Medical Toxicology Commons^™

Bio-Monitoring The Elimination Of Folic Acid-Preventable Spina Bifida And Anencephaly, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Guest Perspective - Dr. Robert L. Brent, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Implications For The Hsf2/Prc1 Interaction And Regulation Of Condensin By Phosphorylation During Mitosis, Lynea Alene Murphy

University of Kentucky Doctoral Dissertations

At the beginning of mitosis, chromosomes are condensed and segregated to facilitate correct alignment later in cytokinesis. Condensin is the pentameric enzyme responsible for this DNA compaction and is composed of two structural maintenance of chromosomes (SMC) subunits and three non-SMC subunits. Condensin mutations generate chromosomal abnormalities due to improper segregation, leading to genome instability and eventual malignant transformation of the cell. Cdc2 phosphorylation of the non-SMC subunits, CAP-G, CAP-D2, and CAP-H, has been demonstrated to be important for condensin supercoiling activity and function. While these subunits are thought to be phosphorylated by Cdc2, the exact sites have not yet …

Nitration And Inactivation Of Manganese Superoxide Dismutase Plays A Critical Role In Metabolic Switch, Muthuswamy Anantharaman

University of Kentucky Doctoral Dissertations

Alzheimer’s disease (AD) is a multifactorial, progressive, age-related neurodegenerative disease. Oxidative stress hypothesis is most prevalent and is gaining significant support. Inspite of the progress achieved on oxidative stress related damages in AD brain; the modification occurring on the various cellular antioxidant enzymes antioxidant has not been identified. Tyrosine nitration, a marker for peroxynitrite induced oxidative damage to protein is widespread in AD brain and Manganese superoxide dismutase (MnSOD), primary mitochondrial antioxidant enzyme is prone to peroxynitrite induced nitration and inactivation. Nitration of proteins involved in energy metabolism has been demonstrated in AD brain, which may explain the altered glucose …

Reciprocal Regulation Of Par-4 And Caspase-8 In The Trail Signaling Pathway, Padhma Ranganathan

University of Kentucky Doctoral Dissertations

Par‐4 is a pro‐apoptotic tumor suppressor that is mutated, suppressed or inactivated in cancer. Par‐4 exploits components of the extrinsic pathway to cause apoptosis selectively of cancer cells. This study identified Par‐4 as an essential component of the apoptotic pathway induced by TRAIL, which selectively targets cancer cells. RNA interference‐mediated knockdown of Par‐4 rendered cancer cells unresponsive to TRAIL‐induced apoptosis. Cells with knocked‐down levels of Par‐4 were deficient in the activation of the apoptosis‐initiator caspase‐8 and the apoptosis‐effector caspase‐3 in response to TRAIL. Par‐4 was identified as a critical mediator of membrane translocation of caspase‐8 and the adapter protein FADD. …

Endothelial Cell Dysfunction By Environmental Contaminants, Elizabeth Grace Oesterling

University of Kentucky Doctoral Dissertations

Within the last few decades, epidemiological evidence has linked exposure to air pollution, both its particles and its organic components, with cardiovascular disease (CVD) progression. CVD is a life long disease with the disruption of the endothelium being the inaugural event in this inflammatory process. The vascular endothelium is extremely susceptible to environmental insults given its tremendous surface area and that it is in constant contact with blood and components circulating within the blood, including xenobiotics. The endothelium is important as a barrier from blood constituents however, dysfunction of this barrier leads to the influx of lymphocytes and granulocytes that …

Translational Regulatory Mechanisms Of The Rat And Human Multidrug Resistance Protein 2, Yuanyuan Zhang

University of Kentucky Doctoral Dissertations

Multidrug resistance protein 2 (MRP2) is the second member the C subfamily in the superfamily of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters. MRP2 is a critical player for generation of bile acidindependent bile flow and biliary excretion of glutathione, glucuronate and sulfate conjugates of endo- and xenobiotics. Dysfunctional expression of MRP2 is associated with Dubin-Johnson Syndrome.

Pathological and physiological states or xenobiotics change the MRP2 expression level. Under some conditions, expression of the human MRP2 and rat Mrp2 proteins are regulated at the translation level. There are several transcription initiation sites in MRP2/Mrp2 gene. The 5’ untranslated regions (5’UTRs) …

Zinc Deficiency And Mechanisms Of Endothelial Cell Dysfunction, Huiyun Shen

University of Kentucky Doctoral Dissertations

Atherosclerosis is a chronic inflammatory disease thought to be initiated by endothelial cell dysfunction. Research described in this dissertation is focused on the role of zinc deficiency in endothelial cell activation with an emphasis on the function of the transcription factors nuclear factor-κB (NF-κB), peroxisome proliferator activated receptor (PPAR), and the aryl hydrocarbon receptor (AhR), which all play critical roles in the early pathology of atherosclerosis. Cultured porcine aortic vascular endothelial cells were deprived of zinc by the zinc chelator TPEN and/or treated with the NF-κB inhibitor CAPE or the PPARγ agonist rosiglitazone, followed by measurements of PPARα expression, cellular …

