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Attenuation Of Parenteral Nutritionassociated Liver Disease By Omega-3 Long-Chain Polyunsaturated Fatty Acids, Emma Monique Tillman

Theses and Dissertations (ETD)

No abstract provided.

Resveratrol Induced Apoptosis In A Human Adenosquamous Carcinoma Cell Line (Cal-27 Cells), Saquib A. Siddiqi

PCOM Biomedical Studies Student Scholarship

Radiotherapy and surgery are the two principal modalities in the treatment of head and neck cancers, and both therapies can result in severe adverse effects and ultimately lower the quality of life. It is of paramount importance to develop reagents that target the cancer cell specifically without affecting the normal non-cancer cells. Using the tongue cancer cell line Cal 27 as a model system, we dissected the molecular mechanism of the resveratrol-induced cancer cell apoptosis. After demonstrating that resveratrol induces the cancer cell apoptosis in a dose- and time-dependent manner, a systemic apoptosis protein array was conducted to identify the …

Inhibition Of Lung Carcinogenesis By Polymethoxyflavones, Noppawat Charoensinphon

Open Access Dissertations

Lung cancer is the leading cause of cancer-related death worldwide. Exclusively found in citrus peels, the inhibitory effects of polymethoxyflavones (PMFs) on 3 human non-small cell lung cancer cells have been investigated. Results showed that monodemethylated PMFs at 5-position potently inhibited lung cancer cells than those of their permethoxylated counterparts. The inhibition of cancer cells caused by monodemethylated PMFs was associated with both extensive cell cycle arrest and apoptosis as a result of modulation of key oncogenic signaling proteins. Treatment with different bioactive compounds in combination may enhance inhibitory effects on lung cancer due to their synergistic interaction among these …

Comparative Gene Analysis And Prediction Of Innate Immunity And Apoptosis Machinery In Hydrothermal Vent Tubeworms, Corey M. Bunce

Master's Theses

Siboglinid tubeworms are an emerging model system for symbiosis in extreme conditions. At deep-sea hydrothermal vents in the Pacific Ocean, they harbor a chemoautotrophic symbiont in a specialized organ, the trophosome, where the bacteria carry out primary production via oxidation of reduced sulfur compounds. The trophosome of siboglinid worms is suggested to be tightly regulated, symbiont-responsive, and developmentally homeostatic. The purported mechanism involves a cellular proliferative or apoptotic response to bacterial signals, environmental cues, or nutrition. Though these processes are well understood in more amenable model systems, there has been little work uncovering the tubeworm’s genetic potential for sensing and …

Med13p Prevents Stress-Independent Mitochondrial Hyperfragmentation And Aberrant Apoptosis Activation In Saccharomyces Cerevisiae By Controlling Cyclin C Nuclear Localization, Svetlana Khakhina

Graduate School of Biomedical Sciences Theses and Dissertations

During aging, and as a result of environmental changes, cells are exposed to elevated levels of reactive oxygen species (ROS). High ROS levels induce lipid oxidation, protein aggregation, mitochondrial hyperfragmentation, DNA damage and programmed cell death (PCD), also called apoptosis. PCD is a highly regulated process and its misregulation has been linked to neurodegenerative diseases and cancer development.

Our hypothesis is that cyclin C plays a role in the initiation of apoptosis. During normal conditions, cyclin C represses the transcription of stress response genes (SRG). In response to stress, cyclin C translocates to the cytoplasm where it facilitates mitochondrial hyperfragmentation …

Modulation Of Bax/Bak Dependent Apoptosis By Sirtuin 3 And Mitochondrial Permeability Transition By Sirtuin 4, Manish Verma

