Pharmacology, Toxicology and Environmental Health Commons^™

Therapeutic Targeting Of Bmp2 In Nf1-Deficient Malignant Peripheral Nerve Sheath Tumors (Mpnsts), Sidra Ahsan

Wayne State University Dissertations

Neurofibromatosis type I (NF1)-deficient malignant peripheral nerve sheath tumor (MPNST) is an aggressive tumor for which the standard treatment is surgical removal with wide margins, often leaving behind cancer cells needing chemotherapy. RAS-GRD is the most widely studied functional target of NF1 implicated in tumorigenesis, however, therapeutic interventions targeting RAS activity have met with limited success. Using gene expression profiling, our lab identified BMP2-SMAD1/5/8 signaling pathway as a therapeutic target in MPNSTs, independent of the NRAS and MEK1/2 regulation. The overall goal of my research was to validate the significance of BMP2 in MPNSTs in novel cellular models, study the …

Combination Of Photodynamic Therapy With Fenretinide And C6-Pyridinium Ceramide Enhances Killing Of Scc17b Human Head And Neck Squamous Cell Carcinoma Cells Via The De Novo Sphingolipid Biosynthesis And Mitochondrial Apoptosis, Nithin Bhargava Boppana

Wayne State University Theses

The ceramide generated via the de novo sphingolipid biosynthesis has been shown to regulate apoptosis and cell death. The de novo sphingolipid biosynthesis includes ceramide synthase (CERS)-dependent acylation of dihydrosphingosine, giving rise to dihydroceramide, which is then converted to ceramide by a desaturase-dependent reaction. The mitochondrial pathway of apoptosis, characterized by induction of Bax associated with mitochondria and cytochrome c release/redistribution. Bcl2, an anti-apoptotic protein blocks apoptosis by inhibiting Bax. Elucidating the role of de novo sphingolipid biosynthesis and mitochondrial apoptosis in PDT, PDT+4HPR and PDT+LCL29 could help in improving the effectiveness on these anti-cancer treatments. The objective of this …

Effect Of Metformin On Global Phosphorylation Profiles Of Primary Skeletal Muscle Cells Derived From Overweight/Obese Insulin Resistant Human Participants, Nishit Shah

Wayne State University Theses

Metformin is a drug from the biguanide class and it has been in use for the treatment of type 2 diabetes for a long time, and it can improve insulin sensitivity in skeletal muscle. However, the mechanism for metformin’s action is unclear. Phosphatases and kinases, and their subunits are the proteins required for dephosphorylation and phosphorylation of proteins in cells during various signaling pathways. Phosphorylation studies of proteins from primary cell culture derived from skeletal muscle tissue from obese/overweight insulin resistant participants will help to understand the regulation of phosphorylation in phosphatases and kinases by metformin.

In the current research, …

Exploring Novel Daptomycin Combinations With Β-Lactam Against Susceptible & Non-Susceptible Enterococcus Species, Animesh Raut

Wayne State University Theses

EXPLORING DAPTOMYCIN COMBINATION WITH β-LACTAM SYNERGY AGAINST SUSCEPTIBLE AND NON-SUSCEPTIBLE ENTEROCOCCI SPECIES

by

ANIMESH RAUT

August 2015

Advisor: Dr. Michael J. Rybak

Major: Pharmaceutical sciences

Degree: Master of Science

Objective: Enterococcus faecalis and Enterococcus faecium are generally resistant to daptomycin and β-lactam antibiotics. However, documented in vitro data suggests synergy between several β-lactam antibiotics and daptomycin against resistant organisms. Primary goal of the study was to check various combinations of β-lactam antibiotics with daptomycin (DAP) and assess the potential of synergy and conclude which could be the superior combination. Study also evaluated potential of β-lactam antibiotics to enhance activity of …

Advancing Computational Toxicology In A Regulatory Setting: A Selected Review Of The Accomplishments Of Gilman D. Veith (1944–2013), Steven P. Bradbury, Christine L. Russom, Patricia K. Schmieder, Terry W. Schultz, Robert Diderich, Charles M. Auer

Steven P. Bradbury

With the passing of Dr. Gilman D. Veith on August 18, 2013, the research community lost one of its true visionaries in the development and implementation of alternative in silico and in vitro toxicology models in human health and ecological risk assessment. His career spanned more than four decades, during which he repeatedly demonstrated vision and leadership to advance alternative testing and assessment research and to guide the adoption of research accomplishments into U.S. and international chemical regulatory programs. His ability to advance toxicological and environmental exposure research, and associated quantitative structure– activity relationships (QSARs), for application in environmental regulatory …

