Medical Pharmacology Commons^™

Heme Oxygenase-1 Affects Cytochrome P450 Function Through The Formation Of Heteromeric Complexes: Interactions Between Cyp1a2 And Heme Oxygenase-1, J. Patrick Connick, James R. Reed, George F. Cawley, Wayne L. Backes

School of Medicine Faculty Publications

Heme oxygenase 1 (HO-1) and the cytochromes P450 (P450s) are endoplasmic reticulum–bound enzymes that rely on the same protein, NADPH-cytochrome P450 reductase (POR), to provide the electrons necessary for substrate metabolism. Although the HO-1 and P450 systems are interconnected owing to their common electron donor, they generally have been studied separately. As the expressions of both HO-1 and P450s are affected by xenobiotic exposure, changes in HO-1 expression can potentially affect P450 function and, conversely, changes in P450 expression can influence HO-1. The goal of this study was to examine interactions between the P450 and HO-1 systems. Using bioluminescence resonance …

Drug Delivery Systems: Exploring Rheological Properties And Therapeutic Effect Of 5-Fu Chitosan Gel For Topical Wound Healing, Samuel Tetteh-Quarshie

Theses, Dissertations and Capstones

Diabetic skin wound is a common complication of diabetes that occurs in about 15% of diabetic patients and often requires prolonged hospitalization for its management and treatment. Natural polymers are used for wound dressing due to their biological adhesiveness, non-toxicity, and biodegradable nature. 5-Fluorouracil (FU) has been shown to alter adipokine expression which is implicated in cutaneous wound repair. Thus, our overall objective was to investigate the utility of chitosan (CS) gel for topical delivery of 5-FU to treat diabetic wounds. We prepared chitosan gel (2% w/w) in serial dilutions of 5-FU (25μg/mL, 2.5μg/mL, 0.25μg/mL, and 0.025μg/mL) and evaluated their …

Cd4+ Effector T Cells Accelerate Alzheimer's Disease In Mice, Jatin Machhi, Pravin Yeapuri, Yaman Lu, Emma Foster, Rupesh Chikhale, Jonathan Herskovitz, Krista L. Namminga, Katherine E. Olson, Mai Mohamed Abdelmoaty, Ju Gao, Rolen M. Quadros, Tomomi Kiyota, Liang Jingjing, Bhavesh D. Kevadiya, Xinglong Wang, Yutong Liu, Larisa Y. Poluektova, Channabasavaiah B. Gurumurthy, R. Lee Mosley, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and …

Precision Nutrition And Advanced Culinary Medicine, Sara B. Police

Pharmacology and Nutritional Sciences Textbook Gallery

This electronic textbook (eBook) accompanies NS801, Precision Nutrition and Advanced Culinary Medicine, a 1-credit, 8-week online medical elective course for the University of Kentucky College of Medicine Office of Medical Education. The eBook provides module-based background information including text, tables, and figures to support each module of the online course:

1. Introduction
2. Culinary Challenges Preparation
3. Emerging Concepts in Precision Nutrition
4. Cardiovascular Disease & Nutritional Considerations
5. Neurological and Mental Health Disorders & Nutritional Considerations
6. Cancer & Nutritional Considerations
7. Gastrointestinal (GI) Health, Microbiome & Nutritional Considerations
8. Renal Conditions & Nutritional Considerations

As an open access textbook supported by the University of Kentucky Libraries …

Efficacy And Safety Of Once-Daily Vibegron For Treatment Of Overactive Bladder In Patients Aged ≥65 And ≥75 Years: Subpopulation Analysis From The Empowur Randomized, International, Phase Iii Study, Susann Varano, David Staskin, Jeffrey Frankel, Denise Shortino, Rachel Jankowich, Paul N. Mudd

Physician Associate Studies Faculty Publications

Background

Overactive bladder (OAB) is common among older adults. The efficacy and safety of vibegron for the treatment of OAB were demonstrated in the international, phase III EMPOWUR trial. This subpopulation analysis from EMPOWUR assessed the efficacy and safety of vibegron in patients aged ≥ 65 and ≥ 75 years.

Methods

In EMPOWUR, patients with OAB were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, once daily for 12 weeks. Coprimary efficacy endpoints were change from baseline at week 12 in average daily number of micturitions and urge urinary incontinence (UUI) …

Opioid Use Disorder: The Timeline For Medication Assisted Therapy, Alexander Cristofori

Capstone Showcase

Opioid Use Disorder is patterns of opioid use leading to withdrawal, giving up important life events in order to use opioids, and excessive time spent using opioids, to name a few diagnostic criteria. The clinical progression of the disorder involves periods of acute exacerbation and remission that are cyclic in nature. Treatment is most effective when it includes both pharmacological and psychosocial modalities, referred to as medication assisted therapy (MAT). Three drugs used commonly in MAT-based treatment for OUD from oldest to newest include Methadone, Buprenorphine-naloxone, and Naltrexone. Treatment program models that prioritize total abstinence from the addictive substance attached …

