Pharmacology, Toxicology and Environmental Health Commons^™

The Impact Of Hiv-1 Tat And Morphine On Spatial Distribution Of Drugs In The Brain., Austin M. Jones

Theses and Dissertations

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.

Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). …

Mitigation Of Nicotine Reward And Withdrawal By The N-Acyl Amino Acids: N-Oleoyl Glycine And N-Oleoyl Alanine, Kimberly Karin

Theses and Dissertations

A growing body of research is exploring the efficacy of N-acyl amino acids (N-oleoyl glycine; OlGly and N-oleoyl alanine; OlAla) in rodent models of drug reward and dependence. In particular, OlGly attenuated the reinforcing effects of nicotine in the mouse nicotine-induced conditioned place preference (CPP) paradigm and reduced somatic and affective signs of mecamylamine-precipitated withdrawal in nicotine-dependent mice. Based on the addition of a methyl group on the head group, OlAla was proposed to have increased metabolic stability compared to OlGly. While OlAla has been assessed in assays of reward and withdrawal of opioids, cocaine, and …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Modulation Of Opioid-Induced Respiratory Depression By Stimulants And Their Associated Monoaminergic Receptor Mechanisms In Mice Using Whole Body Plethysmography, Harrison J. Elder

Theses and Dissertations

Opioid overdose and associated deaths involving opioid-induced respiratory depression (OIRD) began to accelerate beginning in 2015 with the emergence of illicitly manufactured fentanyl and its analogs and currently represents one of the most significant public health challenges in the United States. The increases in overdose deaths have occurred despite the increased availability of the opioid overdose reversal agent, naloxone, to first responders and the public. This new phase of the opioid epidemic has been paralleled by substantial growth in the co-use of opioids with stimulants, particularly methamphetamine. The objective of this dissertation is to ascertain whether fentanyl is particularly resistant …

Effects Of Microcystin-Lr On Channel Catfish (Ictalurus Punctatus) Susceptibility To Microbial Pathogens (Aeromonas Hydrophila And Edwardsiella Piscicida), Alison Marchant

Theses and Dissertations

Microcystin-LR is a hepatotoxin produced by cyanobacteria. Aeromonas hydrophila and Edwardsiella piscicida infections are leading causes of losses in market-sized channel catfish (Ictalurus punctatus). These older fish should have natural immunity in place and a predisposing factor is likely a prerequisite for these disease outbreaks. While microcystin-LR rarely causes mortality in warm-water aquaculture, we believe it may be a predisposing factor that leads to bacterial disease outbreaks during the summer months due to its ability to damage the liver. Our study investigated microcystin-LR’s effects on channel catfish susceptibility to these pathogens. We found that a sublethal dose of microcystin-LR induced …

Understanding Effect Of Ionic Liquid On Metalloproteins: Laccase And Azurin, Aashka Y. Patel

Theses and Dissertations

Interactions between ionic liquids and biomolecules have been of great interest due to the intrinsic properties of ionic liquids and the flexibility to mix and match cations and anions to create unique ionic liquids. A number of ionic liquid-biomolecule studies have focused on the interactions with proteins, including industrially relevant enzymes. One of these, laccase from Trametes versicolor, is a naturally derived enzyme used in the breakdown of phenolic compounds in a wide variety of industries, especially useful in breakdown of lignocellulosic materials. Here, a combination of experiments and molecular dynamics (MD) simulations were used to investigate the interactions …

An In Silico Study Of The Delta Opioid Receptor Using Small Molecules, Emily Dean

Theses and Dissertations

The DOR is the least studied out of the three opioid receptors (Mu, Kappa, and Delta). The most is known of the Mu Opioid receptor (MOR) and the drugs that target it have led to the global opioid epidemic due to their adverse effects of tolerance and addiction. The DOR is not known for the same adverse effects and therefore, is a promising pharmacological target for the development of new opioid ligands. In this thesis, molecular modeling, simulations and other computational methods are introduced in Chapter 1 where these methods are used to study the activation mechanism of DOR (Chapter …

Monitoring Titanium Dioxide Engineered Particles In Rural And Urban Surface Waters, Md Mahmudun Nabi

