Pharmacology, Toxicology and Environmental Health Commons^™

Theranostics For Antiretroviral Biodistribution And Pharmacokinetics, Brendan M. Ottemann

Theses & Dissertations

RATIONALE: Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification, treatment and inevitable elimination of virus in cell and tissue compartments. By employing theranostics, antiretroviral drugs (ARVs) can be tracked in lymph nodes, gut, spleen and liver. Cellular viral reservoirs including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) along with subcellular endosomal structures can now be targeted for drug delivery bringing therapeutics to areas where virus replicates. The overarching idea rests in improving precision targeted ARV delivery. …

Role Of Astrocyte-Derived Extracellular Vesicles In Neuroinflammation Mediated By Drug Abuse, Ke Liao

Theses & Dissertations

Neuronal damage and neuroinflammation is a hallmark feature of HIV-associated neurological disorders (HANDs). Opioids abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Extracellular vesicles (EVs) are essential conduits in HIV and drug abuse-mediated synaptodendritic injury and neuroinflammation. Findings from our group have demonstrated that astrocyte-derived EV (ADEV)-miRNA-29b mediates HIV Tat and morphine-induced neuronal injury, thus underscoring the importance of such interactions in NeuroHIV.

Besides, HIV Tat and morphine-mediated synaptodendritic injury via ADEVs, we are also interested in whether ADEVs contributes to neuroinflammation. Microglia are critical players in …

Delivery Of Small Molecule And Rna Using Synthetic Polymeric Micelles And Multifunctional Exosomes For The Treatment Of Type 1 Diabetes, Yang Peng

Theses & Dissertations

Type 1 diabetes is one of the most challenging chronic autoimmune diseases. The destruction and dysfunction of insulin-secreting β cells are the results of inflammatory infiltration and the synergistic effect of multiple immune cells. The aim of this dissertation is to develop novel and reliable therapeutic approaches to advance the treatment of T1D: including chemical modification of a broad-spectrum immunosuppressant, co-application of small molecule based immune intervention and siRNA based β cell preservative therapy, and administration of a PI3K-δ/γ dual inhibitor to specifically target immune cells, utilizing synthetic polymeric micelles or natural produced multi-functional exosomes derived from human bone marrow …

Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud

Theses & Dissertations

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …

There Must Be Something In The Water: Understanding Pfas Contamination Of Groundwater As A National Security Issue, Kylie N. Ford

Student Theses 2015-Present

This report addresses the widespread pollution of domestic groundwater resources with Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) caused by firefighting activities performed at military installations across the United States. Two former military bases in Southeastern Pennsylvania are used as a single case study: the Naval Air Development Center (NADC) in Warminster and the Naval Air Station Joint Reserve Base (NASJRB) in Horsham. Chapter 1 gives a history of domestic military bases from the perspective of the infrastructure buildup and downsizing that occurred over the 20th Century, along with the environmental degradation revealed during brownfield redevelopment. The chapter then gives specifics about …

Cytotoxicity And Mutagenicity Of Disinfection Byproduct Mixtures Formulated Using Free Chlorine And Monochloramine, Yonas Ghebremedhin

Graduate Theses and Dissertations

Bioassays have been used extensively to assess various toxicity endpoints of drinking water disinfection byproducts (DBPs), but an emphasis on single compounds prevails. In this research, DBP mixtures were assessed using a cytotoxicity test with Chinese Hamster Ovary (CHO) cells and an Ames fluctuation test with Salmonella typhimurium TA-98 and TA-100 with and without S9 rat liver homogenate. Seven whole mixture DBP concentrates were formulated using reconstituted natural organic matter (NOM) extracts from the Upper Mississippi River using scaled disinfectant dosing protocols with free chlorine and monochloramine in the presence and absence of added bromide. DBPs were identified by gas …

Quantifying The Variability In Heavy Metal Concentrations In Produce Grown In Metals-Rich Soil, Harris Lowell Byers

