt-NZDU20070403.111245.
Testo completoAbstract (sommario):
Ageing is a complex phenomenon, characterised by progressive loss of function, decreasing resistance to age-associated pathologies and stress, and increasing rates of mortality. The Free Radical Theory of Ageing implicates reactive oxygen and nitrogen species (ROS/RNS) generation as being integral to the ageing process, subjecting the organism to oxidative stress. Oxidative damage to biomolecules is suggested to be causative in the formation of ageing-associated phenotypes, dysregulation and dysfunction.
Mitochondria are responsible for the production of the majority of ROS/RNS through normal functioning of the respiratory chain. Previous studies have reported increasing mitochondrial dysfunction with age, including oxidative damage to protein, lipid and DNA. Thus, mitochondrial dysfunction is considered by many to be central to the Free Radical Theory of Ageing. However, there are conflicting data on changes in mitochondrial and cellular function and damage on ageing.
To investigate the role of mitochondrial protein oxidative damage in ageing, the heart, brain and liver of young (~ 2 month-old) and old (24 month-old) Wistar rats were fractionated into homogenate, cytosolic and mitochondrial fractions. Mitochondrial function was evaluated by measuring activity of the oxidative phosphorylation Complexes I-V, and correlating activity with quantitation of Complex subunits. The activities of the electron transport chain Complexes (I-IV) were largely unchanged on ageing, and no significant differences were seen in the protein levels of nuclear-encoded Complex I-IV subunits. There was a ~ 40% decrease in ATP synthase activity in heart and liver mitochondria from old rats as compared to young, but no change in the level of the Complex V nuclear-encoded subunit. These results suggest the decreased activity is due to modification of Complex V in heart and liver mitochondria on ageing, rather than changes in expression.
Oxidative stress is a common cause of mitochondrial dysfunction, and is often accompanied by an increase in cellular antioxidant defences. Expression of the mitochondrial antioxidant enzyme, MnSOD, was found to be increased in the liver (+ 74%) and heart (+ 82%), but not brain, in old rats, suggesting oxidative stress in these organs on ageing in rats.
To investigate generalised protein oxidative damage accumulation on ageing, whole tissue homogenate, cytosol and mitochondria were isolated from young and old heart, brain and liver. These fractions were assayed for three markers of protein oxidative damage: protein carbonyl content (a marker for generalised oxidative damage occurring via attack by many ROS/RNS), and ortho-tyrosine and meta-tyrosine accumulation (two markers specific for hydroxyl radical attack on phenylalanine).
There were no consistent age-related changes in these biomarkers in any tissues, and no consistent significant differences between cytosolic and mitochondrial protein oxidative damage for any of the three tissues in the two age cohorts. Mitochondria were further subfractionated into membrane-enriched and matrix-enriched subfractions, but again, protein oxidative damage markers were largely unchanged on ageing.
These results suggest that there is no common pattern of mitochondrial dysfunction during ageing in rats. Increased mitochondrial oxidative stress is a feature of ageing, but generalised protein oxidative damage is neither necessary nor sufficient for development of the ageing phenotype.
13
Hannon-Fletcher, Mary Philomena Anne. "Oxidative stress and biomolecule damage in human IDDM". Thesis, University of Ulster, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322420.
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14
Hemming, Joanna. "Oxidative damage to lung surfactant and lipid membranes". Thesis, Birkbeck (University of London), 2015. http://bbktheses.da.ulcc.ac.uk/117/.
Testo completoAbstract (sommario):
Lung surfactant is a mixed monolayer of lipids and proteins that reduce the surface tension at the air-lung interface to prevent alveolar collapse. Exposure of lung surfactant to ozone pollution has been linked to an increased risk of death due to respiratory diseases. This work aimed to determine the ozone damage caused to lung surfactant at the air-water interface. A range of analytical techniques showed that peptide mimics of surfactant protein B were rapidly oxidised by ozone but no cleavage of the peptides occurred. Neutron reflectivity revealed that the peptides remained at the air-water interface after oxidation but that their interaction with anionic phospholipids, thought to be crucial to their function, was significantly reduced. Neutron and X-ray reflectivity experiments showed that exposure of different lipid monolayers to ozone led to a loss of unsaturated phospholipid material from the interface, whereas oxidised cholesterol remained but the molecules were considerably reorganised. The ozonolysis of whole animal lung surfactant was then investigated and it was shown that material was lost from the interface during reaction and that the monolayer was much less capable of reducing surface tension. Additionally, molecular dynamics simulations were performed, determining that surfactant protein C can significantly influence the ordering of surrounding phospholipids in a monolayer and that palmitoylation of the protein leads to an increase in this ordering effect. Finally, the uses of neutron scattering to explore the oxidation of lipid membranes were investigated. It was shown that neutron reflectivity of supported phospholipid bilayers at the solid-liquid interface is a useful tool for determining their reactivity with different reactive oxygen species. Small angle neutron scattering and off-specular neutron reflectivity were also shown to be valuable methods for exploring the changes in lipid raft formation upon oxidation of phospholipids.
15
Abdallah, Suaad Audat. "Investigation of Oxidative DNA Damage from Ionizing Radiation". University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1349377002.
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16
Gillham, David J. "Aspects of chloroplast protection against photo-oxidative damage". Thesis, University of Bath, 1986. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373393.
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17
Woodall, Alan Anthony. "Carotenoids and the protection of membranes against oxidative damage". Thesis, University of Liverpool, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240900.
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18
Rehman, Almas. "Factors affecting oxidative DNA damage in the human body". Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251611.
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19
Cochemé, Helena Margaret. "Yeast as a model for investigating mitochondrial oxidative damage". Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.614040.
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20
Rajaraman, Gnana Oli [Verfasser], e Helga [Akademischer Betreuer] Stopper. "Oxidative stress : role in genomic damage and disease = Oxidativer Stress / Gnana Oli Rajaraman. Betreuer: Helga Stopper". Würzburg : Universitätsbibliothek der Universität Würzburg, 2012. http://d-nb.info/1024851885/34.
