Pharmacology, Toxicology and Environmental Health Commons^™

Effects Of Electronic Cigarette Liquid Solvents Propylene Glycol And Vegetable Glycerin On User Nicotine Delivery, Heart Rate, Subjective Effects, And Puff Topography, Tory Spindle

Theses and Dissertations

Electronic cigarettes (ECIGs) are a class of tobacco products that use a heating element to aerosolize a liquid, typically containing nicotine, allowing for user inhalation. Despite their rapid growth in popularity, little is known about ECIGs including how certain device and liquid factors influence nicotine delivery, user physiological and subjective responses, and puffing behavior (puff topography). Limited pre-clinical research has demonstrated that the ratio of two solvents commonly found in ECIG liquids, propylene glycol (PG) and vegetable glycerin (VG), may have an influence on the nicotine content of ECIG aerosols. However, the extent to which PG:VG ratio in ECIG liquids …

Lorcaserin As A Potential Opioid-Sparing Adjunct, Kumiko M. Lippold

Theses and Dissertations

Opioids, such as oxycodone, morphine, and fentanyl, are commonly used medications in the treatment of moderate to severe pain. In spite of their efficacious analgesic properties, their increased prescribing rates by physicians and inherent abuse-related effects have led to the ongoing opioid epidemic. Their clinical utility is limited by the risk of adverse dose-dependent side effects, such as constipation and respiratory depression, and the development of tolerance and dependence. Opioid-sparing adjunctive therapies are sought to address these issues by reducing the dose of opioid needed to achieve analgesia through alternative non-opioidergic mechanisms and as a result, reduce the incidence of …

Molecular Brain Adaptations To Ethanol: Role Of Glycogen Synthase Kinase-3 Beta In The Transition To Excessive Consumption, Andrew D. Van Der Vaart

Theses and Dissertations

Alcoholism is a complex neuropsychiatric disease that is characterized by compulsive alcohol use and intensifying cravings and withdrawals, often culminating in physiologic dependency. Fundamental alterations in brain chemistry underlie the transition from initial ethanol exposure to repetitive excessive use. Key mediators of this adaptation include changes in gene expression and signal transduction. Here we investigated gene expression pathways in prefrontal cortex and nucleus accumbens following acute or chronic ethanol treatment, to identify genes with potentially conserved involvement in the long-term response of the corticolimbic system to repeated ethanol exposure. We investigated Gsk3b, which encodes glycogen synthase kinase 3-beta, as a …

5-Ht2b Receptor-Mediated Cardiac Valvulopathy, Pallavi Nistala

Theses and Dissertations

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens …

The Forensic Characterization Of Bacterial And Fungal Organisms In Traditional Chinese Medicine, Julia Grzymkowski, Christopher J. Ehrhardt, Justin L. Poklis, Michelle R. Peace

Undergraduate Research Posters

There has been an increase in use of Traditional Chinese Medicine (TCM) in the United States because they are less expensive and believed to be more effective with less adverse effects in comparison to traditional pharmaceutics. Therefore, sales have increased in the US, despite articles and case studies demonstrating the dangers, such as injury and death, related to TCM, stemming from improper labelling, toxic contaminants, and, in some cases, the presence of pathogenic bacteria. The aim of this study was to perform a survival experiment to demonstrate the importance of proper herbal brewing technique and to conduct a molecular and …

Role Of C121a In Mglur2 Homodimeric Expression And Function, Jong M. Shin

Theses and Dissertations

The group II metabotropic glutamate receptors are known for their involvement in various psychiatric disorders. The mGluR2 in particular is linked with etiology of schizophrenia especially in the context of crosstalk with 5-HT2A. Thus, the mGluR2 has attracted attentions for its potential therapeutic applications. Despite numerous physiological evidences on the actions of mGluR2, its mechanism is still unclear to this day. It is partially due to the lack of understanding in characteristics of mGluR2 homodimer which is its functionally active form. Therefore, the characterization of dimeric interaction serves as a foundation to advanced understanding of the role of mGluR2. On …

Decoding The Signaling Of The D2r-2ar Heteromer: Relevance To Schizophrenia, Miao Huang

Theses and Dissertations

Schizophrenia is a severe mental disorder affecting ~1% of world population. Two G protein coupled receptors (GPCRs): Gi-coupled dopamine D2 receptor (D₂R), and Gq-coupled serotonin 2A receptor (2AR), are targeted by the typical and atypical antipsychotic drugs to treat schizophrenia. These two receptors have been shown to co-localize in brain regions relevant to schizophrenia, including the ventral tegmental area (VTA), striatum, and prefrontal cortex (PFC). Studies in our lab characterized the integrated signaling of the D₂R-2AR heteromer and found that both the Gi activity of D₂R and the Gq activity of 2AR were potentiated …

