Chemical and Pharmacologic Phenomena Commons^™

Structure Activity Relationship Studies Of Novel Diarylpentanoid Analogs Targeting The Androgen Receptor In Prostate Cancer Cells, Haili Coffin, Marco Bisoffi

Student Scholar Symposium Abstracts and Posters

The development of prostate cancer (PCa) relies strongly on the activation of the androgen receptor (AR) signaling pathway by its natural ligand dihydrotestosterone. Furthermore, PCa progression to metastatic disease represents oncogene addiction to AR activity. Androgen ablation therapy is thus a mainstay therapy against this disease, but the development of ligand-independent AR activation and persisting AR expression eventually leads to castration resistant PCa (CRPC). Therefore, down-regulation of AR expression in PCa cells may be an effective therapeutic modality. The diarylpentanoid ca27 has previously been shown to down-regulate AR expression by an unknown mechanism of action. The present work represents a …

A Review Of Ankylosing Spondylitis, Hannah L. Owen

Senior Honors Theses

Ankylosing spondylitis (AS) is a systemic autoimmune disorder that induces ankylosis of the spine (fusion of the vertebrae at their various joints) and inflammatory arthritis of peripheral joints among other symptoms. Overexpression of cytokines, the presence of genetic mutations not exclusive to the human leucocyte antigen (HLA)-B27 region, and environmental factors all have large roles in the progressive development of AS. Although a definitive pathology continues to be sought after, researchers believe the adaptive immune system in AS patients attacks fibrocartilaginous entheses (supportive connective tissue between bone and attached structures like tendon, ligament, and fascia).

AS markedly reduces proper systemic …

Age-Dependent Absolute Abundance Of Hepatic Carboxylesterases (Ces1 And Ces2) By Lc-Ms/Ms Proteomics: Application To Pbpk Modeling Of Oseltamivir In Vivo Pharmacokinetics In Infants., Mikael Boberg, Marc Vrana, Aanchal Mehrotra, Robin E. Pearce, Andrea Gaedigk, Deepak Kumar Bhatt, J Steven Leeder, Bhagwat Prasad

Manuscripts, Articles, Book Chapters and Other Papers

The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and …

Natural Compounds Targeting Major Cell Signaling Pathways: A Novel Paradigm For Osteosarcoma Therapy., Pablo Angulo, Gaurav Kaushik, Dharmalingam Subramaniam, Prasad Dandawate, Kathleen Neville, Katherine Chastain, Shrikant Anant

Manuscripts, Articles, Book Chapters and Other Papers

Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems …

Adoption Of Perioperative Lidocaine Infusion For The Reduction Of Postoperative Pain, Brandon Scott Figueiredo

Doctoral Projects

Laparoscopic capability provides numerous benefits to patients requiring abdominal surgical procedures. However, the use of these techniques has presented the anesthesia provider with a unique set of challenges in terms of perioperative management and postoperative pain reduction. No standardized method has existed to reduce postoperative pain and improve recovery following these procedures. There were three primary goals of this project. The first goal was to conduct a meta-analysis of randomized controlled trials to determine the benefit of the use of intravenous lidocaine infusions to reduce postoperative pain in laparoscopic abdominal surgery. Twelve articles were included in the meta-analysis that pertained …

The Role Of Nicotine, A7 Nicotinic Acetylcholine Receptors And Extracellular Matrix Remodeling In Pulmonary Fibrosis., Glenn Ward Vicary

Electronic Theses and Dissertations

The median survival for idiopathic pulmonary fibrosis (IPF) patients from diagnosis is a dismal 3 years. This condition is characterized by pulmonary fibroproliferation and excess production and disordered deposition of extracellular matrix (ECM) proteins resulting in obliteration of the original tissue architecture, loss of lung function and eventual death due to respiratory failure. The main hindrance to the development of effective treatments against pulmonary fibrosis is the late detection of its progression and is often of unknown cause. Tobacco smoke represents the most important environmental factor linked to the development of pulmonary fibrosis, with over 60% of IPF patients current …

Structural Dichotomy Of The Mind; The Role Of Sexual Neuromodulators, Ion G. Motofei, David L. Rowland

Journal of Mind and Medical Sciences

The mind (mental function) and sexuality represent two distinct environmental functions, but which are supported within the brain by a common (somatic-autonomic) neurobiological substrate. As a consequence, mental function takes on autonomic characteristics from the sexual-autonomic system (like autonomy, duality), while sexual function takes on features from mental functioning (such as lateralization). In this paper we discuss the lateralized action of two classes of sexual neuromodulators: hormones and pheromones. This process of lateralization is assimilated with the structural dichotomy of the mind.

A relatively similar process but related to informational dichotomy of the mind will be presented in a forthcoming …

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to …

Hit Identification For Pkcζ Inhibitors: Structure-Based Optimization, Virtual Screening, And Biological Evaluation, Xiaoxin Wu

Theses and Dissertations (ETD)

Protein kinase C ζ (PKCζ) is believed to be a promising target for the treatment of some diseases, including inflammatory diseases, obesity and diabetes. Hit identification of PKCζ inhibitors was conducted by structure-based modification, virtual screening and biological evaluation. Among all the compounds selected and synthesized, compound JW-1-60A showed moderate activity against PKCζ at 30 μM and 100 μM. The molecular modeling studies showed that the binding mode of JW-1-61A was very close to the binding mode of JP-3-149, a reported PKCζ inhibitor with very potent activity, which might partially explain the moderate activity of JW-1-61A. Based on the structure …

Na/K-Atpase Amplification Of Oxidant Stress; A Universal But Unrecognized Clinical Target?, Zijian Xie, Phd, Joseph I. Shapiro, Md

Marshall Journal of Medicine

The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating …

Role Of Serum Biomarkers In Early Detection Of Diabetic Cardiomyopathy In The West Virginian Population, Adam Shaver, Alexandra Nichols, Ellen A. Thompson, Amrita Mallick, Nandini Manne, Shanmuga Sundaram, Joseph I. Shapiro Md, Komal Sodhi

Biochemistry and Microbiology

Objectives: Diabetic cardiomyopathy (DCM) is an established complication of diabetes mellitus. In West Virginia, the especially high incidence of diabetes and heart failure validate the necessity of developing new strategies for earlier detection of DCM. Since most DCM patients remain asymptomatic until the later stages of the disease when the fibrotic complications become irreversible, we aimed to explore biomarkers that can identify early-stage DCM.

Methods: The patients were grouped into 4 categories based on clinical diabetic and cardiac parameters: Control, Diabetes (DM), Diastolic dysfunction (DD), and Diabetes with diastolic dysfunction (DM+DD), the last group being the preclinical DCM group.

Results: …

Vitamin D Deficiency: "At Risk" Patient Populations And Potential Drug Interactions, Dana Lycans Md, Elias Salloum Md, Matthew K. Wingate Md, Thomas Melvin Md, Grant S. Buchanan Md, Franklin D. Shuler Md, Phd

Marshall Journal of Medicine

Vitamin D is known to play an essential role in calcium homeostasis; however, excessive amounts can have harmful effects. Calcium and vitamin D levels are known to be influenced by drug interactions and pathology ranging from of cancer to cardiovascular disease. Vitamin D supplementation has become widespread, and it is important for clinicians to understand the way that certain conditions and medications interact with vitamin D and calcium homeostasis. The purpose of this review is to outline the benefits and adverse effects of vitamin D and how its levels are affected by certain pathologic and pharmacologic interactions.

Hexokinase Ii Localization Is Independent Of Ampk Activation In Hela Cells, Alyssa Brown

Graduate School of Biomedical Sciences Theses and Dissertations

In order for a cancer cell to thrive, it must alter its metabolism to produce the energy needed for rapid growth. Cells accomplish this by the Warburg Effect, or switching metabolism to aerobic glycolysis, where a cell can rapidly break down sugar into ATP, lactic acid and additional byproducts. Hexokinase 2, the enzyme that catalyzes the first committed step of glycolysis, may also be upregulated in cancer cells to increase glucose breakdown. Similar proteins for metabolism are found in both S. cerevisiae and mammalian cells. S. cerevisiae regulates metabolism through glucose repression, by Snf1 (mammalian homolog: AMPK) activation, which aids …

N-Methyl 4-Methyl Amphetamine N-Alkyl Chain Extension Differentially Affects Ion Flux At The Human Dopamine And Norepinephrine Transporters, Alan C. Harris Jr.

Theses and Dissertations

Amphetamine (AMPH) and its derivatives embody a remarkable breadth of pharmacology. These molecules exert their effects, both therapeutic and pathological, at the human monoamine transporters, which tune synaptic dynamics by evacuating monoamine neuromodulators from the synapse subsequent to neuronal impulses. These transporters are electrogenic, and the transporter-mediated current can be correlated to a surrogate measure of the change in membrane voltage: Ca⁺⁺ currents from co-transfected L-type Ca⁺⁺ channels. The present work makes use of this assay, with which it is possible to derive pharmacodynamic metrics from both substrates and inhibitors. This work presents data on a heretofore-unstudied class …

Molecular Determinants And Interaction Data Of Cyclic Peptide Inhibitor With The Extracellular Domain Of Trkb Receptor, Nitin Chitranshi, Vivek Gupta, Yogita Dheer, Veer Gupta, Roshana Vander Wall, Stuart Graham

Research outputs 2014 to 2021

TrkB is a high affinity receptor for the brain derived neurotrophic factor (BDNF) and its phosphorylation stimulates activation of several intracellular signalling pathways linked to cellular growth, differentiation and maintenance. Identification of various activators and inhibitors of the TrkB receptor and greater understanding their binding mechanisms is critical to elucidate the biochemical and pharmacological pathways and analyse various protein crystallization studies. The data presented here is related to the research article entitled "Brain Derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3β (GSK3β) signalling" [1]. Cyclotraxin B (CTXB) is a disulphide bridge linked cyclic peptide molecule …

The Neurochemistry Of Group Singing: Bonding And Oxytocin, Jason Keeler

Masters Theses

The purpose of this study was to examine the neurochemical correlates of group vocal improvisation and to determine the feasibility of the research methods. One group of four participants sang together in two conditions: pre-composed and improvised. Concentrations of plasma oxytocin and adrenocorticotropic hormone (ACTH) were measured before and after each singing condition to assess levels of hormones associated with social affiliation, engagement and arousal. Successful implementation of the methodology, including recruitment, data collection, and sample analysis, served as the primary outcome of this study. ACTH concentrations decreased in both conditions, and significantly so in the pre-composed singing condition. Mean …

Steroid Receptor Isoform Expression In Drosophila Nociceptor Neurons Is Required For Normal Dendritic Arbor And Sensitivity, Aidan L. Mcparland, Taylor L. Follansbee, Gwendolyn D. Vesenka, Alexandra E. Panaitiu, Geoffrey K. Ganter

Biology Student Publications

Steroid hormones organize many aspects of development, including that of the nervous system. Steroids also play neuromodulatory and other activational roles, including regulation of sensitivity to painful stimuli in mammals. In Drosophila, ecdysteroids are the only steroid hormones, and therefore the fly represents a simplified model system in which to explore mechanisms of steroid neuromodulation of nociception. In this report, we present evidence that ecdysteroids, acting through two isoforms of their nuclear ecdysone receptor (EcR), modulate sensitivity to noxious thermal and mechanical stimuli in the fly larva. We show that EcRA and EcRB1 are expressed by third instar larvae in …

Using Water–Solvent Systems To Estimate In Vivo Blood–Tissue Partition Coefficients, Andrew Lang, Caitlin E. Derricott

College of Science and Engineering Faculty Research and Scholarship

Background: Blood–tissue partition coefficients indicate how a chemical will distribute throughout the body and are an important part of any pharmacokinetic study. They can be used to assess potential toxicological effects from exposure to chemicals and the efficacy of potential novel drugs designed to target certain organs or the central nervous system. In vivo measurement of blood–tissue partition coefficients is often complicated, time-consuming, and relatively expensive, so developing in vitro systems that approximate in vivo ones is desirable. We have determined such systems for tissues such as brain, muscle, liver, lung, kidney, heart, skin, and fat. Results: Several good (p < 0.05) blood–tissue partition coefficient models were developed using a single water– solvent system. These include blood–brain, blood–lung, blood–heart, blood–fat, blood–skin, water–skin, and skin permeation. Many of these partition coefficients have multiple water–solvent systems that can be used as models. Several solvents—methylcyclohexane, 1,9-decadiene, and 2,2,2-trifluoroethanol—were common to multiple models and thus a single measurement can be used to estimate multiple blood–tissue partition coefficients. A few blood–tissue systems require a combination of two water–solvent partition coefficient measurements to model well (p < 0.01), namely: blood–muscle: chloroform and dibutyl ether, blood–liver: N-methyl-2-piperidone and ethanol/water (60:40) volume, and blood–kidney: DMSO and ethanol/water (20:80) volume. Conclusion: In vivo blood–tissue partition coefficients can be easily estimated through water–solvent partition coefficient measurements.

Dietary Intake And Bio-Activation Of Nitrite And Nitrate In Newborn Infants, Jesica Ann Jones

Loma Linda University Electronic Theses, Dissertations & Projects

Nitrate and nitrite are commonly thought of as inert end products of nitric oxide (NO) oxidation, possibly carcinogenic food additives, or well-water contaminants. However, recent studies have shown that nitrate and nitrite play an important role in cardiovascular and gastrointestinal homeostasis through conversion back into NO via a physiological system involving enterosalivary recirculation, bacterial nitrate reductases, and enzyme-catalyzed or acidic reduction of nitrite to NO. The diet is a key source of nitrate in adults; however, infants ingest significantly less nitrate due to low concentrations in breast milk. In the mouth, bacteria convert nitrate to nitrite, which has gastro-protective effects. …

Synthesis And Flammability Testing Of Epoxy Functionalized Phosphorous-Based Flame Retardants, Vladimir Benin, Xuemei Cui, Alexander Morgan, Karl Seiwert

Chemistry Faculty Publications

Several potential new phosphorus-containing flame retardant molecules were evaluated for heat release reduction potential by incorporation of the molecules into a polyurethane, generated from methylene diphenyl diisocyanate and 1,3-propane diol. The heat release reduction potential of these substances was evaluated using the pyrolysis combustion flow calorimeter (PCFC). The polyurethanes were prepared in the presence of the potential flame retardants via solvent mixing and copolymerization methods to qualitatively evaluate their potential reactivity into the polyurethane prior to heat release testing. The functionality of the flame retardants was epoxide based that would potentially react with the diol during polyurethane synthesis. Flammability testing …