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) …

Metformin Alleviates Hepatic Iron Overload And Ferroptosis Through Ampk-Ferroportin Pathway In Hfd-Induced Nafld, Fangzhi Yue, Ying Shi, Shanyu Wu, Lin Xing, Dan He, Lin Wei, Anqi Qiu, Ryan D. Russell, Dongmei Zhang

Health & Human Performance Faculty Publications and Presentations

Highlights

• Metformin alleviates HIO and ferroptosis in HFD-induced NAFLD

• FPN is involved in the molecular mechanism of metformin on HIO in HFD-induced NAFLD

• Metformin upregulates FPN expression by reducing lysosomal ubiquitination degradation

Summary

Metformin prevents progression of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanism is not entirely understood. Ferroptosis, a recently recognized nonapoptotic form of regulated cell death, has been reported to be involved in the pathogenesis of NAFLD. Here, we investigated the effects of metformin on ferroptosis and its potential mechanism in NAFLD. We found that metformin prevented the progression of NAFLD, and alleviated hepatic iron …

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 …

Pharmaceuticals From Natural Products: The Utility Of The Phylogeny, Shaimaa Magdy Saad

Selected Full-Text Master Theses 2021-

About 60% of approved drugs during the last 30 years are either directly or indirectly from natural products. Previous studies have shown that the phylogeny has predictive utility in drug discovery. In this study the pharmacological applications of various naturally-derived drugs were mapped on the phylogeny reconstructed from DNA sequences of the source organisms to decipher phylogenetic patterns that may facilitate drug discovery. A multi-step approach was employed starting with a literature search to compile a comprehensive list of pharmaceutical drugs derived from natural sources. A phylogeny was reconstructed from the source organisms and their pharmacological uses mapped on the …

Potential Neuroprotective Effect Of Artemisinin In A Rotenone-Induced Mice Model Of Parkinson’S Disease, Nada M. Hamada, Hanan Eissa, Nirmeen Megahed, Mohamed H. Daba, Ahlam Elmasry

Mansoura Medical Journal

Background: Parkinson’s disease (PD) is characterized by motor dysfunctions including tremors, rigidity and bradykinesia. Medications for PD alleviate motor symptoms rather than targeting disease pathogenesis. Recently discovered features of artemisinin suggested that it might be used to treat neurodegenerative diseases. Objective: to explore the possible neuroprotective effect of artemisinin in different doses in a rotenone-induced model of PD. Materials & methods: Twenty-five mice were randomly divided into five groups: group 1; negative-control, group 2; positive-control, and groups 3&4&5: artemisinin-treated (30, 40 and 50 mg/kg) respectively. For PD induction, rotenone (3mg/Kg/day) was administered intraperitoneally for 42 days (6 weeks). Behavioral assessment …

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 …

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 …

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 …

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 …

Pharmacometabolomics Profiling Of Preterm Infants Validates Patterns Of Metabolism Associated With Response To Dexamethasone Treatment For Bronchopulmonary Dysplasia., Bradley Stockard, Cheri Gauldin, William E. Truog, Tamorah Lewis

Manuscripts, Articles, Book Chapters and Other Papers

Bronchopulmonary dysplasia (BPD) is one of the most common health complications of premature birth. Corticosteroids are commonly used for treatment of BPD, but their use is challenging due to variability in treatment response. Previous pharmacometabolomics study has established patterns of metabolite levels with response to dexamethasone. We obtained additional patient samples for metabolomics analysis to find associations between the metabolome and dexamethasone response in a validation cohort. A total of 14 infants provided 15 plasma and 12 urine samples. The measure of treatment response was the calculated change in respiratory severity score (deltaRSS) from pre-to-post treatment. Each metabolite was assessed …

A Psychopharmacology Review Of Brexpiprazole, Nicole A. Marion

Conspectus Borealis

Brexpiprazole is an antipsychotic drug often used to help treat schizophrenia and major depressive disorder. This review paper breaks down the drugs history including what it is used for, how it is used, and how it was developed. Pharmacokinetics including administration routes, steady states, and metabolism. This review also describes pharmacodynamics, focusing on drug affinity. It will also discuss pharmacological effects pulling evidence from clinical trials. Last this review will describe the toxicology and safety of brexpiprazole.

