Pharmacology, Toxicology and Environmental Health Commons^™

A Bioaffinity Self-Assembling Gel For Localized Delivery Of Immunotherapeutics, Ngoc Pham

Electronic Theses and Dissertations

Renal cell carcinoma (RCC) is a type of cancer in which malignant cells develop in the kidney tubules. Immune checkpoint inhibitors (ICI), including anti-PD-1 antibodies (aPD1), as monotherapies or in combination settings have advanced to the front-line treatment for patients diagnosed with RCC. Systemic infusion of ICI may render subtherapeutic concentrations in the lesions and increase risks of immune-related adverse events. To overcome these limitations, locoregional drug delivery has gained substantial interests as a modality in immuno-oncology. However, conventional intratumoral injections may be ineffective because the high interstitial fluid pressure in tumors resists drug retention and results in rapid local …

Sex-Specific Effects Of Chaperone And Glial Defenses On Experimental Lewy Body Disease, Tarun Bhatia

Electronic Theses and Dissertations

Lewy body disorders are a group of neurodegenerative conditions characterized by the pathological misfolding and aggregation of the abundant protein, α-synuclein. The most common Lewy body disorders are Parkinson’s disease and dementia with Lewy bodies. Apart from ageing, male sex is a major risk factor for Lewy body disorders, as men are at ~1.5-fold higher risk for these diseases than women. Yet, preclinical studies on Lewy body disorders rarely examine sex as a biological variable, and the mechanisms underlying sex-skewedness in disease risk remain undetermined.

Here, we developed a sex-stratified model of Lewy body disorders by exposing primary neurons harvested …

The Roles Of Pon2 In Mitochondrial Physiology, Lung Tumor Cell Proliferation, And Lung Tumorigenesis., Aaron Whitt

Electronic Theses and Dissertations

Paraoxonase 2 (PON2) is an intracellular, multifunctional enzyme with near-ubiquitous tissue distribution. Within cells, PON2 is localized to mitochondria and endoplasmic reticulum (ER), where it mitigates the formation of reactive oxygen species (ROS). PON2’s chief enzymatic function is its lactonase activity, through which it catalyzes the hydrolysis of a bacterial quorum-sensing molecule, N-(3-oxododecanoyl)-l-homoserine lactone (C12), effectively disrupting bacterial intercellular communication and protecting against infection. C12 is produced by the opportunistic pathogen Pseudomonas aeruginosa and has been shown to disrupt various aspects of eukaryotic host cell physiology and evoke apoptotic cell death through the activity of PON2. Additionally, PON2 has garnered …

Particulate Hexavalent Chromium Inhibits Homologous Recombination Repair By Targeting Rad51 Paralogs In Human Lung Fibroblasts., Aggie R. Williams

Electronic Theses and Dissertations

Hexavalent Chromium [Cr(VI)] is a known human lung carcinogen and general health hazard. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the major theory in its carcinogenic mechanism. Homologous recombination (HR) repair is a DNA repair pathway that prevents CIN by repairing DNA double-strand breaks. RAD51, a key mediator protein of HR repair, along with the RAD51 paralogs (RAD51B, C, D, XRCC2, and 3) are required for HR repair. During HR, RAD51 loads and forms a helical nucleoprotein filament structure to promote DNA strand exchange and stimulate pairing activity of DNA. Cr(VI) exposures have been shown …

Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan

Electronic Theses and Dissertations

Retinal fibrosis is detrimental to vision. Retinal pigment epithelial (RPE) cells contribute to several retinal fibrotic diseases. Upon exposure to TGF-β, a key fibrotic cytokine, RPE cells trans-differentiate to myofibroblasts marked by the integration of α-SMA fibers into F-actin stress fibers, which confer strong contractility. Myofibroblasts produce and contract the collagen-rich fibrotic scar and disrupt retinal architecture. In this study, we investigated the in vitro effects of the putative endocannabinoid compound N-oleoyl dopamine (OLDA) on TGF-β2 induced porcine RPE cell contraction and α-SMA expression. Using an in vitro collagen matrix contraction assay, we found that OLDA inhibited TGF-β2 induced contraction …

Behavioral Effects And Neurobiological Mechanisms Of 3-Aminobenzimide In A Rodent Model Of Chronic Psychological Stress, Liza Wills