Theses and Dissertations

Childhood Pb exposure is associated with a multitude of poor health outcomes. In food-insecure areas, growing fresh produce in residential backyard gardens is one option for parents; however, commonly grown crops are known to accumulate Pb in consumable tissues when grown in metals-rich soils. A variety of produce representing a continuum of consumable tissues were grown in soils collected from two residential vegetable gardens, a former metal foundry, and commercial topsoil purchased from a local hardware store. The concentrations of heavy metals in crop tissues were measured with custom wavelength dispersive X-ray Fluorescence (WD-XRF) spectroscopy and portable energy dispersive X-ray …

Cyanobacterial Harmful Algal Bloom Ecology And Cyanotoxins In The Eutrophic Lake Winnebago-Green Bay Water System, Sarah L. Bartlett

Theses and Dissertations

Cyanobacterial harmful algal blooms (cyanoHABs) are frequently observed in water bodies used for recreation and drinking water production and can be detrimental to humans, animals, and general water quality. CyanoHABs are natural occurrences, but human activities such as agriculture, land use change, and runoff from urban and rural landscapes can promote and accelerate their expansion. The blooms are aesthetically unpleasing scums and can be laden with toxins (cyanotoxins) and toxic or otherwise bioactive peptides (TBPs) that can be harmful to humans and animals. Despite the vast research on cyanoHABs, cyanotoxin and TBP diversity and dynamics within a water column are …

Functional Characterization Of Lt-Hsc Metabolic Activity Dependent On Ahr Activity, Everett Tate

Theses and Dissertations

The cells of the immune system are descended from multipotent hematopoietic stem cells (HSCs) that emerge during development. Multipotency means that a single progenitor HSC can differentiate into any cell of the immune system. HSCs are required to do this for the lifetime of the organism through a process called self-renewal, and as such, any perturbation during development or in the bone marrow can have a trickle-down effect, affecting the self-renewal capacity or ability to terminally differentiate. The aryl hydrocarbon receptor (AHR) is a known regulator of HSCs. The AHR is a transcription factor required for the detoxification of numerous …

Effects Of Mercury On The Dopamine Transporter Cell Surface Expression In Pc12 Cells, Christina Hui

Student Theses

Environmental factors, such as heavy metal exposures, have been suggested to have an impact not only on neurodegenerative disease, such as Parkinson’s disease, but also on psychostimulants abuse and their toxicity. In this study, two questions were addressed: 1) effects of mercuric chloride on parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP⁺) induced cytotoxicity and 2) effects of mercuric chloride on cell surface dopamine transporter. Pheochromocytorma cells (PC12) were treated with various concentrations of mercuric chloride (0.02~2.0 ppm) for 4 hours with and without 0.1 mM MPP⁺. Significant potentiation of toxicity was observed when there was co-treatment with 0.5 ppm …

Acute Exposure To Tcdd Increases Liver Disease Progression In Mice With Carbon Tetrachloride-Induced Liver Injury, Giovan N. Cholico

Boise State University Theses and Dissertations

Liver disease is a worldwide problem and the 9^th leading cause of death in the United States. Common causes of liver disease include alcohol abuse, virus infection, and nonalcoholic fatty liver. Regardless of etiology, liver damage elicits inflammation and drives the activation of hepatic stellate cells (HSCs), which deposit collagen throughout the liver. During chronic injury, excessive collagen deposition, referred to as fibrosis or “scarring”, can progress to cirrhosis, cancer, and organ failure. Emerging evidence indicates a strong association between liver disease and exposure to environmental chemicals. This research investigated mechanisms by which exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo- …

Therapeutic Potential Of Withaferin A Against Non-Small Cell Lung Cancer., Al Hassan Kyakulaga

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer-related deaths worldwide and in the United States. Despite recent advancements in treatment approaches, chemoresistance and metastasis remain a major therapeutic challenge. Withaferin A (WFA), a plant-derived compound has recently emerged as a promising antitumor agent. In the present study, we explored the therapeutic potential of WFA against advanced NSCLC. Briefly, WFA was evaluated for its efficacy, toxicity and pharmacokinetic properties against advanced NSCLC using in vitro and in vivo models. Two human NSCLC cell lines, H1299 and A549 were used in cell culture to determine the anticancer properties of WFA. Repeat dose …

