Chemical and Pharmacologic Phenomena Commons^™

Exploration Of Dopaminergic And Serotonergic Pathways Utilizing Pleiotropic Agents, Charles B. Jones Iii

Theses and Dissertations

2-(Benzoyl)piperidines (BPs) are at a crossroads of therapy and abuse. These compounds are a hybrid between the ADHD medication methylphenidate and abused stimulant cathinones. Here we use computational molecular modeling, synthesis, mutagenesis, and epifluorescence microscopy to further improve the understanding of and potential treatments for several neuropsychiatric disorders. Utilizing the BP scaffold and controlling chirality and aryl substitution, these agents were examined at DAT and SERT. From these investigations it has now been established that R isomer BPs are favored for DAT while S isomer BPs are favored for SERT. Aryl-substitution can greatly affect the selectivity of these agents with …

Cellular Metabolism Is A Viable Therapeutic Target For Radiation-Induced Pulmonary Fibrosis, Josly Pierre-Louis Odoom

Theses and Dissertations

Herein, we provide evidence for cellular metabolic reprogramming as a driver of radiation-induced pulmonary fibrosis (RIPF). We are the first to identify a distinct metabolic signature for RIPF in a cohort of patients with radiographic sequela. We also used a RIPF mouse model to detect the metabolic pathways that enrich during pathogenesis. Our previous work highlighted the importance of lactate, a derivative of the glycolysis end-product pyruvate. Consequently, we took a special interest in the effects of radiation on the glycolysis pathway. We learned that radiation accelerates and reprograms glycolysis to an anabolic state in a pyruvate kinase M2 (PKM2)-dependent …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch

Theses and Dissertations

The field of cancer research has grown immensely in recent decades and has led to a better understanding of the causes of the disease, as well as greatly improved treatment for various types of cancers, especially breast cancer. One of the most effective treatments involves the chemotherapeutic drug doxorubicin (DOX). DOX is an effective tool against all types of breast cancer, especially against triple negative breast cancer. However, DOX causes adverse side effects that include damage to the heart and skeletal muscle, particularly above specific cumulative doses. Recent evidence suggests that embryonic stem cell-derived (ES) exosomes, nanoscale extracellular vesicles that …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

N-Methyl 4-Methyl Amphetamine N-Alkyl Chain Extension Differentially Affects Ion Flux At The Human Dopamine And Norepinephrine Transporters, Alan C. Harris Jr.

Theses and Dissertations

Amphetamine (AMPH) and its derivatives embody a remarkable breadth of pharmacology. These molecules exert their effects, both therapeutic and pathological, at the human monoamine transporters, which tune synaptic dynamics by evacuating monoamine neuromodulators from the synapse subsequent to neuronal impulses. These transporters are electrogenic, and the transporter-mediated current can be correlated to a surrogate measure of the change in membrane voltage: Ca⁺⁺ currents from co-transfected L-type Ca⁺⁺ channels. The present work makes use of this assay, with which it is possible to derive pharmacodynamic metrics from both substrates and inhibitors. This work presents data on a heretofore-unstudied class …