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21
Ndlebe, Thabisile S. "Oxidative Damage in DNA: an Exploration of Various DNA Structures". Diss., Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-05112006-154326/.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2007.Donald F. Doyle, Committee Member ; Bridgette Anne Barry, Committee Member ; Dr. Gary B. Schuster, Committee Chair ; Nicholas V. Hud, Committee Member ; Roger M. Wartell, Committee Member.
22
Cannan, Wendy J. "Mechanisms and Dynamics of Oxidative DNA Damage Repair in Nucleosomes". ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/628.
Testo completoAbstract (sommario):
DNA provides the blueprint for cell function and growth, as well as ensuring continuity from one cell generation to the next. In order to compact, protect, and regulate this vital information, DNA is packaged by histone proteins into nucleosomes, which are the fundamental subunits of chromatin. Reactive oxygen species, generated by both endogenous and exogenous agents, can react with DNA, altering base chemistry and generating DNA strand breaks. Left unrepaired, these oxidation products can result in mutations and/or cell death. The Base Excision Repair (BER) pathway exists to deal with damaged bases and single-stranded DNA breaks. However, the packaging of DNA into chromatin provides roadblocks to repair. Damaged DNA bases may be buried within nucleosomes, where they are inaccessible to repair enzymes and other DNA binding proteins. Previous in vitro studies by our lab have demonstrated that BER enzymes can function within this challenging environment, albeit in a reduced capacity.
Exposure to ionizing radiation often results in multiple, clustered oxidative lesions. Near-simultaneous BER of two lesions located on opposing strands within a single helical turn of DNA of one another creates multiple DNA single-strand break intermediates. This, in turn, may create a potentially lethal double-strand break (DSB) that can no longer be repaired by BER. To determine if chromatin offers protection from this phenomenon, we incubated DNA glycosylases with nucleosomes containing clustered damages in an attempt to generate DSBs. We discovered that nucleosomes offer substantial protection from inadvertent DSB formation. Steric hindrance by the histone core in the nucleosome was a major factor in restricting DSB formation. As well, lesions positioned very close to one another were refractory to processing, with one lesion blocking or disrupting access to the second site. The nucleosome itself appears to remain intact during DSB formation, and in some cases, no DNA is released from the histones. Taken together, these results suggest that in vivo, DSBs generated by BER occur primarily in regions of the genome associated with elevated rates of nucleosome turnover or remodeling, and in the short linker DNA segments that lie between adjacent nucleosomes.
DNA ligase IIIα (LigIIIα) catalyzes the final step in BER. In order to facilitate repair, DNA ligase must completely encircle the DNA helix. Thus, DNA ligase must at least transiently disrupt histone-DNA contacts. To determine how LigIIIα functions in nucleosomes, given this restraint, we incubated the enzyme with nick-containing nucleosomes. We found that a nick located further within the nucleosome was ligated at a lower rate than one located closer to the edge. This indicated that LigIIIα must wait for DNA to spontaneously, transiently unwrap from the histone octamer to expose the nick for recognition. Remarkably, the disruption that must occur for ligation is both limited and transient: the nucleosome remains resistant to enzymatic digest before and during ligation, and reforms completely once LigIIIα dissociates.
23
Clement, Amy Marie. "The Antioxidant Defense Network: Synergistic Combinations to Prevent Oxidative Damage". BYU ScholarsArchive, 2008. https://scholarsarchive.byu.edu/etd/1549.
Testo completoAbstract (sommario):
One of the matchless ironies of the human body is its requirement for the highly reactive oxygen molecule, which has been clearly implicated in many diseases and the aging processes. Oxidants produced by metabolic processes damage cells by starting chemical chain reactions including oxidation of DNA and proteins as well as lipid peroxidation. Damage to DNA can cause mutations and lead to cancer if not reversed by DNA repair mechanisms. Damage to proteins causes enzyme inhibition, denaturation and protein degradation. Lipid peroxidation can cause cell lysis as well as creating mutagenic and carcinogenic by-products. The human body contains antioxidants and enzymes that together work to prevent oxidative damage to cellular components. By and large antioxidants either prevent these reactive oxygen species from being formed or remove them before they cause damage. There are many theories currently that tout the superior nature of diverse antioxidant combinations. One such theory is by Dr. Lester Packer of The University of California at Berkley. Dr. Packer puts forth the hypothesis that there is a superlative combination of five antioxidants that have the ability to "recharge" one another both in the blood plasma and intracellularly. This would result in a greater quality of antioxidant protection for an extended time. The current study evaluates Dr. Packer's theory of antioxidant combination from his book The Antioxidant Miracle. The decay rate of the antioxidants vitamin E, vitamin C, lipoic acid, glutathione, and coenzyme Q10 alone and in combination were determined using the ORAC (Oxygen Radical Absorbance Capacity) assay. The majority of the antioxidants retained activity for longer periods of time when tested alone, rather than in combination as Dr. Packer's theory would suggest. The assay was also preformed (using the same antioxidants and combinations) on oxidatively damaged Raji cancer cells. Cell viability and uptake of antioxidants into the cytoplasm were monitored. Finally, a variety of multivitamins were subjected to the ORAC assay and their antioxidant capacity compared to that of the "Packer Combination". The results suggest that multivitamins are superior antioxidants than the Packer ratio listed in The Antioxidant Miracle.
24
Elliott, Nathan Andrew. "Prevention of Oxidative Damage by Yeast and Human OXR1: A Dissertation". eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/96.
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Hyland, Paul. "DNA damage and mutation during extended culture of T cell clones in vitro : cause or effect of finite life span?" Thesis, University of Ulster, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.232861.
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Kappler, Marion. "Response of THP-1 cells to oxidative damage induced by AAPH". Thesis, University of Canterbury. School of Biological Sciences, 2005. http://hdl.handle.net/10092/2459.
