Chemicals and Drugs Commons^™

Functionalization And Modification Of Naphthaquinone Analogs As Her2 Kinase Inhibitors, Divya Jyothi Lella

Masters Theses & Specialist Projects

HER2 overexpression in breast cancer tumors predicts lower overall survival. Because of the aggressive nature of HER2 tumors and the association with metastatic disease, the HER2 receptor holds great promise as a therapeutic target in metastatic breast cancer. We are developing small molecule inhibitors that bind to the ATP binding site of the tyrosine kinase domain in order to inhibit tyrosine auto-phosphorylation. This process controls biological pathways that mediate the cell growth. In normal cells this process is highly controlled. We are targeting the modification of the side chain of the hydroxy methyl group of 2-Hydroxy methyl-5,8-dimethoxy-1,4-naphthaquinone. These compounds should …

Molecular Chaperone Tools For Use Against Neurodegenerative Diseases, Matthew Tinkham

Senior Honors Projects

A noted characteristic found in several neurodegenerative disorders, including Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and bovine spongiform encephalopathy, is the accumulation of amyloid plaques in the brain. Amyloid plaques contain deposits of fibrillar aggregates of misfolded proteins that disrupt normal functionality in neurons. Certain variants of these misfolded proteins are self-replicating; these self-replicating amyloids are termed prions (for infectious protein). We are interested in how protein misfolding contributes to amyloid formation and how molecular chaperone proteins can change the formation of amyloid deposits. Chaperone proteins function by catalyzing the proper folding of other proteins, the refolding of misfolded proteins, …

Phthalates And Phthalate Alternatives: Effects On Proliferative And Estrogenic Target Genes In Ishikawa Cells, Ranjani Sundar '15, Ping Yin, Serdar E. Bulun

Student Publications & Research

Phthalates are used as plasticizers in many of the products found in medical, household, and industrial applications. Much research has not been completed on the effects of these phthalates as potential endocrine disrupting chemicals (EDCs). As these chemicals are ingested, the mechanism by which they affect the reproductive system is largely unknown. The purpose of this study was to observe how 2 phthalates, Di-n-butyl phthalate (DBP) and Diisononyl phthalate (DINP), and 2 phthalate alternatives, Dioctyl terephthalate (DOTP) and BHT (butylated hydroxytoluene)affect uterine cells in comparison to a vehicle treatment and 17β-Estradiol treatment. Changes in expression of mRNA were observed using …

A Systematic Column Performance Comparison For The Confirmation Of Opioids Used In Pain Management By Lc-Ms, Derek Stallard

Undergraduate Honors Theses

In this study, three different chromatographic column chemistries (C18, Pentafluorophenyl (PFP), Hydrophilic Interaction Chromatography (HILIC)) were compared under optimal conditions to determine which stationary performed best in the separation and detection of a mixture of opioids using LC-MS. Furthermore, these stationary phases were examined in three different column technologies – traditional silica, porous shell, and porous polymer (PRP). The PRP column had the best peak shape for all 13 opioids and dominated for later-eluting compounds. In terms of column reproducibility, the Hamilton C18 column had the lowest %RSD values. The Kinetex HILIC produced the most theoretical plates and best resolution …

Nicotine And What Else?: Hplc Elution Optimization For The Analysis Of Alkaloids Found In Electronic Cigarettes, Jessica L. Murray

Honors Theses

Electronic cigarettes, or e-cigarettes, have been scrutinized by the Food and Drug Administration and other public health organizations for issues related to quality control and efficacy. Erratic nicotine delivery and numerous toxic compounds in refill solutions have been reported. The ultimate goal of this research is to add to the growing amount of knowledge regarding e-cigarette ingredient content, safety, and quality. Standards of the tobacco alkaloids nicotine, anabasine, cotinine, and myosmine were prepared and quantified using high performance liquid chromatography (HPLC). Various elution schemes were tested and adjusted for optimal analyte resolution, and a final elution scheme was developed to …

Analysis Of Ligand Bias In Functional Studies Involving The Allosteric Modulation Of G Protein- Coupled Receptors, Frederick J. Ehlert, Michael T. Griffin

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Introduction

The affinity constants of a ligand for active and inactive states of a receptor ultimately determine its capacity to activate downstream signaling events. In this report, we describe a reverse-engineering strategy for estimating these microscopic constants.

