Medical Pharmacology Commons^™

N-Acetyltranserase 2 (Nat2) Genotype Polymorphism In Cryopreserved Human Hepatocytes And Chinese Hamster Ovary (Cho) Cells., Mariam Refaat Zaky Habil

Electronic Theses and Dissertations

Arylamine N-acetyltransferases, NAT1 and NAT2, catalyze the detoxification and/or activation of drugs and aromatic amine carcinogens. Single nucleotide polymorphisms or SNPs result in different human NAT2 genotypes thus dividing the population into rapid, intermediate, and slow acetylators. We hypothesize allelic variants of NAT2 genotype will decrease levels of N-acetylation, cytotoxicity, oxidative stress, DNA adduct formation, and mutagenesis compared to the reference allele NAT2*4. Cryopreserved human hepatocytes expressing different NAT2 genotypes and NER-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and human NAT2*4, NAT2*5B or NAT2*7B have been used to investigate N-acetylation of different xenobiotics. In …

Mechanisms Of Chromate-Induced Suppression Of Rad51: A One Environmental Health Approach., Rachel M. Speer

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer death. Lung cancer is commonly associated with smoking, however, 1 in 5 women and 1 in 12 men who develop lung cancer are never-smokers. Environmental exposures, therefore, account for a significant portion of lung cancer cases. Hexavalent chromium [Cr(VI)] is a global environmental contaminant and known human lung carcinogen. Cr(VI) and other carcinogenic metals induce chromosome instability, an early event in lung cancer. Structural chromosome instability arises in part due to failed DNA repair. Particulate Cr(VI), the most potent form of Cr(VI), induces DNA double strand breaks and inhibits the high-fidelity DNA …

Soluble Epoxide Hydrolase Inhibition: A Novel Therapeutic Strategy In Alcoholic Liver Disease., Jeffrey Barr Warner

Electronic Theses and Dissertations

Emerging evidence suggests that soluble epoxide hydrolase (sEH) inhibition is a valuable therapeutic strategy for the treatment of numerous diseases. sEH rapidly degrades cytochrome P450-produced epoxygenated lipids (epoxy-fatty acids, epFAs), which generally exert beneficial effects on several cellular processes. sEH hydrolysis of epoxy-fatty acids produces dihydroxy-fatty acids which are typically less biologically active than their parent epoxide. sEH inhibition has shown efficacy in treating numerous pathologies associated with non-alcoholic liver disease, yet no efforts to date have tested the efficacy of sEH inhibition in alcoholic liver disease (ALD). Herein, we measured the levels of sEH expression and epFAs in human …

The Inhibitory Effects Of An Antimicrobial Gel On The Staphylococcus Species, Mara Trinkle

Undergraduate Honors Theses

The prevalence of antibiotic resistant bacteria has made the choices for topical treatments for patients who experience burns wounds extremely limited. The Staphylococcus genus is naturally occurring in and on the human body but can become harmful once it enters the bloodstream. A novel antimicrobial gel has been shown by our laboratory to inhibit both the planktonic growth and biofilm formation of Staphylococcus aureus in previous studies. The antimicrobial gel is made of seven natural compounds including antioxidants (vitamin C and E). We wanted to examine the effects of the antimicrobial gel on numerous other Staphylococcal species because it is …

Engineered Extracellular Vesicles Loaded With Mir-124 Attenuate Cocaine-Mediated Activation Of Microglia, Ernest T. Chivero, Ke Liao, Fang Niu, Ashutosh Tripathi, Changhai Tian, Shilpa Buch, Guoku Hu