Electronic Theses and Dissertations

Major depressive disorder (MDD) is a leading cause of disability worldwide, with a lifetime prevalence rate of approximately 20%. Inadequate pharmacological treatment methods for MDD are a significant debilitating factor. Patient estimates suggest that the treatment resistance rate for pharmacological interventions is over 30%. Postmortem analyses of human tissue of individuals diagnosed with MDD have shown an increase in Poly (ADP-ribose) polymerase 1 (PARP-1) mRNA gene expression in prefrontal cortical white matter when compared to psychiatrically normal brain tissue. In order to further investigate this issue, the present study used the social defeat stress/chronic unpredictable stress (SDS + CUS) rodent …

Operatic Mysticisms: Mountains, Deserts, Waterscapes, Andrew Demczuk

Electronic Theses and Dissertations

Operatic Mysticisms: Mountains, Deserts, Waterscapes examines the ways we encounter environments as readers/viewers of operas, literature, film, and sound recordings, and how each medium requires different detail-gathering techniques. Respective to the previously mentioned mediums, Sun & Sea (2017), Mount Analogue (1952), El Mar La Mar (2017), and Energy Field (2010) are analyzed by engaging with environmental media studies and invention. Reflecting the nature of each landscape—summits of mountains, aporias of deserts, and mysteries of waterscapes—an elemental approach is taken in investigating how these spaces may be noticed, internalized, recorded, and traversed by both the artist and viewer. …

Early Detection Of Atypical Motor And Neurobehavior Of Infants At Risk Secondary To Opioid Exposure: A Prospective Study, Kara Boynewicz

Electronic Theses and Dissertations

Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a …

Real-Time Monitoring Of Cell Death Progress Using Capacitance Spectroscopy, Suyang Wu

Electronic Theses and Dissertations

Biologics, including the monoclonal antibody (mAb), has experienced rapid development in the last decade. However, the price of biologics is often prohibitively high because of the low process efficiency. Delaying the inevitable cell death improves the productivity of upstream bioprocessing, whose success relies on monitoring the cell death onset that indicates the timing for preventive actions.

This study proposes to develop a real-time monitoring model that quantifies the dying cell percentage in lab-scale bioreactors using capacitance spectroscopy. The capacitance spectroscopy contains cell death-related information due to various physical properties changes during the cell death process, e.g., cytoplasmic conductivity change. The …

Translating Particulate Hexavalent Chomium-Induced Chromosome Instability, Loss Of Homologous Recombination Repair And Targeting Of Rad51 From Human Lung Fibroblasts To Human Bronchial Epithelial Cells., Idoia Meaza Isusi

Electronic Theses and Dissertations

Particulate hexavalent chromium [Cr(VI)] is a well-established human lung carcinogen. RAD51, a key protein in homologous recombination repair pathway, is inhibited after prolonged exposure to Cr(VI), leading to an increase in chromosome instability after prolonged exposures in human lung fibroblasts. chromosome instability is the proposed driver of Cr(VI) carcinogenesis. Since tumors from chromate workers develop from epithelial cells, we sought to translate these findings from human bronchial fibroblasts to human bronchial epithelial cells. We hypothesized Cr(VI) inhibits RAD51 after prolonged exposure leading to an increase in chromosome instability in human bronchial epithelial cells (BEP2D). We characterized the cytotoxicity and measured …

Characterizing The Role Of Macrophages In Cisplatin-Induced Kidney Injury And Progression To Chronic Kidney Disease., Sophia M. Sears

Electronic Theses and Dissertations

Cisplatin is a commonly used chemotherapeutic for treatment of many solid-organ cancers. Unfortunately, 30% of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long term declines in kidney function and development of chronic kidney disease (CKD). While traditional rodent toxicity studies have utilized a single, lethal dose of cisplatin, new models of cisplatin-induced kidney injury have revealed that repeated, low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. C57BL/6 mice are one of the most used …

The Role Of Sphingolipids In Aki And The Progression To Ckd: Potential Therapuetic Targets., Nicholas A. Hoffman

Electronic Theses and Dissertations

Acute Kidney Injury (AKI) is most simply defined as a rapid decline in kidney function over a period of hours to days. There is currently a lack of effective treatment options for patients with AKI, highlighting the need to identify new therapeutic targets. Sphingolipids play a number of roles in different models of AKI, suggesting they could be promising future targets for treating kidney injury. Specifically, sphingosine-1-phosphate (S1P) and its receptors (S1PRs) have been implicated in numerous inflammatory disorders and models of AKI. The purpose of this review is to better characterize the role of S1P receptors in models of …

Investigating The Effects Of Perfluorooctanoic Sulfonate (Pfos) And Ethanol On Fatty Liver Disease Using A Modified Niaaa Model., Tyler Charles Gripshover

