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Oxidative Stress Susceptibility of Oligodendrocytes in Major Depressive Disorder is Widespread in the BrainCoulthard, Jacob, Ongtengco, Westley, Garst, Jacob, Chandley, Michelle, Wang-Heaton, Hui, Ordway, Gregory A. 05 April 2018 (has links)
Over 10 million people are affected by major depressive disorder (MDD) in the U.S. annually. Unfortunately, about 1/3 of these people do not achieve adequate remission of symptoms with current antidepressant drugs. It is expected that an improved understanding of the pathobiology of depression will result in the development of more effective antidepressant treatments. Research by this lab in recent years has provided evidence of elevated DNA damage in brain white matter in MDD, discovered by studying brain tissues from human brain donors that had an active diagnosis of MDD at the time of death and age-matched control donors who had no psychiatric illness. Accompanying this DNA damage was an elevation of gene expression of DNA base excision repair enzymes in white matter oligodendrocytes, a major cell type in brain white matter. In addition, gene expression of antioxidant genes in these oligodendrocytes was significantly lower in MDD than in control donors, suggesting that these cells were especially susceptible to the damaging effects of oxidative stress in MDD. This initial data was generated by measuring gene expressions in oligodendrocytes captured from two specific regions of white matter in the brain, the frontal cortex, and amygdala. In the present study, we designed experiments to determine whether these effects are found in oligodendrocytes in other areas of the brain in MDD and to determine whether another cell type in the brain, neurons, are similarly affected. Towards these aims, oligodendrocytes from two other brain regions (occipital cortical white matter and brainstem locus coeruleus) were captured by laser microdissection from MDD and control donors. In addition, CA1 pyramidal neurons were captured from the anterior hippocampus of MDD and control donors. We chose to specifically study hippocampal CA1 pyramidal neurons because these neurons are normally sensitive to oxidative stress, and reasoned that these cells would be among brain neurons most likely affected by conditions of elevated oxidative stress in MDD. Approximately 500 cells were captured from each brain area using immunohistochemically-guided laser capture microdissection. RNA isolated from these cells was converted to cDNA by reverse transcription and subjected to quantitative polymerase chain reactions (PCR). Statistically significant reductions in antioxidant gene expression was observed in oligodendrocytes from MDD donors as compared to control donors regardless of the brain area from which the cells were captured. In contrast, no significant changes in antioxidant gene expression were observed in CA1 pyramidal neurons from MDD donors. Additionally in contrast to findings in oligodendrocytes, levels of gene expression of the DNA repair enzyme, poly(ADP-ribose) polymerase 1 (PARP1) in hippocampal CA1 pyramidal neurons from MDD donors was similar to that from control donors. These findings demonstrate that pathological DNA damage and repair mechanisms occur in brain oligodendrocytes throughout the brain, and similar mechanisms do not appear to affect hippocampal neurons. A better understanding of the cellular systems engaged by oxidative damage to oligodendrocytes in MDD has the potential to lead to the identification of unique targets for the development of novel antidepressant drugs.
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Dopamine Cell Loss within the Nigrostriatal Pathway Due to Oxidative Stress from Chronic MethylphenidateMcWethy, David, Oakes, Hannah, Ketchem, Shannon, Ensley, Tucker, Dema, Blerim, Pond, Brooks B 12 April 2019 (has links)
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects 11% of children in the US alone. Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of ADHD. Given the fact that ADHD symptoms persist in up to 50% of patients, many children receive MPH from childhood to early adulthood. Unfortunately, most of the scientific literature focuses on the short-term consequences of MPH, even though individuals are taking MPH for many years. Previous research has shown that long-term exposure to MPH causes dopamine-releasing neurons within the nigrostriatal pathway to die when exposed to the Parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPH acts by blocking dopamine transporters and norepinephrine transporters, preventing the reuptake and removal of these neurotransmitters following release and increasing the time outside of the protective environment of the neuron’s vesicles. We hypothesize that spontaneous oxidation of excess dopamine to a quinone metabolite is rendering these neurons within this particular pathway to be more sensitive to MPTP. The dopamine quinone may be bound by the antioxidant glutathione (GSH) in an effort to protect the cell against oxidative stress. However, as the finite amount of GSH is depleted, the quinone may lead to the production of highly reactive molecules, leading to mitochondrial damage and cell death which may be accelerated by MPTP. In order to examine this hypothesis, we chose to study adolescent male Swiss-Webster mice, which have been shown to be resistant to MPTP’s toxic effects. They were divided into 3 cohorts and administered either saline (control), 1 mg/kg MPH (therapeutic dose) or 10 mg/kg (abusive dose) via intraperitoneal (IP) injections for 12 weeks. Mice were injected twice daily, Monday through Friday, mimicking a school-week dosing schedule. After 12 weeks, all animals received a drug washout period of 7 days. Then, half of each cohort was treated with MPTP (4 x 20 mg/kg, every 2 hours), while the other half was administered 4 injections of sterile saline. Either 3 or 7 days after MPTP or saline treatment, the mice were sacrificed, brains were removed, and the substantia nigra (SN) and striatum (STR) were collected. These areas of the brain make up the nigrostriatal pathway and are affected by Parkinson’s disease. Oxidative stress related to increased dopamine levels was determined using the glutathione assay to measure GSH content, near-infrared fluorescence dot blots to measure free and protein-bound ortho-quinones, and an ATP luciferase assay to measure mitochondrial function. Interestingly, there was a significant decrease in GSH as the dose of MPH was increased with both saline and MPTP samples. Furthermore, a significant increase in quinones was observed as the dose of MPH increased. We also expect to see a decrease in ATP inversely proportional to the dose of MPH indicating increased oxidative stress. In conclusion, it appears that long-term exposure to MPH sensitizes dopaminergic neurons within the nigrostriatal pathway to oxidative stress, rendering them vulnerable to further insults, such as MPTP exposure. As such, these studies provide insight into the risks of long-term psychostimulant exposure.