Theses and Dissertations

Quantifying and characterizing engineered particles in environmental systems is key for assessing their risk but remains challenging and requires the distinction between natural and engineered particles. The Ph.D. dissertation research described in this thesis contributes to the current attempts to improve environmental nanoparticle analysis and better understand nanoparticle behavior in natural systems, with the focus being on natural streams, and the application of single particle inductively coupled plasma-time of flight-mass spectrometry (SP-ICP-TOF-MS) for distinguishing and tracing the origins of environmental nanoparticles. The objective of this dissertation is to characterize and quantify the concentrations of titanium dioxide engineered particles in urban …

Coastal Stormwater Pond Pollutants And The Potential For Development Of Antimicrobial Resistance In Vibrio And Enterococcus Bacteria, Cassandra L. Horton

Theses and Dissertations

The Southeastern coastal plain is the most rapidly urbanizing region in the United States. Associated landscape changes which increase imperviousness lead to hydrological cycle alterations, increasing runoff of nonpoint source (NPS) pollution. Urban and agricultural NPS runoff is generally discharged into stormwater ponds, which sequester chemical contaminants, nutrients, and microbes to reduce loading into coastal ecosystems. Studies of these ponds have indicated elevated levels of trace metals, antimicrobial compounds, and bacterial contamination (SCSGC 2018).

Interactions of aquatic pathogens Vibrio vulnificus and Enterococcus faecium with trace metals (arsenic, copper, zinc) and clinically relevant antimicrobials (triclosan, ciprofloxacin, oxytetracycline) commonly found in coastal …

Xenobiotic Exposures On Women’S Reproductive Health, Maria Zubizarreta Mcclam

Theses and Dissertations

Environmental and chemical exposures are continually introduced into our bodies. The female reproductive cycle is complex and particularly sensitive to toxic substances. A recent rise in infertility and reproductive diseases and cancers make reproductive toxicity a public health concern. The overall purpose of this dissertation is to explore how environmental and chemical exposures impact women’s reproductive health and overall wellbeing. To do this, a variety of topics related to women’s reproductive health are explored, including how environmental exposures can impact reproduction, methods for studying reproductive dysfunctions, fertility preservation among cancer patients, and the overall wellbeing of female cancer patients.

The …

Identifying Novel Pharmacogenetic Markers For Cancer Treatments: Exploiting Cancers Deficient In The Nucleotide Pool Sanitizing Hydrolases Nudt15 And Nudt18, Jacob Chandler Massey

Theses and Dissertations

The NUDIX hydrolases are a super family of enzymes with purported enzymatic activities of nucleotide hydrolases. The activity of the founding member, NUDT1 (also known as MTH1) is established to be a nucleotide hydrolase for d-8-oxoGTP, which is a mutagenic precursor if incorporated into DNA. Therefore, its activity serves to sanitize the nucleotide pool of mutagenic precursors. While known to be highly conserved among all organisms, the enzymatic and biological functions for nearly all the family members remain largely unexplored and unknown. Substrates of family members have been found to include canonical (deoxy)nucleotide triphosphates, oxidized (deoxy)nucleotide triphosphates, and non-nucleoside polyphosphates. …

Detection Of Microcystin Aerosol Particles, Alexis D. Dabney

Theses and Dissertations

Harmful Algal Blooms (HABs) are a growing global concern due to their increased prevalence and magnitude, frequency, and duration in affecting both aquatic ecosystems and human health (Brooks et al. 2015). In a series of experiments, lab-generated aerosol particles containing Microcystis and Microseira were captured using filters to analyze for concentrations of Microcystin, Saxitoxin, and Lyngbya toxins. The solutions were found to contain aerosols but did not contain detectable levels of Microcystin, Saxitoxin, and Lyngbya toxins following analysis by HPLC-MS. While the techniques for generating aerosols were shown to be effective, the generation and analysis of toxins did not produce …

Biomimetic Strategies To Control Therapeutic Release From Novel Dna Nanoparticles, Robert J. Mosley

