Life Sciences Commons^™

Selective Elimination Of Malignant Melanoma Using The Novel Anti-Tumor Agents, Osw-1 And Peitc, Kausar Begam Riaz Ahmed

Dissertations & Theses (Open Access)

Metastatic melanoma is amongst the most refractory of cancers. Drug resistance and lack of therapeutic selectivity are two main challenges to successful melanoma therapy. Herein, we investigated the mechanims of anticancer activity and therapeutic selectivity of two novel agents, 3β, 16β, 17α-trihydroxycholest-5-en-22-one 16-O-[2-O-4-methoxybenzoyl-β-D-xylopyranosyl]- [1→3]-2-O-acetyl-α-l-arabinopyranoside (OSW-1) and β-Phenylethyl Isothiocyanate (PEITC) in melanoma.

OSW-1 inhibited melanoma cell viability at nanomolar concentrations with minimal toxicity to normal melanocytes. Mechanistic studies revealed that OSW-1 suppressed Disialoganglioside 3 Synthase (GD3S) gene expression in melanoma cells, leading to inhibition of gangliosides GD3 and GD2. GD3 is an abundantly expressed melanoma …

Pregestational Diabetes And Congenital Heart Defects: Role Of Reactive Oxygen Species, Hoda Moazzen

Electronic Thesis and Dissertation Repository

Women with pregestational diabetes are at a high risk of having babies with congenital heart defects (CHDs). The mechanisms of CHD induction in the offspring of women with pregestational diabetes remain elusive. With an ever-increasing rate of diabetes in young adults, there is a pressing need to understand the underlying mechanisms and initiate effective preventative strategies. The aim of this thesis is to study the role of reactive oxygen species (ROS) signalling in heart morphogenesis, unravel molecular mechanisms of CHDs induced by pregestational diabetes and provide new insights on potential therapeutic strategies. To this end, a mouse model of pregestational …

Mechanistics Of Prothymosin Alpha And Nrf2 In The Keap1-Nrf2 Mediated Oxidative Stress Response, Halema Khan

Electronic Thesis and Dissertation Repository

In an effort to dissect the mechanism of interaction of IDPs, in this thesis we focus on Prothymosin a (ProTa) and nuclear factor erythroid 2-related factor 2 (Nrf2), intrinsically disordered proteins, in the Nrf2 mediated oxidative stress response. Kelch-like ECH-associated protein 1 (Keap1) is an inhibitor of Nrf2, a key transcription factor of cytoprotective genes. Under unstressed conditions, Keap1 interacts with Nrf2 in the cytoplasm via its Kelch domain and suppresses Nrf2 activity. During oxidative stress, Nrf2 is released from Keap1 and is shuttled to the nucleus, where it initiates pro cell survival gene transcription. ProTa also interacts with the …

Mitochondrial Involvement In Neuronal Cell Death, Josie J. Gray

Electronic Theses and Dissertations

Neuronal cell death via apoptosis or necrosis underlies several devastating neurodegenerative diseases associated with aging. Mitochondrial dysfunction resulting from oxidative or nitrosative stress often acts as an initiating stimulus for intrinsic apoptosis or necrosis. These events frequently occur in conjunction with imbalances in the mitochondrial fission and fusion equilibrium, although the cause and effect relationships remain elusive. In this thesis, I demonstrate in primary rat cerebellar granule neurons (CGNs) that oxidative or nitrosative stress induces an N-terminal cleavage of optic atrophy-1 (OPA1), a dynamin-like GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. This cleavage event is indistinguishable from …

The Role Of Sirtuin Inhibitors On The Proteomic Responses Of The Mussels Mytilus Galloprovincialis And Mytilus Trossulus To Menadione Induced Oxidative Stress, Hayley C. Chilton

Master's Theses

Global climate change imposes physiological constraints on marine ecosystems that can alter the distribution of intertidal organisms. In one such instance, the native cold-adapted mussel Mytilus trossulus is being replaced along its southern range by the invasive warm-adapted Mytilus galloprovincialis. These blue mussels occur throughout rocky intertidal zones where they are subjected to greatly varying environmental conditions known to induce oxidative stress. We hypothesize that while under acute stress, related Mytilus congeners undergo a shift in redox potential from NADH-fueled respiratory pathways to pathways producing NADPH as a way to decrease the production of reactive oxygen species (ROS) and …

Understanding How Honey Bee Flight And Senescence Are Connected Through Oxidative Stress., Joseph Margotta

UNLV Theses, Dissertations, Professional Papers, and Capstones

The goal of this dissertation was to exploit the tractability of the honey bee (Apis mellifera) to understand how the physiological and cellular mechanisms that determine the onset and duration of senescence are shaped by behavioral development and behavioral intensity. These data reveal how behavior can damage cells and consequently limit lifespan. The honey bee represents the ideal model to address these factors because age, behavior, functional senescence, and lifespan are easily manipulated independently of each other while in its natural environment. I determined if there was a cause-effect relationship between honey bee flight and oxidative stress by comparing damage …

Environmental Stressors: Pathways Of Exposure And Aquatic Invertebrate Response, Carly Jean Nowicki

Wayne State University Dissertations

The need to monitor freshwater and detect impairments prior to observable impacts is crucial to maintain species diversity and ecosystem function. Therefore, understanding the contribution of various matrices (i.e., sediment and water) to chemical exposure is critical for remediation of impacted sites.