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Isolation and Bioassay evaluation of Angiotensin Converting Enzyme inhibitory compounds of Centella asiaticaIchoku, Emmanuel January 2019 (has links)
Magister Pharmaceuticae - MPharm / Hypertension is by far the most common risk factor for cardiovascular disease (CVD), which has been identified as the leading cause of death worldwide and a major economic burden in developing countries. Over the years, there has been an increased interest in isolating and identifying bioactive compounds from medicinal plant, with the aim of finding alternative sources of therapy to some of the problematic synthetic drugs and to validate the therapeutic use of some traditional plants. The renin angiotensin aldosterone system is a key regulator of blood pressure, on which ACE (Angiotensin Converting Enzyme) inhibitors act and have been at the forefront of therapeutic strategy for treatment and management of hypertension and CVD. But despite the success of ACEI’s, their long term use has been associated with side- effects coupled with its contraindication in pregnancy. The plant of interest, Centella asiatica is a widely known medicinal plant, used in treatment of a variety of conditions including hypertension. There is currently no scientific evidence validating its claimed use in hypertension. This study therefore, investigated the ACE inhibitory effects of Centella asiatica.
Crude methanol, ethanol and aqueous extracts of Centella asiatica were assayed for ACE inhibition activity. Methanol and ethanol crude extract(s) was subjected to a bioassay guided fractionation process to isolate and identify the active compounds. A fluorescence based ACE assay was utilized at various stages of the process including HPLC purification stage to screen the fractions and compounds for ACE inhibition activity.
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Identification of MALAT1 as a PRC2-Ezh1 Associated lncRNA Essential for Epigenetic Control of Skeletal Muscle Adaptation and PlasticityEl Said, Nadine H. 08 1900 (has links)
Polycomb Proteins (PcG) are chromatin proteins that control the maintenance of
“transcriptional memory” and cell identity by fixing the repressed state of developmentally regulated genes. This function has been linked to interaction with RNA moieties, in particular long non-coding RNAs (lncRNAs). However, specificity of PcG-RNA interactions has been controversial (Beltran et al., 2016; Chen Davidovich, Leon Zheng, Karen J. Goodrich, & Thomas R. Cech, 2013). In this study we took advantage of recent work published from our lab reporting about a novel and reversible mechanism regulating genome wide Ezh1-PRC2 activation in mouse skeletal muscle cells in response to atrophic stress (Bodega et al., 2017).
Using this physiological, in vivo tool we could identify a functional dynamic crosstalk between Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and PRC2-Ezh1 complex. By combining immuno-fluorescence, biochemistry, epigenomics, ChIRP, DNA and RNA immunoprecipitation we identified a novel pathway in which Malat1 plays a role in compartmentalization, assembly and activity of PRC2 in chromatin, allowing epigenetic plastic response to atrophic stress and recovery. We conclude that Malat1 is an essential partner for PRC2-Ezh1 adaptive function in skeletal muscle cells.
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Differential toxicity of two murine endothelial cells to ROS duress: Understanding oxidative stress-induced blood-brain barrier dysfunctionAlamu, Olufemi Akinyinka January 2020 (has links)
Philosophiae Doctor - PhD / The blood-brain barrier (BBB) is a critical interface between the blood circulation and brain tissue which performs critical selection of circulating molecules that gain access to the brain tissue. Its unique ability to adjust to changes in the constituents of the blood circulation confer in the BBB a dynamic nature enabling changes in its properties to suit the homeostatic needs of the brain.