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondria are dynamic organelles that regulate a myriad of cellular functions, including energy production and metabolic regulation. Mitochondria are also a critical regulator of cell death signaling cascades modulating both apoptotic and necrotic cell death. However, what determines which cell death pathway is activated is still unclear. The mitochondrial/intrinsic pathway of apoptosis is dependent on the activation of pro-apoptotic proteins, Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). Once the integrity of outer mitochondrial membrane (OMM) is compromised, pro-apoptotic intermembrane space proteins like cytochrome c, Smac/Diablo, Omi/HtrA2 and AIF are released into the cytoplasm, which activates the post-mitochondrial …

Novel Roles Of Replication Protein A Phosphorylation In Cellular Response To Dna Damage, Moises A. Serrano

Electronic Theses and Dissertations

Human replication protein A (RPA) is an eukaryotic single-stranded DNA binding protein directly involved in a variety of DNA metabolic pathways including replication, recombination, DNA damage checkpoints and signaling, as well as all DNA repair pathways. This project presents 2 novel roles of RPA in the cellular response to DNA damage. The first elucidates the regulation of RPA and p53 interaction by DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) in homologous recombination (HR). HR and nonhomologous end joining (NHEJ) are 2 distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-PK, the …

A Novel Cardiac Function Of Sumo2/3 And Senp5 Dependent Pathway And Its Physiological Impact On Congestive Cardiomyopathy, Eun Young Kim

Dissertations & Theses (Open Access)

A Novel cardiac function of SUMO2/3 and SENP5 dependent pathway and its physiologic impact on congestive cardiomyopathy

Publication No.___________

Eun Young Kim, M.S.

Supervisory professor: Robert J. Schwartz, Ph.D.

SUMOylation regulates diverse cellular processes including transcription, cell cycle, protein stability, and apoptosis. Although SUMO1 has been extensively studied so far, relevance of SUMO2/3 is unclear, especially in heart. Here we show that failing heart induces SUMO2/3 conjugation. Increased SUMO2/3-dependent modification leads to congestive heart disease such as cardiac hypertrophy by promoting cardiac cell death. Calpain2 and Calpastatin as a novel SUMO2 targets have been known to be involved in mitochondrial-independent …

Susceptibility Of Apoptotic Cells To Hydrolysis By Spla2: Molecular Basis And Mechanisms Defined, Elizabeth Gibbons

Theses and Dissertations

Secretory phospholipase A2 hydrolyzes phospholipids at a lipid-water interface, resulting in pro-inflammatory products being released from cell membranes. Healthy cells are resistant to cleavage by this enzyme, but apoptotic cells become susceptible to its activity. Only bilayers with certain characteristics are able to be hydrolyzed. Most recently, studies in this lab have emphasized the idea that the biophysical state of the bilayer (in terms of lipid order, spacing, and fluidity) is relevant in determining the probability of one phospholipid escaping the membrane to be hydrolyzed. Prior to this study, it had been shown that apoptotic cells undergo biophysical alterations that …

Promoter Polymorphisms In Interferon Regulatory Factor 5, Daniel N. Clark

Theses and Dissertations

The promoter region of interferon regulatory factor 5 (IRF5) contains the rs2004640 T or G single nucleotide polymorphism (SNP) and a CGGGG indel. Both of these polymorphisms have been implicated as genetic risk factors for several autoimmune diseases, including systemic lupus erythematosus, whose pathology involves altered apoptosis and cytokine signaling. The polymorphisms' overall effect is to increase IRF5 levels. IRF5 is a transcription factor of several cytokines, including interferon, and is pro-apoptotic. Thus an alteration of cytokine levels and apoptosis signaling due to high IRF5 levels is the proposed source of autoimmune risk. Each of IRF5's four first exons (1A, …

Expression Of The Chemokine Receptor, Cxcr4, And Its Ligand, Sdf-1, Are Increased In Purkinje Cells Of The Multiple System Atrophy Cerebellum, Megan Welter

Masters Theses

Multiple System Atrophy (MSA) is a sporadic, neurodegenerative disease that consists of three conditions: autonomic dysfunction, Parkinsonism and cerebellar ataxia. Our lab conducted an Affymetrix global gene expression analysis using pons tissue of MSA patients to determine genes that are differentially expressed when compared to non- MSA controls. This study identified upregulated genes, including the C-X-C chemokine receptor type 4, CXCR4, to which stromal cell-derived factor-I (SDF-1) is the natural ligand. The CXCR4/SDF-1 signaling pair has been sho.wn to play multiple roles in the brain, such as inducing neuronal apoptosis and promoting leukocyte recruitment during inflammation. The MSA cerebellum presents …

Biophysical Insights Into The Oligomerization Of Bclxl Apoptotic Repressor, Vikas Bhat

Open Access Dissertations

The BclXL apoptotic repressor, a member of the B-cell lymphoma 2 family of proteins, plays a central role in determining the fate of cells to live or die during physiological processes such as embryonic development and tissue homeostasis. Herein, using a wide array of biophysical methods, I investigate the molecular basis of action of BclXL. Briefly, I provide evidence that BclXL bears intrinsic propensity to oligomerize in solution. Importantly, such oligomerization of BclXL is driven by the intermolecular binding of its C-terminal transmembrane (TM) domain to the canonical hydrophobic groove in a domain-swapped trans fashion, whereby the TM domain of …

Sperm Proteins And Chromatin Dynamics Associated With Male Fertility, Sule Dogan

Theses and Dissertations

The impacts of the paternal genome and proteins transferred to the oocyte through spermatozoa cannot be neglected during mammalian embryonic development. Studies over the past 40 years suggest that sperm chromatin alterations (such as DNA fragmentation induced by either chromatin condensation errors, apoptosis and/or oxidative stress) might be negatively associated with fertilization and early embryonic development [1, 2], [3] [4].However, precise molecular mechanisms by which sperm chromatin integrity and sperm proteins impact early embryonic development still remain unclear. Therefore, the objectives of this study were 1) determine DNA fragmentation induced by apoptosis its relationship with male fertility in spermatozoa from …

Expression Of Dna-Damage Response Genes In Cells Affected By Streptococcus Pneumoniae, Andrea Rodgers Jones

Theses and Dissertations

Proper regulation of apoptosis during pneumococcal pneumonia is essential for resolution of infection. We hypothesized that reactive oxygen species (ROS) produced during infection causes sufficient DNA damage to alter expression of pro-apoptotic proteins. Despite inducing DNA damage, challenge with pneumococci did not cause alterations the expression of the pro-apoptotic protein Puma (p53 up-modulated regulator of apoptosis) at early (4 and 6 hour) and late (16 and 24 hour) time points tested in this study. Puma-dependent global expression patterns were assessed, and the data demonstrated significant changes in expression of various genes (Prdx2, Ripk1, Api5 and IL-10) involved in cell death …

Cytotoxic Properties Of Novel Platinum Compounds, Bbr3610-Dach And Trans-4-Nbd In Tumor Cells: Cellular Effects Of 1, 2-Dach And Nbd Ligands, Vijay Menon

Theses and Dissertations

Platinum-based chemotherapeutics are used for the treatment of a wide range of cancers and a number of attempts have been made toward developing compounds with better cellular stability and similar or enhanced cytotoxicity as compared to their predecessors. The first part of the work reported here focuses on the cellular effects of the metabolically stable dinuclear platinum compound, BBR3610-DACH. Comet assay showed this compound to form interstrand crosslinks, a highly toxic DNA lesion in HCT116 cells, at equimolar concentrations to its parental compound, BBR3610. Cell cycle studies showed that BBR3610-DACH causes G1/S and G2/M cell cycle arrest with S phase …

A C-Terminus Mitochondrial-Localization Region And Bh3 Domain Of Puma Are Required For Apoptotic Function, Liz A. Merwin

Electronic Thesis and Dissertation Repository

Apoptosis is known to contribute to the loss of neurological function in brain injury and several neurodegenerative diseases. The Bcl-2 family of proteins consist of pro-apoptotic and anti-apoptotic members that interact physically and functionally to regulate apoptosis in a cell type and stimulus specific manner. We have previously demonstrated that the Bcl-2 family member Puma plays a key role in triggering neuronal apoptosis under diverse stress conditions. However, the mechanism by which Puma mediates apoptosis remains unclear. Here we found that Puma contains two domains required for its apoptotic function: the BH3 domain and a region in the c-terminus that …

Targeting The Anaphase Promoting Complex/Cyclosome To Induce Mitotic Arrest In Ovarian Cancer., Douglas John Saforo

College of Arts & Sciences Senior Honors Theses

Taxanes are a class of chemotherapeutic drug that act to disrupt microtubule function and cause mitotic arrest and cell death. These drugs are commonly used for cancer treatment, however their effectiveness is dependent on the presence of a functioning spindle assembly checkpoint (SAC). As a result, it is possible for cancer cells to become resistant to microtubule disrupting drugs by inactivating the SAC. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that acts as the master regulator of cell cycle progression. Inhibition of the APC/C should result in disruption of the cell cycle, resulting in arrest during mitosis …

Functional Study Of Hemogen Knockout Mouse Model, Peng Gao

Theses and Dissertations (ETD)

Mouse Hemogen (Hemgn) is regarded as a homologue of human Erythroid Differentiation Associated Gene (EDAG). EDAG overexpression has been postulated for association with some leukemia cases. Meanwhile, Hemgn has been found to contribute to Hoxb4 mediated hematopoietic stem cell expansion. Based on these postulations and evidences, a Hemgn knockout mouse model has been generated to study its function in normal and stress hematopoiesis. I confirmed the Hemgn expression in hematopoietic organs including bone marrow and spleen, as well as round spematids in testis. Hemgn is expressed in mouse hematopoietic stem cells and erythroid progenitor cells. Moreover, Hemgn was also found …

The Role Of Nucleolin In B-Cell Lymphomas And Fas-Mediated Apoptotic Signaling, Jillian F. Wise

Dissertations & Theses (Open Access)

The death receptor Fas has a key role in mediating homeostasis, elimination of defective cells and more recently implicated in cancer promotion. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas-apoptotic signaling is a basis for primary as well as acquired resistance to chemotherapy. We hypothesized that Fas is subjected to direct regulation by inhibitory proteins attained by cancer cells. To screen for potential binding modulators of Fas, we analyzed lymphoma cells for Fas binding proteins. This purification scheme identified high scoring peptides derived from nucleolin, a nuclear protein known to be overexpressed in …

Pim Kinase Inhibition: Single Agent And Combination Approaches In B-Cell Lymphoma, Qingshan Yang

Dissertations & Theses (Open Access)

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are Ser/Thr/Tyr kinases. They modulate B-cell development but become oncoproteins and promote cancer development once overexpressed. Containing three isoforms, Pim-1, -2 and -3 are known to phosphorylate various substrates that regulate transcription, translation, cell cycle, and survival pathways in both hematological and solid tumors.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Elevated Pim kinase levels are common in MCL, and it negatively correlates with patient outcome. SGI-1776 is a small molecule inhibitor selective for Pim-1/-3. We hypothesize that SGI-1776 treatment in MCL will inhibit Pim kinase function, and …

Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

Dissertations & Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the …

Apoptotic And Epigenetic Induction Of Embryo Failure Following Somatic Cell Nuclear Transfer, Aaron Patrick Davis

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The cloning of domestic species has tremendous potential, as the technology can be used in selective breeding, conservation, and the production of transgenic animals. The technique of cloning involves the transplant of DNA from a cell to a recipient gamete. Following transfer to a surrogate, the cloned embryo may successfully complete development to a live offspring. Despite intensive research, the success rate of cloning remains prohibitively low, and the potential benefits of cloning have not yet been realized. Embryos produced from cloning suffer from high rates of embryo degradation, implantation failure, and abortion. The goal of this dissertation research project …

Characterization Of The Apoptotic Functions Of The Hid Hmolog Isolated From Megaselia Scalaris, Shannon Smith

Chancellor’s Honors Program Projects

No abstract provided.

Investigating The Interplay Between Protein Kinases And Caspases, Jacob P. Turowec

Electronic Thesis and Dissertation Repository

The balance between cell survival and death is a crucial process in human development and tissue homeostasis, but is also misregulated in disease. In large part, apoptosis is controlled by caspases, a hierarchical series of cysteine aspartic acid proteases that demolish the cell by cleaving key structural and enzymatic proteins, but emerging paradigms have highlighted the ability of kinases to regulate caspase activity. One way in which kinases can control the progression of apoptosis is through phosphorylation of caspase substrates, which acts to prevent caspase cleavage of that target.

In this thesis, we develop new strategies to study this regulatory …

Development And Characterization Of Caspase Activatable Gfp And A Family Of Fluorescent Reporters, Samantha Elizabeth Bernard Nicholls

Open Access Dissertations

The cellular process of programmed cell death, or apoptosis, is critical in homeostasis and development. In addition it's misfunction is implicated in an array of disease states from cancer to neurodegeration, making it an attractive pathway for drug targeting. A family of proteases, known as caspases, plays a central role in the apoptotic cascade resulting in the ultimate destruction of the cell. We report a genetically encoded dark-to-bright reporter of caspase activity used in E.coli, mammalian cells, and whole organisms which can be used to monitor apoptosis. This reporter, caspase activatable green fluorescent protein (CA-GFP) consists of GFP fused through …

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells To Radiation By Promoting Acidic Ph, Ros, And Jnk Dependent Apoptosis, Melissa Wason

Electronic Theses and Dissertations

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and …

Biochemical And Cellular Mechanisms Of Retina And Retinal Pigment Epithelium Apoptosis, Srinivasa Rao Sripathi

Dissertations, Master's Theses and Master's Reports - Open

Oxidative stress, intense light exposure and oxygen imbalances such as hypoxic or hyperoxic conditions perturb mitochondria, nuclear function and further lead to cellular damage of retina and retinal pigment epithelial (RPE) cells. Our major aim is to understand the various biochemical and proteomic events that occur during the progression of retina and RPE cell death. The comprehensive objectives of this dissertation are to understand the functional aspects of protein expression, posttranslational modifications, protein or lipid binding changes, phenotypic, morphological alterations and their regulation during the retina and RPE apoptosis under oxidative stress. The entire study is divided into four chapters …

Effect Of Folate Deficiency And Aging On Mtor Signaling Network In The Liver Of Dna Polymerase B Haploinsufficient Mice, Amanda Lynn Arrabi

Wayne State University Theses

EFFECT OF FOLATE DEFICIENCY AND AGING ON mTOR SIGNALING NETWORK IN THE LIVER OF DNA POLYMERASE B HAPLOINSUFFICIENT MICE

by

AMANDA ARRABI

August 2013

Advisor: Dr. Ahmad R. Heydari

Major: Nutrition and Food Science

Degree: Masters of Science

The interaction between the dietary nutrients and the human genome causes some alterations in the molecular pathways that could significantly impact the development of cancer. The main approach to such concerns is to closely observe how the diet modifies the gene expressions that control several cellular processes in the human body. Folate deficiency (FD) has established an important role in modulating the …

Transport Pathway Across Hcaecs Uncer Convective Condtitions And The Role Of Apoptosis In Ldl Transport Through Hcaecs, Janpen Phupeerasupong

Dissertations and Theses

No abstract provided.

Drug Treatment Of Kidney Clip-Induced Hypertension In Rats; Peroxidase Tracer Spot Frequency In Rat Aorta After Chemically Induced Apoptosis, Simon Kleinbart

Dissertations and Theses

No abstract provided.