Pharmacology, Toxicology and Environmental Health Commons^™

Anticancer Efficacy Of Methyl-Cantharidimide (Mca) In Liver Cancer, Yidong Li

Theses and Dissertations

Cancer is still one of the major public health challenges worldwide to the present day. Multi-drug resistance (MDR) that occurs in cancer chemotherapies is a non-negligible cause of cancer treatment failure and tumor recurrence. Overexpression of ATP-binding cassette (ABC) transporters is one of the most frequent mechanisms of MDR occurrence. Therefore, the establishment of a chemotherapy agent whose anticancer efficacy would not be affected by the overexpression of ABC transporters is in demand. Methyl-cantharidimide (MCA), a cantharidin (CTD) analog, has been approved in China for clinical liver cancer treatment. This study revealed that MCA was efficacious in the ABCB1-, ABCG2-mediated …

Evaluation Of Pulmonary Toxicity To Inhaled Erbium Oxide Nanoparticles In Golden Syrian Hamsters, Randy Liang

Theses and Dissertations

Erbium oxide nanoparticles (Er2O3 NPs) are used in various products from simple pottery to semiconductors and such usage leads to an elevated risk of accidental occupational exposure. In the present study, the pulmonary toxicity of Er2O3 NPs was assessed by examining tissues and bronchoalveolar lavage fluid (BALF) from the lungs of Golden Syrian Hamsters following inhalation exposure. The study’s goal was to determine the severity and mechanism of toxicity upon exposure to inhaled Er2O3 NPs. Animals were divided into 4 groups all being exposed for 4 hours a day for 8 days: Group-1: room air, Group-2: vehicle control (water), Group-3: …

Evaluation Of The Mechanism Of Cell Death After Exposure To Amorphous Silicon Dioxide Nanoparticles In Rat Pleural Mesothelial Cells And Golden Syrian Hamsters, Rachel P. Renda

Theses and Dissertations

Amorphous Silicon Dioxide Nanoparticles (SiO2 NPs) are widely used in the industrial processes, chemical, and cosmetics industries. Amorphous SiO2 NPs are abundant in the earth’s crust and can be released into the air through industrial and manufacturing activities. Such particles are overlooked and not as commonly studied when compared to their crystalline counterpart. Amorphous SiO2 NPs are pulmonary toxicants; however, the mechanism of toxicity is uncertain. In the current study, toxicity was assessed using both in vitro and in vivo systems to understand a possible mechanism of cell death. Rat Pleural Mesothelial Cells (RPMCs) were exposed to 50-800 μg/ml SiO2 …

Umbralisib Antagonizes Multidrug Resistance In Abcb1- Overexpressing Cancer Cells, Letao Bo

Theses and Dissertations

Overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1, is a major mechanism of multidrug resistance (MDR) and contributes to chemotherapy failure by reducing intracellular drug accumulation. Umbralisib is a dual inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) that was developed for the treatment of hematologic malignancies; however, it was later withdrawn due to safety concerns. In the present study, we found that umbralisib has the potential to reverse ABCB1-mediated MDR. The MTT assay demonstrated that umbralisib significantly sensitized ABCB1-overexpressing KB-C2 and SW620/Ad300 cells, as well as ABCB1-transfected HEK293 cells. Mechanistic assays revealed that umbralisib enhanced …

Prevention Of Inflammation-Associated Neurodegeneration: Assessing The Efficacy Of N,N-Dimethylacetamide (Dma) In Lipopolysaccharide (Lps)-Induced Neuroinflammation Using C57bl/6 Mice, Teeshavi Devi Acosta

Theses and Dissertations

Neurological function is closely linked to both longevity and quality of life. While some degree of neurodegeneration occurs naturally with aging, pathological neurodegeneration leads to devastating functional decline. The mechanisms underlying these processes remain incompletely understood; however, neuroinflammation is recognized as a key driver of neuronal dysfunction and death. Emerging evidence indicates that neuroinflammatory cascades can precede and potentiate hallmark features of neurodegenerative diseases, including synaptic loss and cognitive decline observed in Alzheimer’s disease (AD). Activation of the NF-κB signaling pathway contributes to amyloid beta (Aβ) peptide production, further amplifying a cycle of inflammation and neuronal injury. Preclinical work from …

Environmental Monitoring In Shallow Lakes: Public Health Threats In Urban Waters, Kyleigh E. Johnson