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 …

The Regulation Of Stress Steroid Release In Freshwater Turtles, Yoke Tassent

Honors Program Theses

The goal of this study is to characterize the Hypothalamic-Pituitary-Adrenal (HPA) axis regulators of the stress response in a turtle species, the Red-Eared slider, Trachemys scripta elegans and to determine if NPY acts as a secretagogue for adrenal steroids in reptilian species, as it does in mammals. Here, I caught turtles using baited hoop traps. Then, I used pharmacological injections of ACTH (intermediate in HPA axis), dexamethasone (DEX, a synthetic steroid that blocks ACTH release and induces HPA negative feedback), NPY (starvation hormone), and NPY receptor agonists. Each turtle received a single injection upon capture, and I recorded whether adrenal …

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 …

Estrogen Modulation Of Vta Dopamine Neuron Physiology And Behavioral Responsivity To Variable Social Stressors, Mary R. Shanley

Dissertations, Theses, and Capstone Projects

The behavioral output of different animals, or even the same animal in different contexts, is remarkably variable in response to the same external stimulus. This behavioral diversity is due to the complex integration of external and internal stimuli, through both neuronal and hormonal signals that selects the best behavioral response. By their nature as long-distance signaling molecules, hormones play a critical role in communicating information about internal states across the organism. Many hormones produced in the periphery target the central nervous system to modulate animal behavior, selecting for behaviors that are appropriate over behaviors that are maladaptive in that specific …

Effects Of Fluoxetine/Simvastatin/Ascorbic Acid Combination Treatment On Neurogenesis And Functional Recovery In A Model Of Multiple Sclerosis, Olivia Cameron Webb

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Whereas immune modulation has proven beneficial in multiple sclerosis (MS), we hypothesized that targeting down-stream modulators of neurogenesis and subsequent remyelination may offer an additional, if not superior, point of intervention in an attempt to repair damage and recover lost function. As such, the present study assessed the effectiveness of 30-day administration of the drug combination fluoxetine (5 mg/kg), simvastatin (1 mg/kg), and ascorbic acid (50 mg/kg) (FSA) on an early marker of neurogenesis, doublecortin (DCX), and functional recovery using the Montoya Staircase following lysolecithin-induced focal demyelination of the corpus callosum in middle-aged (10-11 month) male and female rats. Lysolecithin …

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 …

Potential Involvement Of Micro Vesicle Particles In The Synergistic Effects Of Ultraviolet-B Radiation And Platelet -Activating Factor Receptor Agonists On Cytokine Production, Shweta Bhadri

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Cytokines play a pivotal role in regulating inflammation, which is a condition that makes the tissue vulnerable to different pathological and physiological conditions. Thus, how cytokines are regulated is an important area of study. Skin that receives ultraviolet B radiation (UVB), a major pro-oxidative stressor, results in the release of multiple cytokines and chemokines like tumor necrosis factor (TNF)-alpha and interleukin (IL)-8. Previous studies from our group and others have demonstrated synergistic release of TNF-alpha when UVB is combined with IL-1 or the lipid mediator Platelet-activating factor (PAF). Of interest, subcellular microvesicle particles (MVP) have been proposed to play an …

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 …

Extracellular Vesicles From Uvb Irradiated Keratinocytes Contain Cyclobutane Pyrimidine Dimers, Meghana Reddy Ginugu

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Ultraviolet (UV) radiation induces the formation of cyclobutane pyrimidine dimers (CPDs) in genomic DNA, which are normally removed by nucleotide excision repair. However, the fate of these adducts remain largely unexplored. Detection of these photoproducts in body fluids could act as a predictor of UV exposure and enable a better understanding of the pathogenesis of photosensitive skin diseases, such as lupus. Using cultured human keratinocytes exposed to UVB radiation in vitro, ultracentrifugation of cell culture supernatants, and immunodot blot analysis of isolated DNA, we have found that a small fraction of CPDs is released from cells in a dose- and …