Testo completoAbstract (sommario):
Monocyte cells can be damaged when exposed to reactive oxidative species during inflammatory events within the body. This research project has examined in detail the cellular events associated with free radical damage induced death of monocyte cells, using the water soluble peroxyl radical generator 2, 2' -azobis(2-methylpropionamidine) dihydrochloride (AAPH) as a model of inflammation induced oxidative stress. The human monocyte-derived cell line THP-1 was incubated with 10mM AAPH in Earle's Balanced Salt Solution at 37°C for up to 24 hours. Protein hydroperoxide formation was observed to occur after a six hour lag, period which corresponded to the time in which most of the intracellular glutathione was lost from the cell. Cell viability loss, measured by the MTT reduction, was also observed after six hours of incubation while no caspase-3 activation was observed. A control ethanol treatment confirmed that caspase-3 could be activated within the THP-1 cells. Flow cytometry analysis failed to show phosphatidylserine exposure due to the AAPH treatment but DNA staining by propidium iodide confirmed the loss of viability seen with the MTT cell viability assay. This data strongly suggests that THP-1 cells undergo AAPH induced necrosis as a result of cellular damage including GSH loss and protein hydroperoxide formation. Microscopic examination of the cells identified many of the morphological characteristics of necrosis in the AAPH treated cells. Studies on the effect of AAPH on U937 cells were unsuccessful due to the possible presence of intracellular infection, resulting in an increased oxidant stress in the untreated cells.
27
Sohi, Gurmeet Kaur. "Measuring apparent oxidative damage to mitochondrial DNA by HIV antiretroviral therapy". Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42278.
Testo completoAbstract (sommario):
Background/objectives: HIV antiretroviral therapy, specifically nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with mitochondrial DNA (mtDNA) alterations, possibly through mtDNA oxidative damage leading to mitochondrial dysfunction, which is associated with degenerative diseases and aging. A published assay exploits that oxidative damage can slow down/inhibit DNA polymerase progression, such that the PCR amplification of damaged mtDNA template yields less product compared to undamaged mtDNA. I sought to optimize this assay using in-house tools and to quantify apparent mtDNA oxidative damage in cultured cells exposed to NRTIs.
Methods: Three DNA quantification methods were compared: PicoGreen fluorescence quantification, UV spectrophotometry, and qPCR mtDNA copy number. Human hepatocellular carcinoma cells (HepG2) were exposed to hydrogen peroxide (H₂O₂) followed by recovery time to allow mtDNA repair. To determine whether NRTI exposure induces mtDNA damage, human coronary artery endothelial cells (hCAE) cells and human colorectal adenocarcinoma cells (HT29) cells that had been exposed to various NRTIs were subjected to the assay. To assess the assay’s future applicability to clinical samples, human skeletal muscle DNA samples were also assayed.
Results: Quantification of long PCR mtDNA product by UV (CV=6.5%) and qPCR (CV=7.0%) showed lowest variability while PicoGreen quantification was noticeably higher (CV=21%). DNA from H₂O₂-exposed cells showed decreased amplification of long PCR product that increased with repair time. MtDNA depletion occurred in both cultures treated with stavudine. While there was no apparent mtDNA oxidative damage in HT29 cells with any NRTI, both tenofovir and stavudine yielded increased mtDNA oxidative damage in hCAE cells. A wide degree of apparent mtDNA oxidative damage was observed in clinical samples.
Conclusions: The preferred method for DNA quantification is qPCR mtDNA copy number. The observed mtDNA depletion indicated that NRTIs were active in both cell lines. The primary hCAE cells incurred greater mtDNA oxidative damage than cancer-derived HT29 cells. Cancer cells may have enhanced anti-oxidant mechanisms, suggesting that primary cells may be better model for studying mtDNA damage. The broad range of mtDNA damage detected in clinical samples bodes well for the assay’s use with diverse samples.
28
Stathis, Dimitrios [Verfasser]. "Oxidative DNA Damage: From Lesion Chemistry to Biological Implications / Dimitrios Stathis". München : Verlag Dr. Hut, 2012. http://d-nb.info/1025821440/34.
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Quinlan, Gregory John. "Oxidative damage to extracellular proteins and lipids during acute lung injury". Thesis, Imperial College London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281713.
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Fatima, Tehseen Zeb. "Mismatch repair in T. brucei : roles in protection against oxidative damage". Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4554/.
Testo completoAbstract (sommario):
Cells are continuously exposed to different intracellular and extracellular mutagens, which can damage several different molecules, including DNA. To ensure survival, cells have evolved various defence and repair mechanisms. Mismatch repair (MMR) is the mechanism that serves to repair mismatched bases in DNA that are missed by the proof reading activity of DNA polymerases. Besides this, MMR also corrects base mismatches formed by altered bases modified by certain chemical mutagens. Thus, MMR is important to avoid mutagenesis and maintain genome fidelity. MMR is a complex, highly conserved pathway that involves a range of proteins along with several accessory proteins. In T. brucei, as in other eukaryotes, MMR core functions are carried out by bacterial MutS and MutL homologues, working as heterodimers: MSH2α (MSH2-MSH3) and MSH2β (MSH2-MSH6), and MLH1-PMS1, respectively. To date, only MSH2 and MLH1 function have been examined and only in bloodstream form (BSF) T. brucei cells. It was observed that MMR mutants are tolerant towards methylation damage, exhibit microsatellite instability and display elevated rates of homologous recombination between imperfectly matched DNA molecules. This confirmed the role of MMR in genome maintenance in BSF T. brucei. More recently, it was observed that BSF MSH2 mutants were sensitive towards oxidative damage, though the same phenotype was not observed in MLH1 mutants. This suggests that some aspect of the MMR machinery acts to protect BSF T. brucei cells against oxidative stress, but the machinery and mode of action is unknown. In this study we have generated null mutants of MSH2 and MLH1 in procyclic form (PCF) T. brucei cells, and MSH3 and MSH6 mutants in BSF cells. Characterization of tolerance to DNA methylation damage and evaluating microsatellite stability shows that each gene acts in MMR in both the life cycle stages, with the exception of MSH3, where null mutants show no discernible phenotypes. Mutants were also analyzed for their action towards oxidative stress in both the life stages and, remarkably, we find life cycle stage differences, with MSH2 mutants displaying hydrogen peroxide sensitivity and resistance in the BSF and PCF, respectively. The same phenotypes are not seen in MLH1 mutants, and we show that resistance to hydrogen peroxide in PCF cells is due to adaptation during the loss of MSH2. We have also shown that PCF MSH2 mutants may show a decrease in microsatellite instability when subjected to oxidative stress. This leads to the hypothesis that there might be an unidentified system, apart from MMR, present in T. brucei PCF cells that works as a defence in response to oxidative stress and can assume greater prominence when MSH2 is lost. Although we have tried to explore various cellular processes that might contribute this activity, our results are inconclusive. MSH2 and MLH1 have also been epitope tagged to explore the subcellular localization of these proteins and to ask if any changes in expression levels or changes in localisation are seen when subjected to oxidative stress. These preliminary data suggest that both factors are nuclear and cytoplasmic. We have also tried to ask if MSH2 and/or MLH1 co-localize with either MSH5 or MSH4, which are MutS-like factors that act in meiosis in other eukaryotes, but whose functions have not been explored in T. brucei. However, our attempts at this analysis have been unsuccessful.
