Pharmacology, Toxicology and Environmental Health Commons^™

Evaluation Of Microglia’S Structural Variations Within An Organotypic Hippocampal Slice Model After Regionalized Toxic Injury, Jesus Antonio Trejos

Theses and Dissertations

The dendritic cells of the CNS, the microglia (MG), are an initiation point of the immunological response within the post blood-brain barrier (BBB) compartment. Microglia morphology drastically changes in response to cell stress to a much different non-dendritic morphology. This investigation postulates that if the first MG responses to toxic injury are isolated and studied in greater morphological detail there is much to be learned about MG metamorphosis from a baseline (M2) to an activated (M1) state. The organotypic hippocampal slice was the experimental setting used to investigate microglial response to toxic injury. This isolates dendritic cellular responses and associated …

Mobocertinib Antagonizes Multidrug Resistance In Abcb1- And Abcg2-Overexpressing Cancer Cells, Xingduo Dong

Theses and Dissertations

The resistance of cancer cells to multiple drugs, known as multidrug resistance (MDR), remains a significant obstacle that leads to the ineffectiveness of cancer chemotherapy. The overexpression of ATP-binding cassette (ABC) transporters, particularly ABCB1 and ABCG2, has been strongly correlated with MDR. There is an urgent need to explore and identify novel inhibitors targeting ABCB1 and ABCG2 to overcome the related MDR. Mobocertinib (TAK-788) is an orally administered, irreversible EGFR/HER2 inhibitor approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This study …

Combined Cytotoxicity Of The Herbicide Glyphosate And The Fungicide Mancozeb In Mouse Neuroblastoma Cells, Heidi Ebid

Theses and Dissertations

The herbicide glyphosate and the fungicide mancozeb are globally applied on a variety of agricultural crops. Residues of both pesticides are frequently detected in food and water. Combined exposure to both compounds is therefore possible. Glyphosate and mancozeb have been separately investigated in previous studies and were shown to induce neurotoxicity. The current study investigates the cytotoxicity of different glyphosate and mancozeb combinations including mixture of mancozeb + glyphosate, combination of mancozeb followed by glyphosate and combination of glyphosate followed by mancozeb and compares neurotoxicity seen with the combinations to that of glyphosate or mancozeb using mouse neuroblastoma Neuro-2a cells. …

Exploring The Dual Role Of Vegf165 In Bleomycin Induced Lung Injury And Recovery In A Aav Mice Model, Igor Ban

Theses and Dissertations

Pulmonary fibrosis (PF) poses a significant challenge in respiratory medicine due to its complex etiology and progression characterized by excessive lung scarring, leading to compromised pulmonary function. The multifaceted roles of Vascular Endothelial Growth Factor A (VEGF-A) and specifically its isoform VEGF-A165 are critical in this context, given their involvement in angiogenesis, lymphangiogenesis, and tissue repair. The dual nature of VEGF-A165, promoting angiogenesis and potentially exacerbating or mitigating fibrosis, underscores its significance in both the progression and recovery phases of PF. Our work, explores the nuanced functions of VEGF-A165 using AAV1 as a gene delivery vector to overexpress this growth …

Therapeutic Intervention Of Neuroinflammation In Alzheimer Disease By Inhibition Of Classical Complement Pathway Using Anti-C1r Loaded Exosomes, Terjahna Richards

Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disease associated with memory decline and cognitive impairment. It is a growing global health and socioeconomic concern, affecting more than 50 million people worldwide. Current therapeutics focus solely on symptomatic management instead of preventative or curative strategies. This is mainly a result of the complexity of the pathophysiological mechanism and the poor understanding of the disease progression. Recently, studies have focused on bridging knowledge gaps giving rise to substantial evidence on the vital role of neuroinflammation in the progression of AD. Neuroinflammation has been shown to be a precursor to apparent amyloid plaque accumulation …

