Chemicals and Drugs Commons^™

Street Drug Markets Beyond Favelas In Belo Horizonte, Brazil, Elenice De Souza Oliveira, Braulio Figueiredo Alves Silva, Marcos Oliveira Prates

Department of Justice Studies Faculty Scholarship and Creative Works

This study examines whether social disorganization mechanisms that explain clusters of street drug markets in socially disorganized neighborhoods in developed countries can also help explain geographical patterns of drug dealing across neighborhoods in Belo Horizonte, Brazil. Data for this study includes drug arrests from 2007 to 2011 and socio demographic data from the 2010 Census. To examine the influence of exploratory variables on drug market locations, the Negative Binominal regression model was used at two levels of analysis—the Belo Horizonte city center and other neighborhoods including favelas. The findings show that a high hot spot of street drug markets located …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Dancing Through Life: Molecular Dynamics Simulations And Network-Centric Modeling Of Allosteric Mechanisms In Hsp70 And Hsp110 Chaperone Proteins, Gabrielle Stetz, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Hsp70 and Hsp110 chaperones play an important role in regulating cellular processes that involve protein folding and stabilization, which are essential for the integrity of signaling networks. Although many aspects of allosteric regulatory mechanisms in Hsp70 and Hsp110 chaperones have been extensively studied and significantly advanced in recent experimental studies, the atomistic picture of signal propagation and energetics of dynamics-based communication still remain unresolved. In this work, we have combined molecular dynamics simulations and protein stability analysis of the chaperone structures with the network modeling of residue interaction networks to characterize molecular determinants of allosteric mechanisms. We have shown that …

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 …

Real-Time Detection Of Breast Cancer Cells Using Peptidefunctionalized Microcantilever Arrays, Hashem Etayash, Keren Jiang, Sarfuddin Azmi, Thomas Thundat, Kamaljit Kaur

Pharmacy Faculty Articles and Research

Ligand-directed targeting and capturing of cancer cells is a new approach for detecting circulating tumor cells (CTCs). Ligands such as antibodies have been successfully used for capturing cancer cells and an antibody based system (CellSearch®) is currently used clinically to enumerate CTCs. Here we report the use of a peptide moiety in conjunction with a microcantilever array system to selectively detect CTCs resulting from cancer, specifically breast cancer. A sensing microcantilever, functionalized with a breast cancer specific peptide 18-4 (WxEAAYQrFL), showed significant deflection on cancer cell (MCF7 and MDA-MB-231) binding compared to when exposed to noncancerous (MCF10A and HUVEC) cells. …

Elongation Factor-P At The Crossroads Of The Host-Endosymbiont Interface, Andrei Rajkovic, Anne Witzky, William Navarre, Andrew J. Darwin, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) is an ancient bacterial translational factor that aids the ribosome in polymerizing oligo-prolines. EF-P structurally resembles tRNA and binds in-between the exit and peptidyl sites of the ribosome to accelerate the intrinsically slow reaction of peptidyl-prolyl bond formation. Recent studies have identified in separate organisms, two evolutionarily convergent EF-P post-translational modification systems (EPMS), split predominantly between gammaproteobacteria, and betaproteobacteria. In both cases EF-P receives a post-translational modification, critical for its function, on a highly conserved residue that protrudes into the peptidyl-transfer center of the ribosome. EPMSs are comprised of a gene(s) that synthesizes the precursor molecule …

Tnf-Α-Induced Micrornas Control Dystrophin Expression In Becker Muscular Dystrophy., Alyson A. Fiorillo, Christopher R. Heier, James S. Novak, Christopher B. Tully, Kristy J. Brown, Kitipong Uaesoontrachoon, Maria C. Vila, Peter P. Ngheim, Luca Bello, Joe N. Kornegay, Corrado Angelini, Terence A. Partridge, Kanneboyina Nagaraju, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45–47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low …

Bio-Inspired Composite Hydrogels For Osteochondral Regenerative Engineering, Grant N. Gellert, Liangju Kuang, Chunhui Jiang, Nur P. Damayanti, Joseph Irudayaraj, Meng Deng

The Summer Undergraduate Research Fellowship (SURF) Symposium

Treatment of osteochondral defects encompassing injury or degeneration to both the articular cartilage as well as the underlying subchondral bone presents a significant medical challenge. Current treatment options including autografts and allografts suffer from limited availability and risk of immunogenicity, respectively. The long term goal of this work is to develop an integrated scaffold system for treatment of osteochondral defects via in situ regeneration of bone, cartilage and the bone-cartilage interface. Hydrogels composed of polymer networks swollen in water provide an attractive biomaterial platform for regeneration of cartilage. In the present study, we have developed a novel composite hydrogel consisting …

Editorial: Phosphoinositides And Their Phosphatases: Linking Electrical And Chemical Signals In Biological Processes, Susy C. Kohout, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

No abstract provided.

Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors, Bruno Ramos-Molina, Adam N. Lick, Amir Nasrolahi Shirazi, Donghoon Oh, Rakesh Tiwari, Naglaa Salem El-Sayed, Keykavous Parang, Iris Lindberg

Pharmacy Faculty Articles and Research

Cationic cell-penetrating peptides have been widely used to enhance the intracellular delivery of various types of cargoes, such as drugs and proteins. These reagents are chemically similar to the multi-basic peptides that are known to be potent proprotein convertase inhibitors. Here, we report that both HIV-1 TAT47-57 peptide and the Chariot reagent are micromolar inhibitors of furin activity in vitro. In agreement, HIV-1 TAT47-57 reduced HT1080 cell migration, thought to be mediated by proprotein convertases, by 25%. In addition, cyclic polyarginine peptides containing hydrophobic moieties which have been previously used as transfection reagents also exhibited potent furin inhibition in vitro …

Characterization Of The Role That Alternative Ribonucleotide Reductases Play In Restoring Replication In The Presence Of Hydroxyurea In Escherichia Coli, Michael Sadek

PSU McNair Scholars Online Journal

DNA replication is essential for cells to grow and divide. Ribonucleotide reductase is an essential enzyme that is responsible for the formation of deoxyribonucleotides that are used in DNA synthesis during replication. Hydroxyurea is a chemotherapeutic agent that is thought to work by specifically inhibiting the ribonuceotide reductase to prevent replication. However, recent studies in E. coli have shown that following an initial period of inhibition, DNA synthesis then recovers in the presence of hydroxyurea, suggesting that the mode of death and cellular response to hydroxyurea is more complex than originally proposed. The E.coli genome encodes three ribonucleotide reductases that …

Cyclic Rhamnosylated Elongation Factor P Establishes Antibiotic Resistance In Pseudomonas Aeruginosa, Andrei Rajkovic, Sarah Erickson, Anne Witzky, Owen E. Branson, Jin Seo, Philip R. Gafken, Michael A. Frietas, Julian P. Whitelegge, Kym F. Faull, William Wiley Navarre, Andrew J. Darwin, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) is a ubiquitous bacterial protein that is required for the synthesis of poly-proline motifs during translation. In Escherichia coli and Salmonella enterica, the posttranslational β-lysylation of Lys34 by the PoxA protein is critical for EF-P activity. PoxA is absent from many bacterial species such as Pseudomonas aeruginosa, prompting a search for alternative EF-P posttranslation modification pathways. Structural analyses of P. aeruginosa EF-P revealed the attachment of a single cyclic rhamnose moiety to an Arg residue at a position equivalent to that at which β-Lys is attached to E. coli EF-P. Analysis of the genomes …

The Effects Of Arginine Vasopressin On Maternal Behavior And Aggression In Peromyscus Californicus Mothers, Nathaniel Ng

Honors Projects

Research studies since the 1950s have shown that a chemical within the brain called arginine vasopressin (AVP) is associated with the modulation of many different social behaviors in mammals. Some of these behaviors are related to parenting, such as parental care initiation, aggression, social recognition, depression and anxiety. Understanding the physiology behind AVP regulation could allow for the creation of new therapies for treating human social disorders, such as using an AVP receptor antagonist to attenuate anxiety. This project examines how neural injections of AVP and an AVP receptor antagonist affect both maternal care and aggression in female Peromyscus californicus …

Orexin Receptor Activation Generates Gamma Band Input To Cholinergic And Serotonergic Arousal System Neurons And Drives An Intrinsic Ca(2+)-Dependent Resonance In Ldt And Ppt Cholinergic Neurons, Masaru Ishibashi, Iryna Gumenchuk, Bryan Kang, Catherine Steger, Elizabeth Lynn, Nancy Molina, Leonard M. Eisenberg, Christopher S. Leonard

NYMC Faculty Publications

A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz) - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca(2+)-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal …

Evolutionary Convergence Of The Caffeine Biosynthetic Pathway In Chocolate Followed Duplication Of A Constrained Ancestral Enzyme, Andrew J. O'Donnell

Masters Theses

Caffeine biosynthesis is widely distributed in flowering plants and requires three consecutive methylation steps of xanthine alkaloids. Genes that have previously been reported to participate in the multi-step pathway in Coffea sp. (coffee) and Camellia sinensis (tea) encode members of the SABATH family of methyltransferases. Two genes highly expressed in fruits of Theobroma cacao (cacao) are orthologous to the caffeine genes in tea and appear to have diversified following gene duplication. Biochemical characterization of the enzymes (XMTs) encoded by these genes strongly suggest an unprecedented major pathway to theobromine, a precursor to caffeine. These findings imply that caffeine biosynthesis evolved …

