Pharmacology, Toxicology and Environmental Health Commons^™

Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular carcinoma (HCC) is one of the deadliest cancers, with variable presentation, high chemotherapy resistance and early tumor recurrence. In this dissertation, we have systematically enriched, identified and characterized HCC cancer stem cells (CSCs) from 3 different HCC cell lines (Hepa1-6, HepG2, and Hep3B) using in vitro serum-free culture method. Enriched spheroids acquired CSC properties, primarily self-renewal capability, spheroid formation ability, and drug resistance. Heterogeneous CSCs enriched from Hepa1-6 cells demonstrated higher tumor initiation and proliferation capability in vivo, compared to control HCC cells in orthotopic immunocompetent mouse model. EpCAM+ CSCs were significantly enriched within heterogeneous Hepa1-6 CSC spheroids. Consequently, …

A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease In Type 2 Diabetes., Qian Lin

Electronic Theses and Dissertations

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1^△HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1^△HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1^△HBS to 2-month-old db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and …

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences …

Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller

Electronic Theses and Dissertations

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …

Detection Of In-Utero Ethanol Exposure Via Etg And Ets Analysis In Umbilical Cord And Placenta, Jennifer Hanna

Student Theses

Alcohol exposure during pregnancy constitutes one of the leading preventable causes of birth defects, mental retardation and neurodevelopmental disorders in exposed children. According to the 2016 National Survey on Drug Use and Health, alcohol was the second most prevalent substance (8.3%) after tobacco (10%), being this alcohol prevalence higher among 26-44 years old pregnant women than in the 18-25 years old group (9.1 vs 6.5%) (Center for Behavioral Health Statistics and Quality, 2017). The ethanol marker ethyl glucuronide (EtG) has proven to be a specific long-term marker of ethanol in-utero exposure in meconium; however, currently there are scarce or no …

Macrophytes And Atrazine In Ponds Of Southwest Missouri, Christine Michelle Cornish

Graduate Theses/Dissertations

Wetlands are often the ultimate destination of agrochemicals. The increased use of these pollutants has resulted in their increased transport, via runoff and spray drift, into wetlands. Atrazine, a commonly used herbicide, has been detected in surface water, groundwater, soil, and sediment, and has shown to have adverse impacts on aquatic biota, such as fish and amphibians. Few studies have reported on the relationships between atrazine and macrophytes. I measured atrazine concentrations in surface sediments in agricultural, conservation, and golf course ponds of southwest Missouri, and investigated how those concentrations might be related to macrophyte communities, and pond environmental characteristics. …

The Role Of Perivascular Fibrosis In Post-Stroke Glymphatic Impairment And Cerebral Amyloid Angiopathy, Matthew D. Howe

Dissertations and Theses (Open Access)

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral …

Hiv Integrase Inhibitor Pharmacogenetics And Clinical Outcomes: An Exploratory Association Study, Derek E. Murrell

Electronic Theses and Dissertations

As HIV is now primarily a chronic condition, treatment is given life-long with changes as necessitated by alterations in tolerability and efficacy. Thus, personalized medicine may be useful in the prevention of unnecessary drug exposure and avoidable side effects. Three of the four currently available HIV integrase strand transfer inhibitors (INSTIs), raltegravir, elvitegravir, and dolutegravir, are widely utilized antiretrovirals in the USA and exhibit variations in outcomes among subjects. To interrogate differences among subjects receiving these drugs, we investigated the association of several single nucleotide polymorphisms (SNPs) with drug exposure, clinical outcomes, and subject-reported adverse events. HIV+ adults (≥18 years …

Levels Of Heavy Metals In Selected Facial Cosmetics Marketed In Dar Es Salaam, Tanzania, Joseph Yoeza Naimani Philip, Silvia John, Othman Chande Othman

Tanzania Journal of Science

The aim of this study was to determine the levels of heavy metals: lead, cadmium, copper, zinc, arsenic and mercury in facial cosmetics (lipstick, lip glossy, facial powder, foundation, eyeliner, eye shadow and mascara) which were purchased randomly in Dar es Salaam, Tanzania. The levels of lead, cadmium, copper and zinc were determined using Atomic Absorption Spectrometry (AAS). The levels of arsenic were determined using Hydride Generation Atomic Absorption Spectrometry (HGAAS), and levels of mercury were determined using Cold Vapour Atomic Absorption Spectrometry. Prior to determination of the concentration of heavy metals, the samples were acid digested. The average order …