Methods

Our approach involves analyzing responses measured downstream in the signaling pathway of a G protein-coupled receptor under conditions of allosteric modulation and reduced receptor expression or partial receptor inactivation. The analysis also yields estimates of the isomerization constant of the unoccupied receptor, the sensitivity constant of the signaling pathway, and the more empirical parameters of the receptor population including the observed affinities …

The Reversal Effects Of Curcumin, An Herbal Remedy, On The Impairments Induced By Vmat-2 Inhibitor Tetrabenazine, Emily Qian, Samantha E. Yohn

Honors Scholar Theses

Substantial evidence has shown that dopamine (DA), particularly in the nucleus accumbens (NAc), is involved in behavioral activation and effort-related processes, such as overcoming work related response costs. Interference with accumbens DA transmission through administration of the vesicular monoamine transportor-2 (VMAT-2) inhibitor tetrabenazine (TBZ) produces an alteration of response allocation in the concurrent FR5/chow choice procedure, biasing animals toward the lower effort alternative. It has been suggested that these drug-induced shifts in effort-related choice behavior seen in rodents are analogous to symptoms such as psychomotor retardation, anergia, and fatigue, which can be observed in people with depression and other related …

Purple Urine Bag Syndrome: Regulation Of Pyrimidine Enzymes, Ashley N. Broadway

Honors Theses

Purple Urine Bag Syndrome, PUBS, is a unique condition that shows an interesting discoloration of the urine from women who have a chronic catheter. This study focused on the regulation of enzyme activities to determine the effects that may create an environment where PUBS is seen in patients with catheters. In this study, the reductive pyrimidine pathway was used to read out the bacteria Pseudomonas aeruginosa ATCC 15692. This microorganism expresses a pathway that synthesizes indoxyl from tryptophan. The bacteria strains were grown using various carbon and nitrogen sources. Concentrations of acetonitrile at 2 mM and 10 mM, concentrations of …

Metal Stopping Reagents Facilitate Discontinuous Activity Assays Of The De Novo Purine Biosynthesis Enzyme Pure, Kelly L. Sullivan, Loredana C. Huma, Elwood Mullins, Michael E. Johnson, T. Joseph Kappock

Department of Biochemistry Faculty Publications

The conversion of 5-aminoimidazole ribonucleotide (AIR) to 4-carboxy-AIR (CAIR) represents an unusual divergence in purine biosynthesis: microbes and nonmetazoan eukaryotes use class I PurEs while animals use class II PurEs. Class I PurEs are therefore a potential antimicrobial target; however, no enzyme activity assay is suitable for high throughput screening (HTS). Here we report a simple chemical quench that fixes the PurE substrate/product ratio for 24 h, as assessed by the Bratton-Marshall assay (BMA) for diazotizable amines. The ZnSO₄ stopping reagent is proposed to chelate CAIR, enabling delayed analysis of this acid-labile product by BMA or other HTS methods

Physiologically-Based Pharmacokinetic Model For Ertapenem, Whitney Forbes

Electronic Theses and Dissertations

Ertapenem is a carbapenem used to treat a wide range of bacterial infections. What sets ertapenem apart from other carbapenems is its longer half-life which implies it need only be administered once daily. We developed a physiologically-based pharmacokinetic model for the distribution of ertapenem within the body. In the model, parameters such as human body weight and height, age, organ volumes, blood flow rates, and partition coefficients of particular tissues are used to examine the absorption, distribution, metabolism, and excretion of ertapenem. The total and free blood concentrations found were then compared to experimental data. We then examined the sensitivity …

Anti-Gd2 Etoposide-Loaded Immunoliposomes For The Treatment Of Gd2 Positive Tumors, Brandon S. Brown

Dissertations and Theses (Open Access)

Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. Monoclonal antibodies that specifically bind antigens overexpressed on many tumors such as the ganglioside, GD2, can be conjugated to drug-loaded liposomes to create a targeted drug delivery system. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared …

Phage Display Library Screening For Psa-/Lo Prostate Cancer Cell-Binding Peptides, John R. Moore

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and developing therapeutics that target the cells responsible for driving PCa and mediating therapy resistance. My master thesis research employs a phage display library screening technology aiming to identify peptides that preferentially home in to undifferentiated PCa cells, which our lab has previously demonstrated to be intrinsically resistant to castration.

There is now evidence that a population of cells in PCa possesses characteristics associated with stem cells; these cells are referred to as cancer stem cells (CSCs). …

Polyethylene Glycol Containing Rompolymers For The Modification Of Neuro-Protective Hemoglobin, Andrea L. Mccollum

Honors College Theses

Polyethylene glycol (PEG) has shown the ability to improve compatibility when used in combination with cell-free hemoglobin in the treatment of traumatic brain injuries. It has been demonstrated that the covalently bonded PEG increases the hydrodynamic radius of the hemoglobin and hence generates a physical barrier while slowing down the oxygen delivery of the strongly oxidative hemoglobin. In this context, I have been working on the development of synthetic pathways to incorporate PEG into monomers and polymers through both direct modification of (7-oxa)norbornene derivatives and post polymerization modification. Starting from the (7-oxa)norbornene anhydride derivatives, we have developed pathways to cationic …

Characterization Of Extraction Methods To Recover Phenolic-Rich Antioxidants From Blue Green Algae (Spirulina) Using Response Surface Approaches, Ahmad Salamatullah

Department of Food Science and Technology: Dissertations, Theses, and Student Research

Blue green algae (spirulina) is a dietary system that is widely consumed as a whole food or as a supplement in many Asian countries where populations are mostly unaffected by many of the diseases currently afflicting western societies, such as cancer, heart disease and arthiritis. Indeed, spirulina is a rich source of antioxidants with the phenolic compounds playing a significant role. As components of a complex dietary system, phenolic compounds can act alone or through synergistic mechanisms to impart a greater biologic effect than can be elicited by a sum of the individual parts. Therefore, an understanding of the antioxidative …

Childhood Obesity And Familial Hypercholesterolemia: Genetic Diseases That Contribute To Cardiovascular Disease, Alyssa Caudle

Senior Honors Theses

Childhood obesity occurs as the result of an imbalance between caloric intake and energy expenditure. Genetic risk factors for obesity have become an area of research due to its permanency. Mutated genes such as Fat Mass and Obesity Associated (FTO), Leptin (LEP), Leptin Receptor (LEPR), Melanocortin 4 Receptor (MC4R), Adiponectin C1Q and Collagen Domain Containing (ADIPOQ), Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1), and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) all contribute to the development of childhood obesity. In the presence of high cholesterol caused by obesity, the genetic condition known as familial hypercholesterolemia is exacerbated. Familial hypercholesterolemia is caused by a …

Regional-Specific Effects Of Ovarian Hormone Loss On Synaptic Plasticity In Adult Human Apoe Targeted Replacement Mice, Rebecca C. Klein, Shyla Saini, Mary-Louise Risher, Shawn K. Acheson, Rebekah L. Fleming, Hannah G. Sexton, H. Scott Swartzwelder, Scott D. Moore

Biomedical Sciences

The human apolipoprotein ε4 allele (APOE4) has been implicated as one of the strongest genetic risk factors associated with Alzheimer’s disease (AD) and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR) mice were utilized to examine the effects of human APOE …

Sample Limited Characterization Of A Novel Disulfide- Rich Venom Peptide Toxin From Terebrid Marine Snail Terebra Variegata, Prachi Anand, Alexandre Grigoryan, Mohammed H. Bhuiyan, Beatrix Ueberheide, Victoria Russell, Jose Quiñonez, Patrick Moy, Brian T. Chait, Sébastien F. Poget, Mandë Holford

Publications and Research

Disulfide-rich peptide toxins found in the secretions of venomous organisms such as snakes, spiders, scorpions, leeches, and marine snails are highly efficient and effective tools for novel therapeutic drug development. Venom peptide toxins have been used extensively to characterize ion channels in the nervous system and platelet aggregation in haemostatic systems. A significant hurdle in characterizing disulfide-rich peptide toxins from venomous animals is obtaining significant quantities needed for sequence and structural analyses. Presented here is a strategy for the structural characterization of venom peptide toxins from sample limited (4 ng) specimens via direct mass spectrometry sequencing, chemical synthesis and NMR …