31
Allen, William Joseph. "Practical Applications of Molecular Modeling Pertaining to Oxidative Damage and Disease". Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/78000.
Testo completoAbstract (sommario):
Molecular modeling is a term referring to the study of proteins, nucleic acids, lipids, and other bio- or macro- or small molecules at the atomistic level using a combination of computational methods, physico-chemical principles, and mathematical functions. It can be generally sub-divided into two areas: molecular mechanics, which is the treatment of atoms and bonds as Newtonian particles and springs, and quantum mechanics, which models electronic behaviors using the Schrödinger equation and wavefunctions. Each technique is a powerful tool that, when used alone or in combination with wet lab experiments, can yield useful results, the products of which have broad applications in studying human disease models, oxidative damage, and other biomolecular processes that are otherwise not easily observed by experiment alone. Within this document, we study seven different such systems. This includes the mode of inhibitor binding to the enzyme monoamine oxidase B, the active site mechanism of that same enzyme, the dynamics of the unstructured p53 C-terminal domain in complex with globular, structured proteins, the process of the viral protein B2 unbinding from double-stranded RNA, and a focus on the dynamics of a variable loop in the antigenic peanut protein Ara h 2. In addition to those conventional molecular modeling studies, several of which were done in tandem with wet lab experiment, we also discuss the validation of charges and charge group parameters for small molecules used in molecular mechanics, and the development of software for the analysis of lipid bilayer systems in molecular mechanics simulations. As computational resources continue to evolve, and as more structural information becomes available, these methods are becoming an integral part of the study of biomolecules in the context of disease.Ph. D.
32
Bhatkhande, Prajakta S. "Small Molecule Biomarkers Resulting from Radiation and Oxidative Damage to DNA". University of Toledo / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470222983.
Testo completo
33
Ye, Wenjie Ball Louise M. "Oxidative damage to guanine in DNA caused by reactive oxygen species". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,2457.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Environmental Sciences and Engineering,Gillings School of Global Public Health." Discipline: Environmental Sciences and Engineering; Department/School: Public Health.
34
Mikhed, Yuliya [Verfasser]. "The role of DNA damage in the pathogenesis of nitrate tolerance - nitrosative versus oxidative DNA damage / Yuliya Mikhed". Mainz : Universitätsbibliothek Mainz, 2015. http://d-nb.info/1080187529/34.
Testo completo
35
Shaik, Raziya. "Photochemical Generation of the C5' -Uridinyl and Pseudouridinylradical for the Study of Oxidative Damage in RNA". University of Toledo / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1384518841.
Testo completo
36
Alabarse, Paulo Vinicius Gil. "Estresse oxidativo e envelhecimento no encéfalo de ratos machos reprodutores". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/30205.