Levels Of Heavy Metals In Deposited Dust And Soil From Selected Primary Schools In Dar Es Salaam, Joseph Yoeza Naimani Philip, Eliamini Ismail Mkenga, Othman Chande Othman

Tanzania Journal of Science

The objective of this study was to examine the levels of heavy metals, lead, manganese, nickel, copper, chromium and cadmium in standard one and kindergarten classroom dusts and playing ground soils from selected primary schools along Morogoro road highway (Kimara, Mbezi, Kibamba and Kiluvya primary schools) and away from Morogoro road highway (Makabe, Msumi and Mbopo primary schools) as well as in the Dar es Salaam city center (Uhuru, Mzimuni, Dr. Omari Ali Juma, Manzese and Ubungo National House primary schools), Tanzania. The samples were acid digested and the supernatant analyzed using inductively coupled plasma optical emission spectrometer (ICP-OES). The …

One-Compound-Two-Pharmacophores: Design, Synthesis And Antimalarial Activities Of Chloroquinoline-Cassiarin, Thobias M. Kalenga, Monica M. Ndoile, Quintino A. Mgani

Tanzania Journal of Science

This paper describes the design and synthesis of a potential antimalarial compound, chloroquinoline-cassiarin (6) using 4,7-dichloroquinoline and the natural product barakol (1) extracted from the leaves of Cassia siamea as starting materials. In this paper a one compound-two-pharmacophores concept is introduced in which coupling of two known pharmacophores into one has been described. The concept is not only useful to organic synthesis but also to drug development researches. The synthesized compound 6 exhibited potent in vitro antimalarial activity at IC50 = 0.51 µM, and low toxicity where at 20 µM, 80% viability of HeLa cells was observed.

Neuroimaging Biomarkers Of Mtor Inhibition On Vascular And Metabolic Functions In Aging Brain And Alzheimer’S Disease, Jennifer Lee, Lucille M. Yanckello, David Ma, Jared D. Hoffman, Ishita Parikh, Scott Thalman, Bjoern Bauer, Anika M. S. Hartz, Fahmeed Hyder, Ai-Ling Lin

Pharmacology and Nutritional Sciences Faculty Publications

The mechanistic target of rapamycin (mTOR) is a nutrient sensor of eukaryotic cells. Inhibition of mechanistic mTOR signaling can increase life and health span in various species via interventions that include rapamycin and caloric restriction (CR). In the central nervous system, mTOR inhibition demonstrates neuroprotective patterns in aging and Alzheimer’s disease (AD) by preserving mitochondrial function and reducing amyloid beta retention. However, the effects of mTOR inhibition for in vivo brain physiology remain largely unknown. Here, we review recent findings of in vivo metabolic and vascular measures using non-invasive, multimodal neuroimaging methods in rodent models for brain aging and AD. …

An Interview With Cesare Montecucco, Mandë Holford, Andreas Rummel

Publications and Research

Cesare Montecucco is a member of the board of various leading scientific journals. His research focus is on the regeneration of the peripheral nervous system and on the mechanisms of action of toxins and related diseases, including tetanus, botulism, anthrax and Helicobacter pylori-associated diseases. In this interview, we talked to Cesare Montecucco about his career, learning and culture.

Cross Photoreaction Of Glyoxylic And Pyruvic Acids In Model Aqueous Aerosol, Sha-Sha Xia, Alexis J. Eugene, Marcelo I. Guzman

Chemistry Faculty Publications

Aerosols of variable composition, size, and shape are associated with public health concerns as well as with light-particle interactions that play a role in the energy balance of the atmosphere. Photochemical reactions of 2-oxocarboxylic acids in the aqueous phase are now known to contribute to the total secondary organic aerosol (SOA) budget. This work explores the cross reaction of glyoxylic acid (GA) and pyruvic acid (PA) in water, the two most abundant 2-oxocarboxylic acids in the atmosphere, under solar irradiation and dark thermal aging steps. During irradiation, PA and GA are excited and initiate proton-coupled electron transfer or hydrogen abstraction …

Aerosol Microdroplets Exhibit A Stable Ph Gradient, Haoran Wei, Eric P. Vejerano, Weinan Leng, Qishen Haung, Marjorie R. Willner, Linsey C. Marr, Peter J. Vikesland