Mechanism Underlying Ikk Activation Mediated By The Linear Ubiquitin Chain Assembly Complex (Lubac), Hiroaki Fujita, Simin Rahighi, Mariko Akita, Ryuichi Kato, Yoshiteru Sasaki, Soichi Wakatsuki, Kazuhiro Iwai

Pharmacy Faculty Articles and Research

The linear ubiquitin chain assembly complex (LUBAC) ligase, consisting of HOIL-1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains. LUBAC-mediated linear polyubiquitination has been implicated in NF-κB activation. NEMO, a component of the IκB kinase (IKK) complex, is a substrate of LUBAC, but the precise molecular mechanism underlying linear chain-mediated NF-κB activation has not been fully elucidated. Here, we demonstrate that linearly polyubiquitinated NEMO activates IKK more potently than unanchored linear chains. In mutational analyses based on the crystal structure of the complex between the HOIP NZF1 and NEMO CC2-LZ domains, which are involved in the HOIP-NEMO interaction, NEMO mutations …

Antibiotics To Promote Growth In Children?, Zulfiqar Ahmed Bhutta

Department of Paediatrics and Child Health

No abstract provided.

Structural And Biophysical Characterization Of Staphylococcus Aureus Samazf Shows Conservation Of Functional Dynamics, Valentina Zorzini, Lieven Buts, Mike Sleutel, Abel Garcia-Pino, Ariel Talavera, Sarah Haesaerts, Henri De Greve, Ambrose Cheung, Nico A. J. Van Nuland, Remy Loris

Dartmouth Scholarship

The Staphylococcus aureus genome contains three toxin-antitoxin modules, including one mazEF module, SamazEF. Using an on-column separation protocol we are able to obtain large amounts of wild-type SaMazF toxin. The protein is well-folded and highly resistant against thermal unfolding but aggregates at elevated temperatures. Crystallographic and nuclear magnetic resonance (NMR) solution studies show a well-defined dimer. Differences in structure and dynamics between the X-ray and NMR structural ensembles are found in three loop regions, two of which undergo motions that are of functional relevance. The same segments also show functionally relevant dynamics in the distantly related CcdB family despite divergence …

Responsive Polymers For Biosensing And Protein Delivery, Molla R. Islam, Yongfeng Gao, Xue Li, Michael J. Serpe

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

In this feature article, we review some of the most recent advances in the field of materials chemistry for biosensing, disease diagnostics, and drug delivery. Our recent work on the development of responsive polymer-based platforms for biosensing and drug delivery will also be highlighted. This feature article is meant to outline the breadth of the utility of polymer-based materials for select applications, as well as their enormous potential impact on future technologies.

The Abcs Of The Ribosome, Kurt Fredrick, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

An ABC protein that binds the ribosomal exit site suggests a new mechanism for direct regulation of translation in response to changing ATP levels in the cell.

Roles Of Dopamine Receptor On Chemosensory And Mechanosensory Primary Cilia In Renal Epithelial Cells, Viralkumar S. Upadhyay, Brian S. Muntean, Samred H. Kathem, Jangyoun J. Hwang, Wissam A. Aboualaiwi, Surya M. Nauli

Pharmacy Faculty Articles and Research

Dopamine plays a number of important physiological roles. However, activation of dopamine receptor type-5 (DR5) and its effect in renal epithelial cells have not been studied. Here, we show for the first time that DR5 is localized to primary cilia of LLCPK kidney cells. Renal epithelial cilia are mechanosensory organelles that sense and respond to tubular fluid-flow in the kidney. To determine the roles of DR5 and sensory cilia, we used dopamine to non-selectively and fenoldopam to selectively activate ciliary DR5. Compared to mock treatment, dopamine treated cells significantly increases the length of cilia. Fenoldopam further increases the length of …

A Program For Review Of Residents On Anti-Psychotic (Ap) Medications In A County Owned Nursing Facility, Catherine M. Glew Bm, Bs, Cmd, Beth Berklite Rn, Adon, Terri Bauer Rn

Department of Medicine

No abstract provided.

