Medical Sciences Commons^™

Effects Of Disulfiram On The Metabolome Of Mrsa, Surya Teja Naidu

Theses, Dissertations and Capstones

Disulfiram, known as Antabuse®, is an oral drug for the treatment of alcohol dependence. Previous studies have indicated that disulfiram (DSF) exhibits antibacterial effects, particularly against Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Our study delves into the antibacterial mechanism of DSF in MRSA through High-Pressure Liquid Chromatography (HPLC) metabolomics, investigating the underlying mechanism of DSF effects on thiamine and amino acid metabolism. Thiamine pyrophosphate (TPP) plays a crucial role as a cofactor for critical enzymes such as transketolase, pyruvate dehydrogenase, and 2-oxoglutarate dehydrogenase. These enzymes are integral to the carbohydrate metabolism process within bacterial cells. TPP also contributes …

High Body Mass Index Changes Peri-Tumor Adipose Tissue Which In Turn Promotes Triple Negative Breast Cancer, Cora Elizabeth Miracle

Theses, Dissertations and Capstones

Cancer is one of the leading causes of death worldwide, responsible for over half a million deaths each year. There are multiple risk factors associated with the development of cancer. Some of these risks include genetics, smoking, and most recently, obesity (Lewandowska et al., 2019) (De Pergola & Silvestris, 2013). Research has shown that obesity is linked to the promotion of fourteen different cancers, including aggressive triple negative breast cancer (TNBC). Patients that are obese are more likely to develop cancer (Park et al., 2014). In addition, if the patient is obese at the time of a cancer diagnosis, they …

Prenatal Buprenorphine Exposure Reduces Expression Of Myelin Proteins In Neonatal Longs-Evans Rat, Christopher James Grahe

Theses, Dissertations and Capstones

In the USA and especially in WV, there has been a surge in the rise of opioid use disorder (OUD), and with it a rise in neonatal abstinence syndrome (NAS). What makes this rise in NAS so unfortunate is that the Medications for OUD (MOUD) do not prevent the development of NAS. Although the relationship between MOUD and NAS is still unclear, it is thought that buprenorphine, one of the main substances used to treat OUD in pregnant women, may feed into the development of NAS, which may affect mental and physiological development and cause other health problems. Via understanding …

Elucidating The Impact Of Western Diet On Bone Marrow Cytokine Signatures: Understanding Poor Outcomes In Susceptibility To Infection And Progression Of Cancer, Lahari Kondeti

Theses, Dissertations and Capstones

Among other disease outcomes, obesity is associated with 1) reduction in long-lasting immune protection and 2) acquisition of cancer. Given our interest in hematopoietic stem and progenitor cell (HSPC) dynamics, we questioned if similar mechanisms in the bone marrow microenvironment contribute to obesity-induced HSPC alterations responsible for 1) decreased immune protection and 2) transformation of HSPCs in the pathogenesis of hematologic malignancies. The negative effects of obesity on immune protection are most notably established in influenza models. Influenza infection susceptibility is increased and influenza vaccine-induced immunity wains in obese individuals. Ongoing studies aim to define mechanisms for waning immunity at …

Adolescence, Alcohol, And Astrocytes: The Impact Of Adolescent Alcohol Use On Astrocyte-Synaptic Interactions, Structure, Function, And Behavior, Christopher Douglas Walker

Theses, Dissertations and Capstones

Alcohol is the third leading cause of preventable death in the United States and has substantial social and economic burdens. Excessive alcohol consumption in the form of binge drinking is highly prevalent among adolescents and emerging adults. Binge drinking is a form of excessive drinking, defined as consuming enough alcohol on a single occasion to result in blood alcohol concentrations above 0.08%. Approximately 55% of full-time college students aged 18- 22 years old have reported consuming alcohol in a binge manner. Furthermore, studies have shown that approximately 20% of college students meet the criteria for an alcohol use disorder (AUD). …

Examining The Effects Of Exercise-Induced, Physical Stress Overtraining On Stress Biomarkers In Adolescent, C57bl/6 Mice, Curtis Scotty Davis

