Life Sciences Commons^™

Determination Of Genetic Variation In Opioid-Resistant Hospice Patients Using A Pharmacogenomics Approach, Daniel Bianculli

Theses and Dissertations

Managing pain requires a delicate balance between the advantages of opioid analgesia and the possible adverse effects. This balance becomes even more difficult in hospice and palliative care environments where dosage regimens are frequently ambiguous. Some hospice patients experience opioid resistance, in which opioids no longer produce an analgesic effect on a patient. Evidence-based analyses frequently omit this vulnerable population, resulting in a need for concrete procedures. The emergence of pharmacogenomic analysis and personalized treatment presents a solution to this problem by using each patient's genomic data to interpret opiate dosing. This pharmacogenomic study aimed to single nucleotide polymorphisms (SNPs) …

Soluble Epoxide Hydrolase Inhibition: A Novel Therapeutic Strategy For Alcohol-Associated Liver Disease., Jeffrey Warner

Electronic Theses and Dissertations

Introduction Alcohol-associated liver disease (ALD) is a common chronic liver disease and healthcare burden, and a spectrum of pathologies ranging from steatosis to steatohepatitis, fibrosis, and alcohol-associated hepatitis (AH). Despite its prevalence, there are limited effective therapeutic options for the treatment of ALD/AH. Previous evidence suggested that inhibition of soluble epoxide hydrolase (sEH), a lipid metabolism enzyme which degrades beneficial metabolites of dietary polyunsaturated fatty acids, may be a beneficial strategy. The central hypothesis of the current dissertation is that sEH inhibition will ameliorate alcohol-associated liver injury and inflammation in mouse models of ALD. Methods To determine the efficacy of …

Pharmacokinetics Of Single Feeding Of Cannabidiol In Cattle: A Pilot Study, Haley Cornette

Honors College Theses

Cannabidiol (CBD) is a substance that has been used in complementary medicine for many years. However, modern medicine has little knowledge of how this substance is utilized and metabolized in ruminant animals. Regulations on quality assurance and use in animals are lacking, and CBD supplementation in livestock is not approved. If CBD supplements can be shown to be safe and effective, detection in the animal will be important for determining regulation of use. A withdrawal period can then be established to allow time for deterioration of product to safe levels before livestock products enter human markets. This study sought to …

The Evaluation Of The Prokinetic Action Of A Luminally Restricted 5-Ht4 Receptor Agonist In Mice, Emma Schoeling

Graduate College Dissertations and Theses

Serotonin (5-HT) is a neurotransmitter mainly produced in the enteric nervous system (ENS) of the gastrointestinal (GI) system. Serotonin has widespread function throughout the body including regulating mood, cognition, sleep, sex, and appetite. In the context of the gut, the monoamine modulates vasodilation, mucus secretion, pain, and peristaltic reflexes for motility. The 5-HT4 receptor is expressed on enteric epithelial cells and nerve terminals in the intestinal mucosa. The agonists available to act on these receptors are a favorable target to promote epithelial healing, recovery from colitis or constipation, and epithelial cell proliferation. The non-absorbable, luminally restricted, 5-HT4R agonist (5HT4-LA1; Takeda …

To Determine The Role Of The Platelet Activating Factor - Receptor In Folfirinox Therapy-Mediated Microvesicles Particle Generation, Krishna Awasthi

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Given that Pancreatic cancer continues to be one of the primary causes of cancer-related death and that existing treatment options have a poor success rate, it is important to investigate the role of potential factor(s) involved in pancreatic cancer growth or diminishing the effectiveness of chemotherapeutic agents. An alternative regimen for pancreatic cancer treatment called FOLFIRINOX has shown to increase the survival rate and improve Eastern Cooperative Oncology Group (ECOG) performance status score among the pancreatic cancer patients. However, FOLFIRINOX therapy is associated with several side effects. Through mechanisms involving the secretion of microvesicle particles (MVP), studies, including ours have …

Regulation Of Cathepsin L Expression And Activity By Cell Confluence And The Circadian Clock, Prashant Gaikwad

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Cathepsin L is a lysosomal cysteine protease that is encoded by the CTSL gene in humans. Previous results have shown that CTSL expression and activity towards the DNA repair protein XPA are elevated in lysates of confluent/quiescent HaCaT keratinocytes. Because other nuclear proteins, including 53BP1 and histone H3, have also been reported to be CTSL substrates under conditions of cell differentiation, senescence, or quiescence, CTSL expression and activity (cleavage) of multiple nuclear proteins was examined in lysates from HaCaT cells and other cell lines at various days after plating and cell confluency. Our study found that adding CTSL inhibitors to …

Intrinsic Efficacy As A Determinant Of Opioid Effectiveness In Treatment Of Pain-Depressed Behavior, Edna Santos

Theses and Dissertations

Pain is a major public health concern that is commonly associated with behavioral depression, and a major goal in pain treatment is alleviation of pain-related behavioral depression. High-efficacy mu opioid receptor (MOR) agonists (e.g. fentanyl, morphine, oxycodone) are effective to treat pain, but their use is limited by side effects that not only endanger the patient but may also obscure analgesic rescue of pain-depressed behavior. The ongoing epidemic of opioid abuse and overdose deaths has stimulated research to discover non-opioid alternative analgesics; however, this search neglects the clinical potential of safer intermediate-efficacy MOR agonists (e.g. buprenorphine). The objective of the …

Vapourized Cannabis Extract Administration Impairs Memory And Alters Neural Activity In Laboratory Rats, Megan Chladny

Theses and Dissertations (Comprehensive)

Although people have smoked cannabis for millennia, administration of cannabis by heating the dried plant material or distilled extracts to a temperature just below the combustion point (i.e., vapourization or "vaping") has rapidly increased over the past few years (Javadi-Payder, Cole, and Taffe, 2018; Manwell, Charchoglyan, Brewer, Matthews, Heipel, and Mallet, 2014). Conversely, most of the cannabinoid research using rodent models has used parenteral routes of administration to examine the effects of purified cannabis extracts such as ∆⁹-tetrahydrocannabinol (THC), making it difficult to directly compare laboratory research to human drug use. Building on previous studies showing that THC …

A Polypharmacological Approach To Relapse Prevention In An Animal Model Of Heroin Addiction, Scott T. Ewing

Dissertations, Theses, and Capstone Projects

Chemical compounds that target dopamine (DA) D1 or D3 receptors have shown promise as potential interventions in animal models of cue-induced relapse. However, undesirable side effects or pharmacodynamic profiles have limited the advancement of new compounds in preclinical studies when administered as independent treatments. In this series of experiments, we explored the effects of co-administration of a D1-recepter partial agonist (SKF 77434) and a D3-receptor antagonist (NGB 2904) in heroin-seeking rats within a ‘conflict’ model of abstinence and cue-induced relapse. Rats were first trained to press a lever to self-administer heroin and drug delivery was paired contingently with cues (e.g., …

Application Of Cannabidol To Ocular Pharmacokinetics And Pharmacodynamics., Alyssa Laun

Electronic Theses and Dissertations

Cannabidiol (CBD) is the most abundant non-psychotropic cannabinoid constituent of Cannabis sativa. CBD is potentially therapeutic for the eye through antioxidant, anti-inflammatory, and neuroprotective effects. However, the effect of CBD on intraocular pressure (IOP)- the major risk factor for glaucoma- is controversial and large variability exists in the literature. IOP is regulated through aqueous humor (AH) dynamics in trabecular meshwork (TM) tissues. Measurement of CBD in AH and correlation with effects on IOP would clarify what concentrations mediate changes to IOP. Therefore, the overall goal of this dissertation is to measure CBD in ocular tissues and correlate concentrations with …

Heightened Levels Of Microvesicle Particles Resulting From Combination Of Ethanol And Thermal Burn Injury, Chad Alan Brewer

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Ethanol (EtOH), in combination with thermal burn injury, is a clinically significant problem resulting in an increase in morbidity and mortality due to acute multi-organ toxicity from excess systemic cytokine release. This intoxicated thermal burn affects close to 50% of the total numbers of hospital-admitted burn patients and currently has no standard treatment. However, using in vitro cellular and in vivo murine models, our group has provided data implicating the augmented production of the lipid mediator Platelet-activating factor (PAF) in keratinocytes in response to intoxicated thermal burn injury in the subsequent pathology. Of importance, our group has demonstrated that activation …

Replication Stress Induced By The Ribonucleotide Reductase Inhibitors Guanazole, Triapine, And Gemcitabine In Fission Yeast, Mashael Yahya A Alyahya

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Replication stress can be produced by various exogenous or endogenous factors that perturb the movement of replication forks. To overcome the stress, the cells provoke the DNA replication checkpoint to mobilize several pathways to protect the forks, maintain genome integrity, and promote cell survival. Defects in the replication checkpoint cause forks collapse, leading to chromosomal DNA damage or cell death. Although the replication checkpoint is crucial for genome integrity in all eukaryotes, the underlying mechanisms remains to be fully understood. To investigate the mechanisms of DRC, hydroxyurea (HU), an established inhibitor of ribonucleotide reductase (RNR), has been widely used in …

Ahr-Mediated Transcriptional Regulation Of The Human Immunoglobulin Hs1.2 Enhancer, Sydney White

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The 3'IGHRR is thought to be responsible for the transcription of the immunoglobulin heavy chain (IGH) gene locus, which is essential for the production of antibodies. The human 3’IGHRR, which is duplicated in humans, contains the hs3, hs4, and hs1.2 enhancers. Additionally, the hs1.2 enhancer is polymorphic in humans and consists of a 53 bp invariant sequence that can be repeated one to four times. Previous experiments in a mouse and human B-cell line model have shown that the high affinity AhR ligand and environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce hs1.2 enhancer activity in an AhR-dependent manner. The AhR is …

Impaired Β-Cell Neogenesis In A Mouse Model Of Metabolic Syndrome, Modhi Abdullah Alshammari

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Pancreatic islet β-cell plays an essential role in insulin release and hence glucose homeostasis. The maintenance of glucose homeostasis depends on β-cell ability to cope with enough insulin to fulfill metabolic and physiological demands. Adequate insulin release is the result of highly complex and dynamic interplays between acute changes in β- cell electrical activity, exocytosis and chronic adaptations in cellular function, volume, mass and proliferation. All of this appears modulated, to some extent, by the functional presence of Slc12a2 symporters, also known as Na+K+2Cl– cotransporter-1 (Nkcc1), which accumulates intracellular Cl– above its electrochemical equilibrium. Recent studies from our laboratory showed …

Impact Of Theory-Based Interventions On Meaningfulness Of Undergraduate Nursing Pharmacology Student Learning, Betsy L. Mauldin

Nursing Theses and Dissertations

Objective: Nursing pharmacology is a complex and content-dense course, often cited as difficult for nurse educators and students and a reason for not progressing in nursing curricula. Even nurses who experience high academic performance report feeling ill-prepared to adequately perform medication management for nursing practice in the current fast-paced environment. The objective of this five-chapter portfolio is to explain the development and implementation of a two-pronged intervention to facilitate meaningful learning of pharmacology principles within nursing students. Chapter 1 describes an overview of the approach to the intervention.

Methods: Chapter 2 describes one prong of the study intervention, the Pharmacology …

The Effect Of Circadian Clock Modulation On Cisplatin Cytotoxicity, Nadeen Nibal Ahmad Anabtawi

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Cisplatin is a DNA damage-based chemotherapeutic drug widely used to treat various types of cancers; however, the treatment's toxicity restricts its efficiency. Studies have shown that the circadian rhythm controls the DNA damage response and affects the repair pathways of cisplatin-induced DNA damage. Circadian clock modulation, therefore, has been proposed to be a potential mechanism for enhancing cisplatin tolerability. Here we used clock-enhancing molecules to evaluate the effect of pharmacological clock modulation on cisplatin cytotoxicity. Using cultured human cell lines, cisplatin cytotoxicity was found to be attenuated following treatment with circadian-enhancing molecules KS15 and SR8278. Moreover, the protein and mRNA …

Stress-Induced Senescence In Human Dermal Fibroblasts : Effects Of Creatine And Nicotinamide Post Stress Treatment, Venkata Sravya Arikatla

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In skin connective tissue, dermal fibroblasts appear to be the most prevalent cell type. They are in charge of making the extracellular matrix that makes up the skin's connective tissue, and also involved in wound healing. Moreover, they produce Insulin-like growth factor-1 (IGF-1) which helps in activation of Insulin growth factor-1 receptor (IGF-1R). This receptor helps to control cell proliferation and responses to DNA-damaging substances such as UVB radiation, reactive oxygen species (ROS), and therapeutic drugs. According to our findings, lack of IGF-1 expression in the dermis of elderly patients due to fibroblast senescence (senescence is characterized by which cells …