Hjp 272, An Endothelin Receptor Antagonist, And Its Role In Cancer Cell Migration And Invasion, Nabeela Fatima Baig

Theses and Dissertations

Endothelins are a family of versatile peptides composed of 21 amino acids with three isoforms: ET-1, ET-2, and ET-3. As the most abundant of the three isoforms, ET-1 is involved in various biological processes, such as regulation of vascular tone, humoral homeostasis, and neural crest development. However, focus is now being directed towards investigating the functions of the Endothelin axis in the progression of different tumor types including ovarian, prostate, breast, lungs etc. HJP 272 is a novel ETAR antagonist and while our group has previously researched its effects on lung inflammation and preterm birth, this study marks the first …

Characterizing The Role Of Epigenetic Regulator Menin In Pediatric Neuroblastoma Growth Using Pre-Clinical Models, Rameswari Chilamakuri

Theses and Dissertations

Epigenetic regulators such as Menin and MLL1 drive cancer progression, metastasis, and relapse. MLL1 forms a COMPASS complex with its binding partners, including Menin, to function as an epigenetic enzyme H3K4 methyltransferase. H3K4 methyltransferases are known to promote cancer stem cells' (CSCs) self-renewal capacity and metastasis. CSCs are one of the major causes of tumor relapse and metastasis conditions, ultimately leading to poor overall patient survival. Neuroblastoma (NB) is an extracranial solid tumor that accounts for 8-10% of all pediatric cancers, and approximately 50% of patients display metastasis at the time of diagnosis. In this study, we hypothesized and used …

Opioid System's Potential Involvement In Ketamine's Cognitive And Antidepressant-Like Effects In Rats, Fan Zhang

Theses and Dissertations

Depression stands as one of the most pervasive mental health challenges worldwide, including the United States. Conventional antidepressants typically display a delayed onset of therapeutic action (4-8 weeks) and lack efficacy in a substantial portion of patients (over 40% of depressed patients are treatment-resistant). The dissociative anesthetic ketamine, which is a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, has emerged as a promising novel treatment due to its rapid and prolonged antidepressant effects, and it is especially beneficial for treatment-resistant depression. Nevertheless, the precise neurochemical mechanisms underlying ketamine’s antidepressant properties remain elusive, hampering the development of safer and more efficacious treatments. The present …

Investigating The Impact Of Chronic Inflammatory Pain On Ethanol Consumption In Mouse Models., Joshua L. Hunt

Theses and Dissertations

Chronic pain affects nearly 20% of Americans annually and for many alcohol provides a convenient and legally acquired palliative. Population-based studies have suggested a link between increased alcohol use and reduced pain, but chronic or excessive alcohol use potentiates the risk to develop alcohol dependence and neuropathy. However, sex differences in chronic pain and alcohol abuse are still not well understood. In the present study, we investigated whether chronic inflammatory pain using the inflammatory agent Complete Freund’s Adjuvant (CFA) model could alter ethanol consumption in male and female C57BL/6J mice. We observed that only CFA-treated male mice increased their ethanol …

Exploring Serotonin 1b Autoreceptor Mediated Regulation Of Serotonin Transporter In Female Mice, Sanyukta Jalihalkar

Theses and Dissertations

Rationale: Serotonin (5-HT) is a crucial neurotransmitter involved in regulating various physiological processes. Dysregulation of the serotonergic system has been implicated in several neuropsychiatric disorders. Though numerous 5-HT receptors exist, the 5-HT transporter (SERT) is responsible for 5-HT clearance in the brain and periphery. 5-HT_1Bautoreceptors regulate 5-HT release and interact with glycogen synthase kinase-3β (GSK3β), which can modulate SERT function via specific Ser44/48 phosphorylation sites. While these findings suggest a potential interplay between 5-HT_1Band GSK3β-mediated SERT phosphorylation in regulating extracellular 5-HT, the primary causal molecular link remains unknown.

