Medicine and Health Sciences Commons^™

Hormonal Regulation Of Glycine Decarboxylase And Its Metabolic Outcomes, Ruta Milind Jog

Wayne State University Dissertations

The amino acid glycine is involved in generation of multiple critical metabolites including glutathione, heme, and creatinine. Interestingly, in both humans and rodents, circulating glycine levels are significantly reduced in obesity, glucose intolerance, type II diabetes and non-alcoholic fatty liver disease. The glycine cleavage system is the predominant glycine degradation pathway in humans. The rate-limiting enzyme of glycine cleavage system is glycine decarboxylase (GLDC), and loss-of-function mutations of GLDC cause hyperglycinemia. Here, we show that GLDC gene expression is upregulated in livers of mouse models of diabetes and diet-induced obesity as well as in the fasted state in normal animals. …

Transcriptional, Translational, And Enzymatic Metabolic Regulation By L-2 Hyroxyglutarate, Garrett Brinkley

All ETDs from UAB

Recent studies have identified elevated levels of a small metabolite, L-2 Hydroxyglutare (L-2HG), which curiously has no known metabolic roles. Renal tumors, hypoxia as well as larval development, specifically in Drosophila, all have been identified to have high levels of L-2HG. These broad categories suggest L-2HG has a physiological role. This work uncovers the impact of elevated levels of L-2HG in altering normal kidney and renal tumors. With structural similarity to α-Ketoglutarate (αKG), L-2HG acts as a competitive inhibitor to enzymes that utilize αKG as substrates or co-factors. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH). Loss of …

Functional Magnetic Resonance Spectroscopy In First-Episode Schizophrenia: Measuring Glutamate And Glutathione Dynamics At 7-Tesla, Peter Jeon

Electronic Thesis and Dissertation Repository

Schizophrenia is a neuropsychiatric illness without known etiology or cure. Current efforts for symptom treatment still seem to leave a large portion of affected individuals without proper symptom management, with those experiencing symptom relief still having to wrestle with potential side-effects from medication trials. There has been growing evidence suggesting that glutamate and glutathione abnormalities hold major roles in development and manifestation of schizophrenia symptoms.

Magnetic resonance spectroscopy (MRS) provides a non-invasive means to observe in-vivo brain chemistry, including glutamate and glutathione. By adding a functional component to an MRS paradigm (fMRS), such as the color-word Stroop task, it is …

Early Treatment Response In First Episode Psychosis: A 7-Tesla Magnetic Resonance Spectroscopic Study Of Glutathione And Glutamate, Kara Dempster

Electronic Thesis and Dissertation Repository

Approximately one third of patients with schizophrenia fail to respond to dopamine-blocking antipsychotic medications. While treatment resistant schizophrenia (TRS) is generally thought to be present from the onset of first episode psychosis (FEP), prospective identification of these patients remains clinically challenging. We investigated the association of glutamate, and glutathione with time to response in the anterior cingulate cortex (ACC) of minimally-treated patients with FEP (n=26) and healthy controls (n= 27) using an ultra-high field 7T MRI protocol. Higher ACC glutathione at baseline was associated with decreased time to achieve 50% symptom improvement. There were no significant differences between patients and …

Investigating The Role Of Endogenous Atf4 Upregulation On Neuronal Glutathione Level, Fatemeh Mirshafiei

Electronic Thesis and Dissertation Repository

ATF4 is a transcription factor that is activated in response to integrated stress response (ISR). In neurons specifically, ATF4 has been suggested to act as a pro-apoptotic transcription factor. The expression of ATF4, as well as its downstream gene targets have been implicated in both in vivo and in vitro models of Alzheimer’s and Parkinson’s Disease. However, the mechanism by which ATF4 promotes cell death remains unclear. It was previously shown that overexpression of ATF4 in primary cortical neurons caused a reduction in glutathione levels, resulting in oxidative stress-induced cell death. The aim of this project was to investigate whether …

Preclinical Assessment Of Immunocal® As A Preventative Treatment For Traumatic Brain Injury (Tbi) In A Mouse Model Of Closed Head Injury, Elizabeth Eugenia Ignowski

Electronic Theses and Dissertations

Over the past three decades, traumatic brain injury (TBI) has been considered a "silent epidemic" and recognized as an emergent public health problem by the Centers for Disease Control and Prevention (CDC). TBI is defined as a bump, blow, or jolt to the head that disrupts the normal function of the brain. Due to the debilitating effects and prevalence of TBI, novel preventative treatment regimens are highly desirable in at risk populations. According to the CDC groups disproportionately affected by TBI include athletes, people aged 75+, and service men and women, among others. Here, we investigated a unique whey protein …

