Chemicals and Drugs Commons^™

Opioid Medication Use And Blood Dna Methylation: Epigenome-Wide Association Meta-Analysis, Mikyeong Lee, Roby Joehanes, Daniel L. Mccartney, Minjung Kho, Anke Hüls, Annah B. Wyss, Chunyu Liu, Rosie M. Walker, Sharon L.R. Kardia, Thomas S. Wingo, Adam Burkholder, Jiantao Ma, Archie Campbell, Aliza P. Wingo, Tianxiao Huan, Sinjini Sikdar, Amena Keshawarz, David A. Bennett, Jennifer A. Smith, Kathryn L. Evans, Daniel Levy, Stephanie J. London

Mathematics & Statistics Faculty Publications

Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA …

Mechanism Of Antibiotic Permeability Through The Gram-Negative Bacterial Envelope, Olaniyi Alegun

Theses and Dissertations--Chemistry

The outer membrane of Gram-negative bacteria (GN) makes them distinct among superbugs that are associated with the development of antibiotic resistance. The outer membrane, and inner membrane, separated by the periplasm, form a double-membrane barrier to the entry of antibiotics into the cell. Several studies have been conducted to examine the role of outer membrane modifications such as porins, lipopolysaccharides, and efflux pumps on antibiotic resistance. However, there is a paucity of knowledge on how antibiotics behave in the periplasm, to gain access into their target region. My thesis focuses on understanding the mechanism of antibiotic permeability through the cellular …

Succinylated Polyethylenimine Gene Delivery Agents For Enhanced Transfection Efficacy, Md. Nasir Uddin

Theses and Dissertations--Chemistry

Gene therapy aims to treat patients by altering or controlling gene expression. Today, most clinical approaches are viral-based due to their inherent gene delivery activity. However, there is still a significant interest in nonviral alternatives for gene delivery, particularly synthetic lipids and polymers, that do not suffer the immunogenicity, high cost, or mutagenesis concerns of viral vectors. Polymeric vectors are of particular interest due to the ability to further tune the polymer properties through the incorporation of additional functional units such as targeting ligands or shielding domains. Polyethylenimine (PEI), a highly cationic polymer, is often considered a benchmark for polymer-based …

Developments In Gold(Iii) Scaffolds For Protein Bioconjugation And Enhanced Anticancer Activity, Sailajah Gukathasan

Theses and Dissertations--Chemistry

Site-selective modifications of target proteins using specially designed small molecules is a powerful tool that has been extensively utilized in biomedicine. Small molecules can modify proteins either covalently or non-covalently depending on their structures and intrinsic chemical reactivity. Covalent chemical modification presents a more stable and often irreversible interaction with target proteins; unlike non-covalent binders, which form weak, reversible interactions with protein. Therefore, covalent modifiers represent an effective class of therapeutics due to their stability and irreversibility once bound to target proteins of interest. I hypothesized that tuning biocompatible, high-valent gold(III) complexes toward nucleophile-induced reductive elimination will lead to covalent …

Peripherally Restricted Delivery System Provides Insights On The Role Of Cns In Precipitating Opioid-Induced Constipation, Dengpan Liang

University of the Pacific Theses and Dissertations

A serious opioid crisis is affecting public health and economics, eroding people’s quality of life. 80% of patients who receive opioids suffer from adverse effects such as Opioid-induced constipation (OIC). However, there is no efficient medicine for these adverse effects. Notably, mainstream theory supports that analgesia effects are mainly controlled by CNS while OIC is predominately controlled by peripheral. In addition, the sites of action of opioid was based on the assumption that mu-opioid receptor antagonists (PAMORAs), did not cross the blood-brain barrier (BBB). Unfortunately, the BBB crossing of PAMORAs mislead the understanding of the role of the central nervous …

Why Glucagon Matters For Hypoglycemia And Physical Activity In Individuals With Type 1 Diabetes, Sheri R. Colberg

Human Movement Studies & Special Education Faculty Publications

No abstract provided.

Therapeutic Approaches For Respiratory Distress Syndrome, Franck J. Kamga Gninzeko

Theses and Dissertations

Respiratory distress syndrome (RDS) is characterized by shortness of breath and low oxygen levels. RDS affects the neonatal and adult populations. In the neonatal population, RDS can be classified as NRDS (Neonatal respiratory distress syndrome), while in adults, it is known as ARDS (acute respiratory distress syndrome). This dissertation examines a therapeutic approach to NRDS and a mechanistic approach to ARDS with in vivo and in vitro models of lung injury. NRDS is characterized by a deficiency or lack of surfactant. Surfactant is an essential compound composed of phospholipids and proteins to prevent the lungs from collapsing. There are several …

Antiviral Effects Of Metalloshielding: Differential Antiviral Activity Of Polynuclear Platinum And Cobalt Compounds, Mary Zoepfl

Theses and Dissertations

The majority of antiviral drug development has focused on virus-specific discovery targeting discrete steps in the individual life cycles. Although great strides have been made for a number of clinically relevant diseases such as human immunodeficiency virus, influenza virus, and hepatitis B, broad spectrum antivirals do not exist. Broad spectrum antivirals would offer (1) treatment for viruses without specifically-targeted antivirals, (2) treatment for viruses which have developed resistance to their available treatments, and (3) a rapidly deployable treatment option in viral epidemics. Many viruses including human cytomegalovirus (HCMV), HIV, and SARS-CoV-2. rely on heparan sulfate (HS), a highly sulfated glycosaminoglycan …

Examining The Behavioral And Phyisiolgical Effects Of D-Methamphetamine Administered Via E-Cigarette Aerosolization, Srikethan Mahavadi

Theses and Dissertations

Abstract

EXAMINING THE BEHAVIORAL AND PHYISIOLGICAL EFFECTS OF D-METHAMPHETAMINE ADMINISTERED VIA E-CIGARETTE AEROSOLIZATION

By Srikethan Mahavadi, B.S.

A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University

Virginia Commonwealth University, 2021

Principal Investigator: Dr. Keith Shelton, PhD., Department of Pharmacology & Toxicology

E-cigarettes have become increasing popular worldwide. They are primarily used as a means to deliver nicotine to users, but these devices may also be used to administer a wide range of other substances including psychomotor stimulants such as d-methamphetamine. Methamphetamine has been widely abused throughout the United States …

Protein Structure And Interaction: The Role Of Aromatic Residues In Protein Structure And Interactions Between Pyridoxine 5'-Phosphate Oxidase/Dopa Decarboxylase, Mohammed H. Al Mughram

Theses and Dissertations

Naturally developed proteins are capable of carrying out a wide variety of molecular functions due to their highly precise three-dimensional structures, which are determined by their genetically encoded sequences of amino acids. A thorough knowledge of protein structures and interactions at the atomic level will enable researchers to get a deep foundational understanding of the molecular interactions and enzymatic processes required for cells, resulting in more effective therapeutic interventions. This dissertation intends to use structural knowledge from solved protein structures for two distinct objectives.

In the first project, we conducted a bioinformatics structural analysis of experimental protein structures using our …

Behavioral Screening And Chiral Bioanalysis Of Emerging Stimulant-Type Drugs In Rats, Tyson R. Baird

Theses and Dissertations

The epidemic of drug use in the United States and elsewhere in the world has resulted in tragic loss of life and substantial economic costs. Novel psychoactive substances (NPS) are one of the contributors to this problem, and the lack of information about many of these drugs compounds their risk. This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential in order to generate a proactive threat assessment. A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 …

The Landscape Of Accessible Chromatin In Quiescent Cardiac Fibroblasts And Cardiac Fibroblasts Activated After Myocardial Infarction, Chaoyang Yi, Jiangwen Sun, Qianglin Liu, Sanjeeva Dodlapati, Hao Ming, Leshan Wang, Yuxia Li, Rui Li, Zongliang Jiang, Joseph Francis, Xing Fu

Computer Science Faculty Publications

After myocardial infarction, the massive death of cardiomyocytes leads to cardiac fibroblast proliferation and myofibroblast differentiation, which contributes to the extracellular matrix remodelling of the infarcted myocardium. We recently found that myofibroblasts further differentiate into matrifibrocytes, a newly identified cardiac fibroblast differentiation state. Cardiac fibroblasts of different states have distinct gene expression profiles closely related to their functions. However, the mechanism responsible for the gene expression changes during these activation and differentiation events is still not clear. In this study, the gene expression profiling and genome-wide accessible chromatin mapping of mouse cardiac fibroblasts isolated from the uninjured myocardium and the …

Refinement Of Alphafold2 Models Against Experimental And Hybrid Cryo-Em Density Maps, Maytha Alshammari, Willy Wriggers, Jiangwen Sun, Jing He

Computer Science Faculty Publications

Recent breakthroughs in deep learning-based protein structure prediction show that it is possible to obtain highly accurate models for a wide range of difficult protein targets for which only the amino acid sequence is known. The availability of accurately predicted models from sequences can potentially revolutionise many modelling approaches in structural biology, including the interpretation of cryo-EM density maps. Although atomic structures can be readily solved from cryo-EM maps of better than 4 Å resolution, it is still challenging to determine accurate models from lower-resolution density maps. Here, we report on the benefits of models predicted by AlphaFold2 (the best-performing …

Analysis Of The Antimicrobial Activity Of The Novel Chemotherapeutic Drug, Tpp1, Against Pseudomonas Aeruginosa And The Hydrogel Delivery Of Water-Soluble Antimicrobial Compounds, Alex Gasper

