Pharmacology, Toxicology and Environmental Health Commons^™

Development Of Non-Traditional Platinum Anticancer Agents: Trans-Platinum Planar Amine Compounds And Polynuclear Platinum Compounds, Daniel E. Lee

Theses and Dissertations

Development of Non-Traditional Platinum Anticancer Agents: trans-Platinum Planar Amine Compounds and Polynuclear Platinum Compounds

By Daniel E. Lee, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015

Major Director: Nicholas P Farrell, Ph.D., Professor, Department of Chemistry

Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied …

Elaboration And Design Of Α7 Nachr Negative Allosteric Modulators, Osama I. Alwassil

Theses and Dissertations

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at …

Development Of Irreversible Substrate Competitive Probes For Pka Activity, Robert A. Coover

Theses and Dissertations

The current environment for drug discovery and disease treatment relies heavily on genomic analysis, structural biology and chemical biology techniques. With the enormous advances in genomic analysis and structural biology, the use of and desire for targeted therapies has increased. However, as more genomic data for cancer disease state pathology becomes available we must ask increasingly difficult questions and even produce new technologies, such as activity-based probes, to answer these questions.

In particular, targeted kinase inhibitors for the treatment of cancer has become a mainstay for drug development for both industry and academia, but it is evident that the genomic …

Relationship Between Autophagy, Senescence, And Dna Damage In Radiation Sensitization By Parp Inhibition, Moureq Alotaibi

Theses and Dissertations

Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In …

Bacterial Communication And Its Role As A Target For Nanoparticle-Based Antimicrobial Therapy, Kristen Publicover Miller

Theses and Dissertations

The goal of this dissertation is to establish the environmental and public health importance of alternative forms of antimicrobial therapy, specifically those that utilize nanotechnology to combat quorum sensing-controlled bacterial infections. Quorum sensing (i.e. chemical communication) is an inherent characteristic that is essential to bacterial pathogenesis and biofilm formation (where most infections occur). A thorough review of the literature has been conducted to establish an understanding of the state of nanotechnology research as it relates to combatting bacterial infections. This synthesis, provided in Chapter 1, demonstrates how the chemical and structural designs of nanoparticles can be manipulated to specifically target …

High-Content Screening In Zebrafish Embryos Identifies Abamectin As A Potent Neurotoxicant, Tara Diane Raftery

Theses and Dissertations

During development, the nervous system is a sensitive target for chemical exposure in both humans and animal models, and early life-stage exposures can lead to long-term effects on motor activity, sensory function, and cognition. Currently, there are minimal to no developmental neurotoxicity (DNT) data available for thousands of chemicals used in commerce, and it is impractical to screen these chemicals in rodent models using the existing DNT test guideline, as this test is costly, time- and animalintensive, and low-throughput. Therefore, there is a recognized need to use alternative non-mammalian models to support screening and prioritization of chemicals for DNT testing, …

Xlf-Dependent Nonhomologous End Joining Of Complex Dna Double-Strand Breaks With Proximal Thymine Glycol And Screening For Xrcc4-Xlf Interaction Inhibitors, Mohammed Al Mohaini

Theses and Dissertations

DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate …

Expression And Pharmacological Modulation Of Pain-Depressed Behavior In Rats, Michael D. Leitl

Theses and Dissertations

Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This goal of this dissertation was to conduct preclinical research experiments designed to address a set of three inter-related aims that examine the expression, mechanisms and treatment of pain-related depression of Intracranial Self-Stimulation (ICSS) in rats. First, studies evaluated the hypothesis that acute acid-induced depression of ICSS was mediated by a kappa opioid receptor mediated decrease in mesolimbic dopamine release in the nucleus accumbens. Results support a role for depressed mesolimbic dopamine release in pain-related depression of ICSS; however, …

Integrated Nanoscale Imaging And Spatial Recognition Of Biomolecules On Surfaces, Congzhou Wang

Theses and Dissertations

Biomolecules on cell surfaces play critical roles in diverse biological and physiological processes. However, conventional bulk scale techniques are unable to clarify the density and distribution of specific biomolecules in situ on single, living cell surfaces at the micro or nanoscale. In this work, a single cell analysis technique based on Atomic Force Microscopy (AFM) is developed to spatially identify biomolecules and characterize nanomechanical properties on single cell surfaces. The unique advantage of these AFM-based techniques lies in the ability to operate in situ (in a non-destructive fashion) and in real time, under physiological conditions or controlled micro-environments.