Electronic Theses and Dissertations

Perfluoroalkyl Substances (PFAS) are a family of man-made, surfactant-like compounds that are a major environmental contaminant. A multitude of studies have indicated that PFAS are able to induce fatty liver disease and modulate lipid metabolism. However, the distinct mechanism of PFAS influence on the liver and metabolism disruption remains to be elucidated. On the other hand, it is well documented that alcohol consumption has various adverse health impacts including fatty liver disease and subsequent progression to more adverse liver states. To date, there are no published studies on whether PFAS and alcohol can jointly exacerbate fatty liver progression or interact …

Assessing The Role Of Chronic Arsenite Exposure In Disrupting The Egfr Signaling Axis., Christine Kim

Electronic Theses and Dissertations

Chronic arsenic exposure is a risk factor for the development of pulmonary diseases, including lung cancer, but the exact mechanism is not yet fully understood. Many previous studies have relied on acute arsenic exposure (i.e. 1-10 uM arsenic for 24 hours) to study arsenic toxicological effects. However, acute exposure does not reflect the levels or duration of arsenic associated with environmental exposure, or drinking of contaminated well water. This dissertation differentiates the effects of acute versus chronic arsenic exposures on the EGFR signaling axis and suggests possible mechanisms for chronic arsenic-induced pulmonary diseases. The EGFR is a receptor tyrosine kinase …

Identifying The Cardiovascular Effects Of Multiple Pollutants., Katlyn Elizabeth Mcgraw

Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of death from environmental exposures. Although exposure to PM_2.5 is an established risk factor for CVD, the contribution of other hazardous pollutant exposure to CVD is less clear. Overall, this work aimed to examine the effect of pollutants with lesser documented effects on cardiovascular disease using a multi-pronged approach to exposure assessment. The three aims were to examine the relationship between county-level toxic chemical releases and CVD mortality in the contiguous United States between 2002 and 2012, to assess the relationship between individual-level VOC metabolites and vascular function, and to build multipollutant …

Effects Of Respiratory Perturbations On Aging And Healthspan In Daphnia Magna, Millicent Nkiruka Ekwudo

Electronic Theses and Dissertations

Aging is a degenerative process characterized by a decline in physiological functions and cellular activities. Environmental and pharmacological interventions affecting longevity pathways have been extensively studied in model organisms. This study investigated the effect of chronic mild intermittent hypoxia (4 mg O2/L) or mild mitochondrial uncoupling with three doses of 0 (control), 0.1, 1, and 5 μM of 2,4-Dinitrophenol (DNP), on life history and gene expression in four clones of Daphnia magna. Interestingly, clones from intermittent ponds displayed better tolerance to hypoxia and DNP. Although neither treatments extended longevity, hypoxia increased fecundity and body size, and decreased food consumption and …

Analysis Of Metabolites And Therapeutics For Toxic Inhaled Agent Exposure, Abigail Bemah Donkor

Electronic Theses and Dissertations

The inhalation of toxic inhaled agents (TIAs) such as methyl isocyanate and cyanide can compromise an individual’s general health due to their extremely toxic nature. Nonetheless, these gases are used extensively in the electronics, chemical, welding, electroplating industries, etc., increasing the risk of exposure to both civilians and industrial workers. It is therefore very crucial to develop analytical methods for TIA metabolites and therapeutic agents. Methyl isocyanate (MIC), an intermediate in the synthesis of carbamate pesticides is a toxic industrial chemical that causes irritation and damage to the eyes, respiratory tracts, and skin. Due to its reactivity with proteins, protein …

Antiparasitic Peptide From The Ocean: Discovery, Synthesis And Structure-Activity Relationship Study, Kh Tanvir Ahmed

Electronic Theses and Dissertations

Millions of people die every year because of infectious diseases, and malaria is among the top five of the deadliest infectious disease. In 2018, malaria took more than four hundred thousand lives, and more than half of them are children under five years of age. Most malaria-affected parts of the world are also the home of the most underprivileged people. Seemingly, antimalarial drug discovery never achieved the attraction that it requires. Like malaria, another infectious disease that is not extensively explored by drug discovery campaigns is American trypanosomiasis or Chagas disease. More than a hundred years have passed since discovering …

Isolation, Structure Elucidation, And Synthesis Of Natural Products From Marine Cyanobacteria, Keren Solomon

Electronic Theses and Dissertations

This thesis describes the isolation, structure elucidation, and synthesis of natural products from marine cyanobacteria. A crude extract from a cyanobacterium collected in Curacao showed selective affinity for the dopamine D₅ receptor in a screen against a panel of CNS receptors. Due to the high similarity of the D₅ and D₁ receptor, to date there are no known ligands that differentiate them. Attempts to purify the compound responsible for this affinity led to the isolation of the known compound caylobolide A. A second extract from a cyanobacterium collected in Panama underwent bioassay-guided fractionation and yielded the novel …

