Digital Commons Network^™

Vitamin E Δ-Tocotrienol Sensitizes Human Pancreatic Cancer Cells To Trail-Induced Apoptosis Through Proteasome-Mediated Down-Regulation Of C-Flip, Rony A. Francois, Anying Zhang, Kazim Husain, Chen Wang, Sean Hutchinson, Michael Kongnyuy, Surinder K. Batra, Domenico Coppola, Said M. Sebti, Mokenge P. Malafa

Journal Articles: Biochemistry & Molecular Biology

Background: Vitamin E δ-tocotrienol (VEDT), a vitamin E compound isolated from sources such as palm fruit and annatto beans, has been reported to have cancer chemopreventive and therapeutic effects.

Methods: We report a novel function of VEDT in augmenting tumor necrosis factor-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis in pancreatic cancer cells. The effects of VEDT were shown by its ability to trigger caspase-8-dependent apoptosis in pancreatic cancer cells.

Results: When combined with TRAIL, VEDT significantly augmented TRAIL-induced apoptosis of pancreatic cancer cells. VEDT decreased cellular FLICE inhibitory protein (c-FLIP) levels without consistently modulating the expression of decoy death receptors 1, …

Pr55Α Regulatory Subunit Of Pp2a Inhibits The Mob1/Lats Cascade And Activates Yap In Pancreatic Cancer Cells, Ashley L. Hein, Nichole D. Brandquist, Caroline Y. Ouellette, Parthasarathy Seshacharyulu, Charles A. Enke, Michel M. Ouellette, Surinder K. Batra, Ying Yan

Journal Articles: Biochemistry & Molecular Biology

PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or …

Protease-Mediated Growth Of Staphylococcus Aureus On Host Proteins Is Opp3 Dependent, Mckenzie K. Lehman, Austin S. Nuxoll, Kelsey J. Yamada, Tammy Kielian, Steven D. Carson, Paul D. Fey

Journal Articles: Pathology and Microbiology

Staphylococcus aureus has the ability to cause infections in multiple organ systems, suggesting an ability to rapidly adapt to changing carbon and nitrogen sources. Although there is little information about the nutrients available at specific sites of infection, a mature skin abscess has been characterized as glucose depleted, indicating that peptides and free amino acids are an important source of nutrients for the bacteria. Our studies have found that mutations in enzymes necessary for growth on amino acids, including pyruvate carboxykinase (ΔpckA) and glutamate dehydrogenase (ΔgudB), reduced the ability of the bacteria to proliferate within a …

The Impact Of Post Translational Modification On The Aggregation Of The Ss-Amyloid Peptide In The Presence Or Absence Of Lipids, Albert Walton Pilkington Iv

Graduate Theses, Dissertations, and Problem Reports (ETD)

Alzheimer’s disease (AD) is a neurodegenerative condition afflicting 5.7 million Americans with no effective treatments. The pathology of AD is described by the formation of neurotoxic oligomers formed by the self-assembly of amyloid-β (Aβ). The affinity of oligomers for cellular membranes disrupts calcium homeostasis and is believed to be the underlying cause of neurotoxicity; however, due to the metastability of oligomers, it has been difficult to understand their role in membrane interactions and self-assembly. Here we utilize post translational modifications (PTM) to understand the role of specific amino acids on Aβ₄₀-membrane interactions and self-assembly. We employ ThT, AFM, …

Investigation Of Bovine Conceptus Galectins And The Effect Of Bovine Conceptus Secretory Proteins On The Endometrial Epithelial Transcriptome, Heather Lynn Baldwin

Graduate Theses, Dissertations, and Problem Reports (ETD)

Pregnancy loss in cattle is greatest in the first 30 days of gestation. Near d15 of gestation, bovine conceptuses elongate and express LGALS1, an immunosuppressive glycan-binding protein believed to be essential for implantation. However, other members of the bovine galectin family, including LGALS3, LGALS4, LGALS7, LGALS8, LGALS9 and a galectin-13-like gene (LGALS13L), also may be expressed by the elongating conceptus. Therefore, galectin expression in elongating, d16 bovine conceptuses and intercaruncular endometrium as well as elongating, d14 ovine conceptuses and intercaruncular endometrium was assessed by RT-qPCR. Angus heifer and Texel ewes underwent estrous cycle synchronization and either inseminated or not bred. …