Testo completoAbstract (sommario):
A reprodução é capaz de alterar muitos parâmetros relacionados à fisiologia, ao comportamento e à morfologia em vertebrados machos. Trabalhos apresentam relação entre reprodução ou envelhecimento com estresse oxidativo, não havendo trabalho relacionando estresse oxidativo, reprodução e envelhecimento simultaneamente em mamíferos. Para avaliar o estresse oxidativo no encéfalo de ratos machos decorrente da atividade reprodutiva e ao longo do envelhecimento (3, 6, 12 e 24 meses) comparado a animais sem atividade reprodutiva (n = 10 por grupo e por idade), avaliou-se a atividade de enzimas antioxidantes (catalase, glutationa peroxidase, superóxido dismutase, glutationa Stransferase); os níveis de moléculas antioxidantes (glutationa oxidada e reduzida, vitamina C e E); os marcadores de dano oxidativo (peroxidação lipídica, carbonilação de proteínas, nitritos e nitratos), bem como o status oxidante total e a atividade da enzima metabólica aconitase no encéfalo, e os níveis de testosterona e estradiol no soro. ANOVA, seguido do post hoc de Tukey, foi utilizado para avaliar a diferença estatística entre os grupos. Correlação de Spearman e Regressão Linear (método stepwise) foram utilizadas para avaliar alterações relacionadas entre os parâmetros. Os animais machos com atividade reprodutiva apresentaram elevada concentração de testosterona e atividade da aconitase, sugerindo um metabolismo mais elevado que os sem atividade reprodutiva. A atividade das enzimas antioxidantes e a quantidade de moléculas antioxidantes também foram mais elevadas em diversos grupos de animais reprodutores, mas o dano oxidativo mais elevado também foi observado nesses grupos de animais reprodutores. Alterações relacionadas ao envelhecimento foram observadas em ambos os grupos, não havendo padrão. Observou-se elevada atividade das enzimas antioxidantes, bem como maiores danos, no grupo dos animais reprodutores de 6 meses. Nos animais mais velhos (24 meses), observam-se similares níveis dos marcadores de dano oxidativo, atividade de algumas enzimas antioxidantes e de moléculas antioxidantes entre os grupos. Do complexo emaranhado de correlações e regressões observado nesse sistema, destaca-se a influência do envelhecimento nos níveis de testosterona, nitritos e nitratos e na atividade das enzimas aconitase, catalase e glutationa Stransferase (coeficiente padronizado B = 0,53; 0,31; 0,39; 0,78 e 0,23, respectivamente). Os níveis de testosterona se correlacionaram positivamente com diversos parâmetros: catalase 73%, superóxido dismutase 71%, peroxidação lipídica 43%, nitritos e nitratos 50%, aconitase 46% e aconitase reativada 47%. Sugere-se que a atividade reprodutiva eleva o metabolismo, tanto por estímulo hormonal quanto por outras alterações, e.g. alteração comportamental, levando a elevada produção de espécies reativas, causando dano oxidativo e elevando a atividade e a quantidade das defesas antioxidantes. Esses resultados auxiliam na compreensão das alterações causadas pela reprodução relacionadas ao envelhecimento em nível de estresse oxidativo, e sugere bases para explicar os custos relacionados à reprodução.Reproduction causes changes in male vertebrates, including morphological, behavioral, and physiological alterations. Reproduction and aging may alter oxidative stress, but there is no research concerning oxidative stress and reproduction during aging in mammals. We performed a comprehensive study to examine oxidative stress in the brains of male rats with (experienced) or without (naïve) reproductive activity during aging (3, 6, 12, and 24 months of age). Oxidative stress was assessed by measuring the antioxidant enzymes activity (catalase, glutathione peroxidase, superoxide dismutase, glutathione S-transferase), the amount of non-enzymatic compounds (reduced and oxidized glutathione, vitamin C and E), the levels of oxidative damage markers (lipid peroxidation, protein carbonylation, nitrite and nitrate) as well as total oxidant status, and the aconitase metabolic enzyme activity in brain, and the levels of testosterone and estradiol in serum. ANOVA, followed by Tukey post hoc, was used to analyze statistical differences among groups. Spearman Correlation and Linear Regression (stepwise method) were used to analyze relation among parameters. Reproductively active animals exhibited increased testosterone levels and aconitase activity, suggesting an increased metabolism. Despite the Increased antioxidant enzyme activities and increased levels of antioxidant compounds were observed, damage to biomolecules was also observed in experienced rats. During aging changes in oxidative stress were observed in all groups, but no pattern was observed. We found higher activities of antioxidant enzymes, higher amounts of antioxidants, contrasting with higher damage at six months of age between experienced than naïve animals. Some similarities were found in antioxidant activities and levels, and damage between the groups at twenty-four months of age. Correlations and regressions show a very complex web of interactions among the parameters. Aging exerted influence in testosterone, nitrites and nitrates levels, in the aconitase, catalase, and glutathione Stransferase activities (adjusted B value of = -0.53; -0.31; - 0.39; -0.78; and 0.23, respectively). Testosterone levels positively correlated with: catalase 73%, superoxide dismutase 71%, lipid peroxidation 43%, nitrites and nitrates 50%, aconitase 46%, and reactivated aconitase 47%. We suggest that reproductive activity increases metabolism, by hormonal stimuli as by others factors, e.g. behavioral change, and this changes lead to increased production of reactive species, which lead to oxidative damage and increases the antioxidant enzymes activity and non-enzymatic amount. These results add comprehensive data regarding changes in oxidative stress during aging, and suggest an explanation for the costs of reproduction.
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Bona, Silvia Regina. "Melatonina protege o fígado em um modelo experimental de cirrose". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/129635.
Testo completoAbstract (sommario):