Faculty Publications

Suspended aqueous aerosol droplets (<50 μm) are microreactors for many important atmospheric reactions. In droplets and other aquatic environments, pH is arguably the key parameter dictating chemical and biological processes. The nature of the droplet air/ water interface has the potential to significantly alter droplet pH relative to bulk water. Historically, it has been challenging to measure the pH of individual droplets because of their inaccessibility to conventional pH probes. In this study, we scanned droplets containing 4-mercaptobenzoic acid–functionalized gold nanoparticle pH nanoprobes by 2D and 3D laser confocal Raman microscopy. Using surface-enhanced Raman scattering, we acquired the pH distribution inside approximately 20-μm-diameter phosphate-buffered aerosol droplets and found that the pH in the core of a droplet is higher than that of bulk solution by up to 3.6 pH units. This finding suggests the accumulation of protons at the air/water interface and is consistent with recent thermodynamic model results. The existence of this pH shift was corroborated by the observation that a catalytic reaction that occurs only under basic conditions (i.e., dimerization of 4-aminothiophenol to produce dimercaptoazobenzene) occurs within the high pH core of a droplet, but not in bulk solution. Our nanoparticle probe enables pH quantification through the cross-section of an aerosol droplet, revealing a spatial gradient that has implications for acid-base–catalyzed atmospheric chemistry.

Role Of Mcp-1 And Ccr2 In Ethanol-Induced Neuroinflammation And Neurodegeneration In The Developing Brain, Kai Zhang, Haiping Wang, Mei Xu, Jacqueline A. Frank, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Background: Neuroinflammation and microglial activation have been implicated in both alcohol use disorders (AUD) and fetal alcohol spectrum disorders (FASD). Chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) are critical mediators of neuroinflammation and microglial activation. FASD is the leading cause of mental retardation, and one of the most devastating outcomes of FASD is the loss of neurons in the central nervous system (CNS). The underlying molecular mechanisms, however, remain unclear. We hypothesize that MCP-1/CCR2 signaling mediates ethanol-induced neuroinflammation and microglial activation, which exacerbates neurodegeneration in the developing brain.

Methods: C57BL/6 mice and …

The Effect Of Imidacloprid On Honey Bee Queen Fecundity, Jamilyn Martin, Julia D. Fine, Amy Cash-Ahmed, Gene E. Robinson

PRECS 2018

Imidacloprid is a neonicotinoid insecticide commonly used in agricultural settings to control insect pests by acting as an agonist of acetylcholine receptors and inducing paralysis and mortality. In small doses, imidacloprid can cause loss of memory and foraging ability along with impaired learning and a lowered immune response in western honey bees (Apis mellifera). Effects of neonicotinoid insecticides on colony reproduction have been documented including decreased colony expansion, queen failure and replacement, and decreased queen egg laying.

For this study, we examined the effects of imidacloprid on the fecundity of queen bees when their worker attendants were exposed to low …

High Circulatory Leptin Mediated Nox-2-Peroxynitrite-Mir21 Axis Activate Mesangial Cells And Promotes Renal Inflammatory Pathology In Nonalcoholic Fatty Liver Disease, Firas Alhasson, Ratanesh K. Seth, Sutapa Sarkar, Diana A. Kimono, Muayad S. Albadrani, Diptadip Dattaroy, Varun Chandrashekaran, Geoffry Scott, Samir Raychoudhury, Mitzi Nagarkatti, Prakash Nagarkatti, Anna Mae Diehl, Saurabh Chatterjee

Faculty Publications

High circulatory insulin and leptin followed by underlying inflammation are often ascribed to the ectopic manifestations in non-alcoholic fatty liver disease (NAFLD) but the exact molecular pathways remain unclear. We have shown previously that CYP2E1-mediated oxidative stress and circulating leptin in NAFLD is associated with renal disease severity. Extending the studies, we hypothesized that high circulatory leptin in NAFLD causes renal mesangial cell activation and tubular inflammation via a NOX2 dependent pathway that upregulates proinflammatory miR21. High-fat diet (60% kcal) was used to induce fatty liver phenotype with parallel insulin and leptin resistance. The kidneys were probed for mesangial cell …

Preparation And Characterization Of Functionalized Heparin-Loaded Poly-Ɛ-Caprolactone Fibrous Mats To Prevent Infection With Human Papillomaviruses, Daniela Gonzalez, Jorge Ragusa, Peter C. Angeletti, Gustavo F. Larsen