Pathophysiologic Mechanisms Of Immune-Mediated Drug Hypersensitivity Reactions To Sulfonamides, Elham A. Sultan

Electronic Thesis and Dissertation Repository

As sulfonamide hypersensitivity reactions are serious clinical problem, it is necessary to determine which patients tolerate therapy and which patients are at risk. Although the exact pathogenesis of these reactions remains unclear, the imbalance in the production and detoxification of reactive sulfamethoxazole (SMX) metabolites appears to be important in the propagation of these reactions. It is known that these reactive metabolites can cause lymphocytes toxicity and produce reactive oxygen species (ROS) which can damage proteins, lipids, and DNA. The hypothesis of this research is that there are differences in cytotoxicity and expression of oxidative stress to reactive SMX metabolites in …

The Effect Of Red Maple Leaf Toxicosis On Reduced Glutathione Levels In Equine Erythrocytes In Vitro, Madeline A. Rohl

Undergraduate Honors Thesis Projects

Red maple leaf toxicosis is an equine blood disorder resulting from the consumption of wilted red maple (Acer rubrum L.) leaves by horses. Compounds within the leaves of red maple have oxidative effects on equine erythrocytes and can cause hemolysis of erythrocytes, the conversion of hemoglobin to methemoglobin, and the production of Heinz bodies. Reduced glutathione is important in the protection of equine erythrocytes from these oxidative events; however, in the presence of red maple toxin, glutathione is rapidly oxidized and is unavailable. The objective of this study is to determine whether the presence of vitamin C alters levels …

Glutamate And The Biology Of Malignant Glioma, Stephanie Marie Robert

All ETDs from UAB

Malignant gliomas are the most prevalent primary brain tumor. They are highly aggressive and lack effective treatment options. Standard therapy includes a combination of radiation, chemotherapy, and tumor resection; however, even with aggressive treatment, median patient survival remains a dismal 12 – 14 months after diagnosis. Research has focused on understanding the unique biological mechanisms involved in glioma growth and survival in an effort to design novel therapies to treat this devastating disease. In the unique environment of the brain, gliomas have developed the ability to grow and survive at the cost of the normal surrounding brain tissue. Glutamate, the …

Loss Of Multidrug Resistance-Associated Protein 1 (Mrp1/Abcc1) Potentiates Doxorubicin-Induced Cardiotoxicity In Mice, Wei Zhang

Theses and Dissertations--Toxicology and Cancer Biology

Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown.

The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and …

Neuroprotective Effects Of Gamma-Glutamylcysteine Ethyl Ester On An In Vivo Moderate Traumatic Brain Injury-Mediated Model And In Vitro In Cortical Astrocytes And Neurons, Jooyoung Cho

Online Theses and Dissertations

Neurodegeneration is the loss of neuronal structures or functions, while neuroprotection is the delay or prevention of neurodegeneration. In traumatic brain injury (TBI), neurodegeneration can occur as the result of oxidative stress, the imbalance of oxidants and antioxidants levels; therefore, antioxidant approaches can be effective therapeutic methods for neuroprotection by attenuating oxidative stress. Glutathione (GSH), a naturally occurring antioxidant, plays an important role in the maintenance of intracellular redox homeostasis by scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this thesis, we attempted to evaluate the abilities of a GSH precursor, gamma-glutamylcysteine ethyl ester (GCEE), to prevent …

Mrp1: A Target For Hematopoietic Stem Cell Diseases, Cassandra Reiling

Theses and Dissertations--Toxicology and Cancer Biology

Multidrug resistance-associated protein 1 (MRP1) is a member of the adenosine 5’-triphosphate (ATP)-binding cassette (ABC) transporters. MRP1 actively effluxes a variety of endogenous and exogenous substrates from cells, ultimately, working to remove these compounds from the body. MRP1 was initially discovered based on its ability to confer resistance against a variety of chemotherapeutics when overexpressed in cancer cells lines. MRP1 function is important for a number of physiological processes, including regulating cellular and extracellular levels of the anti-inflammatory leukotriene C4 (LTC4) and the antioxidant glutathione (GSH). Our studies have focused on the role of MRP1 in regulating hematopoietic stem cell …