Efficacy Of Pcsk9 Inhibitors Compared To Standard Of Care In Improving The Low-Density-Lipoprotein Cholesterol And Lowering The Risk Of Cardiovascular Events In Patients With Familial Hypercholesterolemia, Nichole Warshany

Capstone Showcase

Familial hypercholesterolemia is an inherited condition that causes patients to have significantly increased levels of LDL cholesterol, which often leads to coronary artery disease. Statin medications are typically prescribed to treat this condition, however these medications have adverse side effects and often subpar efficacy in this patient population. Evidence collected in this literature review yielded evidence that the use of PCSK9 inhibitors in the treatment of patients with familial hypercholesterolemia may be efficacious. Many of these studies were able to show statistically significant improvement of LDL-C and decrease in cardiovascular risk when compared to placebo. In addition, this medication was …

The Efficacy Of In Vitro Fertilization In Treating Infertility Due To Anovulatory Pcos In Comparison To Ovulation Induction Via Letrozole, Amanda Salay

Capstone Showcase

Abstract:

Introduction: Polycystic Ovarian Syndrome (PCOS) is an endocrine disorder found in women of reproductive age that often causes infertility. The first-line treatment for infertility in anovulatory PCOS patients is ovulation induction. In vitro fertilization (IVF) is a third line treatment often used as a last resort. PCOS patients have higher failure risks of first- and second-line medications. Therefore, this review analyzes if adverse pregnancy outcomes (O) are reduced more with IVF (I) versus using letrozole for ovulation induction (C) in women aged 20-30 struggling with infertility due to anovulatory PCOS (P).

Methods: A literature search on Pubmed and EBSCOhost …

Potential Perioperative Complications Due To Difference In Timing Of Systemic Heparinization During Ruptured Aneurysm Coiling, Rouzbeh Kotaki, Ameer E. Hassan, Wondwossen G. Tekle

MEDI 9331 Scholarly Activities Clinical Years

Potential Perioperative Complications Due To Differences in Timing Of Systemic Heparin Distribution During Ruptured Aneurysm Coiling

Introduction:

In general, systematic heparin anticoagulation is standard in regards to neurovascular intervention. When coiling ruptured aneurysms, many neurointerventionalists have their own protocol as to timing of systemic heparinization. There is ample research and literature reviewing the frequency of perioperative events, predictors and outcomes, as well as the efficacy in the use of anticoagulants and/or antiplatelets before, during, and after neurovascular procedures to prevent adverse outcomes. However, there currently exists a dearth of research in regards to timing of distribution of heparin intraoperatively and …

Selective Gsk3b Deletion In Camk2a+ Forebrain Neurons Or Inhibition Via Tideglusib, Decreases Ethanol Consumption In C57bl/6j Mice, Sam Gottlieb, Andrew D. Van Der Vaart, Brennen O'Rourke, Michael F. Miles

Graduate Research Posters

Purpose: We previously identified glycogen synthase kinase-3 beta (Gsk3b) as a central member of a gene network highly regulated by acute ethanol in medial prefrontal cortex (mPFC) and associated with risk for alcohol dependence in humans. Further, we have demonstrated modulation of Gsk3b alters ethanol consumption in rodent models. GSK3B could thus represent a potential new therapeutic target for the treatment of alcohol use disorder (AUD). Here, we investigate the mechanisms of Gsk3b action in ethanol consumption and report preclinical evidence for the selective GSK3B inhibitor, tideglusib, as a therapeutic agent for AUD.

Methods: (1) Selective Cre-induced Gsk3b …

A Transgenic Pig Model Expressing A Cmv-Zsgreen1 Reporter Across An Extensive Array Of Tissues., Amy T Desaulniers, Rebecca A Cederberg, Elizabeth P Carreiro, Channabasavaiah B Gurumurthy, Brett R White

Journal Articles: Pharmacology & Experimental Neuroscience

Since genetic engineering of pigs can benefit both biomedicine and agriculture, selecting a suitable gene promoter is critically important. The cytomegalovirus (CMV) promoter, which can robustly drive ubiquitous transgene expression, is commonly used at present, yet recent reports suggest tissue-specific activity in the pig. The objective of this study was to quantify ZsGreen1 protein (in lieu of CMV promoter activity) in tissues from pigs harboring a CMV-ZsGreen1 transgene with a single integration site. Tissue samples (

Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, And Increase Plasma Β-Hydroxybutyrate, Terry D. Hinds Jr., Justin F. Creeden, Darren M. Gordon, Donald F. Stec, Matthew C. Donald, David E. Stec