Mcnair Research Journal - Summer 2015, Kelly Abuali, Starr Bailey, Krystal Courtney D. Belmonte, Brittaney Benson-Townsend, Jennifer Bolick, Mihaela A. Ciulei, Ashley Crisp, Daniel N. Erosa, Richard V. Foster, Gisele Braga Goertz, Michael A. Langhardt, Kara Osborne, Julienne Jochel Paraiso, Shawn M. Rosen, Bella V. Smith, Jeevake Attapattu, Ernesto H. Bedoy, Michael G. Curtis, Wanda Inthavong, Marielle Leo, Primrose Martin, Tamieka Meadows, Rosa Perez, Jessica Recarey, Shea Silver, Linda Tompkins

McNair Journal

Journal articles based on research conducted by undergraduate students in the McNair Scholars Program

Table of Contents

Biography of Dr. Ronald E. McNair

Statements:

Dr. Neal J. Smatresk, UNLV President

Dr. Juanita P. Fain, Vice President of Student Affairs

Dr. William W. Sullivan, Associate Vice President for Retention and Outreach

Mr. Keith Rogers, Deputy Executive Director of the Center for Academic Enrichment and Outreach

McNair Scholars Institute Staff

Development Of Culturing Methods For Native Mayfly Taxa For Use In Laboratory Toxicity Testing, Kevin Nicholas Rowsey

Theses, Dissertations and Capstones

Salinity is increasing in freshwaters throughout the world due to anthropogenic impacts with the implication of the increases to biological communities only now being realized. Declining mayfly populations in Appalachian streams have generated increased interest in elevated dissolved solids in that region and their effect on benthic macroinvertebrates, particularly the sensitive Ephemeroptera taxa. Field and laboratory evaluations have indicated high sensitivity of mayflies to elevated dissolved solids. The research described herein is part of an ongoing effort to provide opportunity for toxicity testing with native mayflies in the laboratory. A successful endeavor would establish mayfly sensitivity to total dissolved solids …

The Effect Of Silver Nanoparticles On Synaptic Responses In The Lateral Giant Escape Circuit Of The Crayfish, Samantha N. Adkins

Theses, Dissertations and Capstones

The lateral giant neuron in the crayfish is a neuron that controls the reflexive escape response; the context and experience-dependent tuning of this response is critical for survival. Serotonin modulates synaptic responses in this neuron, and social experiences (stress) changes the modulatory role of serotonin. I investigated the mechanisms of induced synaptic response changes and serotonergic modulatory changes after silver nanoparticle exposure to ask if 1) contaminant induced stress changes serotonergic modulation in a manner consistent with social stress and 2) shed light on potential neurotoxic effects of widely used, but poorly understood nanomaterials. Our data show that stress induced …

Approximation Of Fire-Return Intervals With Point Samples In The Southern Range Of The Coast Redwood Forest, California, Usa, Gregory Jones, Will Russell

Faculty Publications, Environmental Studies

A legacy of past fires is evident in the form of blackened basal hollows found throughout the southern range of the coast redwood (Sequoia sempervirens [D. Don] Endl.) forest. A deeper look reveals cambial scars dating back centuries, telling a story of low- to moderate-intensity fires that burned periodically across California’s Central Coast bioregion. While attempts have been made to reconstruct the fire history of this forest type, estimates of the fire-return interval vary widely, and the relationship of the fire-return interval to varying cultural influences is not fully understood. We analyzed 373 fire scars from 70 cross-sections removed from …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Role Of Caveolin-1 And Nrf2 In Nutritional Modulation Of Pcb Toxicity, Michael C. Petriello

Theses and Dissertations--Toxicology and Cancer Biology

Cardiovascular disease is the leading cause of mortality in Western societies and is linked to multiple modifiable risk factors including lifestyle choices. Emerging evidence implicates exposure to persistent environmental pollutants, such as polychlorinated biphenyls (PCBs), as a risk factor for the development or progression of cardiovascular disease. To reduce disease risks, it is critical to identify sensible means of biomedically reducing the toxicity of persistent organic pollutants and related environmental stressors.

First, we tested a hypothesis that endothelial cell inflammation and subsequent cardiovascular toxicity initiated by coplanar PCBs is modulated by the crosstalk between caveolae and Nuclear factor (erythroid-derived 2)-like …

Cross-Talk Between The Tumor Suppressors Par-4 And P53, Tripti Shrestha Bhattarai

Theses and Dissertations--Toxicology and Cancer Biology

This work describes the fascinating interplay between two tumor suppressors Prostate apoptosis response-4 (Par-4) and p53. The guardian of the genome, p53, is frequently mutated in human cancers, and may contribute to therapeutic resistance. However, p53 is intact and functional in normal tissues, and we observed that specific activation of p53 in normal fibroblasts could induce apoptosis selectively in p53-deficient cancer cells. This paracrine apoptotic effect was executed by Par-4 secreted in response to p53 activation. Accordingly, activation of p53 in wild-type mice, but not in p53^-/- or Par-4^-/- mice, caused systemic elevation of Par-4 that induced apoptosis …

An Exploratory Study Of Dog Park Visits As A Risk Factor For Exposure To Drug-Resistant Extra-Intestinal Pathogenic E. Coli (Expec)., Lubna N. Ahmed, Lance B. Price, Jay P. Graham

Environmental and Occupational Health Faculty Publications

Background

Extraintestinal pathogenic E. coli (ExPEC) are common causative agents of urinary tract infections in humans. Dogs have been found to harbor ExPEC. This study tested stool samples from dogs (n = 16), the shoes of dog park visitors (n = 16) and the shoes of controls (n = 16) for ExPEC. Phenotypic resistance of isolates was characterized.