Suppression Of Peroxisomal Enzyme Activities And Cytochrome P450 4a Isozyme Expression By Congeneric Polybrominated And Polychlorinated Biphenyls, Larry W. Robertson, Isabelle Berberian, Tim Borges, Li-Chuan Chen, Ching K. Chow, Howard P. Glauert, Johannes G. Filser, Helmut Thomas

Toxicology and Cancer Biology Faculty Publications

The purpose of this study was to determine the effects of PCBs and PBBs on peroxisome proliferator-activated receptor-alpha-(PPARalpha-) associated enzyme activities or protein levels. Male Sprague-Dawley rats were administered a single IP injection (150 mu mol/kg) of either 3,3',4,4'-tetrabromobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, 3,3',5,5'-tetrabromobiphenyl, 2',3,3',4,5-pentachlorobiphenyl, 3,3',4,4',5-pentachlorobiphenyl, 2,2',3,3',5,5'-hexachlorobiphenyl, or 3,3',4,4',5,5'-hexabromobiphenyl in corn oil (10 ml/kg). One week later, the activities of catalase, peroxisomal fatty acyl-CoA oxidase, and peroxisomal beta-oxidation as well as cytochrome P450 4A (CYP4A) protein content were determined in subcellular liver fractions. None of the peroxisomal enzyme activities were significantly increased by any of the halogenated biphenyl congeners tested. Except for minor …

Commentary: The Daubert Decision, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Letter To The Editor: Further Efforts To Redce The Incidence Of Neural Tube Defects, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Triumph And/Or Tragedy: The Present Food And Drug Administration Program Of Enriching Grains With Folic Acid., Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Developmental Toxicology Drugs, And Fetal Teratogenesis, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Robert Warwick Miller: In Memoriam., Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

How Does The Physician Avoid Prescribong Drugs And Medical Procedures That Have Reproductive And Developmental Risks?, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Replication Fork Regression In Vitro By The Werner Syndrome Protein (Wrn): Holliday Junction Formation, The Effect Of Leading Arm Structure And A Potential Role For Wrn Exonuclease Activity, Amrita Machwe, Liren Xiao, Robert G Lloyd, Edward Bolt, David K. Orren

Toxicology and Cancer Biology Faculty Publications

The premature aging and cancer-prone disease Werner syndrome stems from loss of WRN protein function. WRN deficiency causes replication abnormalities, sensitivity to certain genotoxic agents, genomic instability and early replicative senescence in primary fibroblasts. As a RecQ helicase family member, WRN is a DNA-dependent ATPase and unwinding enzyme, but also possesses strand annealing and exonuclease activities. RecQ helicases are postulated to participate in pathways responding to replication blockage, pathways possibly initiated by fork regression. In this study, a series of model replication fork substrates were used to examine the fork regression capability of WRN. Our results demonstrate that WRN catalyzes …

The Folate Debate., Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Comparison Of The Systemic And Pulmonary Inflammatory Response To Endotoxin Of Neutropenic And Non-Neutropenic Rats, Sabrina M. Heidemann, Maria Glibetic

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

Neutrophil infiltration commonly occurs in acute lung injury and may be partly responsible for the inflammatory response. However, acute lung injury still occurs in the neutropenic host. The objectives of this study are to determine if inflammation and acute lung injury are worse in neutropenic versus the normal host after endotoxemia.

Methods

Rats were divided into four groups: 1) control, 2) neutropenic, 3) endotoxemic and 4) endotoxemic and neutropenic. Tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP-2) were measured in the blood, lung lavage and for mRNA in the lung. Arterial blood gases were measured to determine …

Identification And Characterization Of Ogg1 Mutations In Patients With Alzheimer's Disease, Guogen Mao, Xiaoyu Pan, Beibei Zhu, Yanbin Zhang, Fenghua Yuan, Jian Huang, Mark A. Lovell, Maxwell P. Lee, William R. Markesbery, Guo-Min Li, Liya Gu

Toxicology and Cancer Biology Faculty Publications

Patients with Alzheimer's disease (AD) exhibit higher levels of 8-oxo-guanine (8-oxoG) DNA lesions in their brain, suggesting a reduced or defective 8-oxoG repair. To test this hypothesis, this study investigated 14 AD patients and 10 age-matched controls for mutations of the major 8-oxoG removal gene OGG1. Whereas no alterations were detected in any control samples, four AD patients exhibited mutations in OGG1, two carried a common single base (C₇₉₆) deletion that alters the carboxyl terminal sequence of OGG1, and the other two had nucleotide alterations leading to single amino acid substitutions. In vitro biochemical assays revealed …

Screening Assay For Inhibitors Of Severe Acute Respiratory Syndrome (Sars) Using Seldi-Tof Mass Spectrometry, Khalid M. Elased, Mariana Morris

Pharmacology and Toxicology Faculty Publications

Mass spectrometric methods directed to screening libraries of compounds for agents that inhibit entry of Severe Acute Respiratory Syndrome (SARS) coronavirus (CoV) into cells are provided, along with methods for comparatively evaluating inhibitors of the SARS CoV.