Theses and Dissertations

Lakes are an integral part of urban and suburban communities, providing ecological, recreational, and public health benefits. Many of these lakes are located in densely populated areas and are subject to urban influences on water quality. Algal toxins and Escherichia coli are two common recreational concerns. Algal toxins come from harmful algal blooms that are influenced by nutrient availability and temperature, while bacteria are often introduced through run-off and animal waste. Sampling every 3-4 weeks from May-October 2025 allowed for the assessment of seasonal patterns and site-specific differences across nine lakes in the Richmond area. The highest bacterial concentrations appeared …

Absolute Quantification And Identification Of Rna From Rna-Lipid Nanoparticles Using High Resolution Mass Spectrometry, Jason C. Funderburk

Theses and Dissertations

RNA therapeutics are a rising drug category with potential use for a range of conditions encompassing infectious diseases to therapies for cancer, diseases, and genetic disorders. RNA-lipid nanoparticles (RNA-LNPs) are the prominent delivery method for these therapeutics approved products include mRNA vaccines and polyneuropathy treatments. The emergency use authorizations and orphan drug status of current RNA-LNP drugs has allowed approval without finalization of the regulatory analytical procedures for quality monitoring. The objective of the study was to develop an LC-MS assay to simultaneously measure identity and concentration of two therapeutically relevant intact RNA constructs extracted from RNA-LNPs to enhance quality …

Investigation Of Metals And Incidental Nanomaterials In Wildland-Urban Interface Fire Ashes And Their Impacts On Marine Phytoplankton, Talal Abdullah Alshehri

Theses and Dissertations

Wildfires are natural processes that have played a vital role in ecosystems for millions of years. However, with increasing anthropogenic activities and climate change, wildfires' frequency and intensity have increased. A wildfire is an uncontrolled fire that burns forests, grasses, and savannas. In addition to vegetation combustible materials, wildfire burn structure items such as homes, stores, and storage sheds in areas where the transition zone between urban and wildland is defined as the wildland-urban interface (WUI). Moreover, wildfires in WUI can burn vehicles, including automobiles, tractors, and boats on trails. Recently, there have been concerns regarding the metals, metalloids, and …

Integration Of Mechanism-Driven Computational Modeling And Public Data Resources For Chemical Toxicity Assessment, Elena Chung

Theses and Dissertations

Regulatory toxicology depends primarily on animal testing, which limits throughput, mechanistic interpretability, and applicability to human-relevant endpoints. This dissertation presents computational approaches that integrate publicly available bioactivity data with machine learning to support chemical safety evaluation. Oral carcinogenicity was modeled using curated chemicals from the US Environmental Protection Agency’s Integrated Risk Information System (IRIS) and activity data from over 1,900 PubChem assays. Quantitative structure-activity relationship (QSAR) models trained on statistically prioritized assays demonstrated strong predictive performance and were applied to rank the carcinogenic potential of more than 16,000 compounds. Hepatotoxicity was evaluated using a hybrid modeling approach that combined structural …

Removal Of Fluoroquinolones From Water Systems Employing Rice Husk Composited Sponges Via Nanoadsorption, Dalia Kanaa

Theses and Dissertations

A novel nanocomposite of polyvinyl alcohol formaldehyde (PVF) sponge loaded with green zinc oxide nanoparticles (ZnONP) and referred to as (NP-PVF) was fabricated as a potential adsorbent of ciprofloxacin from water. A simple mechanical foaming process was used to synthesize the adsorbent. Rice husk extract was used to synthesize zinc oxide nanoparticles (ZnONP) for its phytochemicals as reducing agents. A facile and low-energy-dependent extraction method was used that did not require the use of high-temperature annealing. The synthesized nanoparticles showed a maximum UV absorption at 347 nm, which corresponds to a 3.58 eV band gap energy. FTIR confirmed the successful …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

Improving The Safety Of N,N-Dimethylacetamide As A Potential Treatment For Preterm Birth Using A Vaginal Nanoformulation, Asad Mir

Theses and Dissertations

With no available treatment for preterm birth, the field of reproductive medicine has been repurposing small molecule candidates into vaginal nanoformulations as potential treatments for the condition. The commercial solvent N,N-Dimethylacetamide (DMA) has previously been shown to delay and prevent inflammation-induced preterm birth in a mouse model. A vaginal nanoformulation of DMA loaded into a self-nanoemulsifying drug delivery system (SNEEDS) was studied to see if it can also be efficacious. A side by-side histological comparison was done in the more pertinent tissues of the reproductive tract between the traditional formulation of DMA given intraperitoneally (IP) and the vaginal nanoformulation of …

The Effects Of Exosomes In Lead And Lps Induced Inflammation In Microglia, Yitzchak Lax