Findings

ExPEC were present in one-third of the dog stool samples, 9% of the samples from the shoes of dog park visitors and 6% of control samples. Half of the ExPEC isolates were multi-drug resistant.

Discussion

The findings suggest that dogs may …

In Vivo Analysis Of A Salt Bridge At The External Gate Of The Drosophila Melanogaster Serotonin Transporter In Response To Amphetamines, Timothy J. Beenen

Open Access Theses

Monoamine neurotransmitter transporters are membrane proteins responsible for the clearing of biogenic amines from a synapse. These transporters are targets for many important pharmaceuticals including antidepressants, as well as psychostimulant drugs such as cocaine and amphetamines. Amphetamines are believed to elicit their psychostimulant activity primarily by inducing a reversal of the transport cycle and increasing neurotransmitter release into the synapse, though the mechanism of this activity is incompletely understood. Previous in vitro research has suggested functional significance of a conserved salt bridge in the serotonin transporter (SERT) in amphetamine-induced 5-HT efflux. This salt bridge is disrupted in the Drosophila melanogaster …

Elaboration And Design Of Α7 Nachr Negative Allosteric Modulators, Osama I. Alwassil

Theses and Dissertations

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at …

Integrated Nanoscale Imaging And Spatial Recognition Of Biomolecules On Surfaces, Congzhou Wang

Theses and Dissertations

Biomolecules on cell surfaces play critical roles in diverse biological and physiological processes. However, conventional bulk scale techniques are unable to clarify the density and distribution of specific biomolecules in situ on single, living cell surfaces at the micro or nanoscale. In this work, a single cell analysis technique based on Atomic Force Microscopy (AFM) is developed to spatially identify biomolecules and characterize nanomechanical properties on single cell surfaces. The unique advantage of these AFM-based techniques lies in the ability to operate in situ (in a non-destructive fashion) and in real time, under physiological conditions or controlled micro-environments.

First, AFM-based …

Xlf-Dependent Nonhomologous End Joining Of Complex Dna Double-Strand Breaks With Proximal Thymine Glycol And Screening For Xrcc4-Xlf Interaction Inhibitors, Mohammed Al Mohaini

Theses and Dissertations

DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate …

Sperm Dna Oxidative Damage And Dna Adducts, Hueiwang Anna Jeng, Chih-Hong Pan, Mu-Rong Chao, Wen-Yi Lin

Community & Environmental Health Faculty Publications

The objective of this study was to investigate DNA damage and adducts in sperm from coke oven workers who have been exposed to polycyclic aromatic hydrocarbons. A longitudinal study was conducted with repeated measurements during spermatogenesis. Coke-oven workers (n =112) from a coke-oven plant served the PAH-exposed group, while administrators and security personnel (n=67) served the control. Routine semen parameters (concentration, motility, vitality, and morphology) were analyzed simultaneously; the assessment of sperm DNA integrity endpoints included DNA fragmentation, bulky DNA adducts, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo). The degree of sperm DNA fragmentation was measured using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling …

Effects Of Hiv-1 Tat On The Enteric Nervous, Joy Ngwainmbi

Theses and Dissertations

More than 1.2 million people are estimated to be currently living with the human immunodeficiency virus (HIV) in the United States of America. The gastrointestinal (GI) tract is both a major target and an important component of HIV pathogenesis. The GI processes that are dysregulated during HIV infection are controlled by the enteric nervous system (ENS). Indeed, both clinical and experimental studies have implicated the ENS in HIV and simian immunodeficiency virus (SIV) pathogenesis. In addition to direct viral effects, the HIV virus also indirectly affects the GI tract via cellular and/or viral toxins released by infected cells. Trans-activator of …

Structural Determinants Of Abuse-Related Neurochemical And Behavioral Effects Of Para-Substituted Methcathinone Analogs In Rats, Julie S. Bonano

Theses and Dissertations

Methcathinone (MCAT) is the β-ketone analog of methamphetamine, and like its amphetamine analog, MCAT functions as a monoamine releaser that selectively promotes the release of dopamine (DA) and norepinephrine (NE) over serotonin (5-HT). MCAT produces amphetamine-like psychostimulant effects and is classified as a Schedule I drug of abuse by the United States Drug Enforcement Administration (DEA). Recently, synthetic MCAT analogs have emerged as designer drugs of abuse in Europe and the United States and have been marketed under deceptively benign names like “bath salts” in an attempt to evade legal restriction. These dangerous, recently emergent and novel drugs of abuse …