Sonic Hedgehog Is Expressed By Hilar Mossy Cells And Regulates Cellular Survival And Neurogenesis In The Adult Hippocampus, Luis E. Gonzalez-Reyes, Chia-Chu Chiang, Mingming Zhang, Joshua Johnson, Manuel Arrillaga-Tamez, Nicholas H. Couturier, Neha Reddy, Lev Starikov, Jeffrey R. Capadona, Andreas H. Kottmann, Dominique M. Durand

Publications and Research

Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration …

Embryonic Stem Cell-Derived Exosomes Increase The Antiproliferative Activity Of Doxorubicin In Breast Cancer, Alexander M. Hirsch

Theses and Dissertations

The field of cancer research has grown immensely in recent decades and has led to a better understanding of the causes of the disease, as well as greatly improved treatment for various types of cancers, especially breast cancer. One of the most effective treatments involves the chemotherapeutic drug doxorubicin (DOX). DOX is an effective tool against all types of breast cancer, especially against triple negative breast cancer. However, DOX causes adverse side effects that include damage to the heart and skeletal muscle, particularly above specific cumulative doses. Recent evidence suggests that embryonic stem cell-derived (ES) exosomes, nanoscale extracellular vesicles that …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer, Liliya Tyutyunyk-Massey

Theses and Dissertations

Abstract

Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient’s mortality, it is paramount to identify strategies for effectively destroying residual tumor cells.

Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence …

Characterization Of The Novel Interaction Between Neisseria Gonorrhoeae Tdfj And Its Human Ligand S100a7, Stavros Maurakis

Theses and Dissertations

Neisseria gonorrhoeae is an obligate human pathogen that causes the common STI gonorrhea, which presents a growing threat to global health. The WHO estimated 78 million new cases of gonorrhea worldwide in 2017, with estimates of 820,000 new cases in the United States alone according to the CDC. High-frequency phase and antigenic variation inherent in N. gonorrhoeae, coupled with its natural ability to rapidly acquire and stably integrate antimicrobial resistance factors into its genome, have culminated in an infection against which there is no effective vaccine, and for which the list of viable therapeutic options is quickly shrinking. Moreover, no …

Conjugated Bile Acid And Sphingosine 1-Phosophate Prompt Cholangiocarcinoma Cell Growth Via Releasing Exosomes, Waad A. Alruwaili

Theses and Dissertations

Cholangiocarcinoma (CCA) is a fatal primary malignancy that is formed in the bile ducts. Cancer-associated myofibroblasts play a crucial role in CCA proliferation and invasion. Furthermore, there is a growing interest in the role of the exosome in the interaction between the cancer-associated myofibroblasts and cholangiocarcinoma which lead to CCA growth. However how cholangiocarcinoma-derived exosome affect the cancer-associated myofibroblasts in the tumor microenvironment remain unknown. In this study, we examined whether exosome produced by cholangiocarcinoma could involve in the prompt of CCA cells growth by regulation of myofibroblast. We found that cholangiocarcinoma-derived exosome could prompt elevated α-smooth muscle actin and …

Therapeutic Targeting Of Relaxin Signaling In Ischemic Heart Disease, Siva Teja Vk Devarakonda

Theses and Dissertations

Ischemic heart disease is characterized by reduced perfusion of oxygenated blood to the myocardium, potentially resulting in infarction upon occlusion of coronary arteries. While prompt reperfusion and advances in in-hospital care have led to a decline in short term mortality, sustained damage to the ventricle, along with reperfusion injury, can lead to progressive deterioration in cardiac function. Limiting the extent of this initial ischemia-reperfusion injury and combating the course of adverse remodeling remains the scope of several preclinical studies geared towards improving cardiac health after MI. To this, relaxin-2 – the peptide hormone that regulates maternal hemodynamic function during pregnancy …

Using Fundamental Properties Of Light To Investigate Photonic Effects In Condensed Matter And Biological Tissues, Laura A. Sordillo

Dissertations and Theses

Light possesses characteristics such as polarization, wavelength and coherence. The interaction of light and matter, whether in a semiconductor or in a biological sample, can reveal important information about the internal properties of a system. My thesis focuses on two areas: photocarriers in gallium arsenide and biomedical optics. Varying the excitation wavelength can be used to study both biological tissue and condensed matter. I altered the excitation wavelengths to be in the longer near-infrared (NIR) optical windows, in the shortwave infrared (SWIR) range, a wavelength region previously thought to be unusable for medical imaging. With this method, I acquired high …

Pharmacodynamics Of Monoamine Transporter Releasing Agents And Reuptake Inhibitors, Alexa Holloway

Theses and Dissertations

Ligands of the human monoamine transporters encompass a wide range of both illicit and therapeutic drugs that act upon neural circuitry related to reward, motivation, and the processing of salient stimuli. The present study utilizes two methods for analyzing transporter substrates and inhibitors in order to characterize activity and assess potency. The first measures transient changes in intracellular calcium as a surrogate for transporter activity by harnessing the electrical coupling of monoamine transporters and L-type calcium channels. This is used to analyze novel chimera of the strong hDAT inhibitors methylphenidate and ��-PPP in order to assess the contribution of specific …

A High Fructose Diet Alters Affective-Like Behavior And Metrics Of Synaptic Mitochondrial Function Differentially In Male And Female Rats, Alix H. Kloster

Theses and Dissertations

Fructose consumption has become a normalized part of the standard American diet over the past 40 years. While fructose consumption is a known risk factor of metabolic syndrome, there is increasing evidence that fructose consumption influences brain and behavior. Recently, more interest has been focused on mitochondrial dysfunction as a potential link between metabolic stress and modifications of the central nervous system. Mitochondria are in the unique position of both regulating and being vulnerable to alterations in energy homeostasis. Sex-differences are well categorized in the presentation of metabolic symptoms associated with excessive fructose consumption. Thus, it is important to characterize …

Synthesis And Bioevaluation Of Methionine Depletion Agents, Houssine Ikhlef

Electronic Theses and Dissertations

The native polyamines (putrescine, spermidine, and spermine) are low molecular weight amines that exist as polycations at physiological pH. These polycations interact with DNA, RNA, and influence many cellular processes. Intracellular polyamine levels are maintained via a balance of polyamine biosynthesis, catabolism, and transport. Ornithine, an amino acid obtained from L-arginine, is decarboxylated by ornithine decarboxylase (ODC) to form putrescine. The biosynthesis of the higher polyamines, spermidine and spermine, requires the addition of an amino-propyl group donated by decarboxylated S-adenosylmethionine (dc-SAM), which itself is derived from the amino acid L-methionine (Met). Tumor cells are heavily reliant on methionine because it …

It Takes Two To Tango: The Toxin-Chaperone Relationship, Alisha Kellner

Electronic Theses and Dissertations

Cholera toxin (CT) enters the cell via receptor-mediated endocytosis and travels in a retrograde fashion to the endoplasmic reticulum (ER). The catalytic A1 subunit (CTA1) is then displaced from the rest of the holotoxin, unfolds, and is exported to the cytosol where it regains an active conformation for the ADP-ribosylation of its G-protein target. We have shown that the cytosolic chaperones Hsp90 and Hsc70 are required for CTA1 translocation to the cytosol. We have also shown that both are able to independently bind and refold CTA1. Using libraries of CTA1-derived peptides, we have identified a single Hsc70 binding site, YYIYVI …

Investigating The Effects Of Methylphenidate On Cue Salience And Behavioral Flexibility: Role Of D2 Receptors, Mercedes Mcwaters

Graduate Research Theses & Dissertations

Healthy individuals worldwide are using cognitive enhancing drugs in an attempt to remain competitive in society for education, careers, and athletics. Commonly, these individuals are using prescription stimulants, such as methylphenidate (MPH), due to their known acute neuroenhancing effects. While these neuroenhancing effects have been established using a variety of learning, memory, and attention tasks in humans and rodents, little research has investigated the effects of MPH use on specific components of these tasks, such as cue salience. One process that is important for learning the relationship between a cue and a reward is salience, or the heightened perception and …

Investigating The Rho-Kinase (Rock) Signaling Pathway As A Therapeutic Target In Alzheimer’S Disease, Benjamin Wade Henderson