First, AFM-based …

Effects Of Hiv-1 Tat On The Enteric Nervous, Joy Ngwainmbi

Theses and Dissertations

More than 1.2 million people are estimated to be currently living with the human immunodeficiency virus (HIV) in the United States of America. The gastrointestinal (GI) tract is both a major target and an important component of HIV pathogenesis. The GI processes that are dysregulated during HIV infection are controlled by the enteric nervous system (ENS). Indeed, both clinical and experimental studies have implicated the ENS in HIV and simian immunodeficiency virus (SIV) pathogenesis. In addition to direct viral effects, the HIV virus also indirectly affects the GI tract via cellular and/or viral toxins released by infected cells. Trans-activator of …

Structural Determinants Of Abuse-Related Neurochemical And Behavioral Effects Of Para-Substituted Methcathinone Analogs In Rats, Julie S. Bonano

Theses and Dissertations

Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse …

Pemetrexed, A Modulator Of Amp-Activated Kinase Signaling And An Inhibitor Of Wild Type And Mutant P53, Stuti Agarwal

Theses and Dissertations

New drug discoveries and new approaches towards diagnosis and treatment have improved cancer therapeutics remarkably. One of the most influential and effective discoveries in the field of cancer therapeutics was antimetabolites, such as the antifolates. The interest in antifolates increased as some of the antifolates showed responses in cancers, such as mesothelioma, leukemia, and breast cancers. When pemetrexed (PTX) was discovered, our laboratory had established that the primary mechanism of action of pemetrexed is to inhibit thymidylate 22 synthase (TS) (E. Taylor et al., 1992). Preclinical studies have shown that PTX has a broad range of antitumor activity in human …

Synthetic Cannabinoids Versus Delta-9-Tetrahydrocannabinol: Abuse-Related Consequences Of Enhanced Efficacy At The Cannabinoid 1 Receptor, Travis Grim

Theses and Dissertations

In the past ten years, synthetic cannabinoids (SC) have emerged as drugs of abuse. Unlike D⁹-tetrahydrocannabinol (THC), many SCs are associated with serious health complications and death. One way in which THC and SCs differ lies with their enhanced potency and efficacy at the CB₁ receptor. No current methods exist to measure efficacy at the CB₁ receptor in vivo, and the abuse-related properties of SC cannabinoids are not well explored. Here, we utilized CB₁ wild type (WT), heterozygous (HET), and knockout (KO) mice. By employing CB₁ ligands which differ in efficacy we have …

Development Of Clinically Relevant In Vitro Performance Tests For Powder Inhalers, Xiangyin Wei

Theses and Dissertations

While realistic in vitro testing of dry powder inhalers (DPIs) can be used to establish in vitro–in vivo correlations (IVIVCs) and predict in vivo lung doses, the aerodynamic particle size distributions (APSDs) of those doses and their regional lung deposition remains unclear. Four studies were designed to improve testing centered on the behavior of Novolizer®. Different oropharyngeal geometries were assessed by testing different mouth-throat (MT) models across a realistic range of inhalation profiles (IPs) with Salbulin® Novolizer®. Small and large Virginia Commonwealth University (VCU) and Oropharyngeal Consortium (OPC) models produced similar ranges for total lung dose in vitro (TLD …

Novel Compounds As Potential Alzheimer's Disease Therapeutics And Inhibitors Of The Nlrp3 Inflammasome, Jeremy E. Chojnacki

Theses and Dissertations

Alzheimer’s disease is a devastating neurodegenerative disorder and the leading cause of dementia. The disease manifests via several pathologies including neuroinflammation, oxidative stress, metal ion dyshomeostasis, and cell death. To address the multifaceted nature of this disorder, the design of several diverse compounds, targeting many pathological effects, was generated. First, a series of compounds based on curcumin and diosgenin were synthesized following the bivalent design strategy. Two compounds were discovered to have neuroprotective ability, anti-oxidative function, and anti-Aß oligomerization (AßO) properties. A second set of molecules was also designed, wherein a hybrid compound strategy was utilized. Three hybrids were to …

Decision-Support Tool For Residential Pesticides In The South Carolina Coastal Zone, Lisa Claire Wickliffe

Theses and Dissertations

The Environmental Protection Agency (EPA) is charged with ensuring pesticides do not pose unreasonable adverse risks to the public and to the environment. This is a daunting task with over one billion pounds of pesticides used across the nation each year. The U.S. EPA estimates approximately 75% of all pesticide usage in the U.S. are agricultural while 25% is for home, garden, industrial, commercial, and government applications. One area of application of concern to public health and the environment regarding misuse of pesticides is in residential settings. In these instances, individuals may not have any knowledge of identifying whether they …

Estimation Of Aerosolized Antibiotic Resistant Bacteria Concentrations From Wastewater Treatment Facilities Using Spatially-Based Dispersion Modeling, Renee Nichole Dickman