To evaluate various matrices of chemical exposure, I focused on the organic pollutant polychlorinated biphenyls (PCBs) due to their relatively ubiquitous nature, high toxicity, and adverse effects on humans and wildlife. In complementary laboratory and field experiments, I compared the effects of aqueous versus sedimentary exposure of PCBs on invertebrates. In the laboratory, organisms exposed to PCB-contaminated sediments …

Circadian Regulation Of Mtor Signaling Via Bmal1 Dependent Mechanism, Rohini Vishal Khapre

ETD Archive

Understanding mechanisms of aging is important for the treatment and prevention of age-associated pathologies. However, these mechanisms are not well understood. Recently we have demonstrated that the circadian clock (an internal time keeping system) regulates longevity in mammals, but the molecular mechanisms are not known. The aim of our current study is to investigate a possible interconnection between the circadian clock and mTORC1 (mammalian target of Rapamycin) signaling pathway. mTORC1 pathway is a nutrient response pathway involved in many cellular processes many recent studies indicate a role of mTORC1 pathway in aging. Here we demonstrate that circadian system regulates mTORC1 …

The Role Of Exercise In Polychlorinated Biphenyl Induced Cardiovascular Disease, Margaret O'Bryan Murphy

Theses and Dissertations--Nutritional Sciences

Cardiovascular disease remains the leading cause of death in Western societies. Endothelial dysfunction is one of the initiating steps in the development of atherosclerosis. While there is a strong correlation with a person’s genetics, lifestyle factors including smoking, physical activity, and diet can significantly increase a person’s susceptibility to the development of atherosclerosis. In addition to these lifestyle factors, there is a strong body of evidence linking exposure to environmental pollutants including persistent organic pollutants such as polychlorinated biphenyls to increased cardiovascular disease and mortality. It has been well-established that exercise protects against cardiovascular disease, but whether exercise can modulate …

A Functional Genomics Approach To Investigate The Mechanism Of Action Of The Histone Deacetylase Inhibitor Cg-1521, Ann-Christin Gaupel

Legacy Theses & Dissertations (2009 - 2024)

Epigenetic alterations are common in human cancers. Loss of histone acetylation occurs early in tumorigenesis, correlates with advanced stage and poor clinical outcome, and histone acetyltransferases (HATs) and histone deacetylases (HDACs) are aberrantly expressed or recruited to promoters in a variety of cancers. Histone deacetylase inhibitors (HDACis) are attractive anti-cancer therapeutics because of their selectivity for transformed cells and their ability to induce growth arrest, cell death, senescence and differentiation, enhance tumor immunogenicity and inhibit angiogenesis and invasion. However, many questions remain regarding their mechanism(s) of action. While monotherapy with HDACis for solid tumors is not effective, combination therapies show …

Addressing Public Health Risks Of Persistent Pollutants Through Nutritional Modulation And Biomimetic Nanocomposite Remediation Platforms, Bradley J. Newsome

Theses and Dissertations--Chemistry

Due to their relative chemical stability and ubiquity in the environment, chlorinated organic contaminants such as polychlorinated biphenyls (PCBs) pose significant health risks and enduring remediation challenges. Engineered nanoparticles (NPs) provide a novel platform for sensing/remediation of these toxicants, in addition to the growing use of NPs in many industrial and biomedical applications, but there remains concern for their potential long-term health effects. Research highlighted herein also represents a transdisciplinary approach to address human health challenges associated with exposure to PCBs and NPs. The objectives of this dissertation research are two-fold, 1) to develop effective methods for capture/sensing and remediation …

Increase Of Basal Oxidative Stress Levels And Impairment Of Heme Oxygenase-1/Biliverdin Reductase Post-Translational Modification By The Defect Of Parkinson-Related Gene Of Pink1, Zhaoshu Zhang

Theses and Dissertations--Chemistry

Parkinson disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. PINK1, PTEN-induced kinase 1, functions as a serine/threonine kinase as well as a protector of mitochondrial function. Mutations in PINK1 gene result in either mitochondria dysfunction or disruption of kinase signaling pathways involved in the pathogenesis of PD.

In this thesis, oxidative stress levels were examined in the brain of PINK1 knockout mice, and also how heme oxygenase-1 and biliverdin reductase are affected in brain of PINK1 knockout mice. In addition, posttranslational modifications are a way to control the behavior of proteins, so posttranslational …