All ETDs from UAB

Current estimates project that there are approximately 5.4 million Americans affected by Alzheimer’s disease (AD). While this number is expected to dramatically increase in the years to come, there is currently no disease modifying therapeutic to prevent or slow AD progression. Cognitive decline is a clinical hallmark of AD, while accumulation of amyloid-β (Aβ) is a pathological hallmark. Work in the field has demonstrated that mitigating Aβ levels may serve as a rational therapeutic avenue to slow progression of the disease. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that …

Structural And Functional Insights Into Influenza A Virus Ns1-Mediated Rig-I Antagonism, Alexander Jureka

All ETDs from UAB

The influenza virus non-structural protein 1 is well known to antagonize the host innate immune response through its interaction with the innate immune sensor, retinoic acid induc-ible gene I (RIG-I). While the complete mechanism of the NS1:RIG-I interaction remains unclear, we were the first to demonstrate a direct interaction between the NS1 RNA-binding domain (NS1RBD) from the 1918H1N1 influenza virus and the second caspase activa-tion and recruitment domain (CARD2) of RIG-I using NMR. In addition, we also identi-fied that mutation of Arg 21 in the 1918H1N1 NS1RBD to Gln (R21Q) completely abrogated the NS1:CARD2 interaction. Given that CARD2 plays a …

Early Life Stress And Immune Responses In Adult Rat Kidneys, Ijeoma E. Obi

All ETDs from UAB

Globally, human studies show overwhelming associations between adverse childhood experiences and cardiovascular disease (CVD) and CVD risks throughout adult life. As early as 6 years old, there are significant associations between childhood adversity and inflammation, and those association are observed throughout adult life as well. Over a decade ago, rodent models were used to establish the importance of the immune cells in hypertension, which is the major risk factor in developing CVD. Although these associations in humans are important, they pose several limitations that can be overcome by the use of animal models to study the molecular mechanisms that are …

Ventral Hippocampal Input To The Medial Prefrontal Cortex Regulates Social Memory, Mary Leann Phillips

All ETDs from UAB

Both the ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC) are active participants in the neural circuitry activated by social interaction, and are both necessary for certain aspects of social behavior. Additionally, synaptic projections from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) are implicated in several neuropsychiatric disorders. Using the Mecp2 knockout (KO) mouse model of Rett syndrome, an autism-associated disorder with network level deficits in the vHIP and mPFC as well as aberrant social behavior, we strove to determine the role of vHIP-mPFC in social behavior. Here, we show that the vHIP-mPFC projection is hyperactive in …

Endothelial N-Glycan Hypoglycosylation Enhances Cd16+ Monocyte Adhesion: A Role For Alpha-Mannosidases, Kellie Regal Mcdonald

All ETDs from UAB

Monocyte extravasation through the endothelial layer is a hallmark of atherosclerotic plaque development and is mediated by heavily glycosylated surface adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1). Human monocytes have been classified into three distinct groups: classical (anti-inflammatory; CD14+/CD16-), nonclassical (patrolling; CD14+/CD16++), and intermediate (pro-inflammatory; CD14++/CD16+). The CD16+ nonclassical / intermediate monocytes have been implicated in atherosclerosis progression and their levels positively associate with adverse cardiac events. However, there is a relative lack of understanding as to whether there are distinct mechanisms that regulate CD16+ vs. CD16- monocyte adhesion to the inflamed endothelium. Our previous data identified a high-mannose …

The Impact Of Redox Stress In Primary Hyperoxaluria Type 1, Brianna Buchalski

All ETDs from UAB

Primary Hyperoxaluria (PH) is a family of three inborn errors of glyoxylate metabolism resulting in endogenous oxalate overproduction. PH1 is the most common and most severe form of the disorder when compared to PH2 and PH3. PH1 can result in systemic oxalosis or end stage renal disease, and there is currently no cure for this disorder. The only curative treatment is combined liver/kidney transplant. The difficulty in defining a cure for the disorder arises from poor knowledge of the sources of endogenous oxalate and a lack of understanding in the underlying pathophysiology of the disorder. For these reasons, we have …

The Role Of Protein O-Glcnacylation In Regulating Mitochondrial Function, Jalessa Nicole Wright