Theses and Dissertations

Pathogenic bacteria can develop resistance to antibiotics to which they were previously sensitive, resulting in increased morbidity and mortality worldwide [1]. The increase in drug resistance in bacteria is an emerging public health concern. The activated sludge tanks of wastewater treatment plants are known sources of antibiotic resistant bacteria. These resistant bacteria can become aerosolized and disperse downwind. Using previously sampled aerosol concentrations and meteorological data, a Gaussian dispersion model was developed to estimate the concentration downwind from a selected wastewater treatment facility. The emission rate was calculated to be 7,941 CFU/m²/sec ± 2,149 CFU/m²/sec. This value was used in …

Particulate Characterization And Control Evaluation For Carbon Fiber Composite Aircraft Crash Recovery Operations, Matthew R. Ferreri

Theses and Dissertations

Within the United States Air Force (USAF) Advanced Composite Material (ACM) is gaining an increasing use in military aircraft. With the number of aircraft that have increasingly large amounts of ACM materials, the probability of an incident with one of these aircraft also increases. When such an incident occurs the aircraft needs to be disassembled, removed, and later inspected as part of the accident investigation process. This disassembly process is termed “Crash Recovery Operations.” Carbon fibers have been shown to be hazardous to human health and a pilot study raised the suspicion that nanosized aerosol may be generated during the …

Low Dose Sarin Leads To Murine Cardiac Dysfunction, Michael W. Horenziak

Theses and Dissertations

It has been reported that low dose sarin is associated with long-term pathology in the brain and heart; however, the effects of sarin on the heart have yet to be determined. In addition, sarin has been implicated as an etiological agent in Gulf War Illness. Thus, the role of sarin in producing illness has important military consequences. This study used echocardiography, electrocardiography, and histology to determine sarin’s effect on the murine cardiovascular system. C57BL/6J mice were injected with sarin at 0.4 LD50, 0.5 LD50, or saline on two consecutive days and studied for 10 weeks post exposure. The sarin animals …

In Vitro Toxicity Of Silver Nanoparticles In Human Lung Epithelial Cells, Christina R. Kearns

Theses and Dissertations

Nanotechnology is quickly becoming incorporated into everyday products and uses. Silver nanoparticles, specifically, are being used in commercial products, to include aerosols. The purpose of this research was to determine whether silver nanoparticles are toxic to human lung epithelial cells. Different types (coated vs. uncoated), concentrations (10, 50, 100, and 200 µg/mL) and sizes (coated 5 and 80nm, uncoated 10 and 80nm) of silver nanoparticles were used during this study. Toxicity measurements were completed through in vitro techniques. Another study was also completed on toxicity mechanisms by measuring the reactive oxygen species (ROS) generated. Results showed that silver nanoparticles induce …

Effect Of Increased Carbon Dioxide Levels On Urushiol Production In Toxicodendron Radicans And Toxicodendron Toxicarium, Meredith Gilbert

Theses and Dissertations

It is hypothesized that global warming is at least partially due to increased greenhouse gases, one of which is carbon dioxide. An increase in atmospheric carbon dioxide has been shown to stimulate higher rates of plant productivity, including the production of plant toxins like urushiol. Urushiol, a secondary plant compound produced in members of the Anacardiaceae family, causes dermatitis in sensitive individuals. An increase in urushiol production could increase the reactivity of certain individuals to plants like poison oak and poison ivy. To determine how elevated levels of atmospheric carbon dioxide would effect urushiol production, 16 samples of poison ivy …

Three Models Of Anthrax Toxin Effects On The Map-Kinase Pathway And Macrophage Survival, Daniel J. Schneider

Theses and Dissertations

Lethal factor (LF), a component of anthrax toxin, is the primary virulence factor that allows Bacillus anthracis to evade the immune response by blocking the activation of mitogen-activated protein kinase (MAPK) enzymes. This research modifies three published MAPK models to reflect this signal inhibition and to estimate a first-order reaction rate by fitting the models to published viability data for two macrophage cell lines cultured with the LF-producing Bacillus anthracis-Vollum1B strain. One model appears to be ill-suited for this purpose because not all relevant MAPK components could be integrated into the inhibition equations. Despite different underlying parameters and values, the …

Characterization Of A Fluorescent Protein Reporter System, Sandra J. Dias

Theses and Dissertations

Chemical and biological threats are ever present and attacks have occurred throughout the world in both war and peace-time. Multiple government agencies, academia, and private industry are developing detection capabilities to address such threats. The research presented in this paper supports development of a modular synthetic biology based system that detects and reports the presence of a threat agent. Synthetic biology builds upon past research in genetic engineering and seeks to combine broad applications within biotechnology in novel ways. This basic research project will help to demonstrate a proof-of-concept design which will guide future studies on the development of a …