Targeting Monoacylglycerol Lipase For The Reversal And Prevention Of Paclitaxel-Induced Allodynia In Mice, Zachary Curry

Theses and Dissertations

Chemotherapy-induced peripheral neuropathy (CIPN) is a side-effect of chemotherapy causing pain in the hands and feet. In particular, paclitaxel causes CIPN lasting for years without effective treatment. There is a strong need for analgesics to both treat and prevent CIPN. One system containing multiple targets to treat CIPN is the endogenous cannabinoid system. This system consists of cannabinoid type 1 (CB₁) and type 2 (CB₂) receptors primarily expressed on presynaptic neurons and cells of the immune system, respectively. Inhibition of monoacylglycerol lipase (MAGL), which hydrolyzes the endogenous cannabinoid 2- arachidonoylglycerol (2-AG), with JZL184 or MJN110 produces …

Metabotropic Glutamate Receptor 2 Activation: Computational Predictions And Experimental Validation, Amr Ellaithy

Theses and Dissertations

G protein-coupled receptors (GPCRs) are the largest family of signaling proteins in animals and represent the largest family of druggable targets in the human genome. Therefore, it is of no surprise that the molecular mechanisms of GPCR activation and signal transduction have attracted close attention for the past few decades. Several stabilizing interactions within the GPCR transmembrane (TM) domain helices regulate receptor activation. An example is a salt bridge between 2 highly conserved amino acids at the bottom of TM3 and TM6 that has been characterized for a large number of GPCRs. Through structural modeling and molecular dynamics (MD) simulations, …

Complexities Of Chronic Opioid Exposure, Maciej Gonek

Theses and Dissertations

Studies on repeated exposure to opioids have been carried out for decades yet the mechanisms for certain phenomena such as tolerance are still not fully understood. Furthermore, different medications, such as frequently prescribed benzodiazepines, or different disease states, such as HIV, have their own effects and interactions with chronic opioid exposure that are not fully understood. The overall objective of this dissertation was to investigate the complexities of chronic opioid exposure and how different disease states and medications may modulate the effects of chronic opioids. Our findings demonstrate that the administration of diazepam, at doses that are not antinociceptive or …

Survival Model Of Intrahepatic Cholangiocarcinoma; Sex As A Biological Variable, Mary A. Phillippi, Justin L. Mott, Cody J. Wehrkamp, Ying Xie, David Oupicky, Ashley M. Mohr, Bailey A. Stringham

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

The Effects Of The Hiv-1 Tat Protein And Morphine On The Structure And Function Of The Hippocampal Ca1 Subfield, William D. Marks

Theses and Dissertations

HIV is capable of causing a set of neurological diseases collectively termed the HIV Associated Neurocognitive Disorders (HAND). Worsening pathology is observed in HIV+ individuals who use opioid drugs. Memory problems are often observed in HAND, implicating HIV pathology in the hippocampus, and are also known to be exacerbated by morphine use. HIV-1 Tat was demonstrated to reduce spatial memory performance in multiple tasks, and individual subsets of CA1 interneurons were found to be selectively vulnerable to the effects of Tat, notably nNOS+/NPY- interneurons of the pyramidal layer and stratum radiatum, PV+ neurons of the pyramidal layer, and SST+ neurons …

Salvianolic Acid B For Pulmonary Delivery Towards Reversal Of Emphysema, Sneha Dhapare

Theses and Dissertations

A new pathobiologic hypothesis has recently emerged that the alveolar structural destruction and loss in emphysema are caused by the deficiency of vascular endothelial growth factor (VEGF). Therefore, this project hypothesized that such pathobiologic VEGF deficiency of emphysematous lungs can be recovered with a natural caffeic acid tetramer, salvianolic acid B (SalB), through activation of signal transducer and activator of transcription 3 (STAT3), so that emphysema can be reversed as a result of inhibition of induced cell death, stimulation of cell proliferation and migration, and promotion of stem cell recruitment to the lungs.

SalB was first shown to be potently …

Dredging Land Reclamation Causing Mucus Development In Massive Spherical Corals In The Spratly Islands, South China Sea: The Effects On China’S Fishing Industry, Tiffany K. Ho

Undergraduate Research Posters

Images from Asia Maritime Transparency Initiative depicted huge masses of white coral mucus secreted from coral reefs in the Spratly Islands of the South China Sea, an area where several land reclamation projects are occurring. The purpose of this research was to understand how increased sedimentation levels from the dredging land reclamation method affects mucus development in massive corals, such as Acropora, located in these reefs. Journal articles that focused on the biology of coral mucus, bacterial communities associated with coral tissue, mucus, and seawater, coral mortality from different environment impacts, coral coverage of reefs in Spratly Islands, and symbiotic …

Investigating The Modulation And Mechanisms Of Α7 Nicotinic Acetylcholine Receptors In Nicotine Dependence, Asti Jackson