Department of Chemical and Biomolecular Engineering: Faculty Publications

In this study, heparin-loaded poly-ε-caprolactone (PCL) fibrous mats were prepared and characterized based on their physical, cytotoxic, thermal, and biological properties. The main objective of the work described here was to test the hypothesis that incorporation of heparin into a PCL carrier could serve as bio-compatible material capable of inhibiting Human Papillomavirus (HPV) infection. The idea of firmly anchoring heparin to capture soluble virus, vs. a slow heparin release to inhibit a virus in solution was tested. Thus, one material was produced via conventional heparin matrix encapsulation and electrohydrodynamic fiber processing in one step. A second type of material was …

A New Approach To The Development Of An Rsv Anti-Viral Targeted Nanocarrier For Dual Inhibition Of Viral Infection And Replication, Anthony N. Singer

USF Tampa Graduate Theses and Dissertations

Respiratory Syncytial Virus (RSV) is a potentially life-threatening respiratory pathogen that infects approximately 64 million children and immunocompromised adults globally per year. Currently, there is a need for prophylactic and therapeutic approaches effective against primary and secondary RSV infections. This project focuses on the development of a simple, smart, and scalable anti-RSV nanotherapeutic that combines novel cellular antiviral defense mechanisms targeting the inhibition of viral fusion and replication. An ICAM-1 targeted liposomal nanocarrier will be synthesized and coated with a layer of chitosan containing the anti-fusion HR2-D peptide as an extracellular defense mechanism. Additionally, chitosan complexed to dual expressing short …

Variation In Airborne Pollen Concentrations Among Five Monitoring Locations In A Desert Urban Environment, Tanviben Y. Patel, Mark P. Buttner, David Rivas, Chad L. Cross, Dennis A. Bazylinski, Joram S. Seggev

Environmental & Global Health Faculty Research

The urbanization of the Las Vegas Valley has transformed this part of the Mohave Desert into a green oasis by introducing many non-native plant species, some of which are allergenic. Typically, one monitoring station is established per city to obtain pollen counts for an entire metropolitan area. However, variations in pollen concentrations could occur among different microenvironments. The objective of this study is to measure and compare pollen concentrations in five locations in Las Vegas to determine if there are significant differences between microenvironments within the city. Air samples were collected from five sites across the Las Vegas Valley over …

Effects Of Oil On Mollusk And Crustacean Populations, Behavior, And Predator-Prey Interactions, Elizabeth Marie Robinson

LSU Doctoral Dissertations

The Deepwater Horizon blowout and oil spill in April 2010 released ~5 million barrels of oil into the Gulf of Mexico. Approximately 1,773 km of shoreline was oiled along the northern Gulf of Mexico coast, and ~60% of the oiling ended up on Louisiana salt marsh habitat. The objective of this dissertation was to examine the effects of DWH oil on predator-prey relationships between blue crabs and periwinkle snails, as well as mollusk and blue crab population structure. A broad spatial-temporal field study in Barataria and Terrebonne Bays was used to examine the legacy of oil on five species of …

Anti-Tumor Activity Of Phenoxybenzamine And Its Inhibition Of Histone Deacetylases, Mario A. Inchiosa

NYMC Faculty Publications

The principal finding from this study was the recognition that the α-adrenergic antagonist, phenoxybenzamine, possesses histone deacetylase inhibitory activity. Phenoxybenzamine is approved by the United States Food and Drug Administration for the treatment of hypertensive crises associated with tumors of the adrenal medulla, pheochromocytomas. It has several "off label" indications relative to its capacity to relax vascular smooth muscle and smooth muscle of the urogenital tract. The drug also has a long history of apparent efficacy in ameliorating, and perhaps reversing, the severe symptoms of neuropathic pain syndromes. Our interest in this feature of the drug relates to the fact …

Alcohol Consumption Promotes Colorectal Carcinoma Metastasis Via A Ccl5-Induced And Ampk-Pathway-Mediated Activation Of Autophagy, Haodong Zhao, Danlei Chen, Rui Cao, Shiqing Wang, Dandan Yu, Yakun Liu, Yu Jiang, Mei Xu, Jia Luo, Siying Wang

Pharmacology and Nutritional Sciences Faculty Publications

There is a definite relationship between alcohol consumption and colorectal cancer (CRC) development. We investigated effect of alcohol consumption on CRC patients’ progression and prognosis by utilizing epidemiological data and found patients with alcohol consumption increased risks of tumor-node-metastasis (TNM), organ metastasis and poorer prognosis. Because their tumor tissues displayed increased expression of C-C chemokine ligand 5 (CCL5), we hypothesized CCL5 might participate in cancer progression in such patients. Ethanol increased the secretion of CCL5 in two CRC cell lines, HT29 and DLD-1. Treatment with CCL5 directly increased migratory ability of these cells, whereas neutralization or knockdown of CCL5 can …