Cave Cyanobacteria Showing Antibacterial Activity, Vasiliki Lamprinou, Kyriaki Tryfinopoulou, Emmanuel N. Velonakis, Alkiviadis Vatopoulos, Smaragdi Antonopoulou, Elizabeth Fragopoulou, Adriani Pantazidou, Athena Economou-Amilli

International Journal of Speleology

Cave Cyanobacteria - thriving in an ‘extreme’ environment with interesting species biodiversity - are supposed to be a potential source of bioactive compounds. Lipid extracts from pure cultures of two recently established Cyanobacteria from Greek caves, Toxopsis calypsus and Phormidium melanochroun, were used for antibacterial screening against human pathogenic bacteria (reference and clinical isolates). Antimicrobial Susceptibility testing for both taxa was carried out using the disc-diffusion (Kirby Bauer) method, while preliminary data applying the standard broth microdilution method for the determination of the Minimal Inhibitory Concentration (MIC) are given only for T. calypsus. Antibacterial activity was demonstrated against the …

Effect Of Novel Dietary Supplement On Metabolism In Vitro And In Vivo, Robert A. Vaughan, Ailish C. White, Jason R. Beam, Nicholas P. Gannon, Randi Garcia-Smith, Roy M. Salgado, Marco Bisoffi, Kristina A. Trujillo, Carole A. Conn, Christine M. Mermier

Health Sciences and Kinesiology Faculty Articles

Obesity is an increasingly prevalent and preventable morbidity with multiple behavioral, surgical and pharmacological interventions currently available. Commercial dietary supplements are often advertised to stimulate metabolism and cause rapid weight and/or fat loss, although few well-controlled studies have demonstrated such effects. We describe a commercially available dietary supplement (purportedly containing caffeine, catechins, and other metabolic stimulators) on resting metabolic rate in humans, and on metabolism, mitochondrial content, and related gene expression in vitro. Human males ingested either a placebo or commercially available supplement (RF) in a randomized double-blind placebo-controlled cross-over fashion. Metabolic rate, respiratory exchange ratio, and blood pressure were …

Characterization Of Ghrelin O-Acyltransferase Active Site, Leslie Patton

Renée Crown University Honors Thesis Projects - All

Ghrelin, first discovered in 1999, is a 28-amino acid peptide hormone involved in the regulation of appetite, insulin secretion and sensitivity, and many neurological effects such as learning, memory, and depression.^1-6 Ghrelin has been identified to have a unique posttranslational octanoylation carried out by the enzyme ghrelin O-acyltransferase (GOAT). This distinctive modification is a point of interest in studying GOAT whereby blocking the acylation of the ghrelin could potentially halt the activity of the peptide hormone and provide a means of treating obesity, diabetes, and other diseases affected by ghrelin levels. The duration of my project involved working …

Src Homology 2 Domain-Containing 5’-Inositol Phosphatase-2 (Ship2) Is An Effector Of Lymphatic Dysfunction, Germaine D. Agollah

Dissertations and Theses (Open Access)

The lymphatic system is essential for the transport of excess fluid, protein, and foreign materials from interstitial tissues to lymph nodes; for immune surveillance, and to maintain fluid homeostasis. Dysregulated lymphatics can be attributed to pathological conditions including tumor metastasis, inflammation, chronic wounds, obesity, blood vascular disorders, and lymphedema. Of these, lymphedema is the most extreme of lymphatic disorders and is represented by a spectrum of symptoms ranging from mild, subtle presentation to severe, disfiguring, overt presentation. Lymphedema is more manageable in the early stages of disease but severely reduces quality of life with progression. Due to lack of molecular …

Estrogen, Bisphenol A, And Bisphenol S: Regulation Of Cathepsin L Activity And Its Relation To Systemic Lupus Erythematosis, Regina M. Powers

Biology Honors Papers

Systemic Lupus Erythematosis (SLE) is an autoimmune disease that causes the immune system to self-destruct. SLE is nine times more frequent in women than in men, and it has been shown that there is a correlation between high estrogen levels and an increased severity of the disease. This raises a concern about environmental estrogens, including Bisphenol A (BPA) which is found in many plastic products in the United States. BPA can be absorbed by the foods and liquids that are held in the plastic containers and then can enter into the human body. Because of its structural similarity to estrogen, …

The Regulation Of Cathepsin L Activity By Estrogen And Bisphenols A & S: Relationship To Systemic Lupus Erythematosus, Dylan T. Cuva

Biology Honors Papers

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is linked to increased levels of estrogen. Bisphenol A (BPA) is an environmental estrogen that may also play a role in SLE. BPA is used in the production of polycarbonate plastics and epoxy resins, including use in the creation of cans and plastic bottles. This study investigated the role of BPA and other bisphenols on enzyme activity in a murine model for SLE.