N-Acetyltranserase 2 (Nat2) Genotype Polymorphism In Cryopreserved Human Hepatocytes And Chinese Hamster Ovary (Cho) Cells., Mariam Refaat Zaky Habil

Electronic Theses and Dissertations

Arylamine N-acetyltransferases, NAT1 and NAT2, catalyze the detoxification and/or activation of drugs and aromatic amine carcinogens. Single nucleotide polymorphisms or SNPs result in different human NAT2 genotypes thus dividing the population into rapid, intermediate, and slow acetylators. We hypothesize allelic variants of NAT2 genotype will decrease levels of N-acetylation, cytotoxicity, oxidative stress, DNA adduct formation, and mutagenesis compared to the reference allele NAT2*4. Cryopreserved human hepatocytes expressing different NAT2 genotypes and NER-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and human NAT2*4, NAT2*5B or NAT2*7B have been used to investigate N-acetylation of different xenobiotics. In …

Potential Toxicity Of Silver Nanoparticles To Microbial Communities And Macroinvertebrates, Joseph Kusi

Electronic Theses and Dissertations

Silver nanoparticles (AgNPs) are the most common nanomaterials incorporated in commercial products due to their antimicrobial activity. Recently, AgNPs were detected in surface waters suggesting the potential for bioavailability in the aquatic receptor organisms. This dissertation research attempts to understand the potential toxicity of AgNPs on water quality indicators, focusing on the microbial community and amphipods. This study evaluated whether: (1) the antimicrobial properties of AgNPs pose potential risks to microbial communities in pathogen impaired streams; (2) AgNPs can cause a shift in functional diversity and metabolic fingerprinting of microbial communities; (3) survival and growth of Hyalella azteca (amphipods) could …

Development Of A Pharmaceutical Tablet Authentication System Using Spectroscopic Techniques In Combination With Multivariate Chemometric Methods, Md Nayeem Hossain

Electronic Theses and Dissertations

The spread of falsified drugs is increasing worldwide. Currently, 10%-30% of drugs in the world are falsified. Unfortunately, the supply chain system of developing countries (from manufacturers to customers) is not well monitored and suffers the highest rates of fraudulent activities. Also, the rise of product procurement from the internet increases the chance of American consumers' exposure to poor quality drugs. To combat this horrendous activity, surveillance of pharmaceutical materials is required in the supply chain system. Spectroscopic techniques (e.g., Near-Infrared and Raman spectroscopies) can be a potential solution to authenticate samples in different locations; they are non-destructive, safe, rapid, …

Tobacco Product-Derived Aldehydes: Effects On Circulating Angiogenic Cells & Implications For Cardiovascular Disease., Jordan B. Lynch

Electronic Theses and Dissertations

Cardiovascular disease (CVD) is the leading cause of death worldwide. Tobacco smoke is the most significant modifiable risk factor in CVD development and contains numerous toxic compounds, including aldehydes, which have been linked to CVD. Formaldehyde, acetaldehyde, acrolein, and crotonaldehyde have been identified as significant contributors to cigarette-induced health effects, but the mechanism of these effects is not well understood. These aldehydes are also found in aerosols produced by e-cigarettes (e-cigs). The goal of this dissertation was to explore the systemic, hematological, and endothelium-related effects of exposure to tobacco products and constituent aldehydes and to identify potential mechanisms of injury. …

Dual Role Of Antimicrobial Peptide Cathelicidin In Alcohol-Associated Liver Disease., Fengyuan Li

Electronic Theses and Dissertations

Patients with alcohol-associated liver disease (ALD) have high morbidity and mortality in its severe forms. One of the major features in different forms of ALD is the altered gut microbiota. Antimicrobial peptides (AMPs) play a crucial role in maintaining gut microbiota homeostasis. LL-37 (known as CRAMP in mouse) is the sole member of the human cathelicidin family and has piqued great research interest for its dual role in modulating microbiota and the immune response in metabolic diseases. Inflammasome activation is an important component of the liver pathophysiology in ALD and requires two signals for its full activation to induce the …

Volatile Organic Compound Exposure And Cardiometabolic Syndrome Risk In A Nationally Representative Cohort., Stacey Lane Konkle