Objectives: To investigate if 5-HT_1B activation by …

Biodistribution Comparison Of Fentanyl And Morphine Following Acute And Repeated Expsoure, Rosamond M. Goodson

Theses and Dissertations

The ongoing opioid crisis constitutes a dire public health threat that has resulted in staggering loss of life. In 2021, opioids were implicated in over 75% of the approximately 107,000 deaths attributed to drug overdose (CDC), and synthetic opioids such as fentanyl and its analogues are key drivers of the surge in opioid fatalities in recent years. Although fentanyl is a μ opioid receptor agonist, it has several distinct attributes compared to other drugs in this category, such as morphine. These include enhanced lipophilicity, heightened potency to induce respiratory depression, more rapid entry into the central nervous system, reduced sensitivity …

Effects Of Short-Term Pesticides Exposure On Swimming Behavior, Tissue Morphology, Oxidative-Nitrative Stress, Antioxidant Expression, And Cellular Apoptosis In Kidneys Of Goldfish, Esmirna Cantú

Theses and Dissertations

The prevalence of pesticides in the aquatic environment continues to increase due to anthropogenic activities and poses a threat to aquatic organisms. The aim of this study was to determine the short-term exposure (one-week) of pesticide mixtures (metolachlor, linuron, isoproturon, tebucanazole, alconifen, atrazine, pendimethalin; azinphos-methyl) on swimming behaviors, kidney morphology, and expression of nitrotyrosine protein (NTP), dinitrophenyl protein (DNP), superoxide dismutase (SOD), catalase (CAT), renin, and cellular apoptosis in goldfish (Carassius auratus). Results indicated that both low- and high-dose pesticide mixtures decreased the distance swimming behavior. Histological analysis showed pesticide exposure alters kidney morphology. DNP, NTP, and renin expressions, and …

From Oceans To Public Health: Impact Of Climate Change And Socioecological Factors On Non-Cholera Vibrio Spp., Karlen Enid Correa Vélez

Theses and Dissertations

Climate change-induced stressors, such as temperature, salinity, pH, and wildfire, are contributing factors to the increase in frequency of Vibrio infections, altering Vibrio geographical constraints. At the same time, the expansion of the coastal population is resulting in increased input of treated municipal wastewater into areas that are also experiencing Vibrio proliferation. Given that increases in ocean temperature and sea level coupled with increases in human activity in coastal waters support greater Vibrio-human interactions, it is important to examine factors and mechanisms within this socio-ecological coupled system that may further strengthen this interaction. This study aimed to better understand the …

Transdisciplinary Approaches To Community Engagement, Research Translation And Science Communication Through Application Of The Socio-Environmental Report Card Process And Product In Murrells Inlet, South Carolina, Ekaterina Negodyaeva Altman

Theses and Dissertations

Public health and environmental sustainability are interlinked. Three pillars of sustainable development are society, environment, and economy are supported and reinforced by healthy populations. Balancing these values in a long-term vision and application requires active involvement of communities and stakeholders in decision-making process of management of environmental resources and personal health choices. Transdisciplinary sustainability science provides a framework for addressing complex issues in sustainability and generates actionable knowledge to link science and policy and involved stakeholders in the scientific process. Transdisciplinary research processes use co-design, co-production, and co-implementation framework to create and re-integrate useful knowledge into practice on a local …

Infection Intensity And Prevalence From Perkinsus Marinus In The Eastern Oyster, Crassostrea Virginica (Gmelin 1791) And Their Association With Salinity, Temperature, And Sex In South Carolina Estuaries, Deja E. Best

Theses and Dissertations

This project aimed to identify the associations between the infection intensity and prevalence of Perkinsus marinus infection (i.e., Dermo ) in the Eastern oyster, Crassostrea virginica (Gmelin), with extrinsic environmental factors such as changes in salinity and temperature along with oyster host factors such as sex ratio. The objectives of the study were to: (1) identify significant associations between the dependent variables, P. marinus prevalence and infection intensity, in relation to salinity and water temperature which may be affected by climate change; and (2) identify any intrinsic factors related to sex (i.e., male, female, intersex, and indeterminant) that may affect …