Base teórica: As doenças hepáticas representam um grande problema de saúde pública, sendo responsáveis por um considerável número de atendimentos e internações hospitalares, com crescente índice de mortalidade. A melatonina (MLT), uma potente molécula antioxidante, tem-se mostrado benéfica em diversas situações patológicas, incluindo as hepáticas. Objetivo: O objetivo foi avaliar os efeitos da MLT na cirrose hepática induzida por CCl4 em ratos machos Wistar. Métodos: Utilizaram-se 20 ratos machos Wistar, (230-250g), divididos em 4 grupos: I: Controle (CO), II: CO+MLT, III: CCl4 e IV: CCl4+MLT. O CCl4 foi administrado i.p.: 10 aplicações de 5 em 5 dias, 10 aplicações de 4 em 4 dias, e 7 aplicações de 3 em 3 dias. A MLT (20mg/Kg i.p.) iniciada na 10ª semana, perdurando até o final do experimento na 16ª semana. Resultados: Como resultados apresentados nos dois artigos, observamos que a MLT no grupo CCl4+MLT, em relação ao grupo CCl4, diminuiu os níveis séricos das enzimas AST, ALT e FA. Na avaliação do estresse oxidativo, diminuiu a LPO avaliada por TBARS e F2-isoprostanos; aumentou a atividade da enzima antioxidante (SOD) e diminuiu a expressão da NQO1; aumentou a expressão do fator de transcrição Nrf2 e diminuiu a expressão de seu inibidor o Keap1. Na avaliação do estresse do RE, diminuiu a expressão de proteínas preditoras de estresse do RE, GRP78 e ATF6. Na avaliação das proteínas e fatores de choque térmico, diminuiu a expressão da HSP70 e do HSF1. No processo inflamatório, diminuiu a presença de infiltrado inflamatório e a expressão das proteínas NF-KB/p65 e da iNOS. No processo fibrogênico, diminuiu os septos e a presença de nódulos de fibrose, além de diminuir a expressão das proteínas TGF-β1 e da α-SMA. No processo de angiogênese, diminuiu a expressão do VEGF. Conclusão: Com este estudo, demonstramos que a MLT, uma indolamina sintetizada a partir do aminoácido triptofano, protegeu o parênquima hepático da progressão da fibrose induzida em ratos pelo CCl4.Background: Conclusion Liver diseases represent a major problem in public health, accounting for a significant number of hospitalizations and care, with increasing mortality rates. Melatonin (MLT) is a powerful antioxidant molecule, that has demonstrated to be beneficial in various pathological situations, including liver diseases. Objective: The aim was to evaluate the effects of MLT in liver cirrhosis induced by CCl4 in male Wistar rats. Methods: We used 20 male Wistar rats (230- 250g) divided into 4 groups: I : control (CO), II: CO + MLT, III: CCl4 and IV: CCl4 + MLT. The CCl4 was administered ip: 10 applications in 5 to 5 days , 10 applications in 4 to 4 days and 7 applications in 3 to 3 days. The MLT (20 mg / kg ip) started at the 10th week and lasted until the end of the experiment, at 16 weeks. Results: As results presented in the two articles, we found that the MLT in the CCl4+MLT group when compared to CCl4 group, decreased serum levels of AST, ALT and FA enzymes. In the evaluation of oxidative stress, decreased LPO measured by TBARS and F2- isoprostanes; increased the activity of the antioxidant enzyme (SOD) and decreased the expression of NQO1; increased expression of the transcription factor Nrf2 and decreased the expression of its inhibitor Keap1. In the assessment of ER stress, decreased the expression of proteins predictors of ER stress, GRP78 and ATF6. In the evaluation of proteins and heat shock factors, decreased expression of HSP70 and HSF1. In the inflammatory process, decreased inflammatory infiltration and the expression of proteins NF-KB/p65 and iNOS. In the fibrogenic process, decreased the sept and the presence of nodules of fibrosis, in addition to decreasing the expression of TGF-β1 protein and α-SMA. In the process of angiogenesis, decreased expression of VEGF. Conclusion: In this study, we demonstrated that MLT, an indoleamine synthesized from tryptophan, protected the liver parenchyma from fibrosis progression induced by CCl4 in rats.
38
Sadi, Gokhan. "Oxidative Damage And Regulation Of Antioxidant Enzymes In Streptozotocin Induced Diabetic Rats". Phd thesis, METU, 2009. http://etd.lib.metu.edu.tr/upload/2/12611222/index.pdf.
Testo completoAbstract (sommario):
Increased oxidative stress and impaired antioxidant defense mechanisms are believed to be the important factors contributing to the pathogenesis and progression of diabetes mellitus. The products of lipid peroxidation and protein oxidation reactions were all found to be elevated significantly (p<0.05) in diabetic animals and supplementing the animals either individually or in combination, with two powerful antioxidants DL-&
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-lipoic acid (LA) and vitamin C (VC) brought this increment toward the control values. Considering Cu-Zn SOD, CAT and GST-Mu, there was a significant decrease in all activities in diabetic group as compared with control animals. RT-PCR and Western blot analysis results demonstrated that this decrease in activity is regulated at the level of gene expression, as both mRNA and protein expressions were also suppressed for these enzymes. However, in diabetic animals both the mRNA expressions and the activities of two other antioxidant enzymes, namely Mn SOD and GPx, did not change, indicating that the control of activities of these two enzymes were not at the level of genes. Supplementing the diabetic animals with VC increased all CAT, Cu-Zn SOD, GPx, and GST-Mu activities without changing both mRNA and protein expressions suggesting the possible role of post-translational modifications. On the other hand, the effect of VC on Mn SOD was observed at mRNA levels reflecting a transcriptional regulation. Furthermore, supplementing the animals with LA increased the CAT, Cu-Zn SOD, Mn SOD and GPx activities in diabetic rats but different from VC, LA also increased mRNA of CAT and protein levels of CAT, Cu-Zn SOD and Mn SOD suggesting both transcriptional and translational regulation showed by LA. Combined application of antioxidants also increased the CAT, Cu-Zn SOD, Mn SOD and GPx activities toward the control values, but this time there were no statistically significant change in their mRNA expressions even though protein amounts of both CAT and GPx were augmented. That is, when given together, these antioxidants exert their effects mainly at the level of protein synthesis. As a conclusion, diabetes and the resulting oxidative stress coordinately regulate the activities of the antioxidant enzymes at different regulatory points. LA and VC, two powerful antioxidants affect all antioxidant enzyme activities at different levels of transcription and translation. The results indicated the presence of very intricate control mechanisms regulating the activities of antioxidant enzymes in order to prevent the damaging effects of oxidative stress.
39
Xu, Meng. "Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair". FIU Digital Commons, 2014. http://digitalcommons.fiu.edu/etd/1576.