Theses and Dissertations

Exosomes are membrane bound subcellular vesicles formed through membrane budding of a cell and play important roles in cell-cell communication. Studies have demonstrated inflammatory changes in various cell types depending on the etiology of the exosomes such as exosomes from cancer cells or exosomes derived from mesenchymal stem cells. The purpose of this study was to determine the inflammatory consequences of exosomes in microglial cells following exposure to lead, lipopolysaccharides (LPS) and lead+LPS. The cultured mouse microglial cells were treated at 0.01 μM, 0.1 μM and 1 μM of lead,- three environmentally relevant levels and LPS was used at 10 …

Developing Stiripentol Analogs As Potential Ldh Inhibitors For The Treatment Of Glioblastoma, Anshika Y. Jain

Theses and Dissertations

Glioblastoma multiforme (GBM) is a highly proliferative brain tumor that has a 5-year survival rate of ~7 %. Temozolomide (TMZ) is the current standard of care therapeutic for GBM. However, 50% of patients develop resistance to TMZ. Therefore, further investigation for new GBM therapeutics is necessary to overcome this issue of drug resistance. GBM patients are known to overexpress lactate dehydrogenase (LDH), which is inversely correlated with their survival. This key glycolytic enzyme catalyzes the interconversion of pyruvate and lactate and plays an important role in cancer proliferation and invasion. Therefore, we aimed to inhibit LDH for developing therapeutics for …

Identification Of Pharmacophore Modifications That Enhance Bmp-Receptor Agonism, An Investigation To Understand The Development Of Potential Therapeutic Interventions, Maleka T. Stewart

Theses and Dissertations

Bone morphogenetic proteins (BMPs) are the largest subfamily of the Transforming Growth Factor (TGF)-ß superfamily. BMPs are renowned for their pivotal role in cellular functions such as cell growth, apoptosis, and differentiation. Yet, BMPs have also been attributed to the maintenance of adult tissue homeostasis. BMPs elicit physiological function at the cell membrane via a heterotetrameric complex composed of two Type I and two Type II serine-threonine kinase BMP receptors. Activation of BMP transmembrane receptors results in activation of either canonical (Smad-dependent) and/or non-canonical (Smad-independent) signaling. Given the physiological importance of this intricate communication between receptor activation and induction of …

Unleashing Serine Palmitoyltransferase In Test Tubes And Mice, Matthew W. Peart

Theses and Dissertations

Canonically known both for structural contributions to lipid bilayers and roles in cell signaling, the sphingolipids comprise a dynamic, multifaceted class of molecules which are studied to understand homeostatic cell biology as well as pathophysiology. Sphingolipids contribute to tissue-specific structures such as myelin, a multilayer membrane that allows for rapid conduction of action potentials along neuronal axons. All sphingolipids are downstream products of the rate-limiting and initiating enzyme in the de novo sphingolipid synthesis pathway, Serine palmitoyltransferase (SPT). Demonstrative of its status as the enzyme that catalyzes a crucial step in a biochemical pathway, SPT activity is strictly regulated. This …

Scopolamine-Induced Modulation Of Serotonin And Dopamine Transporters Activity: Behavioral And Molecular Insights Into Rapid Antidepressant Action, Deepak Karunakaran

Theses and Dissertations

Major depressive disorder (MDD) affects over 350 million individuals worldwide and is characterized by profound dysregulation of serotonin (5-HT) and dopamine (DA) systems that govern mood, reward processing, and motivation. The serotonin transporter (SERT) and dopamine transporter (DAT), both dynamically regulated through phosphorylation, serve as critical determinants of synaptic monoamine signaling. Despite decades of therapeutic development, current antidepressants require 4-6 weeks to achieve efficacy, and approximately one-third to half of patients develop treatment-resistant depression. The emergence of rapid-acting antidepressants like ketamine represents a paradigmatic shift, demonstrating symptom relief within hours; however, ketamine's therapeutic potential remains constrained by abuse liability, dissociative …

Mdma Enantiomers: An Exploration Into 5-Ht2ar Necessity In Non-Hallucinogen Induced Frontal Cortex Plasticity, Maya C. Gaines-Smith

Theses and Dissertations

Entactogen 3,4-methylenedioxymethamphetamine (MDMA) has gained increasing attention as a potential psychotherapeutic, particularly for psychiatric disorders that have proven to be resistant to traditional treatments. Despite its growing popularity, the complete neurobiological mechanism of MDMA enantiomers, as well as the role of sex in these mechanisms, remains to be fully elucidated. Current ongoing research implicates agonism of the serotonin (5-HT) 2A receptor (5-HT_2AR) and neuroplastic growth in the success of other psychoactive and hallucinogenic pharmacotherapeutics, highlighting the importance of understanding the role that the 5-HT_2AR plays in the therapeutic mechanism of action of MDMA enantiomers. The culmination …