Theses and Dissertations

Tobacco dependence dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. Nicotine, the main addictive component of tobacco, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). The homomeric α7 nAChR is one of the most abundant receptors found in the brain and has unique features in comparison to other nAChR subtypes such as high calcium permeability, low probability of channel opening, and a rapid desensitization rate. α7 nAChR agonists reduce nicotine's rewarding properties in the conditioned place preference (CPP) test and i.v. self-administration. Recently, the peroxisome proliferator-activated receptor …

Identification Of “Kratom” (Mitragyna Speciosa) Alkaloids In Commercially Available Products, Julia Grzymkowski, Michelle R. Peace, Justin Poklis

Undergraduate Research Posters

“Kratom” is the common name for the botanical mitragyna speciosa. It is a tree native to Southeast Asia in which leaves contain the psychoactive alkaloids mitragynine and 7-hydroxymitragynine. Kratom is often ingested as teas, chewed, or smoked. It acts as a stimulant in small doses and as an opioid in large doses. Overdoses can result in vomiting, seizures, and death. Recently the Drug Enforcement Agency (DEA) placed Kratom on Schedule 1, but, due to public outcry, it was almost immediately removed.

Eleven kratom based products were obtained from various tobacco shops, “headshops” and via the internet including: Choice brand …

Three Dimensional Homology Modeling Of Organic Cation Transporter 3 To Identify Structural Elements Mediating Transporter-Substrate Interactions, Hebing Liu

Theses and Dissertations

Organic cation transporters (OCTs) play a pivotal role in the absorption, tissue distribution, and excretion of a diverse array of substances, and currently the nature of the biochemical interactions between substrate and OCTs are unknown. Therefore, identifying which amino acid residues are critical for OCT-substrate interactions is of central importance to understanding and predicting interactions between drugs and OCTs. A three-dimensional (3-D) homology model of human OCT3 was generated using the crystal structure of a high affinity phosphate transporter from Piriformospora indica (PiPT) as template, and putative binding pocket for the prototypical hOCT3 ligand 1-methyl-4-phenylpyridinium (MPP⁺) was identified …

Alpha6 Beta2 Subunit Containing Nicotinic Acetylcholine Receptor Contributions To Abuse-Related Effects Of Nicotine And Alcohol, Alexandra M. Stafford

Theses and Dissertations

Pharmacotherapies for tobacco and alcohol cessation are only modestly successful, so it is important to better understand mechanisms underlying their use and abuse. The overarching goal of this research is to assess a6b2 subunit containing nicotinic acetylcholine receptor (a6b2*nAChR; *denotes possible assembly with other subunits) contributions to abuse-related effects of nicotine and alcohol. In the absence of a6b2*nAChR-selective agonists, a6b2*nAChR gain-of-function (a6L9’S) mice provide a tool for selective activation of a6b2*nAChRs. Using the a6L9’S mice together with nicotine doses sub-threshold for stimulation of native nAChRs, these studies tested the hypothesis that activation of a6b2*nAChRs is sufficient to promote neurochemical and …

Ethanol Reversal Of Oxycodone Tolerances, Joanna C. Jacob

Theses and Dissertations

Oxycodone is a semi-synthetic opioid originally developed as a safer alternative to morphine. It is commonly prescribed for its pain-relieving effects, but has recently been implicated as a major underlying cause of the current opioid epidemic due to its clinical limitations that include tolerance, dependence and a high abuse liability. Simultaneous consumption of opioids and ethanol has been shown to increase the risk of overdose and death from opioids in opioid-tolerant individuals. We hypothesized that ethanol reversed opioid tolerance and previous studies showed that ethanol reversed morphine tolerance. This dissertation investigated whether ethanol reversed tolerance to other opioids in mice, …

Role Of Mitochondrial Beta-Oxidation In Ethanol Response: A Candidate Gene Study Using Caenorhabditis Elegans, Harini Pallikarana Tirumala

Theses and Dissertations

Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United States, and the fifth leading risk factor for premature death and disability, globally. There are currently very few treatment options for AUD and there is a need for effective preventive and treatment strategies for this condition. AUD risk has a significant hereditary component, with the contribution of genetic factors being estimated to be about 50%. The Davies-Bettinger laboratory uses C. elegans as a model organism to study the contribution of genetic factors in modulating neuronal responses to ethanol. In this project, we examined the role …

Knockout Of Sphingosine Kinase 1 Attenuates Renal Interstitial Fibrosis In Unilateral Ureteral Obstruction (Uuo) Model, Xiwen Zhang

Theses and Dissertations

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and an important signaling molecule that plays a significant role in fibrosis. S1P synthesis is catalyzed by sphingosine kinases (SphKs), which phosphorylate sphingosine into S1P. The present study tested the hypothesis that SphK1-S1P signaling pathway participates in the kidney damage in unilateral ureteral obstruction (UUO) model. Wild type and SphK1 knockout mice were subjected to UUO for 7 days or 14 days and then four groups of kidneys were collected: wild type control group (WT-C), wild type UUO group (WT-UUO), SphK1-/- control group (KO-C) and SphK1-/- UUO group (KO-UUO). The mRNA level of …

Investigations Of The Effects Of Different Ventilation Structures On Physiologically Based Pharmacokinetic Modeling (Pbpk) Simulations, Karen A. Yokley

Biology and Medicine Through Mathematics Conference

No abstract provided.