Dysfunction of the BBB has been established to be pivotal to the initiation and/or maintenance of an array of neurological disorders, most of which involve the production of excess reactive oxygen species (ROS) and oxidative stress in their pathophysiology. Thus, clinical trials of exogenous antioxidant agents have been proposed and initiated, with most results being inconclusive. Extensive studies of the impact, capacity and plasticity of endogenous antioxidants in the cells that constitute the blood-brain barrier, especially the brain endothelial cells, therefore, became necessary for the rational choice, timing, and the mode of application of antioxidants in the management of oxidative stress-mediated neurological diseases.
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Multifunction and Underlying Mechanisms of Siphonaxanthin on Chronic Metabolic Diseases / 慢性代謝疾患に対するシフォナキサンチンの多機能性とその作用メカニズムZheng, Jiawen 25 March 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21833号 / 農博第2346号 / 新制||農||1068(附属図書館) / 学位論文||H31||N5205(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 澤山 茂樹, 教授 佐藤 健司 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM
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The effects of silver nanoparticles on the expression of protein biomarkers of cell stress, apoptosis and inflammation by the human liver cancer cell line, HepG2Volkmann, Tina January 2021 (has links)
>Magister Scientiae - MSc / Nanoscience is the study of phenomena and objects at the nanoscale (around 1-100 nm), socalled
nanomaterials. These nanomaterials exhibit novel properties that are often very
different to those of the bulk materials used for their synthesis. Hence, nanoparticles are
widely commercialised, especially silver nanoparticles (AgNPs) due to their antimicrobial
properties and some other useful phenomena. This commercialisation leads to inevitable
exposure to the environment and humans, which leads to inhalation, ingestion or dermal
uptake of AgNPs by the human body culminating in distribution to several major organs,
including the liver. Both chronic and acute exposure to AgNPs have been linked to detrimental
effects in both in vitro and in vivo studies. These include oxidative stress, induction of
inflammation, DNA damage, cell death and many others.
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Impairment of proteasome function in podocytes leads to chronic kidney disease / 糸球体足細胞におけるプロテアソーム機能不全は慢性腎臓病を引き起こすMakino, Shinichi 24 September 2021 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23462号 / 医博第4769号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 渡邊 直樹, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM
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Biomarkery oxidačního stresu erytrocytů u novorozence - follow-up studie / Oxidative stress biomarkers of the erythrocyte in the newborn - a follow-up studyZubatá, Karolína January 2018 (has links)
Charles University University of Porto Faculty of Pharmacy in Hradec Králové Faculty of Pharmacy Department of Pharmacology and Toxicology Department of Biological Sciences Student: Karolína Zubatá Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultants: Susana Rocha, Ph.D., prof. Alice Santos-Silva, Ph.D. Title of diploma thesis: Oxidative stress biomarkers of the erythrocyte in the newborn - a follow-up study Increased levels of oxidative stress (OS) have been described in healthy, full-term newborns as a consequence of the drastic changes introduced by birth and by the exposure to extrauterine environment. Our intention was to examine the OS levels in red blood cells (RBCs) of neonates and to further understand the changes that the newborn organism undergoes with its newly- acquired autonomy as this knowledge is limited and there are no reference values. Umbilical cord blood samples were collected from a small population of newborns (n = 8) and several hematological and biochemistry parameters were evaluated. Our experimental data consist of OS biomarkers measurements performed in different fractions of blood (RBC membrane, total RBCs and plasma): membrane bound hemoglobin (MBH), lipid peroxidation (LPO), quantification of catalase (CAT) and glutathione peroxidase (GPx) activities,...
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Vliv znečištěného ovzduší na markery oxidačního poškození u novorozenců / The effect of air pollution on oxidative stress markers in newbornsAmbrož, Antonín January 2020 (has links)
In everyday life, humans are exposed to toxic substances of anthropogenic origin. These substances can also be found in the ambient air and their impact poses a long-term risk for human health. Respirable particulate matter (PM) of aerodynamic diameter < 2.5 µm (PM2.5) is intensively studied, along with carcinogenic polycyclic aromatic hydrocarbons (PAHs), bound to it, such as benzo[a]pyrene (B[a]P), a reference carcinogenic PAH. Owing to small size, PM2.5 can penetrate the human body primarily via the airways and represent an increased health risk compared to larger particles. The negative health impacts of anthropogenic PM2.5, generated e.g. by fossil fuel combustion, are linked with its small size, relatively large surface, as well as with PAHs and other substances adsorbed on PM surface. PAHs, generated by an incomplete combustion of organic matter, can enter organism either via ingestion of contaminated food, water or via inhalation of polluted air. PAHs affect organisms via genotoxic, mutagenic, carcinogenic, embryotoxic and other adverse effects. One of the common denominators of these effects is oxidative stress, which is also considered to be the main mechanism of action caused by PM in the human organism. Oxidative damage induced by reactive oxygen species (ROS) may affect any cellular...
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