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 …

The Role Of Omega-3 Polyunsaturated Fatty Acids In Blood Pressure Regulation And Secondhand Smoke-Induced Vascular Dysfunction, Emily Anna Wheeler

Biomedical Sciences ETDs

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may lower cardiovascular disease risk by reducing blood pressure (BP). We hypothesized that fat-1 transgenic mice, which convert n-6 PUFAs to n-3 PUFAs, would have improved vascular function in BP regulation and following secondhand smoke (SHS) exposure, compared to wild type (WT) mice.

BP was recorded in mice fed an n-6 PUFA, or standard chow diet. On the n-6 PUFA diet fat-1 mice had a lower mean arterial pressure and a greater decrease in diastolic BP when treated with an ACE inhibitor, compared to WT mice. No differences were observed on the chow diet. …

Effect Of Biosurfactant And Biochar On Ecosystem Functions And Oil Remediation In Crude Oil Contaminated Wetland Soils, Zhuo Wei

LSU Doctoral Dissertations

Decontamination of oil spill from coastal wetland soils requires a delicate approach. Remediation strategies using biochar, biosurfactant, and nutrient additions have been proposed. However, there is little information on application of these with combination for treatment of crude oil-contaminated wetland soil. Therefore, incubation studies were carried out to investigate the impact of biochar and rhamnolipid (RL) biosurfactant along with nitrogen (N) application on petroleum hydrocarbon degradation in a Louisiana coastal saline marsh and their impacts on greenhouse gas (GHG) emission. Additionally, the toxicity of crude oil as well as remediation materials on coastal wetland ecosystem were assessed at three levels: …

Environmental Risk Factors For Inflammatory Bowel Disease: Triclosan And Other Consumer Antimicrobials, Katherine Z. Sanidad

Doctoral Dissertations

Inflammatory bowel disease (IBD) has become a serious health problem since the incidence and prevalence of IBD has dramatically increased throughout the world. There is evidence that environmental factors are primarily responsible for the increase of IBD, therefore, it is important to identify novel environmental risk factors to reduce the risk of IBD and its associated diseases. Antimicrobials used in consumer products might serve as environmental risk factors for IBD and its associated diseases. Triclosan (TCS), triclocarban (TCC), benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are widely used antimicrobial ingredients in consumer products and are ubiquitous contaminants in …

A Novel Infield Metagenomic Approach To Evaluating Surface Water Quality In Lake Warner, Brooke Stebbins

Masters Theses

In January 2010, a magnitude 7.0 earthquake devastated Haiti, one of the poorest countries in the Western Hemisphere. Haiti’s weak sanitation infrastructure and limitations in the public health system made the country susceptible to the spread of waterborne diseases. Following the earthquake, cholera rapidly spread through Haiti, killing 4,672 people in 5 months and leaving thousands hospitalized (MSNBC, 2010). Cholera is an infectious diarrheal disease caused by the pathogen, Vibrio cholerae, which results in severe dehydration with a high mortality risk. The source of the epidemic was traced to the Artibonite River, the island’s longest and most essential drinking …

Markov Decision Process Approach To Strategize National Breast Cancer Screening Policy In Data-Limited Settings, Vijeta Deshpande

Masters Theses

Early diagnosis is a promising strategy to reduce premature mortalities and for optimal use of resources. But the absence of mathematical models specific to the data settings in LMIC’s impedes the construction of economic analysis necessary for decision-makers in the development of cancer control programs. This thesis presents a new methodology for parameterizing the natural history model of breast cancer based on data availabilities in low and middle income countries, and formulation of a control optimization problem to find the optimal screening schedule for mammography screening, solved using dynamic programming. As harms and benefits are known to increase with the …

Study Of The Inflammatory And Fibrotic Pathology In The Gut Following Microcystin Exposure Under Conditions Of Non-Alcoholic Fatty Liver Disease., Sutapa Sarkar

