Pharmacology, Toxicology and Environmental Health Commons^™

From Seed To Sky: Impacts Of Explosive Compounds On Vegetation Across Spatial And Developmental Scales, Stephen M. Via

Theses and Dissertations

Explosive compounds are broadly distributed across the globe as a result of nearly two centuries of munitions use in warfare and military activities. Two explosive compounds have seen disproportionate use; RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) and TNT (2-methyl- 1,3,5-trinitrobenzene), being the most commonly found explosives in the environment. The effects of explosives on biota have been studied in great detail; however, there is a general lack of understanding with regard to broader ecological impacts of these contaminants. My dissertation objective was to follow the impacts of explosive compounds on vegetation across scales. Impacts on vegetation at the species scale alter community composition via …

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 …

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 …

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 …

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 …

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, …

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 …

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 …

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

Undergraduate Research Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results of …

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 …

The Roles Of Several Kinases In Mice Tolerant To Delta-9-Tetrahydrocannabinol, Matthew C. Lee

Theses and Dissertations

It has been suggested that the CB1 G-protein-coupled receptor is internalized following agonist binding and activation of the second messenger pathways. The process of desensitization and resensitization is intimately involved with receptor internalization. Phosphorylation alters tolerance to cannabinoids thus contributing to tolerance. It is proposed that phosphorylation enhances the down-regulation of the CB1 receptor. These findings led us to look at which kinase(s) may be involved in cannabinoid tolerance. We therefore hypothesize that by preventing phosphorylation of the CB1 receptor, we may reverse tolerance. We evaluated our hypothesis by testing the role of several kinases in tolerance: protein kinase A …

Evidence That Nicotine Can Acutely Desensitize Central Nicotinic Cholinergic Receptors In Vivo, John Randolph James

Theses and Dissertations

Current concepts concerning nicotine's central nervous system (CNS) mechanism(s) of action suggest that this drug is producing its effects via an interaction at nicotiniccholinergic receptors (nAChRs) which open a membrane cation channel. Following initial opening of the channel, nicotine appears to induce a rapid desensitization of the nAChRs, closing the channel and resulting in a cessation of nicotine's effects. Research presented here will provide evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in the discriminative stimulus (DS) paradigm. The ability of nicotine to elicit DS control of behavior was significantly reduced via …

Pharmacological Manipulation Of Protein Kinase C Modulates The Growth And Lineage Commitment Of Enriched Human Myeloid Progenitor Cells Induced By Hematopoietic Growth Factors, Fei Li

Theses and Dissertations

The activity of protein kinase C (PK-C) has been implicated in regulating the growth and differentiation of both normal and neoplastic hematopoietic cells. We have examined the effects of the PK-C activators, phorbol 12,13- dibutyrate, mezerein, and bryostatin 1, on the proliferation and lineage commitment of enriched CD34+ human myeloid progenitor cells stimulated by lL-3, GM-CSF, stem cell factor and the lL-3/GM-CSF hybrid cytokine plXY321. Coadministration of these PK-C activators with plateau concentrations of rlL-3 or rGM-CSF induced 100-150% increase in the number of day 14 CFU-GM.with a selective stimulation on neutrophil and macrophage lineages while inhibiting eosinophilic growth. plXY321 …

Effects Of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (Tcdd) On The In Vitro Antibody Response: Differential Effects On The B Lymphocyte Depending On The State Of In Vivo Activation And The Modulation By Serum-Derived Growth Factors, Dale L. Morris

Theses and Dissertations

Previous reports have indicated a dichotomy in the actions of TCDD on humoral immunity, both in vitro and in vitro, in which enhancements and suppression have been identified. The latter effect has been correlated with induction of liver P4501A1 enzyme activity, a response which is regulated by the Ah-gene locus. Additionally, the primary alteration in suppression of antibody responses is in the differentiation of the B cell. Therefore, the current investigation was undertaken to determine the relationship between these dual actions of TCDD on humoral immunity as related to its direct actions on B lymphocyte function. Specific emphasis was placed …