Δ-9-Thc Effect On The Dopamine Transporter, Brooke E. Nielsen

Student Theses

Understanding the mechanism behind drugs of abuse is one of the key elements to understanding why addiction is so prevalent in society. The goal of this research was to determine the effect that a popular cannabinoid, Δ -9-tetrahydrocannabinol has on the regulation of dopamine neurotransmitter in the synapses. It was hypothesized that the addictive high users experience from using Δ-9-THC had a direct effect on lowering the dopamine transporter protein on cell surface causing a buildup of dopamine in the synapse. The results of the study show that the higher concentration of Δ-9-THC that the cells were exposed to caused …

Transcriptional Correlates Of Proximal-Distal Identify And Regeneration Timing In Axolotl Limbs, S. Randal Voss, David Murrugarra, Tyler B. Jensen, James R Monaghan

Neuroscience Faculty Publications

Cells within salamander limbs retain memories that inform the correct replacement of amputated tissues at different positions along the length of the arm, with proximal and distal amputations completing regeneration at similar times. We investigated the possibility that positional memory is associated with variation in transcript abundances along the proximal-distal limb axis. Transcripts were deeply sampled from Ambystoma mexicanum limbs at the time they were administered fore arm vs upper arm amputations, and at 19 post-amputation time points. After amputation and prior to regenerative outgrowth, genes typically expressed by differentiated muscle cells declined more rapidly in upper arms while cell …

Zolpidem Facilitated Sexual Assaults: A Hair Method Validation, Danielle N. Chasworth

Student Theses

A liquid chromatography tandem mass spectrometry (LC-MSMS) method was developed and validated to detect for the presence of zolpidem in human hair samples. Zolpidem is a sedative hypnotic whose adverse effects make it a common drug found in drug facilitated crimes (DFC). It is important to be able to detect and quantitate the drug after a long period of time due to the victim’s delayed reporting of the crime. Hair’s long window of detection makes it a useful matrix for DFC investigations. The linear range of the assay was targeted at 2 pg/mg to 1,000 pg/mg and experiments designed to …

Defining The Radioresponse Of Mossy Cells, Devon Ivy

Electronic Theses, Projects, and Dissertations

Clinical radiotherapy is used to treat a variety of brain tumors within the central nervous system. While effective, it can result in progressive and debilitating cognitive impairment that can diminish quality of life. These impairments have been linked to hippocampal dysfunction and corresponding deficits in spatial learning and memory. Mossy cells are a major population of excitatory neurons located within the dentate hilus and highly involved in hippocampal circuitry. They play critical roles in spatial navigation, neurogenesis, memory, and are particularly vulnerable to a variety of neurotoxic insults. However, their sensitivity to ionizing radiation has yet to be investigated in …

Off-Target Based Drug Repurposing Using Systems Pharmacology, Brent M. Kuenzi

USF Tampa Graduate Theses and Dissertations

The goal of this study was to identify novel drug repurposing opportunities in cancer by utilizing the off-target profiles of clinically relevant kinase inhibitors. This was based on the observation that the global target profiles of compounds are largely ignored and that many compounds have activity that cannot be explained by their cognate target alone. Additionally, by utilizing clinically relevant compounds, any results would hold a high potential for eventual clinical implementation. We utilized a systems pharmacology approach utilizing cell viability-based drug screening to identify compounds with beneficial off-target activity and then using chemical and phosphoproteomics in order to elucidate …

Functions Of Ecosystems: Stream Metabolism As An Efficient And Effective Means To Gage The Health And Understand The Interworking Of Urban Streams In A Watershed Of Rock Island, Il, Ryan Johnson, Dr. Kevin Geedey

Celebration of Learning

Stream metabolism is a critical functional measure of stream health that integrates physical parameters like slope and discharge, with ecosystem functions like photosynthesis and respiration. Stream metabolism is widely studied; however, urban stream metabolism remains poorly understood. Stream metabolism was measured for five streams ranging from 1^st to 5^th orders from October 11^th to October 18^th 2017 and four streams ranging from 1^st to 4^th order from October 22^nd to 25^th 2017 located within an approximately 9.3 square kilometer watershed of Rock Island, IL that has an urban to suburban type of …