Preparation And Efficacy Evaluation Of Chicken Egg Yolk Sourced Igy Against The Venoms Of Cobra, Krait, Russell’S Viper, And Saw-Scaled Viper, Gayathri G

Theses and Dissertations

Envenomation resulting from snakebites is widely recognized as an alarming health risk in tropical and sub-tropical areas. The big four snakes including Naja naja, Bungarus caeruleus, Daboia russelli, Echis carinatus are responsible for most of the envenomation in India. The current therapy for snake envenomation is immunoglobulins, produced from serum or plasma of horses or sheep. To overcome the drawbacks of current antivenom, chicken egg yolk (IgY) antibodies have recently emerged as one of the most promising research avenues.

In this study, the efficacy of chicken egg yolk sourced antisnake venom (ASV) IgY against the big four venoms was evaluated …

Harvesting Health: The Role Of City Policy In Urban Agriculture And The Downstream Effects On Youth, Lesley Leake

Theses and Dissertations

Contextualizing environmental health within the socio-ecological framework, acknowledges the diverse factors at play in the environment-human dynamic. The research design, methods, and study populations of each chapter vary to match the socio-ecological level(s) of focus and reinforce the translational and interdisciplinary nature of this research. Chapter 2 examines the policy-supports for urban agriculture using a mixed-methods case-study of the City of Charleston, SC to understand how municipal policy (societal) impacts urban agriculture implementation (community) and what impact this has on residents (relationship and individual). Chapter 3 centers on the potential impact of urban farms (community) and their programming (community and …

Investigation Of The Environmental Factors Regulating The Biomass And Toxin Production Of The Benthic Cyanobacterium Microseira Wollei In Lake Wateree, South Carolina, Kara Clyburn

Theses and Dissertations

Impacts from anthropogenic activities and climate change are significantly altering nitrogen (N) cycling processes and biological productivity along the freshwater to marine continuum, and the acceleration rate of excessive N and phosphorus (P) concentrations entering aquatic environments is unprecedented. As a result, nutrient pollution is contributing to the increasing magnitude and duration of cyanobacterial harmful algal blooms (cHABs), oxygen (O2) depletion, loss of biodiversity, and impacts to human and ecosystem health. Lake Wateree, South Carolina (SC) is a freshwater drinking and contact recreational water resource with elevated symptoms of eutrophication, including the increasing prevalence of the N2 fixing benthic cyanobacterium …

Optimization Of A Nanotechnology-Based System For The Treatment Of Electroplating Wastewater, Madeleine Mary Meyer

Theses and Dissertations

To protect humans and the environment, human actions that may expose living organisms to toxic metals are heavily regulated in developed countries. The use and production of toxicants in commercial applications is tightly controlled in the United States of America by federal and state laws. Due to this fact, United States manufacturing companies are required to control the amount of regulated toxicants that leave their facilities. Toxic metals in wastewater are heavily regulated by federal and state law, with manufacturing facilities permitted individually for the concentrations of metals they are allowed to discharge via their wastewater. From previous research conducted …

Effect Of Short-Term Exposure To Pesticide Mixture On Tissue Architecture, Body Fluid Conditions, Nitrative Stress And Osmoregulation Of American Oyster, Crassostrea Virginica, Asif Ahmed

Theses and Dissertations

Pesticides are used widely to control weeds and pests in agricultural settings but harm non-target aquatic organisms. We examined the effect of short-term exposure (one week) to pesticide mixtures (low dose: 0.5 μg/L Roundup®, 0.5 μg/L 2,4-D, and 0.4 μg/L atrazine; high dose: 1 μg/L Roundup®, 1 μg/L 2,4-D, and 0.8 μg/L atrazine) on American oyster (Crassostrea virginica, an important shellfish and seafood species) under controlled laboratory conditions. Histological analyses demonstrated the atrophy in oysters' gills, digestive glands, and connective tissue. The protein concentrations and glucose levels dropped significantly in the high-dose treatment. The number of hemocytes in connective tissue …