Theses and Dissertations

The inherent chemical, mechanical, and structural properties of nucleic acids make them ideal candidates for the formulation of tunable, personalized drug nanocarriers. However, none so far have exploited these properties for the controlled release of therapeutic drugs. In this dissertation, a biomimetic approach to controlling drug release is exhibited by specifically manipulating the architecture of novel, DNA nanoparticles to take advantage of drug binding mechanisms of action. Rationally designed DNA strands were immobilized on gold surfaces via a terminal thiol modification. Immobilized monomers can be manipulated to form distinct monolayer architectures including flat, folded, coiled, or stretched structures. Increasing the …

Improving Nutrition And Food Safety Knowledge Of Small-Scale Fish Processors In Delta State, Nigeria, Grace Adeola Adegoye

Theses and Dissertations

Introduction: Fish is an affordable animal source food that provides nutrition and serves as a source of income for many people especially women in Nigeria. Smoking and sun drying are the processing methods in practice that expose the fish products to possible contaminants which may consequentially negate their nutritive value.

Aim: To improve the knowledge of fish processors on nutrition and safe fish handling.

Methodology: A 3-day participatory training was organized to train 122 fish processors, 95 women, and 25 men. The training was conducted in the three senatorial districts in Delta State, Nigeria. Knowledge was assessed using the pre …

Evaluating Soil Health Changes Following Cover Crop And No-Till Integration Into A Soybean (Glycine Max) Cropping System In The Mississippi Alluvial Valley, Alexandra Gwin Firth

Theses and Dissertations

The transition of natural landscapes to intensive agricultural uses has resulted in severe loss of soil organic carbon (SOC), increased CO₂ emissions, river depletion, and groundwater overdraft. Despite negative documented effects of agricultural land use (i.e., soil erosion, nutrient runoff) on critical natural resources (i.e., water, soil), food production must increase to meet the demands of a rising human population. Given the environmental and agricultural productivity concerns of intensely managed soils, it is critical to implement conservation practices that mitigate the negative effects of crop production and enhance environmental integrity. In the Mississippi Alluvial Valley (MAV) region of Mississippi, USA, …

Removal Of Arsenic (Iii) And Arsenic (V) From Aqueous Solution Via Common Sunflower Helianthus Annuus By Phytoremediation, Irving A. Vazquez Hurtado

Theses and Dissertations

Phytoremediation provides a cost-effective, non-invasive technique to remove contaminants from the soil and groundwater. Sunflowers are fast growing and have a showed effective at removing various pollutants from soil, including lead and other heavy metals. Health issues related to arsenic are mainly attributed to exposure of arsenite, whereas arsenate is much less toxic. The common sunflower Helianthus annuus was the species used to remove both arsenic (III) and As(V) ions from hydroponics solutions. In the present study sunflower seeds were germinated for a week, placed under the sun for a day and subsequently placed in a nutrient solution to aid …

Comparative Assessment Of The Fate And Toxicity Of Chemically And Biologically Synthesized Silver Nanoparticles Toward Juvenile Clams, Mercenaria Mercenaria, Amar Yasser Al-Rshim

Theses and Dissertations

Engineered nanomaterials (ENMs) with unique nanoscale properties, including novel optical behavior and superparamagnetic, are continually being developed for biomedical and industrial applications. In specific biomedical applications, ENMs are surface-functionalized using polymers, proteins, and other stabilizing agents to facilitate their resistance to salt-induced aggregation. Since their colloidal stability in high ionic-strength matrices, functionalized ENMs are anticipated to be persistent aquatic contaminants. Despite their potential environmental significance, the persistence of surface-functionalized ENMs as individually stabilized nanoparticles in marine environments is largely unknown. Further, few studies have investigated the fundamental factors that influence ENMs uptake and fate/transport processes in ecologically susceptible aquatic biota, …

Describing The Impact Of The Sales Of Antibiotics On The Environment And In Population Health, Andrés Gaviria-Figueroa

Theses and Dissertations

The role of antibiotics in human health is of significant importance in the advancement of the medical field. It has contributed to an improvement of the quality of life and the age expectancy of the population. Antibiotic resistance is an expected consequence of the use of antibiotics. Bacteria have developed biological mechanisms that would help them become resistant to antibiotics. The uncontrolled use of antibiotics is significantly contributing to the ability of bacteria to become resistant to those antibiotics. This study, using the model of the Socio-Ecological Coupling of Antibiotic Resistance, explains how social and environmental factors interact and impact …