The Protective Effects Of Mir-210 Modified Endothelial Progenitor Cells Released Exosomes In Hypoxia/Reoxygenation Injured Neurons, Sri Meghana Yerrapragada

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Endothelial progenitor cells (EPCs) have been shown to provide beneficial effects on oxidative stress. Exosomes (EXs) released from these stem cells could be one of the major contributors, as they are known to convey the benefit of one cell to another cell via microRNAs (miRNA). At first, we determined that EPCs release more EXs when they are serum-starved for 48 hours., and by determining the microRNA-210 (miR-210) levels in the EXs, we found that miRNA is being transferred from cells to EXs. Meanwhile, miR-210 is gaining popularity in reducing elevated oxidative stress levels. In this study, we investigated the role …

Functions Of Atr Kinase In Terminally Differentiated Human Epidermal Keratinocyles And In Human Ex-Vivo Skin After Exposure To Ultraviolet B Radiation, Vivek Shashank Nag Gogusetti

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The functions of Ataxia telangiectasia and Rad-3 related protein (ATR) is very much important in a cell, as it is a DNA damage response protein, which plays an important role in cell division, DNA repair and apoptosis. This protein helps in proliferation in the actively DNA dividing normal cells and in cancer cells. The functions of ATR in a proliferating cell are well studied and known to involve regulation of replication fork and cell cycle progression after DNA damage. Whereas, in a non-replicating cell, the functions of ATR are not so well known. In the human body, most of the …

Xeroderma Pigmentosum A Deficiency Results In Increased Generation Of Microvesicle Particles In Response To Ultraviolet B Radiation, Christian Lea Rajeshkumar

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Xeroderma Pigmentosum is a genetic disorder in which ability to repair DNA damage such as from UV radiation is decreased. Nucleotide excision repair is known for repairing DNA damage caused by UV radiation and XPA plays a major role in recognizing and eliminating abnormal section of DNA. Therefore, XPA deficiency decreases repair efficiency of DNA. Of note, XPA deficiency is linked with photosensitivity. Microvesicle particles are membrane-bound particles which are released into the extracellular environment in response to multiple stimuli including the lipid Platelet activating factor (PAF). Previous studies have shown that XPA deficiency can induce increase production of reactive …

Insulin-Like Growth Factor-1 (Igf-1) Impacts P53-Regulated Gene Products In Uvb-Irradiated Human Keratinocytes And Skin Epidermis, Abdulrhaman Mohammed Mohammed Alkawwar

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Skin cancer is the most prevalent human malignancy and is primarily caused by ultraviolet (UV) wavelengths of sunlight. However, the fact that most skin cancers occur in people over the age of 60 indicates that advantaged age is a second skin cancer risk factor. Why geriatric skin is prone to developing skin cancers is not clear, but several studies have shown that dermal fibroblasts in geriatric skin express lower levels of the hormone insulin-like growth factor-1 (IGF-1) than young adult skin and that deficient IGF-1 signaling negatively impacts how epidermal keratinocytes respond to UVB radiation. A major regulator of the …

Identification Of New Metabolic Mutations In The Fission Yeast Schizosaccharomyces Pombe That Sensitize The Cell To Hydroxyurea, Alaa Mahdi

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Cancer is a life-threatening illness and innovative research is therefore required to fuel the development of new anti-cancer therapies. As an anti-proliferative drug, hydroxyurea (HU) has been used in the treatment of various neoplastic and non-neoplastic diseases such as sickle cell anemia, psoriasis, and viral infections. HU is a well-known inhibitor of ribonucleotide reductase (RNR), an enzyme that generates dNTPs for DNA replication and repair. In our genetic screen in fission yeast looking for mutants with defects in checkpoint response, we also found a set of mutants that are highly sensitive to HU but with a functional checkpoint response. It …

Topical Photodynamic Therapy Generates Microvesicle Particles, Oladayo Ayobami Oyebanji