Pipecolic Acid And Novel Insights Into Cerebral Malaria, Akua E. Mensah

Theses and Dissertations

Cerebral malaria (CM), a severe manifestation of Plasmodium infection, prompts our investigation into the nuanced role of pipecolic acid in its pathophysiology. To unravel the molecular intricacies, we conducted in vitro lysine labeling techniques of mice infected with P. berghei ANKA parasites, and human P. falciparum grown in vitro, aiming to discern the impact of Plasmodium on pipecolic acid production. Previous observations indicated an elevation in pipecolic acid levels correlating with neurological decline in children with CM. In our study, confirming elevated pipecolic acid presence in the plasma and brain tissues of CM patients and the animal model of CM, …

Analyzing The Effects Of Data Variability & Volume On Predicting Particulate Matter (Pm2.5): Insights From A Machine Learning Approach, Jada A. Macharie

Theses and Dissertations

Accurately predicting PM_2.5 concentrations are imperative to the future of public health and environmental policies. Machine learning models incorporating spatial and temporal datasets to predict PM_2.5 are often limited by data availability constraints and poor resolution satellite imagery.

Pharmacokinetic Modeling Of Metonitazene And Isotonitazene Using In Vitro And In Vivo Models And Comparison To Human Postmortem Casework, Justine P. Sorrentino

Theses and Dissertations

Metonitazene and isotonitazene are two benzimidazole opioids that are contributing to the opioid crisis nationwide. Limited pharmacokinetic data has been published on these nitazene compounds, therefore this study sought to determine if these two structurally similar opioids would have comparable half-lives and clearance utilizing in vitro and in vivo models. Using the data determined in the pharmacokinetic study, and by testing human postmortem cases, this study aimed to inform interpretation of these drugs detected in human casework. Sample analysis for all aspects of the study was performed utilizing LC/MS/MS. In vitro pharmacokinetics of both drugs were examined using a human …

Streptozotocin-Induced Diabetes Increases Kidney Toxicity In Rats Exposed To Ochratoxin A, Belkys Gonzalez

Theses and Dissertations

Due to the rising occurrence of diabetes in the population and the prevalence of OTA exposure via ingestion of contaminated foodstuffs, there is a need to assess the possible renal interaction of a diabetic disease state in concurrence with OTA exposure. Sprague Dawley rats were treated with streptozotocin to induce experimental diabetes and then orally exposed to 0.5 mg/kg body weight OTA once a day for 21 days. Renal biomarkers and light microscopy were evaluated to assess the interaction between diabetic nephropathy and OTA exposure. LLC-PK1 proximal tubule cells were used as an in vitro model to assess the potential …

Exposure To Dithiocarbamate Fungicide Ziram Results In Hepatic And Renal Toxicity In Long-Evan Rats, Jeffrey Chen

Theses and Dissertations

Ziram is a broad spectrum fungicide that is used on a variety of crops. It has been shown to display a wide array of toxicological effects, however, there is still a scarcity of mechanistic data regarding how it facilitates those effects. One of its presumed mechanisms of toxicity is due to the production of oxidative stress. However, whether the production of oxidative stress is due to its dimethyldithiocarbamate backbone, its metal moiety, or a combination of both, is still unknown. Contributing to the production of oxidative stress is ziram’s ability to alter essential metal homeostasis through transchelation of other essential …

Determination Of Genetic Variation In Opioid-Resistant Hospice Patients Using A Pharmacogenomics Approach, Daniel Bianculli

Theses and Dissertations

Managing pain requires a delicate balance between the advantages of opioid analgesia and the possible adverse effects. This balance becomes even more difficult in hospice and palliative care environments where dosage regimens are frequently ambiguous. Some hospice patients experience opioid resistance, in which opioids no longer produce an analgesic effect on a patient. Evidence-based analyses frequently omit this vulnerable population, resulting in a need for concrete procedures. The emergence of pharmacogenomic analysis and personalized treatment presents a solution to this problem by using each patient's genomic data to interpret opiate dosing. This pharmacogenomic study aimed to single nucleotide polymorphisms (SNPs) …

Production Of Vp3-Only Aav2 Vlp In E. Coli, Chengyu Fu

Theses and Dissertations

Adeno-associated virus (AAV) is a widely used vector for gene therapy. However, few studies have focused on producing AAV-based virus-like particles (VLP) in E. coli. This project aimed to express VP3 of AAV2 or co-express VP3 of AAV2 with other proteins, such as E. coli chaperones and/or assembly-activating protein (AAP) in E. coli under different expression conditions and explore the potential to produce VP3-only VLP of AAV2 in situ in E. coli. The constructed plasmid pET15ΔHis-VP3 was used to express VP3 under different conditions. The results demonstrated that most expressed VP3 was in inclusion bodies in all tested conditions. Although …