Testo completoAbstract (sommario):
Trinucleotide repeat (TNR) expansion is the cause of more than 40 types of human neurodegenerative diseases such as Huntington’s disease. Recent studies have linked TNR expansion with oxidative DNA damage and base excision repair (BER). In this research, we provided the first evidence that oxidative DNA damage can induce CAG repeat deletion/contraction via BER. We found that BER of an oxidized DNA base lesion, 8-oxoguanine in a CAG repeat tract, resulted in the formation of a CTG hairpin at the template strand. DNA polymerase β (pol b) then skipped over the hairpin creating a 5’-flap that was cleaved by flap endonuclease 1 (FEN1) leading to CAG repeat deletion. To further investigate whether BER may help to shorten an expanded TNR tract, we examined BER in a CAG repeat hairpin loop. We found that 8-oxoguanine DNA glycosylase removed the oxidized base located in the loop region of the hairpin leaving an abasic site. Apurinic/apyrimidinic (AP) endonuclease 1 then incised the 5’-end of the abasic site leaving a nick in the loop. This further converted the hairpin into an intermediate with a 3’-flap and a 5’-flap. As a 5’-3’ endonuclease, FEN1 cleaved the 5’-flap, whereas a 3’-5’ endonuclease, Mus81/Eme1, removed the 3’-flap. The coordination between FEN1 and Mus81/Eme1 ultimately resulted in removal of a CAG repeat hairpin attenuating or preventing TNR expansion. To further explore if pol β bypass of an oxidized base lesion, 5’,8-cyclodeoxyadenosine, may affect TNR instability, we examined pol β DNA synthesis in bypassing this base lesion and found that the lesion preferentially induced TNR deletion during BER and Okazaki fragment maturation. The repeat deletion was mediated by the formation of a loop in the template strand induced specifically by the damage. Pol β then skipped over the loop structure creating a 5’-flap that was efficiently removed by FEN1 leading to repeat deletion. Our study demonstrates that pol β-mediated BER plays an important role in mediating TNR deletion and removing a TNR hairpin to prevent TNR expansion. Our research provides a molecular basis for further developing BER as a target for prevention and treatment of neurodegenerative diseases caused by TNR expansion.
40
Struthers, Louise. "An investigation of DNA damage induced by oxidative stress in neuronal cells". Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/29576.
Testo completoAbstract (sommario):
This project aimed to investigate the hypothesis that oxidative DNA damage has a role in neuronal dysfunction. Reactive oxygen species (ROS) are known to damage important cellular macromolecules, including DNA. They have been implicated in many pathological conditions, including common neurodegenerative disorders, but the mechanisms of cellular dysfunction and death involved remain unclear. Oxidative DNA damage was therefore studied in an in vitro model system and pathological tissue. A novel, sensitive assay based on the fortuitous finding that avidin binds directly to the DNA lesion 8-oxodeoxyguanosine (8-oxodG) was used in these investigations. Pre-lethal DNA damage was assessed in terminally differentiated human neuroblastoma IMR32 cultures after exposure to various forms of oxidative stress (hydrogen peroxide, UVA irradiation and paraquat). Avidin binding was significantly increased in these cells, indicating the presence of oxidative DNA damage; repairable and non-repairable damage were both detected. Binding was decreased by pre-incubation with the antioxidant -tocopherol or iron chelator desferrioxamine, demonstrating the involvement of ROS in the mechanism of DNA damage induced during oxidative stress. Avidin binding was also assessed visually in cells exposed to hydrogen peroxide via fluorescent microscopy, and was shown to be located primarily within the nucleus. Once again, levels of damage were decreased after incubation with -tocopherol. Finally preliminary studies were carried out to assess levels of oxidatively-damaged DNA in spinal cord sections from patients suffering from MND compared to age-matched control subjects. Binding was once again detected directly in situ using immunofluorescence microscopy. The novel methodology used allows the demonstration of oxidative DNA damage directly in situ. The direct demonstration of damage may help elucidate the mechanisms involved in cellular dysfunction produced by oxidative stress, and so might provide a greater understanding of the causes of the most common neurodegenerative diseases.
41
Wang, Jen-Yeu. "Human PC4 Prevents Mutagenesis and Killing by Oxidative DNA Damage: a Dissertation". eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/287.
Testo completoAbstract (sommario):
Chapter II Abstract
Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Saccharomyces cerevisiae mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide-induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub1Δ mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show that XPG recruits PC4 to a bubble-containing DNA substrate with a resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate.
Chapter III Abstract
Previously I established that (1) PC4 significantly suppresses oxidative mutagenesis via its single-strand DNA binding activity, (2) a partial suppression of H2O2-induced lethality was observed in a sub1Δ rad2Δ yeast double mutant compared to the sub1Δ mutant, and (3) PC4 interacts with XPG physically and functionally. These results led me to believe that suppression of oxidative mutagenesis and lethality by PC4 is partially due to its function in an XPG/Rad2-dependent pathway and through additional unidentified mechanism(s). In this chapter, I present studies aimed at investigating different DNA repair pathways in which PC4/Sub1 might participate. I address the possible roles of PC4/Sub1 in transcription-coupled repair (TCR) in terms of its binding specificity to oxidative DNA lesions and its ability to allow efficient resumption of transcription after oxidative DNA damaging treatment. To ask if PC4/Sub1 interacts with other DNA repair proteins to protect cells from oxidative DNA damage, I analyzed spontaneous mutation rates among a series of isogenic, haploid yeast mutant strains deficient of SUB1, base excision repair (BER) and/or nucleotide excision repair (NER) functions. I further analyzed genetic interactions between SUB1 and genes critical to various DNA damage avoidance/tolerance mechanisms, such as mismatch repair (MMR), homologous recombination (HR) and translesion synthesis (TLS).
42
Eyre, Tina Ann. "Informatic analysis of proteins with a role in oxidative damage and ageing". Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445475/.
Testo completoAbstract (sommario):
Ageing is a complex, universal process that remains very poorly understood, particularly in mammals. This thesis attempts to increase our understanding of ageing by predicting the structure of the uncoupling proteins, membrane proteins with a possible role in the modulation of oxidative damage, and therefore of ageing. A 3-dimensional model of the uncoupling proteins is generated, based on an analysis of known membrane proteins structures. In order to assess the accuracy of this model it is compared to the actual structure of a homologous protein, solved after the modelling was complete. A homology packing model is produced that, in combination with predictions of likely functional residues, will be of use in establishing the mechanism of action of the uncoupling proteins. Additionally, this thesis investigates the regulation of ageing by the insulin-like signalling pathway and the transcription factor DAF-16. Longevity- and ageing-associated transcription factor binding sites are identified, due to their over- or under-representation within genes regulated by this pathway. Direct and indirect DAF-16 target gene classes are identified, and possible mechanisms of feedback control of the pathway are investigated, including the identification of other transcription factors whose expression is regulated by DAF-16. Although this work is a valuable starting point, considerable further work will be required before a full understanding of the regulation of ageing is obtained. Finally, this thesis has provided insights into membrane protein structure and its pre diction. A comprehensive analysis of these structures was performed and the results used to develop a modelling method that is applicable to structure prediction for all membrane proteins. Although buried transmembrane helix faces were identified with relatively high accuracy, a greater understanding of membrane protein structure is required before reliable 3-dimensional models can be produced using this method. The opening of a structural genomics project focused on membrane proteins is helping to bring the realisation of this aim closer to the present. This work was generously supported by the Biotechnology and Biological Sciences Research Council.