Female Reproductive Toxicity Of Harmful Algal Blooms-Produced Toxin Microcystin, Yingzheng Wang

Theses and Dissertations

Harmful algal blooms (HABs) have become a global emerging environmental concern; however, its impact on women’s reproductive health is poorly understood. Microcystin-LR (MC-LR) is the most common and hazardous type of HAB toxin. Using both a chronic oral exposure mouse model and an acute exposure mouse model, I found that human-relevant exposure to MC-LR could compromise follicle ovulation via affecting follicle maturation. Both in vivo mouse exposure model and encapsulated in vitro follicle growth (eIVFG) model revealed that exposure to MC-LR did not affect follicle development, but significantly reduced the expression of some follicle maturation-related genes, such as Lhcgr and …

Behavioral And Physiological Effects Of Heavy Metals On Fish: A Review And Preliminary Results, Diana V. Morales

Theses and Dissertations

Pollution, specifically heavy metal pollution, in various bodies of water has been a significant issue for decades. Research has been conducted on heavy metals and their effects on the environment, larger fish species, and humans since the 1970s (Skidmore, 1964; Adeniyi et al., 2007; Adeosun et al., 2015; Bawuro et al., 2018). It is known that zinc is a neurotoxin in some species and causes harm to the environment. It is also known that it causes harm to people if it is ingested or if they are exposed to it for long periods of time (Mahurpawar, 2015; Mizuno and Kawahara, …

Repurposing Metformin And Antifolates For The Treatment Of Hepatocellular Carcinoma, Sherouk Mohamed Tawfik

Theses and Dissertations

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Due to its safety, wide availability and previously reported anti-cancer effects, metformin (MET) serves to be a possible therapeutic agent when combined with other well-known anti-cancer agents. The aim of this study was to investigate the potential anti-cancer effects of MET, an anti-diabetic agent, when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate …

Selective Gsk3Β Inhibition Mediates An Nrf2-Independent Anti-Inflammatory Microglial Response, Mohamed H. Yousef

Theses and Dissertations

Glycogen Synthase Kinase 3 (GSK3) is associated with the proinflammatory phenotype of microglia and has been shown to act in concert with Nuclear factor kappa B (NF-κB). . GSK3 is also a suppressor of Nuclear factor erythroid 2-related factor 2 (Nrf2), the principal regulator of redox homeostasis. Agreeing with the oxidative paradigm of aging, Nrf2 is often deregulated in parainflammatory and neurodegenerative diseases. In this study, we aimed to explore a multimodal disease-modifying utility of GSK3 inhibition, beyond neuronal proteopathologies, Furthermore, we aimed to underscore the difference in therapeutic value between the two GSK3 paralogs by isoform-selective chemical inhibition.

The …

N, N-Dimethylacetamide Targets Neuroinflammation In Alzheimer’S Disease In In Vitro And Ex Vivo Models, Zenghui Wei

Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder with no cure, accounting for 60-80% of cases of dementia. While the two pathologic hallmarks of AD, senile plaques from extracellular deposition of amyloid β-protein (Aβ) and tau-based neurofibrillary tangles (NFT), have been known for decades, the pathogenesis of AD remains unclear. In recent years, anti-neuroinflammatory treatment has entered the spotlight in AD research. In previous studies, we have shown that N,N-dimethylacetamide (DMA), a common drug excipient, is a potent anti-inflammatory agent. In the current work, we investigate the effect of DMA on neuroinflammation and its mechanism of action in in-vitro and ex-vivo …

Dithiocarbamates Mancozeb And Disulfiram Induce Striated Muscle Myopathy And Neuropathy In Long-Evans Rats, Olivia Stephenson