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Photodynamic therapy (PDT) involves the use of light at an appropriate wavelength acting on a photosensitizing chemical to cause cell death via generation of reactive oxygen species. PDT has been useful in the management of skin conditions (like acne, psoriasis) and cancers like superficial skin, esophageal and non-small cell lung cancers. In addition to these therapeutic effects, previous murine studies from our group have demonstrated that topical PDT induces immunosuppression in vivo. Thus, topical PDT of skin can generate systemic effects through unknown mechanisms. Our group showed that PDT induces an immunosuppressive effect which occurs partly via Platelet-Activating Factor Receptor …

Role Of Exercise In Macrophage Polarization Of Perivascular Adipose Tissue And Adipose Tissue Inflammation In Hypertensive Mice Model, Venkata Sai Usha Sri Polaki

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Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. It can lead to severe health complications and increase the risk of heart disease, stroke, and sometimes death. Perivascular adipose tissue (PVAT) is known as the adipose tissue (AT) surrounding all the blood vessels and plays a critical role in the pathogenesis of the vascular disease. In vascular pathologies, PVAT increases in volume and becomes dysfunctional, with altered cellular composition and molecular characteristics. Macrophages have been found to accumulate in PVAT during hypertension, which might be involved …

Effects Of Creatine And Nicotinamide On Experimentally Induced Senescence In Dermal Fibroblasts, Avinash Satyanarayan Mahajan

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Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce Insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation found in sunlight. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer in geriatric patients. The present studies were designed to test the hypothesis that pro-energetics like creatine monohydrate and nicotinamide …

The Feeding Pattern Of C57bl/6j Mice, Yakshkumar Dilipbhai Rathod

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The feeding pattern and control of energy intake in social mice are poorly understood. Here, we determined and quantify the normal nocturnal feeding pattern of group-housed male and female mice of the C57BL/6J genetic background fed a chow diet. Mice at 10 and 20weeks of age showed the expected age-dependent increase in lean and fat mass being them more pronounced in males. Under ad libitum conditions, male and female mice ate comparable amounts of food per unit of body weight irrespective of gender. The analysis of the feeding microstructure revealed that energy intake in females is the result of significantly …

Multiple Genotoxic Agents Activate Atr Kinase Signaling In Quiescent Human Cells, Mariyyah Ahmed O. Madkhali

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The ATR protein kinase is activated in response to DNA damage and other forms of genotoxic stress caused by both environmental carcinogens and anti-cancer drugs. However, much of our understanding of ATR kinase function is limited to proliferating cells in which DNA replication stress is the primary signal for ATR activation and where the major regulatory targets of ATR signaling are proteins involved in DNA synthesis and cell cycle progression. Here we have used HaCaT keratinocytes maintained in a non-replicating, quiescent state in vitro to examine how cell killing by different genotoxic agents is impacted by cell growth status and …

Investigation Of Riluzole’S Synaptic Protection Mechanism Through Hsf1-Bdnf Axis, Yi Zhang

Theses and Dissertations (ETD)

The FDA-approved amyotrophic lateral sclerosis (ALS) drug Riluzole has great potential in treating Alzheimer’s disease (AD) based on promising animal data as well as its known action on modulating synaptic transmission. However, its detailed mechanism of action is not fully understood. Here, we proposed work aiming to address this aspect via focus- ing on the Heat Shock Factor 1 (HSF1)-dependent mechanisms. We found that Riluzole could increase HSF1 and BDNF (Brain-Derived Neurotrophic Factor) expression both at transcriptional and translational levels. CA1 (Cornu Ammonia, the first region in the hip- pocampal circuit), is its main target. We also demonstrated a protective …

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of …

Elucidation Of The Molecular Mechanisms Of Electrically-Induced Cardioprotection, Anne Elizabeth Roessler

Dissertations

Cardiovascular disease is the leading cause of death worldwide. A myocardial infarction (MI), commonly known as a heart attack, is a major event in cardiovascular disease characterized by reduced blood flow to the heart. The ischemia and reperfusion (I/R) injury associated with an MI results in a region of dead tissue in the heart called an infarct, the size of which influences patient prognosis. In the 1980s, it was discovered that short, non-lethal episodes of I/R, termed ischemic preconditioning (IPC), can protect the heart against a subsequent MI. Ischemic preconditioning demonstrated the phenomenon of endogenous cardioprotection. Cardioprotection has great potential …