Role Of The Calcium Plateau In The Neuronal Injury And Behavioral Morbidities Following Organophosphate Intoxication, Laxmikant S. Deshpande, Robert E. Blair, Kristin F. Phillips, Robert J. Delorenzo

Neurology Publications

Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular …

Pharmacological Blockade Of The Calcium Plateau Provides Neuroprotection Following Organophosphate Paraoxon Induced Status Epilepticus In Rats, Laxmikant S. Deshpande, Robert E. Blair, Beverly A. Huang, Kristin F. Phillips, Robert J. Delorenzo

Neurology Publications

Organophosphate (OP) compounds which include nerve agents and pesticides are considered chemical threat agents. Currently approved antidotes are crucial in limiting OP mediated acute mortality. However, survivors of lethal OP exposure exhibit delayed neuronal injury and chronic behavioral morbidities. In this study, we investigated neuroprotective capabilities of dantrolene and carisbamate in a rat survival model of paraoxon (POX) induced status epilepticus (SE). Significant elevations in hippocampal calcium levels were observed 48-h post POX SE survival, and treatment with dantrolene (10 mg/kg, i.m.) and carisbamate (90 mg/kg, i.m.) lowered these protracted calcium elevations. POX SE induced delayed neuronal injury …

Exploring Pharmacological And Behavioral Mechanisms Involved In Alcohol Dependence During Adolescence, Rabha Mousa Younis

Theses and Dissertations

Alcoholism is a serious illness that is marked by uncontrollable drinking and physical dependence to alcohol. Long-term alcoholism has been linked to many health concerns such as cirrhosis of the liver and cardiovascular disease. Alcohol is one of the most commonly used drugs among adolescent populations. Given that adolescence is a unique developmental stage during which alcohol has long-term effects on future drug-taking behavior; it is essential to understand how early exposure to alcohol during adolescence may affect the abuse liability of the drug later in life. Indeed, most alcohol users start during adolescence suggesting that exposure to alcohol during …

Acute And Chronic Effects Of Inhalants In Intracranial Self-Stimulation, Matthew Tracy

Theses and Dissertations

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a …

The Impact Of Urbanization On Mosquito-Borne Viruses, Nikhita Puthuveetil

Undergraduate Research Posters

Mosquito-borne diseases such as yellow fever, dengue, and West Nile are rapidly emerging across the globe. Their emergence is often aided by the growth of their vector population, or the organisms that transmit the virus to the host. Urbanization and land use often destroys the habitat of the virus and its vector. However, the virus and its vector often survive despite the changes to its environment. The goal of this paper is to find out exactly how urbanization and changes in land use affect mosquito-borne viruses and how these viruses survive despite the destruction of their habitats. To understand how …

Discriminative Stimulus Properties Of Endogenous Cannabinoid Degradative Enzyme Inhibitors, Robert Owens Ii

Theses and Dissertations

Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the chief degradative enzymes of N-arachidonoyl ethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), respectively, elicits no or partial substitution for Δ⁹-tetrahydrocannabinol (THC) in drug discrimination procedures. However, combined inhibition of both enzymes fully substitutes for THC, as well as produces a full constellation of cannabimimetic effects. Because no published report to date have investigated whether an inhibitor of endocannabinoid hydrolysis will serve as a discriminative stimulus, the purpose of this doctoral dissertation was to investigate whether C57BL/6J mice would learn to discriminate SA-57 (4-[2-(4-Chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester), a …

High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park

Theses and Dissertations

Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of I_Cl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking I_Cl,swell. Our experiments showed that 45 nM Ebs can fully block …

Role Of Vav2 In Podocyte Inflammasome Activation And Glomerular Injury During Hyperhomocysteinemia, Sabena Conley

Theses and Dissertations

Hyperhomocysteinemia (hHcys) is a widely known pathogenic factor in the progression of end-stage renal disease (ESRD) and it is also associated with an increased risk for injurious cardiovascular pathologies during ESRD. HHcys is linked to the formation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, characterized as a critical early mechanism initiating the inflammatory response. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) mediate the activation of the NLRP3 inflammasome in podocytes in response to elevated levels of homocysteine (Hcys) in vitro and in vivo. However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The …