Replenishment Of Essential Natural Resources: An Assessment Of The Ability Of Freshwater Algae To Enhance Crop Quality And Soil Health, Lala Christina Ek

Theses and Dissertations

Disregard for soil, an essential natural resource, hinders global food production. Food insecurity is a major concern for both public health officials and environmental scientists due to soil quality decline, pollution, and climate change. Alternatives or targeted additions to chemical fertilizers can bolster soil quality, improve crop yields, lengthen crop shelf life, and mitigate environmental pollution. One potential alternative to chemical fertilizers is replacement of them with biological soil amendments, including algae, to enhance crop growth and improve soil health. Research was conducted at the University of South Carolina-Columbia campus garden to determine impacts of non-toxic freshwater algae on crop …

Integrated Wastewater Surveillance For Sars-Cov-2 And Antibiotic Resistant Bacteria: Implications For Public Health And Environmental Management, Mirza Isanovic

Theses and Dissertations

While current technologies have inadvertently resulted in wastewater treatment plants (WWTPs) becoming major sources of global antibiotic resistance gene (ARG) dissemination, wastewater can be leveraged to provide vital community-level health information. This project examined both of these aspects through wastewater-based surveillance of SARS-CoV-2 and metagenomic analysis of specific ARGs collected from both activated sludge and bioaerosols. In this study, we investigated treatment steps between the influent and final treated effluent to identify the point at which viral RNA is below detection. Additionally, we examined air surrounding high turbulence treatment steps to test for the presence of SARS-CoV-2 RNA in WWTP-generated …

Quantification Of The Internalization Of A Commercially Available Silver Nanoparticle To The Bacterium Escherichia Coli, Samantha Mcneal Case

Theses and Dissertations

Nanoparticles (NPs), materials with dimensions ranging from 1 to 100 nanometers, are widely used in various consumer products, with silver nanoparticles (AgNPs) being the most prominent. Exposure to AgNPs occurs through multiple sources, including food packaging, supplements, and disinfectants, owing to their antimicrobial properties. Prior research has identified adverse health effects, such as cytotoxicity, toxicity, and Ag bioaccumulation resulting from AgNP exposure to bacteria in biological systems and the environment. However, most studies employ pristine, highly concentrated NPs, which may not accurately represent realistic exposure scenarios at environmentally relevant concentrations. This project investigates the fate and internalization of AgNPs, found …

Molecular Mechanisms Of Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators On Sarin Surrogate-Induced Toxicities, Darby Caroline Stanford

Theses and Dissertations

Organophosphorus compounds (OPs), both nerve agents and insecticides, may induce damage leading to long-term neurological deficits. Oxime 20, the lead compound from a platform of substituted phenoxyalkyl pyridinium oximes (US Patent 9,227,937), is an oxime that reactivates OP-inhibited acetylcholinesterase (AChE) and has displayed neuroprotection within the brain of rats in in vivo tests where the currently approved treatment, pralidoxime (2-PAM), has not. This research investigated the neuroprotective effect of novel oxime therapy. Gene expression in rat piriform cortex was analyzed to determine if neurotoxicity, stress, and synaptic plasticity-associated genes were down-regulated by Oxime 20 following a sublethal dose of sarin …

Interspecies Differences In Organophosphate Anticholinesterase Inhibition Potency And Reactivation Using Novel Oximes, Katie Elizabeth Strickland

Theses and Dissertations

Organophosphates are insecticides which result in acute adverse signs when exposed at toxic doses by animals and lead to death if left untreated. The current treatment for organophosphate toxicity includes atropine and the federally approved oxime 2-PAM. However, 2-PAM is not very effective at crossing the blood brain barrier which results in prolonged inactivation of acetylcholinesterase, which is the primary target of organophosphates, in the brain even after administration. The novel oximes, Oxime 15 and Oxime 20, are able to cross the blood brain barrier and reactivate the inhibited acetylcholinesterase. In this experiment with six animal species frequently used in …