Journal Articles: Pharmacology & Experimental Neuroscience

MicroRNA-124 (miR-124), a brain-enriched microRNA, is known to regulate microglial quiescence. Psychostimulants such as cocaine have been shown to activate microglia by downregulating miR-124, leading, in turn, to neuroinflammation. We thus rationalized that restoring the levels of miR-124 could function as a potential therapeutic approach for cocaine-mediated neuroinflammation. Delivering miRNA based drugs in the brain that are effective and less invasive, however, remains a major challenge in the field. Herein we engineered extracellular vesicles (EVs) and loaded them with miR-124 for delivery in the brain. Approach involved co-transfection of mouse dendritic cells with Dicer siRNA and RVG-Lamp2b plasmid to deplete …

Endocrine Significance Of Sars-Cov-2'S Reliance On Ace2, Eric Lazartigues, Mirza Muhammad Fahd Qadir, Franck Mauvais-Jarvis

School of Medicine Faculty Publications

The current COVID-19 pandemic is the most disruptive event in the past 50 years, with a global impact on health care and world economies. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a coronavirus that uses angiotensin-converting enzyme 2 (ACE2) as an entry point to the cells. ACE2 is a transmembrane carboxypeptidase and member of the renin-angiotensin system. This mini-review summarizes the main findings regarding ACE2 expression and function in endocrine tissues. We discuss rapidly evolving knowledge on the potential role of ACE2 and SARS coronaviruses in endocrinology and the development of diabetes mellitus, hypogonadism, and pituitary and …

Β-Amyloid And Tau Drive Early Alzheimer's Disease Decline While Glucose Hypometabolism Drives Late Decline, Tyler C. Hammond, Xin Xing, Chris Wang, David Ma, Kwangsik Nho, Paul K. Crane, Fanny Elahi, David A. Ziegler, Gongbo Liang, Qiang Cheng, Lucille M. Yanckello, Nathan Jacobs, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

Clinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer’s disease (AD), suggesting that Aβ may not be the optimal target for treating AD. The evaluation of Aβ, tau, and neurodegenerative (A/T/N) biomarkers has been proposed for classifying AD. However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally throughout the progression of AD. Here, using the random forest machine learning method to analyze participants in the Alzheimer’s Disease Neuroimaging Initiative dataset, we show that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ …

Efficacy Of A Novel Mitochondrial-Derived Peptide In A Porcine Model Of Myocardial Ischemia/Reperfusion Injury, Thomas E. Sharp, Zhenwei Gong, Amy Scarborough, Eric S. Goetzman, Murtuza J. Ali, Pablo Spaletra, David J. Lefer, Radhika H. Muzumdar, Traci T. Goodchild

School of Medicine Faculty Publications

With the complexities that surround myocardial ischemia/reperfusion (MI/R) injury, therapies adjunctive to reperfusion that elicit beneficial pleiotropic effects and do not overlap with standard of care are necessary. This study found that the mitochondrial-derived peptide S14G-humanin (HNG) (2 mg/kg), an analogue of humanin, reduced infarct size in a large animal model of MI/R. However, when ischemic time was increased, the infarct-sparing effects were abolished with the same dose of HNG. Thus, although the 60-min MI/R study showed that HNG cardioprotection translates beyond small animal models, further studies are needed to optimize HNG therapy for longer, more patient-relevant periods of cardiac …

Evolving Role For Pharmacotherapy In Nafld/Nash, Suzanna L. Attia, Samir Softic, Marialena Mouzaki

Pediatrics Faculty Publications

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise …

A Follow-Up Phone Call To Post-Operative Patients Using The Five A’S, Brittney Ochs

Doctor of Nursing Practice Final Manuscripts

Abstract

Background: The 2016 National Survey on Drug Use and Health reported that 53 percent of people that misused pain relievers in the past year received them from a friend or relative. The NIDA describes that from 2002 to 2008 that drug abuse in service members went from 2% to 11%. Often patients are initially prescribed and introduced to opioid medication for acute pain. One such circumstance is in the perioperative period that could provide an opportunity to promote opioid-sparing techniques to reduce the exposure to opioids.