Theses and Dissertations

Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic with increased risks of chronic inflammation in obese and elderly population. It has become a major public health concern due to the unavailability of proper therapeutic approaches. NAFLD is a condition of the liver involving wide spectrum of events including accumulation of fat in the liver and inflammation, which can progress to a fibrotic and cirrhotic phenotype, often termed as non-alcoholic steatohepatitis (NASH). In this backdrop, exposure to environmental toxins from harmful algal blooms could prove detrimental to the overweight, obese or elderly population. NAFLD not only affects the liver …

Investigating The Relationship Of Copd, Lung Cancer, And Polycyclic Aromatic Hydrocarbons From Ambient Air Pollution, Daniel John Kilpatrick

Theses and Dissertations

Polycylic aromatic hydrocarbons (PAHs) are a group of chemically-related compounds with a well-established body of evidence of adverse human health impacts. Additionally, there is a growing area of research on the health outcomes following PAH exposure via air pollution, specifically with chronic obstructive pulmonary disorder (COPD) and lung cancer. The purpose of this dissertation was to investigate the strength of associations among PAHs, COPD, and lung cancer from ambient (outdoor) air pollution. The first objective was to determine if there is a potential environmental link among PAHs, COPD, and lung cancer occurrence among nonsmokers using data from the National Health …

Revisiting The Standard Soil Test: The Potential Of Macro- And Microbiological Measures To Improve Agricultural Health And Productivity, Gabriel Jacob Kenne

Theses and Dissertations

The agricultural ecosystem has become the largest non-ice-covered terrestrial ecosystem on the planet and has significant direct and indirect impacts on the global health of both the environment and humanity. Recent shifts in modern agriculture are beginning to focus on the health of soil versus a focus traditionally on crop health and yield at any cost. By managing farmland regeneratively, systems are able to reverse many of the problems created by conventional land management such as erosion and unwanted nutrient runoff, and simultaneously create opportunities to move C from the atmosphere back into the soil. While the ways in which …

Microcystin Exposure And Liver Injury Outcomes In Nafld, Muayad Albadrani

Theses and Dissertations

Non-alcoholic fatty liver disease (NAFLD) is an emerging worldwide pandemic which is highly prevalent among obese individuals including children and adults. In a NAFLD condition, exposure to environmental contaminants or toxins can act as a second/ multiple hit, which leads to the progression of simple steatosis to NASH and ultimately may result in liver cirrhosis. With climate change today, elevated levels of microcystins are an emerging problem in fresh water bodies, which are a source of drinking water. Individuals are therefore at risk of exposure to microcystin through consuming contaminated water. In the progression of NAFLD from one clinical stage …

Excess No Stabilizes The Luminal Domain Of Stim2 In A Cys-Specific Manner Thereby Regulating Basal Calcium Homeostasis And Store-Operated Calcium Entry, Matthew Novello

Electronic Thesis and Dissertation Repository

Stromal-interaction molecule 2 (STIM2) is an endoplasmic reticulum (ER) membrane-inserted Ca²⁺-sensing protein which, together with the plasma membrane Ca²⁺ channel Orai1, regulates basal Ca²⁺ homeostasis and store-operated Ca²⁺ entry (SOCE). Recent evidence suggests that S-nitrosylation, which is the covalent attachment of a nitric oxide (NO) moiety to a cysteine thiol, can attenuate the function of the paralog STIM1 protein. Compared to STIM1, STIM2 also functions as a basal Ca²⁺ homeostatic feedback regulator. Therefore, the objective of my study was to evaluate the susceptibility of STIM2 to S-nitrosylation and the effects that this …

Developing A Dissociative Nanocontainer For Peptide Drug Delivery, Michael Patrick Kelly

Dissertations, Theses, and Capstone Projects

The potency and specificity of bioactive peptides have propelled these agents to the forefront of pharmacological research. However, delivery of peptides to their molecular target in cells is a major obstacle to their widespread application. A Trojan Horse strategy of packaging a bioactive peptide within a modified protein cage to protect it during transport, and releasing it at the target site, is a promising delivery method. Recent work has demonstrated that the viral capsid of the P22 bacteriophage can be loaded with an arbitrary, genetically-encoded peptide, and externally decorated with a cell-penetrating peptide, such as HIV-Tat, to translocate across in …