Theses and Dissertations

Mancozeb (MZ), an ethylene bis-dithiocarbamate complexed with the metals manganese and zinc, is a broad-spectrum fungicide used primarily on orchards and vineyards. Disulfiram (DS, Antabuse®), a diethyldithiocarbamate, is an FDA-approved drug used for alcohol aversion therapy. Both dithiocarbamates (DTCs) have shown neurological effects including motor impairment, muscle weakness, and hind-limb paralysis, although the mechanism of toxicity is not understood. The purpose of this study is to determine how these neurotoxic compounds are damaging striated muscle of rats. Adult, male Long-Evans rats were administered either 250mg/kg MZ or 750mg/kg DS via oral gavage 3x/week for four weeks. Animals were euthanized 24 …

Repurposing An Anti-Epileptic Drug For The Treatment Of Glioblastoma, Anjali Yadav

Theses and Dissertations

Glioblastoma multiforme (GBM) is a grade IV malignant glioma. It is a highly proliferative form of brain tumor with 5-year survival rate ~ 5% indicating a high mortality rate. Current treatment strategies for GBM include surgery, radiation, and chemotherapy. Surgical resection is challenging due to vital function of brain and as GBM often metastasizes in different brain regions. Additionally, development of resistance against the standard of care drug temozolomide (TMZ) is a major challenge in GBM management. GBM is also shielded with the blood brain barrier (BBB) which prevents the entry of several drugs. Therefore, a new drug must overcome …

Evaluating The Effects Of Mechlorethamine On The Dermal-Epidermal Junction, Trishaal Janardhanam Raghavendra Rao

Theses and Dissertations

Sulfur Mustard (SM) is a chemical warfare agent first utilized on the battlefield more than 100 years ago. To the present time, no antidote to combat the dermatotoxicity of SM exists. Mechlorethamine (HN2) is a derivative of SM which is used in anticancer therapy. Dermal exposure of HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication) which limits its clinical usefulness. The primary purpose of the present study was to investigate the mechanisms of vesication caused by HN2 using an in vivo mouse ear vesicant model (MEVM). The ears of male or female C57BL/ 6J mice were exposed to a …

Mechanisms And Treatment Of Pain-Depressed Behavior In Male And Female Mice, Clare M. Diester

Theses and Dissertations

One of the largest discrepancies between preclinical and clinical assessment of pain and analgesia is the type of behavioral endpoint used. Although most preclinical research has historically focused on drug effectiveness to block reflexive withdrawal behaviors stimulated by a noxious stimulus, increasing evidence shows that drug-induced restoration of pain-depressed behaviors provides increased clinical translation with decreased susceptibility to false-positives. Accordingly, the first portion of this dissertation designed a behavioral battery that featured pain-depressed behaviors as well as more conventional pain-stimulated behaviors for testing candidate analgesics in male and female mice. The main findings are as follows. (1) Intraperitoneal injection of …

Using Molecularly Imprinted Polymers For The Selective Extraction Of Analytes, Haley A. Mulder

Theses and Dissertations

Sample preparation is a critical steps in bioanalysis. Traditional methods such as solid-phase extraction and liquid-liquid extraction are laborious and ultimately incapable of properly separating target analytes from matrix and interferents. The co-extraction of these components interferes with the analytical instrument’s ability to properly detect and quantitate analytes. Molecularly imprinted polymers (MIPs) are synthetic polymers that have been “imprinted” with a template analyte in a co-polymer system. MIPs are capable of selectively extracting analytes from complex biological matrices and can be employed in off-line, benchtop extractions or for on/in-line instrument extractions. MIPs offer faster and more selective sample preparation, leading …

Modulating Ketamine’S Locomotor Activating And Reinforcing Effects Through Drug Combinations, Tegshjargal Baasansukh

Theses and Dissertations

Major Depressive Disorder (MDD) affects approximately 280 million people worldwide. The standard of care for pharmacological treatment of MDD has been monoaminergic antidepressants (MAA). However, MAAs have serious clinical limitations including a relatively slow onset of action and up to 40% of patients failing to respond and being diagnosed as “treatment resistant”. Ketamine, an N-methyl-D-aspartate antagonist, was originally approved for use as an injectable anesthetic. In addition, ketamine has been shown to rapidly improve depressive symptoms in patients with treatment resistant depression. In 2019, (S)-ketamine was approved as a nasal spray (Spravato®) for patients with MDD and treatment-resistant depression in …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …