Pharmacology Commons^™

Overexpressed Somatic Alleles Are Enriched In Functional Elements In Breast Cancer., Paula Restrepo, Mercedeh Movassagh, Nawaf Alomran, Christian Miller, Muzi Li, Chris Trenkov, Yulian Manchev, Sonali Bahl, Stephanie Warnken, Liam Spurr, Tatiyana Apanasovich, Keith Crandall, Nathan Edwards, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Asymmetric allele content in the transcriptome can be indicative of functional and selective features of the underlying genetic variants. Yet, imbalanced alleles, especially from diploid genome regions, are poorly explored in cancer. Here we systematically quantify and integrate the variant allele fraction from corresponding RNA and DNA sequence data from patients with breast cancer acquired through The Cancer Genome Atlas (TCGA). We test for correlation between allele prevalence and functionality in known cancer-implicated genes from the Cancer Gene Census (CGC). We document significant allele-preferential expression of functional variants in CGC genes and across the entire dataset. Notably, we find frequent ...

Alternative Splicing Promotes Tumour Aggressiveness And Drug Resistance In African American Prostate Cancer., Bi-Dar Wang, Kristin Ceniccola, Sujin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A Garcia-Blanco, Steven R Patierno, Norman H Lee

Pharmacology and Physiology Faculty Publications

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and ...

A Novel Micro Cold Atmospheric Plasma Device For Glioblastoma Both In Vitro And In Vivo., Zhitong Chen, Hayk Simonyan, Xiaoqian Cheng, Eda Gjika, Li Lin, Jerome Canady, Jonathan H Sherman, Colin Young, Michael Keidar

Pharmacology and Physiology Faculty Publications

: Cold atmospheric plasma (CAP) treatment is a rapidly expanding and emerging technology for cancer treatment. Direct CAP jet irradiation is limited to the skin and it can also be invoked as a supplement therapy during surgery as it only causes cell death in the upper three to five cell layers. However, the current cannulas from which the plasma emanates are too large for intracranial applications. To enhance efficiency and expand the applicability of the CAP method for brain tumors and reduce the gas flow rate and size of the plasma jet, a novel micro-sized CAP device (µCAP) was developed and ...

Applied Drug Development And Combinatorial Strategies For Antimicrobial Treatment, Steven K. Lai Hing

Andrews Research Conference

Streptococcus mutans JH1140 is a strain of bacteria which produces a lantibiotic product, named mutacin 1140. Mutacin 1140 has been shown to be effective at inhibiting Gram-positive bacterial infections caused by Staphylococcus aureus and Streptococcus pneumoniae. Mutacin 1140 is a ribosomally synthesized peptide antibiotic that undergoes extensive posttranslational modifications (PTM). We have found that Mutacin 1140 and an aminoglycoside, Kanamycin, when combined together, act synergistically against Staphylococcus aureus. This was determined by performing serial kill curve dilution overlays on solid media, followed up with kill curve by microdilution plate, and most recently confirmed with kill curve CFU count plates on ...

Effects Of Anandamide Administration On Components Of Reward Processing, Howard C. Cromwell

Howard Casey Cromwell

A Variant Pfcrt Isoform Can Contribute To Plasmodium Falciparum Resistance To The First-Line Partner Drug Piperaquine, Satish K. Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Annie N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J. Egan, David A. Fidock

Biological Sciences Faculty Publications

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC₉₀) or 50% parasite killing (50% lethal dose [LD₅₀]). This mutation also reversed ...

The Role Of Complement Component C5a In Nociceptive Sensitization, Charles A. Warwick

Theses and Dissertations

The complement system is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other complement components in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund’s adjuvant were accompanied by C5a upregulation and were markedly reduced by C5a receptor (C5aR1) knockout (KO) or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced ...

Evaluation Of Perfluorohexane Sulfonate (Pfhxs) Exposure To Risk Of Liver Disease Caused By High Fat Fructose Diet, Dwight C. Anderson

Senior Honors Projects

Perfluorohexane sulfonate (PFHxS) has been used in products as surfactants[AS1] . These products include fluoropolymers and as protective and water-resistant coatings to different materials such as carpets, paper, and textiles. Also, evidence of PFHxS exposure has been reported in firefighters who use certain film forming foams. Current investigations have shown widespread exposure to PFHxS in the environment, specifically in drinking water. There has also been evidence of PFHxS accumulation in humans, with a half-life lasting several years.

PFHxS is one of several perfluoronated alkyl substances (PFAS). Other PFASs are considered to be hepatotoxic in rodents and potentially in humans. Studies ...

Hiv-1 Protease Inhibitors From Marine Brown Alga: A Literature Review, Eric Nunez Aguilar

McNair Research Journal SJSU

The human immunodeficiency virus type 1 (HIV-1) causes an infectious disease that if left untreated can progress to acquired immunodeficiency syndrome (AIDS) and be fatal. Finding a cure and more treatments for HIV has become a top priority in medical research, and due to the cost of synthetic HIV medication, finding a low-cost alternative is essential. Marine pharmacology has provided a possible solution to costly HIV medication through compounds derived from marine brown algae that inhibit the HIV-1 protease (PR). The objective of this study is to emphasize the necessity for further research in HIV-1 protease inhibition using marine wildlife-derived ...

Constitutive Activation Of Kappa Opioid Receptors At Ventral Tegmental Area Inhibitory Synapses Following Acute Stress., Abigail M Polter, Kelsey Barcomb, Rudy W Chen, Paige M Dingess, Nicholas M Graziane, Travis E Brown, Julie A Kauer

Pharmacology and Physiology Faculty Publications

Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also ...

Therapeutic Modulation Of Cancer Metabolism With Dichloroacetate And Metformin, Nathan Patrick Ward

Graduate Theses and Dissertations

The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in the VM-M3 model of GBM. We demonstrated that metformin potentiated DCA-induced superoxide production and that this was required for enhanced cytotoxicity towards VM-M3 cells with the combination. Similarly, rotenone enhanced oxidative stress ...

In Vitro Studies On Metabolism Of Salvinorin A, Lukasz M. Kutrzeba, Vardan T. Karamyan, Robert C. Speth, John S. Williamson, Jordan K. Zjawiony

John S. Williamson

Microbial transformation of natural products is a well established model for mammalian metabolism. Salvinorin A, a diterpenoid isolated from the hallucinogenic mint Salvia divinorum Epling & Játiva-M (Lamiaceae), is a potent non-nitrogenous κ-opioid receptor agonist. The metabolism of salvinorin A has still not yet been well established. Thirty fungal species were screened for the ability to metabolize salvinorin A. We observed that salvinorin A undergoes fast hydrolysis of the acetate group at carbon atom C2, resulting in formation of the pharmacologically inactive product, salvinorin B. Ex vivo experiments were also performed using organelle fractions isolated from rat liver and brain. Crude ...

Design And Optimization Of Rsv F For Vaccination, Elizabeth R. Wilson

Honors Projects and Posters

Respiratory syncytial virus (RSV) is a common infection that affects most infants by the age of two, as well as a large percentage of the elderly population. Currently, the majority of prevention lies in the hands of the caretakers: wash hands frequently, avoid contact if sick or have babies wear masks, keep young children away from babies, avoid crowds during outbreaks. As these methods are not always feasible, this project aims to develop a vaccine for RSV by focusing on the fusion (F) glycoprotein. This protein is necessary for the virus to infect, as it assists the virus in fusing ...

Enzyme-Dependent Fluorescence Recovery Of Nadh After Photobleaching To Assess Dehydrogenase Activity Of Isolated Perfused Hearts., Angel Moreno, Sarah Kuzmiak-Glancy, Rafael Jaimes, Matthew W Kay

Pharmacology and Physiology Faculty Publications

Reduction of NAD(+) by dehydrogenase enzymes to form NADH is a key component of cellular metabolism. In cellular preparations and isolated mitochondria suspensions, enzyme-dependent fluorescence recovery after photobleaching (ED-FRAP) of NADH has been shown to be an effective approach for measuring the rate of NADH production to assess dehydrogenase enzyme activity. Our objective was to demonstrate how dehydrogenase activity could be assessed within the myocardium of perfused hearts using NADH ED-FRAP. This was accomplished using a combination of high intensity UV pulses to photobleach epicardial NADH. Replenishment of epicardial NADH fluorescence was then imaged using low intensity UV illumination. NADH ...

Enhanced Salmonella Virulence Instigated By Bactivorous Protozoa And Investigation Of Putative Protozoan G Protein-Coupled Receptors Associated With Bacterial Engulfment, Matt T. Brewer

Matthew T. Brewer

The protozoa are a diverse group of eukaryotic microorganisms that employ a variety of life strategies. Many protozoa are free-living while others are commensal organisms that thrive within the gut of vertebrates. In addition, a relatively small group of parasitic protozoa represent serious health threats to humans and animals. Certain free-living, commensal, and parasitic protozoa are bactivorous and rely on bacteria as a food source. However, some intracellular bacterial pathogens survive engulfment and thrive within these protozoa. This dissertation describes the investigation of Salmonella hypervirulence following bacterial engulfment and characterizes physiologic interactions between various protozoa and bacteria. Initial studies entailed ...

Proteome Dynamics During Postnatal Mouse Corpus Callosum Development., Alexander I Son, Xiaoqin Fu, Fumikazu Suto, Judy S Liu, Kazue Hashimoto-Torii, Masaaki Torii

Pharmacology and Physiology Faculty Publications

Formation of cortical connections requires the precise coordination of numerous discrete phases. This is particularly significant with regard to the corpus callosum, whose development undergoes several dynamic stages including the crossing of axon projections, elimination of exuberant projections, and myelination of established tracts. To comprehensively characterize the molecular events in this dynamic process, we set to determine the distinct temporal expression of proteins regulating the formation of the corpus callosum and their respective developmental functions. Mass spectrometry-based proteomic profiling was performed on early postnatal mouse corpus callosi, for which limited evidence has been obtained previously, using stable isotope of labeled ...

Discovery Of Thienoquinolone Derivatives As Selective And Atp Non-Competitive Cdk5/P25 Inhibitors By Structure-Based Virtual Screening, Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, John S. Williamson

John S. Williamson

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP ...

A Role Of Central Nell2 In The Regulation Of Feeding Behavior In Rats., Jin Kwon Jeong, Jae Geun Kim, Han Rae Kim, Tae Hwan Lee, Jeong Woo Park, Byung Ju Lee

Pharmacology and Physiology Faculty Publications

A brain-enriched secreting signal peptide, NELL2, has been suggested to play multiple roles in the development, survival, and activity of neurons in mammal. We investigated here a possible involvement of central NELL2 in regulating feeding behavior and metabolism. In situ hybridization and an immunohistochemical approach were used to determine expression of NELL2 as well as its colocalization with proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the rat hypothalamus. To investigate the effect of NELL2 on feeding behavior, 2 nmole of antisense NELL2 oligodeoxynucleotide was administered into the lateral ventricle of adult male rat brains for 6 consecutive days, and changes ...

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the ...

Chemogenetic Stimulation Of The Hypoglossal Neurons Improves Upper Airway Patency, Thomas Curado, Kenneth Fishbein, Huy Pho, Michael Brennick, Olga Dergacheva, David Mendelowitz, +Several Additional Authors

Pharmacology and Physiology Faculty Publications

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus ...