Medicinal Chemistry and Pharmaceutics Commons^™

The Role Of Line-1 Transposable Element In Methamphetamine Neurotoxicity In The Neurogenic Zones, Dongyue Yu

Wayne State University Theses

Methamphetamine (METH) is a widely abused psychostimulant, which can cause neurotoxicity in the striatum and hippocampus. Several epigenetic changes were identified after binge METH exposure, including histone modification, DNA methylation, and changes in miRNA levels. We have shown that binge METH increases expression and activity of Long INterspersed Element (LINE-1), a transposable element, in doublecortin-positive neurons within rat neurogenic zones [1]. The goal of the present study was to identify which type(s) of cells show increases in LINE-1 following binge METH exposure, and determine whether binge METH-induced increases in LINE-1 are associated with cell death. To achieve this goal, male …

Axonal Transport, Parkin, And Α-Synuclein; Novel Therapeutic Targets To Treat Methamphetamine Neurotoxicity, Bryan Andrew Killinger

Wayne State University Dissertations

Methamphetamine (METH) is a commonly abuse psychostimulant. Exposure to chronic high doses of METH can result in neurotoxicity primarily characterized by damage to striatal dopaminergic (DAergic) axons. There are currently no therapeutic interventions for METH neurotoxicity. To some extent damage to striatal DAergic axons is reversible and DAergic axon function may return following abstinence from METH. The reversible nature of METH neurotoxicity suggests that normal striatal function could be restored following exposure to METH. However, potential targets to treat METH neurotoxicity are needed. Axonal transport is required for restoration of DAergic axon components damaged or lost following METH. Here we …

Underlying Mechanisms Of Arsenic-Induced Tumorigenesis: From Epigenetics To Malignancy, Lingzhi Li

Wayne State University Dissertations

Arsenic is a well-recognized environmental health threat with the capability of inducing a number of human diseases, including cancer. The aim of this dissertation is to unveil the mechanisms underlying the carcinogenic activities of environmental arsenic. The biological functions of arsenic had been studied for decades. However, there are still many questions that remain to be fully answered, such as whether and how arsenic contributes to the epigenetic regulations and migration or metastasis control of the cancer cells. In this regard, we focused our attention on both histone modifications and miRNA regulations in the arsenic-induced malignant transformation of the cells, …

Human Kinome In Skeletal Muscle Insulin Resistance, Yue Qi

Wayne State University Dissertations

Protein kinases play fundamental roles in regulation of biological processes and functions, such as insulin signaling and glucose metabolism. Dysregulation of protein kinases may cause impaired cell signaling and human diseases, such as metabolic syndrome and type 2 diabetes (T2D). Skeletal muscle is the main site responsible for insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is one of the key features of the pathogenesis of T2D. Therefore, malfunction of protein kinases and their interaction proteins may contribute to the molecular mechanism of insulin resistance in human skeletal muscle. However, no large scale profiling study has been reported to …

Folate Receptor Alpha Targeted Delivery And Characterization Of Polyethyleneimine-Graft-Polycaprolactone-Block-Poly(Ethylene Glycol) Containing Sirna Micelleplexes, Steven Jones

Wayne State University Dissertations

This dissertation focuses on the ability of polyethyleneimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) folate decorated tri-block copolymers ability to deliver a targeted dose of siRNA. The micelleplexes that are formed upon electrostatic interaction with siRNA are used to deliver siRNA in a targeted manner to ovarian cancer cells that over-express Folate Receptor-α (FRα). Each conjugate showed suitable sizes below 200 nm with full siRNA condensation ability. Furthermore, flow cytometry and western blot analysis demonstrated that the best FRα targeted polymer was able to effectively deliver siRNA which resulted in protein knockdown of Toll-like receptor 4 (TLR4). Consequently, TLR4 knock down within SKOV-3 cells …

Transferrin Receptor Targeted Delivery Of Sirna For Gene Therapy, Yuran Xie

Wayne State University Dissertations

Gene therapy is thought to be a solution for various difficult to treat diseases such as cancer. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence disease related gene have been exploit in different diseases. However, lack of safe and efficient siRNA delivery systems limits the application of siRNA therapy in clinic. Transferrin receptor (TfR) is an essential transmembrane receptor involved in iron uptake. TfR universally express in most cells/ tissues but upregulated in certain cells, for example, many cancer cells and activated T cells (ATCs). To overcome the biological barriers and increase siRNA delivery efficiency, in …

Protein Phosphatase 2a Interactions In Islet And Human Skeletal Muscle In Diabetes, Divyasri Damacharla

Wayne State University Dissertations

Type 2 Diabetes is a metabolic disorder associated with insulin resistance and consequent high blood glucose levels. Under normal conditions, in response to high blood glucose levels, pancreatic beta cells produce insulin. The secreted insulin is dis-tributed to tissues thereby stimulating insulin stimulated glucose uptake. However, maximum glucose disposal takes place in skeletal muscle. Thus, studying beta cells and skeletal muscle in respect to diabetes is crucial. Protein Phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases belonging to PhosphoProteinPhospha-tase (PPP) family. It constitutes about 80% of all serine/threonine phosphatases. It is regulated by numerous regulatory subunits as well …

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 …

Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea, Cristian G. Bologa, Subramani Mani, Oleg Ursu

Biomedical Sciences ETDs

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process.

The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this …

Implementation Of Universal Hplc Analysis For Counterfeit Medication: A Partnership Of Purdue University And The Kilimanjaro School Of Pharmacy, Jordyn Mccord, Michael Mavity, David Wintczak

Purdue Journal of Service-Learning and International Engagement

Jordyn McCord and Michael Mavity are 2016 graduates of both biological engineering and pharmaceutical sciences. David Wintczak is a third-year pharmacy doctoral candidate. Here, in their second article published in PJSL, they describe a weeklong study abroad course at the Kilimanjaro School of Pharmacy in Tanzania, designed to engage students in the implementation of methods for detecting counterfeit medications.

Synthetic And Biological Exploration Of (+)-Boldine - Identification Of Potential Cns Receptor Ligands, Sujay Joseph

Theses and Dissertations

(+)-Boldine, an aporphine alkaloid, is reported to be biologically active at various Central Nervous System(CNS) receptors. However, only a few Structure Activity Relationship(SAR) studies have been conducted using boldine’s aporphine scaffold. A library of novel analogs was synthesized from boldine to understand the effect of bisbenzylation at C2 and C9 positions on the affinity and selectivity at the serotonin receptors.

Spectroscopic Studies Of Anthracyclines: Structural Characterization And In Vitro Tracking, Zeineb Farhane, Hugh Byrne, Malgorzata Baranska

Articles

A broad spectroscopic characterization, using ultraviolet-visible (UV-vis) and Fourier transform infrared absorption as well as Raman scattering, of two commonly used anthracyclines antibiotics (DOX) daunorubicin (DNR), their epimers (EDOX, EDNR) and ten selected analogs is presented. The paper serves as a comprehensive spectral library of UV-vis, IR and Raman spectra of anthracyclines in the solid state and in solution. The particular advantage of Raman spectroscopy for the measurement and analysis of individual antibiotics is demonstrated. Raman spectroscopy can be used to monitor the in vitro uptake and distribution of the drug in cells, using both 488 nm and 785 nm …

Hiv Vaccines: Progress, Limitations And A Crispr/Cas9 Vaccine, Omar A. Garcia Martinez

Biology: Student Scholarship & Creative Works

ABSTRACT: The HIV-1 pandemic continues to thrive due to ineffective HIV-1 vaccines. Historically, the world’s most infectious diseases, such as polio and smallpox, have been eradicated or have come close to eradication due to the advent of effective vaccines. Highly active antiretroviral therapy is able to delay the onset of AIDS but can neither rid the body of HIV-1 proviral DNA nor prevent further transmission. A prophylactic vaccine that prevents the various mechanisms HIV-1 has to evade and attack our immune system is needed to end the HIV-1 pandemic. Recent advances in engineered nuclease systems, like the CRISPR/Cas9 system, have …

Impacts From The Use Of Antibiotics In Livestock: Methods Of Transmission Of Antibiotic Resistance From Livestock To Humans, Kristin M. Walden

Biology: Student Scholarship & Creative Works

Antibiotic use in livestock production has been around since the 1950s. Antibiotic feed is used in livestock and other meat producing animals for three reasons: illness prevention, illness treatment, and growth promotion. Unfortunately, since the time that antibiotics were first invented, antibiotic resistant bacteria have become a threat to public health. There are many studies showing methods of transmission of antibiotic resistance from livestock to humans. Antibiotic resistance can spread from livestock to soil, water, insects, and food, which ultimately comes into contact with humans. A proposed study to measure antibiotic resistance when eliminating antibiotic feed will provide a hypothesis …

Exploring The Effect Of Novel Small Molecules On Oligodendrocyte Precursor Proliferation, Sagune Sakya

University Scholar Projects

Gliomas, a type of brain tumor, can be difficult to treat and have a poor survival rate. One pathway that leads to glioma formation is excessive signaling by platelet derived growth factors (PDGF) through PDGF receptor α (PDGFRα). Through this research, I found that novel compounds that downregulate PDGFRα decrease proliferation of Oli-neu cells, an oligodendrocyte precursor cell model, and identified signaling pathways through which these compounds may exert their effect. Further investigation may identify targets for development of glioma treatments.

Stabilization Of Gp120 Outer Domain For Hiv-1-1 Vaccine Immunogen Design, Duoyi Hu

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

The sole envelope glycoprotein spike on the surface of Human Immunodeficiency Virus (HIV-1) is composed of two subunits: gp120 and gp41. The gp120 consists of three domains: the inner domain, outer domain and bridging sheet, to which the viral primary receptor CD4 binds and induces a conformational change in gp120 to expose the co-receptor binding site. Previous studies have found that the outer domain of gp120 is relatively more stable than the inner domain and bridging sheet. When superimposed, the co-crystal structures of CD4-gp120 complex and VRC01-gp120 complex revealed that the CD4-binding site (CD4-BS) antibody VRC01 actually mainly bound to …

Investigation Of The Tailoring Steps In Pradimicin Biosynthesis, Kandy L. Napan

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

This research focused on the investigation of the late steps in the biosynthetic pathway of the novel antifungal and antiviral pradimicins A-C. Pradimicins were first isolated from the soil bacterium Actinomadura hibisca. These bioactive molecules are assembled by a type II polyketide biosynthetic pathway. Although the biosynthetic gene cluster of pradimicin has been identified, the functions of the biosynthetic genes and how they work collaboratively to form the final structures of pradimicins remain unknown. This research aims to functionally characterize the enzymes involved in the late steps of the biosynthetic route.

The early biosynthetic steps of pradimicins have been …

Evaluation Of Cytotoxicity Profile And Intracellular Localisation Of Doxorubicin-Loaded Chitosan Nanoparticles, Gabriele Dadalt Souto, Zeineb Farhane, Esen Efeoglu, Alan Casey, Jennifer Mcintyre, Hugh Byrne

Articles

In the emerging field of nanomedicine, targeted delivery of nanoparticle encapsulated active pharmaceutical ingredients (API) is seen as a potential significant development, promising improved pharmacokinetics and reduced side effects. In this context, understanding the cellular uptake of the nanoparticles and subsequent subcellular distribution of the API is of critical importance. Doxorubicin (DOX) was encapsulated within chitosan nanoparticles to investigate its intracellular delivery in A549 cells in vitro. Unloaded (CS-TPP) and doxorubicin-loaded (DOX-CS-TPP) chitosan nanoparticles were characterised for size (473±41 nm), polydispersity index (0.3±0.2), zeta potential (34±4 mV), drug content (76±7 µM) and encapsulation efficiency (95±1%). The cytotoxic response to …

Chemotherapeutic Efficiency Of Drugs In Vitro: Comparison Of Doxorubicin Exposure In 3d And 2d Culture Matrices, Alan Casey, Mahmoud Gargotti, Franck Bonnier, Hugh Byrne

Articles

The interest in the use of 3D matrices for in vitro analysis, with a view to increasing the relevance of in vitro studies and reducing the dependence on in vivo studies, has been growing in recent years. Cells grown in a 3D in vitro matrix environment have been reported to exhibit significantly different properties to those in a conventional 2D culture environment. However, comparison of 2D and 3D cell culture models have recently been noted to result in differing responses of cytotoxic assays, without any associated change in viability. The effect was attributed to differing conversion rates and effective concentrations …

Chemical Investigation Of Antarctic Marine Organisms & Their Role In Modern Drug Discovery, Jacqueline Lee Fries

USF Tampa Graduate Theses and Dissertations

The chemicals produced by biological systems, whether proteins, peptides, or terpenes, will always provide an intriguing topic for researchers. Invisibly controlling every aspect of nature, these molecules are responsible for life, evolution, and death. Specifically, here is described the secondary metabolites produced by Antarctic marine organisms as well as others, and how they are used to defend or attract other animals while potentially providing health benefits to mankind. This is done through collection, extraction, and separation of individual specimens. The respective mixtures of compounds after isolation are then analyzed via spectroscopic methods such as nuclear magnetic resonance spectroscopy, mass spectrometry, …