Customer Discovery And Applied Research And Development For An Environmental Nanotechnology, Paul Michael Vecchiarelli

Theses and Dissertations

Technology transfer is a process by which an innovative technology, typically produced in a non-commercial setting such as academia, is developed into a potential market opportunity. The first phase of technology transfer, once a technology has been developed, is to identify a customer segment and determine a value proposition that describes what need the technology will fulfill for them. This phase has been systematized into a framework known as customer discovery. Success in customer discovery will indicate technological gaps, such as scale-up, prototyping, and realistic testing, that are needed to deliver the value proposition to the initial customer. Both phases …

Parent Perspectives On Barriers And Facilitators To Optimal Healthcare And Medical Screenings For Children With Down Syndrome In South Carolina, Vinita Oberoi Leedom

Theses and Dissertations

Children with Down syndrome (DS) often have co-occurring conditions affecting vision, hearing, sleeping, and more. Screenings, as recommended by the American Academy of Pediatrics (AAP), can help prevent secondary disability, and allow children to thrive. Studies have evaluated the receipt of recommended screenings, but barriers and facilitators surrounding access to screenings and care have not been described.

Parents of 24 children with DS in SC were recruited through schools and family support groups. One-hour long interviews were conducted in English and Spanish. Information was collected on health, healthcare quality, respiratory concerns, pandemic effects, access to care, and knowledge about AAP …

Effects Of Occupationally Military-Relevant Particle Mixtures (Sio2, Cdo, Cr2O3) On A549 Human Pulmonary Epithelial Cells, Isabella M. Muffoletto

Theses and Dissertations

In the course of maintaining a safe, mission-ready aircraft fleet and operational runways, United States Airmen experience a range of occupational risks. These risks include inhalable hazards generated from oft-used maintenance practices, such as blasting which emits silica from the media abrasives as well as contaminants from the exterior coatings. Additional inhalation hazards range from engine and fuel emissions, chemical agents, radiation, and explosives, to naturally occurring and human-manufactured biopathogens. Of notable concern are emissions in forward-deployment areas, including urban pollution, particulates released from runway construction and maintenance activities, and combustion from burn pits containing hazardous and unknown combinations of …

Overexpression Of Abcc1 And Abcg2 Confers Resistance To Bmn-673, A Poly (Adp-Ribose) Polymerase (Parp) Inhibitors, Qiuxu Teng

Theses and Dissertations

Cancer remains a growing public health challenge worldwide. Although the development of chemotherapies has effectively reduced the cancer death rate and improved patients’ prognosis, the frequent occurrence of multi-drug resistance (MDR) in cancer has caused impairments on the efficacy of many structure-unrelated anticancer agents, leading to treatment failure and recurrence. One of the most common causes of MDR is the overexpression of ATP-binding cassette (ABC) transporters on cancer cell membranes, which transport anticancer drugs out of cancer cells, thereby reducing the intracellular drug concentration. BMN-673 (talazoparib) is a potent poly (ADP-ribose) polymerase (PARP) inhibitor that is approved for BRCA-mutated HER2-negative …

Mancozeb Exposure Results In Oxidative Stress And Disruption Of Mitochondrial Complexes Iii & Iv In Transformed Human Colon Cells, Amanda Dhaneshwar

Theses and Dissertations

The ethylene bisdithiocarbamate pesticides, a subclass of the dithiocarbamate pesticides, are broad spectrum organometallic fungicides used on a variety of crops. The fungicide Mancozeb is comprised of an ethylene bisdithiocarbamate backbone complexed to the metals manganese and zinc. Ingestion of food containing pesticide residue and occupational exposure are common routes of Mancozeb exposure. Previous work demonstrated that Mancozeb exposure to HT-29 colon cancer cells resulted in cytotoxicity, apoptosis, and disruption of mitochondrial complex I, II, and V activity. The current study investigated the effect of Mancozeb exposure on mitochondrial complex III and IV activity and oxidative stress parameters in the …