Evaluation Of The Antagonism Of Nicotine By Mecamylamine And Pempidine In The Brain, Thomas Jeffrey Martin

Theses and Dissertations

Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. Although the mechanism of action of these compounds has been studied extensively in the periphery, little is known about their mechanisms of action in the brain. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, …

An Evaluation Of The Central Neurotoxic Effects Of Aroclor 1254, A Commercial Mixture Of Polychlorinated Biphenyls, In Mice, Diane L. Rosin

Theses and Dissertations

Polychlorinated biphenyls (PCBs) are industrial compounds whose ubiquitous environmental contamination has been known since the late 1960's. Incidents of human intoxication have been reported, most notably, the "Yusho" incident that affected over 1600 people in Japan in 1968. A broad spectrum of adverse effects are produced by PCBs, including some neurological symptoms. While examination of the toxic effects of PCBs has received much attention, there has been little work on the neurotoxicity of PCBs. The intent of the experiments presented in this thesis is to provide further information on the central neurotoxicity of PCBs in mice.

A commercial mixture of …

Psychopharmacological Analysis Of Central Muscarinic And Nicotinic Receptors, Leonard T. Meltzer

Theses and Dissertations

Arecoline and nicotine are two psychoactive cholinergic alkaloids. Arecoline is primarily a muscarinic agonist while nicotine, at low doses, is a nicotinic agonist. The experiments in this dissertation investigated two major areas: (1) the role of different factors in the development of tolerance to the behavioral effects of arecoline and nicotine, and (2) the possible mechanism and site of action of the discriminative stimulus (DS) effects of arecoline and nicotine.

The role of dispositional and physiological factors comfiared to behavioral factors in the development of tolerance to the effects of arecoline and nicotine on operant behavior was assessed in Experiments …

The Effects Of Streptozotocin-Induced Diabetes On Responses To Opiates And Other Centrally-Acting Pharmacologic Agents, Glenn Stuart Simon

Theses and Dissertations

Diabetes mellitus affects millions of people. Although diabetics can lead relatively normal lives, all treatments for the disease are symptomatic and not curative. The purpose of this investigation was to determine whether the sensitivity to opiates and other selected centrally-acting drugs in animals is altered by streptozotocin (STZ)-induced diabetes. A second objective was to determine which aspect of the diabetic syndrome primarily was responsible for the altered sensitivity. Other experiments were performed in an attempt to elucidate the mechanism whereby this altered sensitivity occurred.

STZ-induced diabetes or dextrose-induced transient hyperglycemia did not have a significant effect on the duration of …

The Responsiveness Of Murine Tumors To Maleic Vinyl Ether, Paal Christian Klykken

Theses and Dissertations

Studies were undertaken to characterize the immune status of mice bearing the Lewis lung carcinoma (LLC) and to maximize the cure rate of LLC and Madison l09 carcinoma (Ml09) bearing mice by employing the immunomodulator maleic vinyl ether (MVE) in combination with surgery or radiotherapy.

The pattern of immunodeficiency in mice bearing the LLC appeared to be in contrast to most studies. LLC mice with a minimal tumor burden were found to have a diminished ability to phagocytize sheep erythorcytes (SRBC) or elicit an antibody response to the same antigen. Vascular clearance and phagocytic uptake of ⁵¹Cr-labeled SRBC into …

Mechanisms Of Drug Distribution In Rat Submaxillary Gland In Vitro, James W. Putney Jr.

Theses and Dissertations

The access of drugs to variofis sites of action in the body is impeded by a succession of membranes. Likewise, the removal of a drug or foreign substance from the body is similarly dependent on the ability of the substance under consideration to permeate biological barriers. A con-committant problem generally arises concerning the overall time course of drug action: that of drug storage through binding or similar processes. Schanker (196h) however, has stated that "Although the mechanisms of localization and those of membrane transfer are in many respects different problems, there are some instances in which they are inseparable parts …