Theses, Dissertations and Capstones

Exercise has long been established as a therapeutic modality to improve health and related physical fitness, sports performance, and injury/risk reduction in both adults and adolescents (Haff & Triplett, 2015; Kaminsky, 2010). Nonetheless, there is a lack of research investigating the negative effects of exercise overstress (i.e., overtraining syndrome) in these populations, particularly adolescents (Brenner & American Academy of Pediatrics Council on Sports Medicine and Fitness, 2007; Matos & Winsley, 2007). The objective of this study was to examine hormone biochemical markers, anthropometric markers, and behavioral traits, which are associated with overtraining syndrome, in adolescent C57BL/6 mice. A total of …

Current And Novel Neuroregenerative Therapies, Arrin Brooks

Theses, Dissertations and Capstones

Underlying the physical and cognitive deficits consequent of many neuropathologies is one common factor, the loss of neurons. While neurodegenerative diseases, stroke, and traumatic brain injury arise from a variety of etiologies, they all ultimately result in injury and/or death of neuronal cells and concomitant functional deficits. In the present work we primarily focus on current and potential treatments for localized lesions, particularly those in the striatum of Parkinson’s disease (PD) or the cortex as in stroke. First, we discuss a new surgical technique for deep brain stimulator (DBS) placement, as DBS is a mainstay treatment for movement disorders including …

A Systems Approach To Dissecting The Role Of The Mucosal Microbiome In Disease, Lexie Christine Blalock

Theses, Dissertations and Capstones

The microbial community harbored by the mammalian gastrointestinal tract, collectively called the gut microbiota, plays a critical role in host health, metabolism, and immunity. Quantifiable changes in the gut microbiota have been implicated in a myriad of pathologies, including autoimmune, metabolic, and neurodegenerative diseases. Because of the gut microbiota’s plasticity, manipulating this community for therapeutic benefit presents as a novel strategy to combat modern diseases. Yet, only a fraction of the total microbial diversity that exists within the gut has been successfully cultured in a laboratory, leaving the clinical implications and functional attributes of many gut microbes undetermined. To address …

Crippling Rapid Evolution Of Metastasis And Drug Resistance In A549 Non-Small Cell Lung Cancer Cells With The Clinically Relevant Hsp90 Inhibitor Auy922, Nickolas Anthony Bacon

Theses, Dissertations and Capstones

The ability for species to evolve new features in response to changing circumstances in order to survive and propagate is a ubiquitous observation on both the macroscopic and microscopic levels of living systems. It should be no surprise, then, that diseases such as cancer utilize their own forms of adaptation to perpetuate themselves when exposed to external threats. Indeed, concepts drawn from Darwinian evolution are now widely accepted to help explain certain aspects of carcinogenesis and malignant progression, the sum of which have come to be known as the theory of tumor evolution. Since metastasis and drug resistance are features …

The Effect Of Upper-String Musician Practice Session On Scapular Kinematics, Connor James Brown

Theses, Dissertations and Capstones

Background: Shoulder pain is common in the upper-string musician population. [43,49] Pain has been linked with injury and impairments. Altered scapular kinematics has been associated with patients diagnosed with shoulder injury or impairment. Fatigue of the shoulder complex through repeated arm motions has been shown to alter scapular kinematics, resulting in shoulder pathologies, including rotator cuff impingement syndrome. [12,15,28] Upper string musicians have been documented with practicing multiple hours in a day and it could be inferred those practice sessions could be fatiguing. [24,49]

Purpose: This study aimed to examine the effect of upper string musician practice session …

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 …

Role Of Thymidine Phosphorylase In Type 2 Diabetes-Associated High-Risk Of Thrombosis, Adam Belcher

Theses, Dissertations and Capstones

Cardiovascular diseases (CVDs), such as ischemic heart disease and stroke, are the leading causes of death globally that disproportionally affects patients with type 2 diabetes mellitus (T2DM) at a 2-4-fold rate compared to non-diabetic patients. These CVDs result from a blood clot, also known as a thrombus, formed in arteries that can block blood flow resulting in tissue damage and death. Antiplatelet drugs, such as aspirin and clopidogrel, used to prevent thrombosis have been found to be less effective in diabetics and increase the risk of hemorrhagic events. The T2DM epidemic has made it imperative to find therapies that decrease …

Ankle Muscle Activation And Mechanics During The Ebbet's Foot Drills, Quentin Adam Archuleta

Theses, Dissertations and Capstones

Introduction: The ankle is a complex structure of three joints that allow multiplanar motion (Brockett & Chapman, 2016). Lateral ankle sprains (LAS) are the most common injury seen today in both the general and athletic populations and have a high recurrence rate. When left untreated or mistreated, it often leads to developing chronic ankle instability or osteoarthritis, which a lower quality of life. Dr. Russ Ebbets created a set of foot drills with the claim that they can strengthen the muscles of the lower leg, lessen lower leg aliments, and the chances of a severe ankle sprain (Ebbets, 2011a). …

Role Of Na/K-Atpase Non-Enzymatic Signaling In Renal Proximal Tubule Sodium Transport, Shreya Tapan Mukherji

Theses, Dissertations and Capstones

The renal proximal tubule (RPT) is the center stage for renal handling of Na+ , a potent determinant of systemic Na+ and volume homeostasis in health and disease. In the RPT, through its classic ion-pumping function, Na + /K+ -ATPase (NKA) generates the Na+ gradient that drives apical Na+ absorption, mostly through Na+ /H+ exchanger (NHE3). In contrast, pharmacological evidence suggests that the activation of the NKA non-enzymatic signaling function, through Src and other signaling partners, triggers a cellular redistribution of NKA and NHE3 that decreases transcellular Na+ flux in cultured RPT cells. However, the physiological relevance of the nonenzymatic …

Na/K-Atpase Alphα1 Regulates Adipogenesis Via Its Conserved Caveolin Binding Motif, Minqi Huang

Theses, Dissertations and Capstones

The Na/K-ATPase (NKA) was identified in 1957 by Dr. Jens C. Skou. It belongs to the P-type ATPase family, which can actively transport ions across cell membranes by using the energy from adenosine triphosphate (ATP) hydrolysis. During the second half of the 20th century, the molecular mechanism of the NKA catalytic cycle was clarified, and the isoform diversity of NKA in different species and organs was identified. The active ion transport through NKA generates cell membrane ion gradients and the electric potential. Hence, the enzymatic function of NKA is critical for cell viability as well as multiple physiological processes including …

Potential Counter Regulatory Effects Of A Gut Microbiota Metabolite In Alleviating Down-Regulation Krüppel-Like Factor 4 In Intestinal Inflammation, Ylva Forslund

Theses, Dissertations and Capstones

Inflammatory bowel disease (IBD) is a medical condition characterized by chronic inflammation of the intestinal epithelium. Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is vital for maintaining intestinal epithelial homeostasis. KLF4 promotes differentiation of goblet cells that generate the protective mucus layer. Reduced goblet cell number and defective mucus layer are associated with IBD. Shortchain fatty acids (SCFA) are known to play an important role in the maintenance of a strong and healthy intestinal epithelial layer and also in goblet cell differentiation. However, whether the positive effects of SCFAs on goblet cells are mediated, at least partly, via …

Targeting Epigenetic Mechanisms In Endometriosis, Sarah Elizabeth Brunty

Theses, Dissertations and Capstones

Endometriosis is a complex and elusive gynecological disease in which the inner lining of the uterus grows in locations outside of the uterus and forms lesions. It is known to affect 1 in 9 women of reproductive age worldwide. Symptoms of endometriosis include severe pain, heavy periods, and infertility. While multiple theories of origin exist, none fully encompass all aspects of the disease, although all theories agree that this is an inflammation-driven disease. Due to this, many researchers are turning towards epigenetics to explain the initiation and progression of endometriosis. However, what is causing these epigenetic changes is still a …

The Epigenetic Effects Of Omega-3 Fatty Acids In Diffuse Large B-Cell Lymphoma, Tanner Jeffrey Bakhshi

Theses, Dissertations and Capstones

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It is an aggressive cancer, with 50-70% of patients diagnosed at an advanced stage and 30-50% of patients not cured by chemoimmunotherapy. DLBCL is almost always caused by genetic damage sustained during the germinal center (GC) reaction. The mechanisms that govern the GC reaction bear a striking resemblance to those that drive DLBCL. Genomic studies have shown that some of its most common mutations occur in genes that encode epigenetic modifiers, including the lysine (histone) acetyltransferases CREBBP and p300. These mutations prevent the acetylation of multiple histone residues, …

Role Of Atp1a1 In Skeletal Muscle Growth And Metabolism, Laura C. Kutz

Theses, Dissertations and Capstones

Skeletal muscle comprises approximately 30% of total body mass, and loss of muscle mass and dysfunctional muscle metabolism are implicated in multiple disease states, including type 2 diabetes, heart failure, and septic shock. As such, understanding the mechanisms of skeletal muscle growth and atrophy, including pharmaceutical targets that may prove safe and effective, is therefore an important goal of current research on skeletal muscle physiology. One potential target in skeletal muscle development and function that has not been fully explored is the Na/KATPase (NKA), especially the α1 isoform. This isoform has a unique signaling function that has previously been shown …

Dysfunctional Mitochondrial Biogenesis: A Potential Underlying Cause For Metabolic Diseases, Caroline Ann Hunter

Theses, Dissertations and Capstones

Mitochondria are essential organelles that play crucial roles in many aspects of cellular homeostasis. More importantly, the mitochondria are home to the majority of the metabolic pathways within the cell and are responsible for producing most of the cell’s useable energy in the form of adenine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In mammals, the majority of OXPHOS complex subunits are encoded by nuclear deoxyribonucleic acid (DNA); however, 13 core subunits essential for the function of OXPHOS complexes I, III, IV, and V are encoded in the mitochondrial (mt) DNA (mtDNA) and are synthesized within the mitochondria by its own …

Measurement Precision And Reliability Of Supraspinatus Tendon Strain Using Speckle Track Analysis Of Ultrasound Images, Gregory Alan Mcclanahan

Theses, Dissertations and Capstones

Introduction: Ultrasound speckle tracking is an emergent method in studying musculoskeletal physiology and disease. For a method to be effective and useful, it needs to be precise and reliable. The precision and reliability of supraspinatus tendon strain measurements have not been explored. The purpose of this study was to examine the precision and reliability of speckle tracking to measure supraspinatus tendon strain.

Methods: Forty-two (42) participants participated in this study. Five (5) ultrasound images of the participant’s right shoulder supraspinatus tendon were collected during a maximal voluntary isometric abduction contraction. Cine loop video files of the 5 imaging trials …

Mechanistic Study Of Diatrizoic Acid Induced Proximal Tubule Cytotoxicity, Dakota Blake Ward

Theses, Dissertations and Capstones

Radiocontrast media (RCM) are necessary for many diagnostic procedures such as arteriography, percutaneous coronary intervention (PCI), and computed tomography. Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital-associated kidney damage accounting for 10-25% of cases worldwide. The mechanisms of contrast-induced renal impairment are not entirely known, but diminished renal hemodynamics, inflammatory responses, and direct cytotoxicity have been hypothesized. The purpose of this study was to investigate the mechanisms of direct cytotoxicity observed in HK-2 cells following treatment with diatrizoic acid (DA) and to determine the source of this damage. Mitochondrial function, endoplasmic reticulum (ER) stress, oxidative …

Naktide Targeted To Adipocytes Ameliorates Western Diet Induced Obesity, Rebecca D. Pratt

Theses, Dissertations and Capstones

Obesity has become a worldwide epidemic and is a major risk factor for metabolic syndrome. It is believed that cellular oxidant stress plays a key role in both the development and maintenance of obesity as well as its associated comorbidities such as diabetes, cardiovascular disease, and nonalcoholic steatohepatitis (NASH). We have previously reported that systemic administration of pNaKtide, which targets the Na/K-ATPase oxidant amplification loop was able to decrease oxidative stress and adiposity in mice fed a high fat and fructose supplemented western diet (WD). As adipocytes are believed to play an active role in the development of obesity and …

Regulation Of Na-K-Atpase By Arachidonic Acid Metabolites In Intestinal Epithelial Cells, Niraj Nepa

Theses, Dissertations and Capstones

The integral membrane protein sodium potassium adenosine triphosphate (Na-K-ATPase), has been extensively studied in various animal cell models. Na-K-ATPase is a multifunctional enzyme which plays a significant role in cellular physiology by regulating electrochemical potential, cell volume, pH, cytosolic calcium, and many nutrient and electrolyte transport processes. As such, it has been implicated in the pathogenesis of inflammatory bowel diseases (IBD) and has been shown to play a vital role in the malabsorption of nutrients and electrolytes. In this context, a significant amount of research has been done over the last two decades to understand the mechanisms of alteration of …

The Effect Of Moderate Alcohol Consumption On Sodium-Dependent Nutrient Co-Transport In Intestinal Epithelial Cells In Vitro And In Vivo, Molly Rae Butts

Theses, Dissertations and Capstones

Background: Alcohol consumption leads to a variety of different health consequences including cardiovascular disease, cancer and malnutrition. This malnutrition is in part due to a sub-optimal diet but also due to the malabsorption of nutrients along the small intestine. Many studies have shown that ethanol directly decreases nutrient absorption along the small intestine; however, few studies have investigated the effect of a moderate dose of ethanol on the transmembrane nutrient co-transporters that line the brush border membrane of the small intestine. The primary fuel source for the small intestine, glutamine, as well as for the entire body, glucose, are …

Interplay Between Genetic Predisposition And Diet In Advancing Obesity And Type 2 Diabetes In The Tallyho Mouse, Jacaline Parkman

Theses, Dissertations and Capstones

Obesity is a global epidemic, affecting all ages. It is one of the leading causes of preventable death, as it increases the risk of type 2 diabetes (T2D), hypertension, cardiovascular disease, nonalcoholic fatty liver disease, and some cancers. Obesity is a complex disease that is caused by a combination of genetic and environmental factors such as diets high in fat and sedentary life style. Despite our increased knowledge of obesity development and progression, current obesity treatments have not stopped the rise in obesity rates. There are still many unknowns related to the underlying mechanisms of obesity that need to be …

Role Of Cytochrome P450 2b6 Polymorphisms In Unexpected Methadone Death, Taha Ahmad

Theses, Dissertations and Capstones

Methadone is a synthetic, long-acting opioid prescribed as an analgesic for chronic pain. It has a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. Cardiotoxicity is caused by elevated (S)-methadone levels by prolonging the QT interval of the heart’s electrical cycle. In 2014, methadone accounted for only 1% of all opioids prescribed for pain, but was responsible for 3,400 of the 14,838 individuals (~23%) who died in the United States from overdoses due to prescription …

Potential Applications Of Capsaicinoids In Small Cell Lung Cancer Therapy, Jamie Rae Friedman

Theses, Dissertations and Capstones

Lung cancer continues to be the leading cause of cancer related mortality worldwide. Lung cancer is not a single disease but an umbrella that encompasses two major classifications, nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC represents about 15- 20% of all lung cancer cases and is almost exclusively diagnosed in smokers. Typically, patients will respond very well to first line treatment, but face inevitable relapse. The fact that SCLC still carries a grim 5-year survival rate of less than 5% highlights the lack of advancement in treatment options to effectively improve patient response and survival. …

Endogenous Antioxidant Overexpression As An Adjuvant To Diet Or Exercise Intervention As Therapy To Counteract Obesity And Beneficially Shift The Gut Microbiome, Deborah Lynn Amos

Theses, Dissertations and Capstones

Oxidative stress plays a key role in metabolic syndrome which includes obesity and cardiometabolic diseases. It is implicated that oxygen-derived free radicals generated during the mitochondrial electron transport chain alter the function of specific biological components, thus activating obesogenic pathways such as glucose and lipid signaling. Research on this topic is of vital importance as obesity is a high-risk factor in the development and progression of severe, debilitating, life-threatening maladies such as cardiometabolic diseases, chronic inflammatory pathologies, and cancer. Furthermore, there is no universal effective therapy to combat the rising rates of obesity with over 1.9 billion (39%) adults classified …

Understanding Pseudomonas Aeruginosa Alginate Regulation And Its Link To Chronic Lung Infections In Cystic Fibrosis Patients, Roy Al Ahmar

Theses, Dissertations and Capstones

Cystic Fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This disorder results in thick lung secretions which compromise the patient’s immune system. Chronic lung infections with Pseudomonas aeruginosa biofilms is a major factor that contributes to poor outcome for clinical treatment. The overall hypothesis of this dissertation is that small colony variant and pyrimidine biosynthesis are linked with biofilm formation, alginate production is dependent on MucA proteolysis, rifaximin can be repurposed to treat biofilm infection and multiplex PCR can be used to rapidly measure the bacterial cell density in …