Cytotoxicity Of Copper (Ii) Octanoate On Mouse Hippocampal Astrocytes, Ali A. Shohatee

Theses and Dissertations

Copper, as an essential trace element, is crucial for various biological processes but has also been utilized as a constituent of various pesticides for decades. Copper (II) octanoate is a pesticide utilized as a fungicide and is approved for use in the production of certified organic foods. Previous studies have implicated copper as an inducer of oxidative stress and activator of the Nrf2-ARE pathway. Nrf2 is essential in regulating the transcription of various genes to alleviate toxicity such as those involved in glutathione synthesis and detoxification. Due to the limited toxicological data, this study into the potential induction of oxidative …

Evaluating The Influence Of Concurrently Available Non-Drug Reinforcers On Drug Reinforcement Using Sophisticated Preclinical Models Of Substance Use Disorder, Madison M. Marcus

Theses and Dissertations

The maladaptive allocation of behavior towards cocaine and away from other concurrently available non-drug reinforcers (e.g., family, health, work, etc.) is a key characteristic of cocaine use disorder (CUD) that is embedded into multiple diagnostic criteria for CUD. Accordingly, basic research conducted in a drug-vs-food “choice” context has improved our fundamental knowledge of the behavioral and neurobiological mechanisms of drug reinforcement. However, to date, these preclinical studies have only been conducted with food as the alternative reinforcer. The extent to which other non-drug reinforcers compete with cocaine-taking behavior is unknown. The studies in this dissertation establish two sophisticated discrete-trial cocaine-vs-alternative …

Novel Strategies In Head And Neck Tumor Therapy; Contribution Of Senescence In Therapy Response, And Resistance Development After Cisplatin Treatment, Fereshteh Ahmadinejad

Theses and Dissertations

Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local, and distant metastasis and disease relapse as well as cisplatin-induced resistance are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in both p53 wild- type HN30 and p53 mutant HN12 head and neck cancer models. We also show that tumor cells can escape from senescence both in vitro and in vivo. We further established a cisplatin-resistant cell line from HN30 parental cell line that underwent brief senescence …

Intrinsic Efficacy As A Determinant Of Opioid Effectiveness In Treatment Of Pain-Depressed Behavior, Edna Santos

Theses and Dissertations

Pain is a major public health concern that is commonly associated with behavioral depression, and a major goal in pain treatment is alleviation of pain-related behavioral depression. High-efficacy mu opioid receptor (MOR) agonists (e.g. fentanyl, morphine, oxycodone) are effective to treat pain, but their use is limited by side effects that not only endanger the patient but may also obscure analgesic rescue of pain-depressed behavior. The ongoing epidemic of opioid abuse and overdose deaths has stimulated research to discover non-opioid alternative analgesics; however, this search neglects the clinical potential of safer intermediate-efficacy MOR agonists (e.g. buprenorphine). The objective of the …

Epithelial Membrane Protein 3 (Emp3b) Is A Novel Regulator Of Sympathetic Nervous System Development In Zebrafish., Jessica M. White

Theses and Dissertations

Notable progress has been made in understanding the development of the neural crest (NC). Neural crest cells (NCCs) can be divided into 4-5 subpopulations. A major lineage among trunk NC derivatives are sympathoadrenal (SA) cells, which give rise to the sympathetic nervous system (SNS). Trunk NCCs follow a ventromedial migration pathway where signals derived from the dorsal aorta instruct migrating NCCs to a SA cell fate. Defects in NC development can result in syndromes known as neurocristopathies. Neuroblastoma is one of the most common forms of pediatric cancer affecting nearly 800 infants each year in the United States (Takita et …