Establishing A Floor: Minimum Remediation Requirements For Meth Labs, Chelsea Bobo

William & Mary Environmental Law and Policy Review

No abstract provided.

Vaccine-Preventable Diseases In Travelers, Edith Mirzaian, Jeffery A. Goad, Ani Amloian, Fady Makar

Pharmacy Faculty Articles and Research

Travel to the developing world is increasing among those from developed countries, placing them at risk for vaccine preventable and non-vaccine preventable diseases. From 2007-2011, the GeoSentinel Network reported 737 returned travelers with a vaccine preventable disease. While it is essential that clinicians use vaccines when available for a disease of risk, they should also be aware that the vast majority of diseases acquired by travelers are non-vaccine preventable. The vaccine preventable diseases can be divided into routine travel vaccines, special travel vaccines and routine vaccines used for travel. The routine travel vaccines include Hepatitis A and B, typhoid; special …

Metabolic Reprogramming Induced By Ketone Bodies Diminishes Pancreatic Cancer Cachexia, Surendra K. Shukla, Teklab Gebregiworgis, Vinee Purohit, Nina V. Chaika, Venugopal Gunda, Prakash Radhakrishnan, Kamiya Mehla, Iraklis I. Pipinos, Robert Powers, Fang Yu, Pankaj K. Singh

Robert Powers Publications

Background: Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in …

Electrophoretic Particle Guidance Significantly Enhances Olfactory Drug Delivery: A Feasibility Study, Jinxiang Xi, Xiuhua A. Si, Rachel Gaide

University Faculty Publications and Creative Works

Intranasal olfactory drug delivery provides a non-invasive method that bypasses the Blood-Brain-Barrier and directly delivers medication to the brain and spinal cord. However, a device designed specifically for olfactory delivery has not yet been found. Methods: In this study, a new delivery method was proposed that utilized electrophoretic forces to guide drug particles to the olfactory region. The feasibility of this method was numerically evaluated in both idealized 2-D and anatomically accurate 3-D nose models. The influence of nasal airflow, electrode strength, and drug release position were also studied on the olfactory delivery efficiency. Findings: Results showed that by applying …

Epc-Derived Microvesicles Protect Cardiomyocytes From Ang Ii-Induced Hypertrophy And Apoptosis, Shenhong Gu, Wei Zhang, Ji Chen, Ruilian Ma, Xiang Xiao, Xiaotang Ma, Zhen Yao, Yanfang Chen

Pharmacology and Toxicology Faculty Publications

Cell-released microvesicles (MVs) represent a novel way of cell-to-cell communication. Previous evidence indicates that endothelial progenitor cells (EPCs)-derived MVs can modulate endothelial cell survival and proliferation. In this study, we evaluated whether EPC-MVs protect cardiomyocytes (CMs) against angiotensin II (Ang II)-induced hypertrophy and apoptosis. The H9c2 CMs were exposed to Ang II in the presence or absence of EPC-MVs. Cell viability, apoptosis, surface area and β-myosin heavy chain (β-MHC) expression were analyzed. Meanwhile, reactive oxygen species (ROS), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS), and their phosphorylated proteins (p-Akt, p-eNOS) were measured. Phosphatidylinositol-3-kinase (PI3K) and NOS inhibitors were used …

Protein Binding Drug-Drug Interaction Between Warfarin And Tizoxanide In Human Plasma, Eduard Mullokandov, Jennifer Ahn, Andrew Szalkiewicz, Mariana Babayeva

Touro College of Pharmacy (New York) Publications and Research

The goal of the in vitro research was to evaluate the potential for inhibition of warfarin protein binding by tizoxanide. Warfarin was of particular interest for the present investigation because it has been shown to be highly bound to plasma proteins and is a narrow therapeutic index drug. Tizoxanide is an active metabolite of an anti-infective prodrug nitazoxanide and also highly protein-bound medication. Both drugs are expected to be co-administered clinically. Protein binding of warfarin was investigated using a centrifugal ultrafiltration technique. Co-administration of tizoxanide significantly inhibited protein binding of warfarin for all concentrations tested. Tizoxanide increased free fraction (fu) …