Senior Independent Study Theses

Cancer is one of the leading causes of death in the world, and it is commonly linked with bacterial infections that often complicate treatments. Recently, chemotherapeutics have been developed that are able to act as anti-cancer agents using delocalized lipophilic cations (DLCs) that are able to specifically target mitochondrial membranes of cancer cells. TPP1 is a newly developed chemotherapeutic drug that has activity against bladder cancer and melanoma cell lines in vitro. In order to determine if TPP1 has antimicrobial activity, TPP1 was tested against a common bacteria, Pseudomonas aeruginosa, to determine if antimicrobial activity was present. This testing was …

Marijuana And Patents: The Complicated Relationship Between Patent Rights And The Federal Criminalization Of Marijuana, Reza Roghani Esfahani, Howard Bromberg

Articles

Difficult questions arise in the context of marijuana-related inventions, patent procurement, and patent enforcement. These questions are a subset of the contradictions in the law of marijuana, where the federal government prohibits marijuana use and yet many of the states legalize, regulate, and tax it. This federal prohibition could discourage research into the health effects of marijuana and makes it difficult for marijuana-related innovations to satisfy statutory patentability requirements. It also renders enforcement of marijuana patents questionable, making marijuana businesses and patent owners vulnerable to nonpracticing patent entities, sometimes called "patent trolls."

Investigating The Mitochondrial Protein Mitoneet In C. Elegans Models Of Aging And Alzheimer's Disease, Jacob Ryan Boos

Graduate Theses, Dissertations, and Problem Reports (ETD)

Oxidative stress is an imbalance between reactive oxygen species production and elimination, favoring the former. Reactive oxygen species serve as important signaling molecules for physiological homeostasis. However, when produced in excess, these once important signaling molecules become detrimental, disrupting cellular functions, and ultimately leading to cell death. In aging, reactive oxygen species production is increased, accompanied with reductions in oxidative stress resistance, increasing the risk for developing age-related diseases including cardiovascular disease, cancer, stroke, and neurodegenerative diseases. The outer mitochondrial membrane iron-sulfur cluster containing protein mitoNEET (CISD1; gene CISD1) has shown to be a mediator of mitochondrial function and …

Biologic Tnf-Α Inhibitors Reduce Microgliosis, Neuronal Loss, And Tau Phosphorylation In A Transgenic Mouse Model Of Tauopathy, Weijun Ou, Joshua Yang, Juste Simanauskaite, Matthew Choi, Demi M. Castellanos, Rudy Chang, Jiahong Sun, Nataraj Jagadeesan, Karen D. Parfitt, David H. Cribbs, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Background

Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via …

The Benefits Of Astaxanthin To Improve Pain Relief In Patients With Painful Diabetic Neuropathy: An Open-Label, Randomized Controlled Trial, Rizaldy Taslim Pinzon, Mary Rose Angelina Budi Harsana

Pharmaceutical Sciences and Research

Treatment of diabetic neuropathy is still carried out by providing symptomatic therapy, which only improves ± 50% of the total symptoms felt by patients, but does not tackle the underlying causes of the disease. Astaxanthin is a potent antioxidant, anti-inflammatory, and anti-diabetic carotenoid that could be an additional treatment option. We aimed to measure the effectiveness of administering astaxanthin as an additional therapy to improve the impact of pain and discomfort experienced daily by diabetes mellitus patients with painful diabetic neuropathy. We conducted a randomized experimental study with an open label design of 36 patients who had been diagnosed with …

Itraconazole Nanocomposites Prepared Via Rotary Evaporator Drying Of Nanomilled Suspensions, Alexander Santos Coelho

Theses

The aim of this study is to explore the feasibility of rotary evaporation for drying wetmilled drug suspensions as a novel approach to produce drug nanocomposites that exhibit fast redispersion and immediate drug release. To this end, the physical stability of the nanomilled itraconazole (drug) suspensions, a.k.a., nanosuspensions, during the milling and storage; the drying of the itraconazole nanosuspensions via the rotary evaporator; and the type/loading of various polymers/surfactants (dispersants) on aqueous redispersion and drug release from the nanocomposites were examined. Our results suggest that smaller drug particle size, owing to nanomilling, and smaller nanocomposite particle size, owing to optimized …

A Snapshot Investigation Into The Availability And Access To Codeine-Containing Medications Amongst The Irish Population., Katie O'Brien, Pádraig Mckeown, Joseph Phelan

International Undergraduate Journal of Health Sciences

Codeine phosphate is a mild to moderate analgesic and has a weak cough suppressant activity that is available to purchase as an over the counter (OTC) painkiller in Ireland as a compound product. In recent years, countries such as Australia have introduced laws that prohibit the sale of the drug without a valid prescription. This move by Australia begs the question as to why this legislation was introduced and should Ireland follow suit.

The primary aims of the study were to determine knowledge among the general public of codeine-containing medications and their usage levels. The survey also investigated whether current …