Dual Inhibition Of The Pi3k/Akt And Mek5/Erk5 Pathways For The Treatment Of Breast Cancer, Thomas Douglas Wright

Electronic Theses and Dissertations

Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects …

Investigation Of Riluzole’S Synaptic Protection Mechanism Through Hsf1-Bdnf Axis, Yi Zhang

Theses and Dissertations (ETD)

The FDA-approved amyotrophic lateral sclerosis (ALS) drug Riluzole has great potential in treating Alzheimer’s disease (AD) based on promising animal data as well as its known action on modulating synaptic transmission. However, its detailed mechanism of action is not fully understood. Here, we proposed work aiming to address this aspect via focus- ing on the Heat Shock Factor 1 (HSF1)-dependent mechanisms. We found that Riluzole could increase HSF1 and BDNF (Brain-Derived Neurotrophic Factor) expression both at transcriptional and translational levels. CA1 (Cornu Ammonia, the first region in the hip- pocampal circuit), is its main target. We also demonstrated a protective …

The Role Of Secretory Phospholipase A2 Group Iia In Obesity And Metabolism, Michael S. Kuefner

Theses and Dissertations (ETD)

Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases previously implicated in inflammation, atherogenesis, and antibacterial actions. These enzymes hydrolyze glycerophospholipids at the sn-2 position releasing lysophospholipids and fatty acids. Though studies have shown PLA2G2A is pro-inflammatory and promotes atherosclerosis, no research has analyzed the role of this enzyme in obesity and metabolism. Studies in the past 5-10 years utilizing various knock- out or over-expression mouse models have analyzed the role of different secretory phospholipase A2s (sPLA2) in metabolic diseases. From these studies, it is known that at least seven of the 11 sPLA2 …

The Effects Of Aqueous Atorvastatin On Steroidogenesis Of Xenopus Laevis At Environmentally Relevant Concentrations, Jeremy Johnson

Master's Theses

Statin drugs are a class of drug that work to reduce endogenous production of cholesterol by competitively inhibiting 3-hydroxy-3-methyl-glutaryl-CoA reductase (Hmgcr) thus inhibiting production of mevalonic acid in the mevalonate pathway. Atorvastatin (Lipitor) is one of the most widely prescribed statin drugs and contamination of wastewater effluent is a growing environmental concern because of the potential to interfere with steroidogenesis in wildlife. Amphibians may be particularly susceptible to the effects of atorvastatin contamination because of their highly permeable integument. I used an amphibian model, Xenopus laevis to test the hypothesis that chronic exposure to low concentrations of atorvastatin …

Molecular Responses To Deepwater Horizon Oil Spill Contaminants In Estuarine Fish, Elizabeth Jones

Dissertations

The 2010 Deepwater Horizon (DWH) oil spill resulted in the oiling of approximately 2100 km of shoreline. During that time, resident organisms had to contend with the effects of multiple contaminants and suboptimal environmental conditions. This research examines the molecular effects of DWH oil spill contaminants in estuarine fish (CyprinodonvariegatusandFundulusgrandis) across multiple life stages, contaminant concentrations, and in conjunction with environmental stressors.

Our results indicate that:

1. Oil elicits substantial transcriptional effects across life stages in C. variegatus. In adults, exposure to low concentrations of oil and dispersant results in transcriptional effects related …

Pregestational Diabetes Induced Congenital Heart Defects And Coronary Artery Malformations; Mechanisms And Preventative Therapies, Anish Engineer

Electronic Thesis and Dissertation Repository

Congenital heart defects (CHDs) arise from perturbations in complex molecular and cellular processes underlying normal embryonic heart development. CHDs are the most common congenital malformation, occurring in 1 to 5% of live births, and are the leading cause of pediatric mortality. Adverse genetic and environmental factors can impede normal cardiogenesis and increase the likelihood of CHDs. Pregestational maternal diabetes increases the risk of CHDs in children by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. The aim of …