Purpose of Project: To assess discharge medication characteristics and reinforce discharge medication instructions …

Fall Prevention Assessment In The Intermediate Care Patient Population, Dawn Rose

Doctor of Nursing Practice Final Manuscripts

Fall Prevention Assessment in the Intermediate Care Patient Population

Falls cause greater than 600,000 deaths per year and are the most common injury in people over 65 years of age. Fall prevention in the acute care setting has been identified as key goal in the most recent JCAHO review process. Falls on an intermediary care unit lead to an increased rate of morbidity, delayed discharge, and excess cost expenditure.

Even with appropriate evidence-based tools in place, Hospital A’s intermediate care unit, recorded an increased rate of falls; the highest rate in its health care system. An investigation identified factors contributing …

Twice-Daily Doravirine Overcomes The Interaction Effect From Once-Weekly Rifapentine And Isoniazid In Healthy Volunteers., Edwin Lam, Joseph Schaefer, Richard Zheng, Tingting Zhan, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Doravirine (DOR) is a non‐nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus‐1 (HIV‐1). Its use in combination with rifapentine (RPT), an anti‐tuberculosis antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV‐1 co‐infected with tuberculosis. We conducted a prospective, phase I, open label, two‐period, fixed sequence, drug interaction study to evaluate the effect of once‐weekly RPT and isoniazid (INH) on the pharmacokinetics of DOR in healthy volunteers. DOR 100 mg was administered alone twice‐daily for 4 days in period 1. In period 2, once‐weekly RPT+INH was co‐administered with multiple doses of …

Myeloid-Specific Deficiency Of Pregnane X Receptor Decreases Atherosclerosis In Ldl Receptor-Deficient Mice, Yipeng Sui, Zhaojie Meng, Se-Hyung Park, Wei-Wei Lu, Christopher Livelo, Qi Chen, Tong Zhou, Changcheng Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Abstract The pregnane X receptor (PXR) is a nuclear receptor that can be activated by numerous drugs and xenobiotic chemicals. PXR thereby functions as a xenobiotic sensor to coordinately regulate host responses to xenobiotics by transcriptionally regulating many genes involved in xenobiotic metabolism. We have previously reported that PXR has pro-atherogenic effects in animal models, but how PXR contributes to atherosclerosis development in different tissues or cell types remains elusive. In this study, we generated an LDL receptor-deficient mouse model with myeloid-specific PXR deficiency (PXR^ΔMyeLDLR^−/−) to elucidate the role of macrophage PXR signaling in atherogenesis. The …

Photoactivatable Cre Recombinase 3.0 For In Vivo Mouse Applications, Kumi Morikawa, Kazuhiro Furuhashi, Carmen De Sena-Tomas, Alvaro L. Garcia-Garcia, Ramsey Bekdash, Alison D. Klein, Nicholas Gallerani, Hannah E. Yamamoto, Seon Hye E. Park, Grant S. Collins, Fuun Kawano, Moritoshi Sato, Chyuan Sheng Lin, Kimara L. Targoff, Edmund Au, Michael C. Salling, Masayuki Yazawa

School of Medicine Faculty Publications

Optogenetic genome engineering tools enable spatiotemporal control of gene expression and provide new insight into biological function. Here, we report the new version of genetically encoded photoactivatable (PA) Cre recombinase, PA-Cre 3.0. To improve PA-Cre technology, we compare light-dimerization tools and optimize for mammalian expression using a CAG promoter, Magnets, and 2A self-cleaving peptide. To prevent background recombination caused by the high sequence similarity in the dimerization domains, we modify the codons for mouse gene targeting and viral production. Overall, these modifications significantly reduce dark leak activity and improve blue-light induction developing our new version, PA-Cre 3.0. As a resource, …

A Review Of Human Immunodeficiency Virus, Sophie Silver

Senior Honors Theses

Human immunodeficiency virus, also referred to as HIV, is a devastating virus which has infected millions. Characterized as a retrovirus, HIV has an RNA genome, which is reverse transcribed into DNA upon entry into the host cell. HIV primarily affects CD4⁺ T cells and is diagnosed by the significant reduction of CD4⁺ T cells. While no cure has been discovered yet, antiretroviral therapy (ART) has been demonstrated as an effective treatment option. In the progression of HIV, additional HIV-associated diseases may arise, including HIV-associated psoriasis and sensory neuropathy. In addition to the use of ART, clinicians often prescribe …

The Effect Of Β-Caryophyllene On Isoproterenol-Induced Myocardial Infarction, Farah M. Jamal Laham

Theses

Cannabinoid type 2 receptors (CB2), a key member of the endocannabinoid system have recently emerged as a crucial therapeutic target for cardiovascular diseases (CVDs). Downregulation of CB2 receptors has been witnessed in various cancers, neurological and cardiovascular disorders. Thus, the activation of CB2 receptors may protect against ISO-induced myocardial infarction (MI) in rats. The present study investigates the cardioprotective effect of a selective cannabinoid type 2 receptor agonist β-caryophyllene (BCP), a dietary phytocannabinoid, and a natural bicyclic sesquiterpene against isoproterenol (ISO)-induced MI in rats. Male albino Wistar rats were pre-and co-treated with β-caryophyllene (50 mg/kg, orally) twice daily for 10 …

Neuroligin-1 Is Altered In The Hippocampus Of Alzheimer's Disease Patients And Mouse Models, And Modulates The Toxicity Of Amyloid-Beta Oligomers, Julien Dufort-Gervais, Chloé Provost, Laurence Charbonneau, Christopher M. Norris, Frédéric Calon, Valérie Mongrain, Jonathan Brouillette

Pharmacology and Nutritional Sciences Faculty Publications

Synapse loss occurs early and correlates with cognitive decline in Alzheimer’s disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level …

Adverse Aftereffects Of Methotrexate As Chemotherapy On Cognitive Deficits In Rat Models, Jubin Kang

Senior Honors Theses

Patients with acute lymphoblastic leukemia have a high five-year survival rate thanks to methotrexate (MTX). However, cognitive side effects are reported, characterized as chemo brain. The study investigated if impulsiveness is part of the aberrant cognitive functions after being exposed to MTX in the early stage of physical development. Adolescent rats were injected with either phosphate-buffered saline (PBS) or MTX. The novel object recognition (NOR) task was conducted a month after the injections to measure the memory deficits. The discounting task was performed after the rats completed training on a fixed-ratio one schedule for both levers. The NOR test showed …

Modulator Therapy For Cystic Fibrosis: An Exploration Of Current Research, Jessalyn Rombocos

Senior Honors Theses

Developing a drug therapy that addresses the root cause of cystic fibrosis (CF) by increasing CFTR protein levels has long been a research challenge. After genetic therapy failed because a suitable delivery system could not be found, researchers began searching for small organic molecules that could act as chaperones for CFTR. These molecules, known as modulators, allowed CFTR to be assembled correctly and function similarly to wild type CFTR. Since 2012, four modulator drugs have been developed, tested, and approved by the FDA. In October 2019, Trikafta was approved as the first triple-combination modulator drug and has completely revolutionized CF …

Biological Sex Influences Susceptibility To Acinetobacter Baumannii Pneumonia In Mice, Sílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, Dane Parker

Publications and Research

Acinetobacter baumannii (A. baumannii) is an extremely versatile multidrug-resistant pathogen with a very high mortality rate; therefore, it has become crucial to understand the host response during its infection. Given the importance of mice for modeling infection and their role in preclinical drug development, equal emphasis should be placed on the use of both sexes. Through our studies using a murine model of acute pneumonia with A. baumannii, we observed that female mice were more susceptible to infection. Likewise, treatment of male mice with estradiol increased their susceptibility to infection. Analysis of the airway compartment revealed enhanced inflammation and reduced …