Reduction In Urinary Arsenic With Bottled-Water Intervention, Arun B. Josyula, Hannah Mcclellen, Tracy A. Hysong, Margaret Kurzius-Spencer, Gerald S. Poplin, Stefan Stürup, Jefferey L. Burgess

Dartmouth Scholarship

The study was conducted to measure the effectiveness of providing bottled water in reducing arsenic exposure. Urine, tap-water and toenail samples were collected from non-smoking adults residing in Ajo (n=40) and Tucson (n=33), Arizona, USA. The Ajo subjects were provided bottled water for 12 months prior to re-sampling. The mean total arsenic (microg/L) in tap-water was 20.3+/-3.7 in Ajo and 4.0+/-2.3 in Tucson. Baseline urinary total inorganic arsenic (microg/L) was significantly higher among the Ajo subjects (n=40, 29.1+/-20.4) than among the Tucson subjects (n=32, 11.0+/-12.0, p<0.001), as was creatinine-adjusted urinary total inorganic arsenic (microg/g) (35.5+/-25.2 vs 13.2+/-9.3, p<0.001). Baseline concentrations of arsenic (microg/g) in toenails were also higher among the Ajo subjects (0.51+/-0.72) than among the Tucson subjects (0.17+/-0.21) (p<0.001). After the intervention, the mean urinary total inorganic arsenic in Ajo (n=36) dropped by 21%, from 29.4+/-21.1 to 23.2+/-23.2 (p=0.026). The creatinine-adjusted urinary total inorganic arsenic and toenail arsenic levels did not differ significantly with the intervention. Provision of arsenic-free bottled water resulted in a modest reduction in urinary total inorganic arsenic.

Abdominal Pain With Rigidity Secondary To The Anti-Emetic Drug Metoclopramide, Nadeem Ullah Khan, Junaid A. Razzak

Department of Emergency Medicine

We report a case of abdominal pain with rigidity, mimicking an acute abdomen, caused by metoclopramide, a common anti-emetic drug. Extrapyramidal symptoms are commonly reported side-effects of this medication. They generally include involuntary movements of limbs, torticollis, oculogyric crisis, rhythmic protrusion of tongue, trismus, or dystonic reactions resembling tetanus, etc. Abdominal rigidity due to this medication, resembling an acute abdomen, has not been reported previously. This case report illustrates the importance of considering medication side-effects when evaluating a patient with abdominal pain and rigidity.

Length-Dependent Degradation Of Single-Stranded 3' Ends By The Werner Syndrome Protein (Wrn): Implications For Spatial Orientation And Coordinated 3' To 5' Movement Of Its Atpase/Helicase And Exonuclease Domains, Amrita Machwe, Liren Xiao, David K. Orren

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The cancer-prone and accelerated aging disease Werner syndrome is caused by loss of function of the WRN gene product that possesses ATPase, 3' to 5' helicase and 3' to 5' exonuclease activities. Although WRN has been most prominently suggested to function in telomere maintenance, resolution of replication blockage and/or recombinational repair, its exact role in DNA metabolism remains unclear. WRN is the only human RecQ family member to possess both helicase and exonuclease activity, but the mechanistic relationship between these activities is unknown. In this study, model single-stranded and 3' overhang DNA substrates of varying length and structure were …

Competition Between The Dna Unwinding And Strand Pairing Activities Of The Werner And Bloom Syndrome Proteins, Amrita Machwe, Enerlyn M. Lozada, Liren Xiao, David K. Orren

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The premature aging and cancer-prone Werner and Bloom syndromes are caused by defects in the RecQ helicase enzymes WRN and BLM, respectively. Recently, both WRN and BLM (as well as several other RecQ members) have been shown to possess a strand annealing activity in addition to the requisite DNA unwinding activity. Since an annealing function would appear to directly oppose the action of a helicase, we have examined in this study the dynamic equilibrium between unwinding and annealing mediated by either WRN or BLM.

RESULTS: Our investigation into the competition between annealing and unwinding demonstrates that, under standard reaction …

A Mechanistic Study Of The Protective Effects Of S-Adenosyl-L-Methionine Against Hepatotoxicity Of Acetaminophen, Marcus V. Terneus Jr.

