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Articles 1 - 21 of 21
Full-Text Articles in Pharmacology
Soluble Epoxide Hydrolase Inhibition: A Novel Therapeutic Strategy For Alcohol-Associated Liver Disease., Jeffrey Warner
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 …
Investigation Of Human N-Acetyltransferases (Nat1 And Nat2) Genetic Polymorphisms In Susceptibility To Aromatic Amine And Alkylaniline Genotoxicity., Mariam Habil
Electronic Theses and Dissertations
Arylamine N-acetyltransferases, NAT1 and NAT2, catalyze the detoxification and/or activation of carcinogens. Single nucleotide polymorphisms or SNPs result in different human NAT1 and NAT2 genotypes. We hypothesize that different NATs alleles will impact levels of N-acetylation, HPRT mutations, DNA damage and oxidative stress induced by carcinogens. NER-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and NAT1*4, NAT1*14B, NAT2*4, NAT2*5B or NAT2*7B have been used to investigate N-acetylation of benzidine, β-naphthylamine (BNA), and 4, 4’-methylene bis (2-chloroaniline) (MOCA) as aromatic amines and 3,4-dimethylaniline (3,4-DMA) as one of alkylanilines and their associated toxicity. Our …
Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan
Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan
Electronic Theses and Dissertations
Retinal fibrosis is detrimental to vision. Retinal pigment epithelial (RPE) cells contribute to several retinal fibrotic diseases. Upon exposure to TGF-β, a key fibrotic cytokine, RPE cells trans-differentiate to myofibroblasts marked by the integration of α-SMA fibers into F-actin stress fibers, which confer strong contractility. Myofibroblasts produce and contract the collagen-rich fibrotic scar and disrupt retinal architecture. In this study, we investigated the in vitro effects of the putative endocannabinoid compound N-oleoyl dopamine (OLDA) on TGF-β2 induced porcine RPE cell contraction and α-SMA expression. Using an in vitro collagen matrix contraction assay, we found that OLDA inhibited TGF-β2 induced contraction …
Particulate Hexavalent Chromium Inhibits Homologous Recombination Repair By Targeting Rad51 Paralogs In Human Lung Fibroblasts., Aggie R. Williams
Particulate Hexavalent Chromium Inhibits Homologous Recombination Repair By Targeting Rad51 Paralogs In Human Lung Fibroblasts., Aggie R. Williams
Electronic Theses and Dissertations
Hexavalent Chromium [Cr(VI)] is a known human lung carcinogen and general health hazard. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the major theory in its carcinogenic mechanism. Homologous recombination (HR) repair is a DNA repair pathway that prevents CIN by repairing DNA double-strand breaks. RAD51, a key mediator protein of HR repair, along with the RAD51 paralogs (RAD51B, C, D, XRCC2, and 3) are required for HR repair. During HR, RAD51 loads and forms a helical nucleoprotein filament structure to promote DNA strand exchange and stimulate pairing activity of DNA. Cr(VI) exposures have been shown …
Characterizing The Role Of Macrophages In Cisplatin-Induced Kidney Injury And Progression To Chronic Kidney Disease., Sophia M. Sears
Characterizing The Role Of Macrophages In Cisplatin-Induced Kidney Injury And Progression To Chronic Kidney Disease., Sophia M. Sears
Electronic Theses and Dissertations
Cisplatin is a commonly used chemotherapeutic for treatment of many solid-organ cancers. Unfortunately, 30% of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long term declines in kidney function and development of chronic kidney disease (CKD). While traditional rodent toxicity studies have utilized a single, lethal dose of cisplatin, new models of cisplatin-induced kidney injury have revealed that repeated, low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. C57BL/6 mice are one of the most used …
The Role Of Sphingolipids In Aki And The Progression To Ckd: Potential Therapuetic Targets., Nicholas A. Hoffman
The Role Of Sphingolipids In Aki And The Progression To Ckd: Potential Therapuetic Targets., Nicholas A. Hoffman
Electronic Theses and Dissertations
Acute Kidney Injury (AKI) is most simply defined as a rapid decline in kidney function over a period of hours to days. There is currently a lack of effective treatment options for patients with AKI, highlighting the need to identify new therapeutic targets. Sphingolipids play a number of roles in different models of AKI, suggesting they could be promising future targets for treating kidney injury. Specifically, sphingosine-1-phosphate (S1P) and its receptors (S1PRs) have been implicated in numerous inflammatory disorders and models of AKI. The purpose of this review is to better characterize the role of S1P receptors in models of …
N-Acetyltranserase 2 (Nat2) Genotype Polymorphism In Cryopreserved Human Hepatocytes And Chinese Hamster Ovary (Cho) Cells., Mariam Refaat Zaky Habil
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 …
Paraoxonase 2 Is Critical For Non-Small Cell Lung Carcinoma Proliferation., Aaron Whitt
Paraoxonase 2 Is Critical For Non-Small Cell Lung Carcinoma Proliferation., Aaron Whitt
Electronic Theses and Dissertations