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Bedi, Fernand Mel. "Synthesis and Fate of Oligonucleotides Containing the Oxidative Damage Product 3'-Oxothymidine". University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1429183009.
Testo completo
44
Wang, Jen-Yeu. "Human PC4 Prevents Mutagenesis and Killing by Oxidative DNA Damage: a Dissertation". eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/287.
Testo completoAbstract (sommario):
Chapter II Abstract
Human positive cofactor 4 (PC4) is a transcriptional coactivator with a highly conserved single-strand DNA (ssDNA) binding domain of unknown function. We identified PC4 as a suppressor of the oxidative mutator phenotype of the Escherichia coli fpg mutY mutant and demonstrate that this suppression requires its ssDNA binding activity. Saccharomyces cerevisiae mutants lacking their PC4 ortholog Sub1 are sensitive to hydrogen peroxide and exhibit spontaneous and peroxide-induced hypermutability. PC4 expression suppresses the peroxide sensitivity of the yeast sub1Δ mutant, suggesting that the human protein has a similar function. A role for yeast and human proteins in DNA repair is suggested by the demonstration that Sub1 acts in a peroxide resistance pathway involving Rad2 and by the physical interaction of PC4 with the human Rad2 homolog XPG. We show that XPG recruits PC4 to a bubble-containing DNA substrate with a resulting displacement of XPG and formation of a PC4-DNA complex. We discuss the possible requirement for PC4 in either global or transcription-coupled repair of oxidative DNA damage to mediate the release of XPG bound to its substrate.
Chapter III Abstract
Previously I established that (1) PC4 significantly suppresses oxidative mutagenesis via its single-strand DNA binding activity, (2) a partial suppression of H2O2-induced lethality was observed in a sub1Δ rad2Δ yeast double mutant compared to the sub1Δ mutant, and (3) PC4 interacts with XPG physically and functionally. These results led me to believe that suppression of oxidative mutagenesis and lethality by PC4 is partially due to its function in an XPG/Rad2-dependent pathway and through additional unidentified mechanism(s). In this chapter, I present studies aimed at investigating different DNA repair pathways in which PC4/Sub1 might participate. I address the possible roles of PC4/Sub1 in transcription-coupled repair (TCR) in terms of its binding specificity to oxidative DNA lesions and its ability to allow efficient resumption of transcription after oxidative DNA damaging treatment. To ask if PC4/Sub1 interacts with other DNA repair proteins to protect cells from oxidative DNA damage, I analyzed spontaneous mutation rates among a series of isogenic, haploid yeast mutant strains deficient of SUB1, base excision repair (BER) and/or nucleotide excision repair (NER) functions. I further analyzed genetic interactions between SUB1 and genes critical to various DNA damage avoidance/tolerance mechanisms, such as mismatch repair (MMR), homologous recombination (HR) and translesion synthesis (TLS).
45
Coombs, Anne-Marie. "A study of near-ultraviolet radiation induced oxidative damage in Escherichia coli". Thesis, University of Bath, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.380929.
Testo completo
46
Holbrook, Kailea J. Ms. "Effects of Acclimation on Temperature Tolerance and Oxidative Damage in Daphnia magna". Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etd/3068.
Testo completoAbstract (sommario):
Freshwater zooplankton crustacean Daphnia frequently face strong temperature fluctuations in its natural environment, which necessitates adaptive plastic responses. This study focuses on changes in lipid peroxidation and total oxidative capacity in Daphnia tissues in response to long-term and short-term temperature changes.
Long-term acclimation to 28ºC helped Daphnia survive longer at lethally high temperatures. This difference, however, was not accompanied by changes in lipid peroxidation, indicating that it isn’t a good measure of damage or predictor of temperature tolerance.
On the other hand, total oxidation capacity was lower 28ºC- than in 18ºC-acclimated Daphnia, suggesting that acclimation resulted in higher amounts of antioxidants in Daphnia tissues. Exposure to hypoxia, known to up-regulate antioxidant pathways in Daphnia, further elevated heat tolerance in 28ºC- acclimated individuals. Yet, manipulations of glutathione, an important antioxidant, while predictably affecting oxidative capacity, didn’t influence heat tolerance in Daphnia, suggesting that other antioxidants may play a significant role in it.
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Ghosh, Avik Kumar. "Charge migration and one-electron oxidation at adenine and thymidine containing DNA strands and role of guanine N1 imino proton in long range charge migration through DNA". Diss., Available online, Georgia Institute of Technology, 2007, 2007. http://etd.gatech.edu/theses/available/etd-05132007-000502/.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2008.Wartell, Roger, Committee Member ; Bunz, Uwe, Committee Member ; Doyle, Donald, Committee Member ; Fahrni, Christoph, Committee Member ; Schuster, Gary, Committee Chair.
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Timms, Andrew Robert. "Spontaneous mutagenesis in stressed Escherichia coli". Thesis, Open University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244410.
Testo completo
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Wolfreys, Alison Mandy. "Molecular mutation spectra of 6-thioguanine resistant human T-lymphocyte and UV-irradiated lymphoblastoid mutants". Thesis, University of Sussex, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266549.
Testo completo
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Lassen, Natalie. "Roles of aldehyde dehydrogenases (ALDHs) against oxidative stress /". Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2006.
Cerca il testo completoAbstract (sommario):
Thesis (Ph.D. in Toxicology) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 119-138). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;