Pharmacology and Nutritional Sciences Faculty Publications

The inverse relationship of plasma bilirubin levels with liver fat accumulation has prompted the possibility of bilirubin as a therapeutic for non-alcoholic fatty liver disease. Here, we used diet-induced obese mice with non-alcoholic fatty liver disease treated with pegylated bilirubin (bilirubin nanoparticles) or vehicle control to determine the impact on hepatic lipid accumulation. The bilirubin nanoparticles significantly reduced hepatic fat, triglyceride accumulation, de novo lipogenesis, and serum levels of liver dysfunction marker aspartate transaminase and ApoB100 containing very-low-density lipoprotein. The bilirubin nanoparticles improved liver function and activated the hepatic β-oxidation pathway by increasing PPARα and acyl-coenzyme A oxidase 1. …

Deep Brain Stimulation Of The Subcallosal Cingulate Gyrus In The Treatment Of Treatment Resistant Depression, Megan Caravas, Melanie Sov

Physician Assistant Capstones, 2020-current

Objective: a systematic review to determine the efficacy of deep brain stimulation (DBS) targeting the subcallosal cingulate gyrus (SCG) for the treatment of treatment resistant depression (TRD). Methods: PubMed database was utilized in a search for clinical randomized control trials that were completed after the year 2000, using the terms deep brain stimulation, treatment resistant depression, and subcallosal cingulate gyrus. Results: Three clinical trials were chosen based on specific inclusion criteria as noted in the PRISMA flow chart (Chart 1). The results of the three articles showed various discrepancies. Two of the three studies demonstrated some statistical significance in reduction …

Natural Product Heme Oxygenase Inducers As Treatment For Nonalcoholic Fatty Liver Disease, David E. Stec, Terry D. Hinds Jr.

Pharmacology and Nutritional Sciences Faculty Publications

Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological condition by which the liver accumulates fat. The incidence of NAFLD has reached all-time high levels driven primarily by the obesity epidemic. NALFD can progress to nonalcoholic steatohepatitis (NASH), advancing further to liver cirrhosis or cancer. NAFLD is also a contributing factor to cardiovascular and metabolic diseases. There are currently no drugs to specifically treat NAFLD, with …

Electrophysiological And Imaging Calcium Biomarkers Of Aging In Male And Female 5×Fad Mice, Adam O. Ghoweri, Lara Ouillette, Hilaree N. Frazier, Katie L. Anderson, Ruei-Lung Lin, John C. Gant, Rachel Parent, Shannon Moore, Geoffrey G. Murphy, Olivier Thibault

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker.

OBJECTIVE: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on …

Manf Is Neuroprotective Against Ethanol-Induced Neurodegeneration Through Ameliorating Er Stress, Yongchao Wang, Wen Wen, Hui Li, Marco Clementino, Hong Xu, Mei Xu, Murong Ma, Jacqueline A. Frank, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in …

Fluorescence Spectroscopic And Molecular Modelling Studies On The Molecular Interaction Mechanism Of Bromodeoxyuridine With Human Serum Albumin, Amira Adlin Roslan

Student Works (2020-2029)

The interaction of a nucleoside analogue, bromodeoxyuridine (BrdU) with human serum albumin (HSA) was studied to investigate the binding phenomenon and analyze the protein conformation upon BrdU binding. Multiple spectroscopic techniques, viz. intrinsic and three-dimensional (3-D) fluorescence, ultraviolet-visible (UV-Vis) absorption and circular dichroism (CD) spectroscopy along with molecular docking were used. A decrease in the Stern-Volmer constant (Ksv) with the increase in temperature suggested BrdU-induced quenching of protein fluorescence as static quenching and thus implied BrdU−HSA complex formation. This was also supported by UV-Vis absorption spectral results, showing hyperchromism in the absorption spectrum of HSA upon BrdU addition. Intermediate binding …

Chronic Effects Of Methylphenidate On Neuronal Viability And Plasticity, Hannah Oakes

Electronic Theses and Dissertations

Methylphenidate (MPH) is the most commonly prescribed drug to treat Attention Deficit Hyperactivity Disorder (ADHD). ADHD is now considered a life-long disorder; therefore, patients take MPH from adolescence into adulthood, highlighting the need for research studying chronic MPH use. MPH increases dopamine and norepinephrine within the synaptic cleft; therefore, chronic use of MPH may lead to changes within important dopaminergic pathways. One pathway, the mesolimbic pathway, includes the hippocampus, an area where adult neurogenesis occurs. We investigated the effects of chronic low and high doses of MPH on neurogenesis and examined levels of a few key proteins linked to cell …

Great Expectations: Phosph(On)Ate Prodrugs In Drug Design—Opportunities And Limitations, Victoria Yan

Dissertations and Theses (Open Access)

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil …

Research Amidst The Pandemic, Howard Burris

HCA Healthcare Journal of Medicine

Cancer patients need access to promising investigational therapies, available only through clinical trials, and the emergence of COVID-19 and the resulting pandemic became an emerging threat to fulfilling that need. Many academic medical centers were pausing their clinical research programs, diverting their resources and sheltering their teams. Sarah Cannon, the Cancer Institute of HCA Healthcare, made the decision to stay safe, but stay the course.