Theses, Dissertations and Capstones

Hepatic toxicity is known to be associated with excessive doses of the over-the-counter analgesic, acetaminophen (APAP). APAP overdose is the leading cause of drug-induced liver failure in the United States. APAP hepatotoxicity is dependent on the biotransformation of APAP by cytochrome P450 to the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). APAP, when taken in excessive doses, can lead to severe liver damage with the potential to progress to liver failure. Despite substantial efforts in past studies, the mechanism by which APAP induces such damaging effects is not completely understood. Recent discoveries suggest that glutathione (GSH) depletion, protein alkylation and reactive metabolite …

Counseling Patients Exposed To Ionizing Radiation During Pregnancy, Robert L. Brent

The Selected Works of Robert Brent

Health physicists and knowledgeable clinicians have the responsibility to counsel women of reproductive age about the reproductive risks of ionizing radiation exposure before conception or during pregnancy. It is important to realize that lay individuals have many misconceptions about the reproductive risks of ionizing radiation. Many patients who have already had or will undergo some type of radiological test are apprehensive about the reproductive and developmental risks of diagnostic radiological procedures. Epidemiological studies and animal studies indicate that high exposures of ionizing radiation can cause miscarriage, congenital malformations, growth retardation, stillbirth, and cancer. With the exception of cancer, there are …

Simultaneous Measurement Of Water Volume And Ph In Single Cells Using Bcecf And Fluorescence Imaging Microscopy, Francisco J. Alvarez-Leefmans, José J. Herrera-Pérez, Martín S. Márquez, Victor M. Blanco

Pharmacology and Toxicology Faculty Publications

Regulation and maintenance of cell water volume and intracellular pH (pH_i) are vital functions that are interdependent; cell volume regulation affects, and is in turn affected by, changes in pH_i. Disruption of either function underlies various pathologies. To study the interaction and kinetics of these two mechanisms, we developed and validated a quantitative fluorescence imaging microscopy method to measure simultaneous changes in pH_i and volume in single cells loaded with the fluorescent probe BCECF. CWV is measured at the excitation isosbestic wavelength, whereas pH_iis determined ratiometrically. The method has a time resolution of …

26Al-Containing Acidic And Basic Sodium Aluminum Phosphate Preparation And Use In Studies Of Oral Aluminum Bioavailability From Foods Utilizing 26Al As An Aluminum Tracer, Robert A. Yokel, Aaron A. Urbas, Robert A. Lodder, John P. Selegue, Rebecca L. Florence

Pharmaceutical Sciences Faculty Publications

We synthesized ²⁶Al-containing acidic and basic (alkaline) sodium aluminum phosphates (SALPs) which are FDA-approved leavening and emulsifying agents, respectively, and used them to determine the oral bioavailability of aluminum incorporated in selected foods. We selected applicable methods from published syntheses (patents) and scaled them down (∼3000- and 850-fold) to prepare ∼300–400 mg of each SALP. The ²⁶Al was incorporated at the beginning of the syntheses to maximize ²⁶Al and ²⁷Al equilibration and incorporate the ²⁶Al in the naturally-occurring Al-containing chemical species of the products. Near infrared spectroscopy (NIR) and X-ray powder diffraction (XRD) were used …

Effects Of Tamoxifen On Mitochondrial Nos Activity: Alteration In The Intramitochondrial Ca2+ Homeostasis, Sandeep S. Joshi

Theses, Dissertations and Capstones

Tamoxifen (Tam) is an anticancer drug that induces oxidative stress and apoptosis via mitochondria- and nitric oxide (NO)-dependent pathways. Here, we report that therapeutic concentrations of Tam stimulate the mitochondrial NO synthase (mtNOS) activity of isolated rat liver mitochondria by increasing the intramitochondrial ionized Ca²⁺ concentration ([Ca²⁺]_m). Tam decreases transmembrane potential (∆ψ) due to increased [Ca²⁺]_m that neutralizes the negative charges of the inner mitochondrial membrane. Thus, the present study reports a novel mechanism for the widely used anti- caner drug, Tam.

Mechanism Of Cancer Selective Apoptosis By Par-4, Sushma Gurumurthy

University of Kentucky Doctoral Dissertations

Despite distinct dissimilarities, diverse cancers express several common pro-tumorigenic traits. We present here evidence that the pro-apoptotic protein Par-4 utilizes one such common tumorigenic trait to become selectively activated and induce apoptosis in cancer cells. Elevated PKA activity noted in cancer cells activated the apoptotic function of ectopic Par-4 or its SAC domain, which induces apoptosis selectively in cancer cells and not in normal or immortalized cells. PKA preferentially phosphorylated Par-4 at the T155 residue within the SAC domain in cancer cells. Moreover, pharmacological-, peptide- or siRNA-mediated inhibition of PKA activity in cancer cells resulted in abrogation of both T155 …