Oxidative Stress For An Acute Bout Of Bikram Yoga In Healthy, Trained Adults, Kimberly Anne Trocio

UNLV Theses, Dissertations, Professional Papers, and Capstones

BACKGROUND:Generation of free radicals resulting in oxidative damage has been linked to cellular damage, aging, and human disease. Many studies have reported that physical exercise can contribute to oxidative stress. Further, exercise in a hyperthermic environment can promote additional oxidative stress. It is important to consider that practices in yoga may be beneficial in reducing oxidative stress according to some studies. The compound effects of exercise and hyperthermic exposure are experienced in the practice of Bikram yoga, the original "hot" yoga. Because Bikram yoga and other hot exercise classes are an increasingly growing fitness trend, it is necessary to investigate …

Trpm2 In The Central Nervous System: Physiological Role And Critical Regulatory Pathways, Jillian C. Belrose

Electronic Thesis and Dissertation Repository

TRPM2 is a non-selective cation channel which is permeable to calcium. Although expression is highest in the brain, the physiological role for TRPM2 in neurons was unknown. Furthermore, our understanding of the pathways regulating TRPM2 channel function required further investigation. In this thesis, we identified that TRPM2 is required for NMDAR-dependent long-term depression (LTD). No change in NMDAR expression or function was observed following genetic deletion of TRPM2. Instead, the loss of NMDAR-LTD in TRPM2 knockout mice results from diminished GSK-3β activation. We next examined whether age in vitro could facilitate TRPM2 currents. We demonstrate that diminished glutathione with age …

Physiological And Toxicological Roles Of Abc Transporters In Cellular Efflux Of Substrates, Donna J. Coy

Theses and Dissertations--Toxicology and Cancer Biology

ATP-binding cassette (ABC) transporters are transmembrane proteins that transport a wide variety of substrates across intra and extra-cellular membranes. A few examples of endo and xenobiotic substrates are metabolic products, lipids, sterols, and drugs. An important function of ABC transporters involved in export is to prevent intracellular the buildup of toxic products. Several ABC transporters have also been associated with drug resistance upon treatment with chemotherapeutic agents. P-glycoprotein (P-GP) and the multidrug resistant (MRP) transporters of the ABC C family are examples of transporters that confer chemo-resistance.

We have studied two unique roles of ABC transporters in the liver and …

Prognostic Significance Of Xct Polymorphisms And Expression In Patients With Advanced Pancreatic Cancer Treated With Chemotherapy, Tzu-Chuan Jane Huang Md

Dissertations & Theses (Open Access)

The plasma membrane x_c^- cystine/glutamate transporter mediates cellular uptake of cystine in exchange for intracellular glutamate and is highly expressed by pancreatic cancer cells. The xCT gene, encoding the cystine-specific xCT protein subunit of x_c^-, is important in regulating intracellular glutathione (GSH) levels, critical for cancer cell protection against oxidative stress, tumor growth and resistance to chemotherapeutic agents including platinum. We examined 4 single nucleotide polymorphisms (SNPs) of the xCT gene in 269 advanced pancreatic cancer patients who received first line gemcitabine with or without cisplatin or oxaliplatin. Genotyping was performed using Taqman real-time PCR …

Role Of Gsh Metabolism In Mediating Stromal-Leukemia Interaction And Promoting Cell Survival And Drug Resistance In Chronic Lymphocytic Leukemia, Wan Zhang

Dissertations & Theses (Open Access)

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries. The interaction between CLL cells and the bone marrow stromal environment is thought to play a major role in promoting the leukemia cell survival and drug resistance. My dissertation works proved a novel biochemical mechanism by which the bone marrow stromal cells exert a profound influence on the redox status of primary CLL cells and enhance their ability to sustain oxidative stress and drug treatment. Fresh leukemia cells isolated from the peripheral blood of CLL patients exhibited two major redox alterations when they were cultured alone: …

Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu

All ETDs from UAB

Changes in the glioma microenvironment including oxygen (O2) levels, supply of amino acid such as L-glutamate and L-cystine and glutathione (GSH) concentrations play a critical role in glioma biology. Previous data from our laboratory and others have implicated the L-cystine/L-glutamate exchanger, system xc- in the invasion and proliferation of cancers including glioma. The central aim of this dissertation was to characterize the contribution of L-cystine uptake, GSH synthesis and L-glutamate release to migration and proliferation of glioma cells. In my first study, I examined the role of system xc- mediated L-glutamate release on glioma migration. I show that activation of …