Effects Of Bpa And Alternatives On Human Health Concerning The Nflpa, Jeremy Martell

Biology Undergraduate

No abstract provided.

Investigation Of Dual Stage Acridones As A Potent Malaria Treatment, Stephanie Huezo

Dissertations, Masters Theses, Capstones, and Culminating Projects

The need for potent antimalarials to prevent the emergence of drug resistant Plasmodium falciparum is urgent. Discovery of novel acridone chemotypes have shown promise for a new antimalarial drug treatment. Presently, two acridone chemotypes have intrinsic antimalarial potency against chloroquine sensitive and multidrug resistant parasites. Acridones lacking an N10 side chain are known as chemotype I acridones, whereas, chemotype II acridones are defined as having an alkyl side chain at the same position. The N10 substitution of chemotype II acridones is thought to target heme and inhibit hemozoin formation within the parasite’s digestive vacuole, and is known to provide synergistic …

Effects Of Cannabidiol On Contractions And Calcium Signaling In Rat Ventricular Myocytes, Ramez M. Ali, Lina T. Al Kury, Keun-Hang Susan Yang, Anwar Qureshi, Mohanraj Rajesh, Sehamuddin Galadari, Yaroslav M. Shuba, Frank Christopher Howarth, Murat Oz

Mathematics, Physics, and Computer Science Faculty Articles and Research

Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca2+ was measured in cells loaded with the Ca2+ sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca2+ currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1 μM) caused a significant decrease in the amplitudes of …

Pharmaceutical Integrated Stress Response Enhancement Protects Oligodendrocytes And Provides A Potential Multiple Sclerosis Therapeutic., Sharon W Way, Joseph R Podojil, Benjamin L Clayton, Anita Zaremba, Tassie L Collins, Rejani B Kunjamma, Andrew P Robinson, Pedro Brugarolas, Robert H. Miller, Stephen D Miller, Brian Popko

Anatomy and Regenerative Biology Faculty Publications

Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental …

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

Synthesis And Evaluation Of Substituted Coumarin Derivatives As Inhibitors Of Monoamine Oxidase B, Ian A. Kieffer

Chemistry Theses

Monoamine oxidase B (MAO B) is of clinical importance due to its perceived role in neurodegenerative diseases such as Parkinson’s, making inhibitors of MAO B popular candidates for drug design. A series of coumarin derivatives have been prepared and assayed, revealing that the synthesized inhibitors act through a competitive mode of inhibition. In addition, these inhibitors are potent with Ki values in the nanomolar range. Overall, substitution at the 3- position of the coumarin was found to be important to inhibitor potency and further study of 3-aryl coumarin substitution computationally led to the prediction of 3-(3-aminophenyl)-6-hydroxycoumarin as a lead compound …

Kaposi Sarcoma Herpesvirus Induces Ho-1 During De Novo Infection Of Endothelial Cells Via Viral Mirna-Dependent And -Independent Mechanisms, Sara Botto, Jennifer Totonchy, Jean K. Gustin, Ashlee V. Moses

Pharmacy Faculty Articles and Research

Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, antiinflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated …

Elucidation Of A Novel Pathway In Staphylococcus Aureus: The Essential Site-Specific Processing Of Ribosomal Protein L27, Erin A. Wall

Theses and Dissertations

Ribosomal protein L27 is a component of the eubacterial large ribosomal subunit that has been shown to play a critical role in substrate stabilization during protein synthesis. This function is mediated by the L27 N-terminus, which protrudes into the peptidyl transferase center where it interacts with both A-site and P-site tRNAs as well as with 23S rRNA. We observed that L27 in S. aureus and other Firmicutes is encoded with a short N-terminal extension that is not present in most Gram-negative organisms, and is absent from mature ribosomes. The extension contains a conserved cleavage motif; nine N-terminal amino acids are …

Development Of Non-Traditional Platinum Anticancer Agents: Trans-Platinum Planar Amine Compounds And Polynuclear Platinum Compounds, Daniel E. Lee

Theses and Dissertations

Development of Non-Traditional Platinum Anticancer Agents: trans-Platinum Planar Amine Compounds and Polynuclear Platinum Compounds

By Daniel E. Lee, Ph.D.

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University.

Virginia Commonwealth University, 2015

Major Director: Nicholas P Farrell, Ph.D., Professor, Department of Chemistry

Platinum anticancer compounds with cis geometry, similar to cisplatin, have been explored to circumvent the cisplatin resistance; however, they were not considered broadly active in cisplatin cells due to exhibiting similar or same cell death mechanism as cisplatin. Platinum compounds with trans geometry were less studied …