Non-small cell lung carcinoma (NSCLC) comprises 85% of lung cancer diagnoses and is plagued by drug resistance. Thus, elucidating the underlying mechanisms of NSCLC is paramount to expand future treatment options. Paraoxonase 2 (PON2), an intracellular enzyme with arylesterase and lactonase functions, has well-established anti-atherosclerotic activity. Recent studies show PON2 is overexpressed in a variety of tumors and confers drug resistance, although these interactions have not been thoroughly examined in NSCLC. Thus, we sought to investigate the role of PON2 in cellular proliferation using PON2-knockout mice, primary mouse cells, and NSCLC cell lines. Using these approaches, we demonstrate that PON2 …
Development Of Bar-Peptide Nanoparticles And Electrospun Fibers For The Prevention And Treatment Of Oral Biofilms., Mohamed Yehia Mahmoud
Development Of Bar-Peptide Nanoparticles And Electrospun Fibers For The Prevention And Treatment Of Oral Biofilms., Mohamed Yehia Mahmoud
Electronic Theses and Dissertations
Background: Periodontal diseases are globally prevalent inflammatory disorders that affect ~47% of U.S adults. Porphyromonas gingivalis (Pg) has been identified as a “keystone” pathogen that disrupts host-microbe homeostasis and contributes to the initiation and progression of periodontitis. Pg associates with oral streptococci in supragingival plaque and this interaction represents a potential target for therapeutic intervention. Previously our group developed a peptide (designated BAR), that potently inhibits Pg/Streptococcus gordonii (Sg) adherence in vitro and Pg virulence in a murine model of periodontitis. While efficacious, BAR (SspB Adherence Region) provided transient inhibition and required higher concentrations of BAR to disrupt established …
Development Of A Lectin-Fc Fusion Protein With Antiviral And Anti-Cancer Activity., Matthew William Dent
Development Of A Lectin-Fc Fusion Protein With Antiviral And Anti-Cancer Activity., Matthew William Dent
Electronic Theses and Dissertations
This thesis describes the development of a novel lectin-Fc fusion protein and its antiviral and anti-cancer activity. The molecule, Avaren-Fc (AvFc), is a fusion of a variant of the actinomycete lectin actinohivin (Avaren) and the Fc region of human IgG1, and is selective for the terminal α1,2-mannose residues found at the ends of high-mannose-type glycans that can be found on the surface of certain heavily glycosylated viruses and cancer cells. Here, AvFc was found to be able to neutralize simian immunodeficiency virus as well as Hepatitis C virus with nanomolar IC50 values. Furthermore, AvFc recognizes a number of cell …
Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush
Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush
Electronic Theses and Dissertations
There are thirteen known endogenous EGF-like ligands. We previously reported that Betacellulin (BTC) increases ligand-mediated corneal wound healing more than Epidermal Growth Factor (EGF) [Peterson et al. (2014) IOVS 55(5):2870-80], although the molecular reason for this is unknown. Despite being better at promoting wound healing via enhanced cell migration, BTC has reduced receptor affinity and weaker induction of EGFR phosphorylation. These data indicate that BTC’s response is not due to enhanced affinity or EGFR-kinase activity. Receptor phosphorylation and proximity ligation assays indicate that BTC treatment significantly increases ErbB3 phosphorylation and EGFR:ErbB3 heterodimers. BTC traffics EGFR at a faster rate than …
Egfr Signaling From The Early Endosome., Julie A. Gosney
Egfr Signaling From The Early Endosome., Julie A. Gosney
Electronic Theses and Dissertations
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR dimerizes with another ErbB family receptor, leading to kinase domain activation and transphosphorylation of C-terminus tyrosine residues. These phosphotyrosines act as crucial regulators of EGFR signaling as effector proteins dock to the receptor at these sites. The receptor undergoes clathrin-mediated endocytosis into early endosomes, where it can then be trafficked to a lysosome for degradation. However, the kinase domain of EGFR retains its activity during trafficking, suggesting that EGFR can continue …
Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit
Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit
Electronic Theses and Dissertations
Hepatocellular carcinoma (HCC) is one of the deadliest cancers, with variable presentation, high chemotherapy resistance and early tumor recurrence. In this dissertation, we have systematically enriched, identified and characterized HCC cancer stem cells (CSCs) from 3 different HCC cell lines (Hepa1-6, HepG2, and Hep3B) using in vitro serum-free culture method. Enriched spheroids acquired CSC properties, primarily self-renewal capability, spheroid formation ability, and drug resistance. Heterogeneous CSCs enriched from Hepa1-6 cells demonstrated higher tumor initiation and proliferation capability in vivo, compared to control HCC cells in orthotopic immunocompetent mouse model. EpCAM+ CSCs were significantly enriched within heterogeneous Hepa1-6 CSC spheroids. Consequently, …
A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease In Type 2 Diabetes., Qian Lin
Electronic Theses and Dissertations
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1△HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1△HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1△HBS to 2-month-old db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and …
Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller
Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller
Electronic Theses and Dissertations
The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …
The Effects Of Polychlorinated Biphenyls Exposure On Non-Alcoholic Fatty Liver Disease : Role Of Aryl Hydrocarbon Receptor., Hongxue Shi
Electronic Theses and Dissertations
Polychlorinated biphenyls (PCBs) are detectable in serum of 100% of adults in US, and has been associated with fatty liver disease in epidemiological studies. PCBs are classified as either dioxin-like (DL) or non-dioxin-like (NDL) PCB based on their ability to activate the aryl hydrocarbon receptor (AhR). We used exposures that reflect human bioaccumulation patterns, which resembles Aroclor 1260 with a low level of the DL-PCB, PCB 126. Our aim was to determine if this exposure will activate the human and mouse AhR and examine if receptor activation influences these steatotic responses due to PCB exposures. DL-PCBs exposure-induced AhR activation in …
Age-Related Host Factors Regulate Lung Cancer Progression., John Caleb Greenwell
Age-Related Host Factors Regulate Lung Cancer Progression., John Caleb Greenwell
Electronic Theses and Dissertations
Cancer is largely a disease of the elderly. In the United States alone, 87% of all cancers in 2017 will be diagnosed in individuals aged 50 years or older. Among them, lung cancer is the deadliest, accounting for 1 in 4 cancer deaths. The 5-year survival rate is below 20%, a number which has not changed substantially over the past several decades. This underscores a desperate need for new strategies in prevention, early detection and treatment of this deadly disease. While tobacco use is unquestionably the number one risk factor for the development of lung cancer, the majority of diagnoses …
Novel Insight Into The Liver-Lung Axis In Alcohol-Enhanced Acute Lung Injury., Lauren G. Poole
Novel Insight Into The Liver-Lung Axis In Alcohol-Enhanced Acute Lung Injury., Lauren G. Poole
Electronic Theses and Dissertations
Background. Individuals who chronically abuse alcohol are almost 4 times more likely to develop Acute Respiratory Distress Syndrome (ARDS), the most severe form of Acute Lung Injury (ALI), but the mechanisms by which alcohol abuse sensitizes the lung to injury are poorly understood. However, the lung appears to share many parallel mechanisms of injury with the liver- a primary target of alcohol abuse. The overarching goal of this dissertation was therefore to expand on established mechanisms of alcohol-induced liver injury to ask innovative questions about mechanisms of alcohol-enhanced acute lung injury, as well as to develop new tools that may …
Isolation Of Egfr-Containing Early Endosomes., Julie A. Gosney
Isolation Of Egfr-Containing Early Endosomes., Julie A. Gosney
Electronic Theses and Dissertations
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR undergoes clathrin-mediated endocytosis. This spatial regulation of the receptor is an important regulator of receptor expression as it mediates its degradation. Endocytosis also has implications on EGFR downstream signaling, though the details are not fully understood. The goal of this thesis is to develop a method to isolate early endosomes in order to study downstream effectors associated with activated EGFR in this compartment. HeLa cells were used to test various …
A Plant-Made Cholera Toxin B Subunit Enhances Mucosal Wound Healing And Protects Against Ulcerative Colitis And Colon Cancer., Keegan J Baldauf
A Plant-Made Cholera Toxin B Subunit Enhances Mucosal Wound Healing And Protects Against Ulcerative Colitis And Colon Cancer., Keegan J Baldauf
Electronic Theses and Dissertations
This dissertation describes the previously unidentified effects of a plant-produced recombinant cholera toxin B subunit (CTBp) on the gastrointestinal (GI) tract and its ability to protect against inflammation in a mouse model of colonic injury and ulcerative colitis (UC). To comprehensively analyze CTBp’s impacts on the GI tract, we employed global analysis methodologies based on multi-color flow cytometry to analyze immune cell populations in GI and systemic lymphatic compartments, gene expression microarray to decipher transcript-level changes in the colon and small intestine, and 16S rRNA sequencing to characterize fecal microbiota. Based on a drastic shift observed in the immune cell …
Mechanisms And Intervention Strategies For Alcohol And Hiv-Antiretroviral Therapy-Induced Liver Injury., Hridgandh Donde
Mechanisms And Intervention Strategies For Alcohol And Hiv-Antiretroviral Therapy-Induced Liver Injury., Hridgandh Donde
Electronic Theses and Dissertations
Chronic alcohol consumption is a leading cause of liver disease and liver-related death worldwide. Alcoholic liver disease includes, hepatic steatosis, steatohepatitis and ultimately fibrosis and cirrhosis. Emerging evidence has established the important role of the “gut-liver” axis in the development of alcoholic liver disease (ALD). Our recent work indicated that chronic alcohol induced perturbations in the gut microbiome and consequent changes in fatty acids have a major impact on the development of intestinal barrier dysfunction and ALD. The aim of this study was to investigate whether treatment with tributyrin - a butyrate prodrug results in protection against ALD in terms …