All ETDs from UAB

The attachment of O-linked-N-acetylglucosamine (O-GlcNAc) to the serine/threonine residues of proteins has emerged as an important regulatory mechanism in transcriptional regulation, protein activation as well as cell survival. Several studies have reported that elevated O-GlcNAc levels have adverse effects on mitochondrial function. These negative effects have been linked to O-GlcNAc modification of mitochondrial proteins that are integral across multiple metabolic cell processes i.e. VDAC, NDUFA9 and DRP-1. Mitochondrial complexes I, III and IV all contain subunit proteins that are O-GlcNAc modified and increased O-GlcNAcylation of these proteins is associated with deficits in oxidative phosphorylation in these models. Conversely, it has …

Dysregulation In The Central Nervous System Upon Mcmv Infection In Newborn Mice, Cathy Yea Won Sung

All ETDs from UAB

Human cytomegalovirus (HCMV) infection is a major cause of morbidity in infants and children throughout the world. Between 0.2-1.2% of all live births is infected with HCMV in the United States. Approximately 5-15% of these newborn babies will develop long-term neurological damage resulting in motor disorders, mental retardation, and sensorineural hearing loss. Although the neurological sequelae associated with congenital HCMV infections are well characterized, little is known about the pathogenesis of the damage to the central nervous system (CNS). To study the pathogenesis of congenital HCMV infection, we have developed a mouse model in which newborn mice are infected intraperitoneally …

Novel Biomarkers For Parkinson Disease, Shijie Wang

All ETDs from UAB

Parkinson disease (PD) is the second most common neurodegenerative disorder with no reliable biochemical biomarkers for disease prediction or progression, nor disease-modifying treatments to slow the relentless progression. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known to increase LRRK2 kinase activity and increase the risk for late-onset PD. In this thesis, I discovered that LRRK2 is secreted into exosomes in urine and CSF, where LRRK2 kinase activity, reflected by autophosphorylation at pS1292 site, is preserved and reflective of cytosolic LRRK2 levels. In a cohort of biosamples from LRRK2 mutation carriers and matched controls, with and without PD, …

The Anti-Tumor Effects Of Hur Inhibition In Glioblastoma, Jiping Wang

All ETDs from UAB

Glioblastomas (GBMs) are the most malignant primary brain tumor. GBMs represent 14.7% of total primary CNS tumors and 47.7% of malignant CNS tumors. The median survival of GBM is 18-20 months, while five-year survival rate is only 5.6%. GBMs are maintained by glioma stem cells (GSCs), and poor treatment outcomes are linked to the high resistance of GSCs to radiation and chemotherapy, and the immunosuppressive tumor microenvironment. The mRNA binding protein HuR is a key regulator of tumor growth and development based upon the fact that HuR targets mRNAs that are broadly involved in tumorigenesis. We have previously shown that …

Identification Of Two Spop-Mediated Pathways In Prostate Cancer Progression, Joshua Fried

All ETDs from UAB

Prostate cancer is one of the most common malignancies and causes of cancer related death in men. Morbidity is primarily attributed to late-stage and metastatic disease. Re-cent genomic screening studies have revealed that the Speckle type Poz Protein (SPOP) is the most frequently altered gene by missense mutations in prostate cancer. Interestingly, all of the identified mutations were located in the substrate binding domain of SPOP. Here, two pathways highlighting the impact of SPOP mutation on prostate cancer are pre-sented. First, evidence showing that one of the naturally occurring SPOP mutations, ser-ine 119 to asparagine (S119N), induces radiosensitivity and an …

Integration Of Yeast Phenomics And Cancer Pharmacogenomics To Model Precision Medicine, Sean Santos

All ETDs from UAB

Precision medicine aims to optimize disease treatment by considering the differential influence of functional genetic variation on phenotypic outcomes and therapeutic efficacy. However, current precision medicine paradigms lack consideration of the abundance of genetic interaction and ensuing complexity of phenotypes, thus thwarting resolution of gene-drug interaction at a systems level and ‘precise’ predictions for most patients. Yeast phenomics enables quantitative, high-resolution experimental modeling of gene-drug interaction phenotypes at a systems level by measuring growth curves for the ~6000 yeast knockout/knockdown library strains, which can guide a more global resolution of disease and treatment complexity at the organism level. We postulate …