Electronic Theses and Dissertations

BACKGROUND: The relative importance of environmental exposures such as volatile organic compounds (VOCs) is one of the paramount public health priorities of our time, yet is presently unstudied. VOCs are ubiquitous in the environment and have been associated with numerous adverse health effects, including a number of cardiovascular and metabolic effects that are components of Cardiometabolic Syndrome (CMS). OBJECTIVES: To examine the relationship between CMS and individual-level exposures to VOCs, measured as urinary metabolites of VOCs (UM-VOCs), in a nationally representative sample. METHODS: Associations between urinary biomarkers of exposure to 19 parent VOCs and CMS were assessed using the National …

Tobacco-Derived Aldehydes: Platelet Activation, Thrombosis, And The Role Of Trpa1., Andre Dwayne Richardson

Electronic Theses and Dissertations

Cigarette smoking is the single largest risk factor for cardiovascular disease (CVD) pathophysiology. Numerous researchers have shown potential associations between aldehydes in tobacco-derived aerosols from mainstream cigarette smoke (MCS) or electronic cigarettes (e-cigs) and their cardiotoxicity by damaging blood vessel endothelium. The severity of exposure to these toxicants can furthermore lead to adverse cardiovascular outcomes such as myocardial infarctions, stroke, coronary and peripheral artery disease, or atherosclerosis due to blood clots, a pro-thrombotic event. However, the mechanisms by which levels of harmful and potentially harmful constituents (HPHCs) such as aldehydes induce thrombosis are not well-known. Of specific interest, evidence has …

The Role Of Slc7a11 In Controlling Extracellular And Intracellular Redox Environments Of Lung Fibroblasts - Potential Targets For Intervention In Aging And Idiopathic Pulmonary Fibrosis., Yuxuan Zheng

Electronic Theses and Dissertations

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition by fibroblasts. Aging and oxidative stress increase the susceptibility to IPF. Redox couples, cysteine/cystine (Cys/CySS) and glutathione/glutathione disulfide (GSH/GSSG), and their redox potentials (E_h) quantify oxidative stress. Fibroblasts from old mice maintain more oxidized extracellular E_h(Cys/CySS) than young mice. Microarray shows down-regulation of Slc7a11 potentially mediates this age-related oxidation. Slc7a11 is the key component of system X_c^-, an antiporter that imports CySS and exports glutamate. The first aim of this dissertation is to investigate the mechanistic link between Slc7a11 …

The Cardiovascular Effects Of Tobacco Product-Derived Aldehydes: Contribution Of Transient Receptor Potential Ankyrin-1., Lexiao Jin

Electronic Theses and Dissertations

Cardiovascular diseases (CVD) are the leading cause of death in most countries and are significant health and financial burden worldwide. Smoking contributes to more than 480,000 premature deaths annually -- accounting for one of every five deaths in the United States each year. Numerous studies have shown that smoking increases the risk of factors including endothelial dysfunction, thrombosis, and atherosclerosis, which may lead to an incidence of myocardial infarction, coronary artery disease, and stroke. Electronic cigarettes (e-cigarettes) are a new kind of tobacco product, and some studies show that e-cigarettes also could induce CVD since both e-cigarettes and conventional tobacco …

Human Genetics, Psychotropic Drugs, And Acts Of Violence, Selma Jolanda Eikelenboom-Schieveld

Electronic Theses and Dissertations

From the start of the use of psychoactive prescription medications in the 1950s, physicians reported paradoxical adverse reactions, ranging from newly developing depressions to an increase in existing mood disorders, and extremely violent and bizarre acts of suicide and homicide. In this research, it is hypothesized that the pharmacological properties of the prescribed drugs or the interaction between the drugs and the enzymes that are primarily responsible for their metabolism (cytochrome P450s) could cause these reactions. Given that acts of violence could be medication-induced, the role of the rate of drug metabolism is discussed. Genetic testing of certain CYP450s could …

Characterizing The Roles Of Neutral Ceramidase In Cisplatin-Induced Kidney Injury., Sophia M. Sears

Electronic Theses and Dissertations

Cisplatin is a commonly used chemotherapeutic agent with a dose-limiting nephrotoxicity. 30% of patients given cisplatin develop acute kidney injury (AKI). AKI increases risk of chronic kidney disease (CKD) development and mortality. Patients that don’t develop clinical AKI are still at risk for long term declines in renal function. Currently, there are no FDA approved agents to treat or prevent cisplatin-induced kidney injury (CDDP-KI). In this study, we demonstrated that neutral ceramidase (nCDase) knockout provides protection from AKI in the high-dose model of CDDP-KI. However, in the repeated low dose cisplatin (RLDC) model of injury and we found nCDase knockout …