In Vitro Toxicity Of Aluminum Nanoparticles In Human Keratinocytes, Stephanie Mccormack-Brown

Theses and Dissertations

Nanotechnology promises to be the defining technology of the 21st century. At an annual investment of $1B, it provides significant contributions to manufacturing, medicine, energy conservation, and the environment. Nanoparticles are structures with at least one dimension in the 1 to 100 nanometer (nm) range. DoD and US Air Force interest in aluminum nanoparticles (AL NPs) stems from its ability to enhance combustion jet fuel, thus increasing fuel efficiency. The addition of AL NPs to JP-8 may pose a unique dermal hazard to aircraft maintenance workers. There is no published data on AL NP toxicity effects on human skin. This …

In Vitro Toxicity And Inflammation Response Induced By Copper Nanoparticles In Rat Alveolar Macrophages, Brian M. Clarke

Theses and Dissertations

Nanotechnology is a thriving industry and has the potential to benefit society in numerous ways. However, not all environmental and human health concerns of nanomaterials have been addressed. Thus, the purpose of this research was to investigate the toxicity and inflammation potential (using cytokines TNF-alpha and IL-6 as indicators) of various sized copper nanoparticles (40, 60, and 80 nm) in rat alveolar macrophages. Toxicity measurements were accomplished by means of in vitro techniques and toxicity mechanisms were studied by measuring reactive oxygen species (ROS) production. In addition, cytokine measurements used enzyme-linked immunosorbent assay (ELISA) methods. Results show copper nanoparticles as …

Optimization Of Therapeutic Strategies For Organophosphate Poisoning, Gregory G. Seaman

Theses and Dissertations

The National Preparedness Vision requires the U.S. be prepared to prevent, protect against, respond to, and recover from all hazards associated with a chemical attack. Results of this study demonstrate that we cannot protect service members and first responders as required following a nerve agent attack. The research presented herein aimed to construct a physiologically based pharmacokinetic model to determine optimal therapeutic strategies for organophosphate (nerve agent) poisoning. The constructed model integrated organophosphates and two antidotes, atropine and oximes. Model results reasonably mirrored literature data and anecdotal observations of organophosphate poisoning. Results suggest a symptoms-based dosing strategy of atropine and …

Comparative Analysis Of Airborne Chemical Exposure To Air Force Small Arms Range Instructors, Eric J. Cameron

Theses and Dissertations

This study examines airborne chemical exposure to Air Force small arms range instructors during M16 firing of lead and lead-free bullets. Historical range information collected from 63 active duty Air Force bases identified that two thirds of the Air Force military ranges within the Continental United States are currently firing lead-free ammunition. Average 8-hr TWA exposures for lead during M16 firing of leaded ammunition were 17% of the Occupational Exposure Limit (OEL). Task exposures, representing worst case conditions, were found to be 1.2 time the OEL. Two indoor and four outdoor firing ranges currently firing frangible lead-free ammunition were evaluated …

In Vitro Toxicity Of Aluminum Nanoparticles In Rat Alveolar Macrophages, Andrew J. Wagner

Theses and Dissertations

Nanomaterials, which are by definition in the 1 - 100 nanometer range, have numerous possible benefits to society, but currently there is a lack of data that characterizes these materials effects on human health and environment. In general nanomaterials are of interest to the Air Force because of their applications in electronics, sensors, munitions and energetic/reactive systems. Nanoparticles such as aluminum have been considered for enhancing propulsion in solid rocket fuel. To date, only a few studies have looked at the toxicological effects of direct exposure to nanoparticles, none with aluminum. It is important to increase the understanding of the …

In Vitro Toxicity Of Cadmium Oxide Particles In Brl 3a Rat Liver Cells, Janice M. Shelley

Theses and Dissertations

For the last decade or so, in vitro toxicology has been studied as a method for determining human toxicity, as well as hazard identification and characterization. One purpose of in vitro studies is to determine the possibility of developing systems in which the toxicity of chemicals can be quantified, without heavy reliance on animal experimentation. Specific data pertaining to cadmium toxicity in humans through use of in vitro methods and models is sparse, at best. There is a need to complete more studies and collect more data to study particular chemicals and their effects and to complete proper evaluation and …

Deterministic Intracellular Modeling, Jacqueline B. Young

Theses and Dissertations

The United States Air Force is interested in the potential side effects at the cellular level from exposure to mission-essential chemicals. Presently, Air Force toxicology studies are conducted to help shed light in identifying potential hazards to workers. However, it takes a considerable amount of money, resources, and time to obtain and analyze experimental results from toxicology studies. The necessity for innovative methods that enable researchers to more effectively generate and analyze data is apparent.