Medical Toxicology Commons^™

Redox-Mediated And Ionizing-Radiation-Induced Inflammatory Mediators In Prostate Cancer Development And Treatment, Lu Miao, Aaron K. Holley, Yanming Zhao, William H. St. Clair, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

SIGNIFICANCE: Radiation therapy is widely used for treatment of prostate cancer. Radiation can directly damage biologically important molecules; however, most effects of radiation-mediated cell killing are derived from the generated free radicals that alter cellular redox status. Multiple proinflammatory mediators can also influence redox status in irradiated cells and the surrounding microenvironment, thereby affecting prostate cancer progression and radiotherapy efficiency.

RECENT ADVANCES: Ionizing radiation (IR)-generated oxidative stress can regulate and be regulated by the production of proinflammatory mediators. Depending on the type and stage of the prostate cancer cells, these proinflammatory mediators may lead to different biological consequences ranging from …

Fused In Sarcoma Is A Novel Regulator Of Manganese Superoxide Dismutase Gene Transcription, Sanjit Kumar Dhar, Jiayu Zhang, Jozsef Gal, Yong Xu, Lu Miao, Bert C. Lynn, Haining Zhu, Edward J. Kasarskis, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

AIMS: FUsed in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein that possesses diverse roles, such as RNA splicing, RNA transport, DNA repair, translation, and transcription. The network of enzymes and processes regulated by FUS is far from being fully described. In this study, we have focused on the mechanisms of FUS-regulated manganese superoxide dismutase (MnSOD) gene transcription.

RESULTS: Here we demonstrate that FUS is a component of the transcription complex that regulates the expression of MnSOD. Overexpression of FUS increased MnSOD expression in a dose-dependent manner and knockdown of FUS by siRNA led to the inhibition of MnSOD gene transcription. …

Redox-Modulated Phenomena And Radiation Therapy: The Central Role Of Superoxide Dismutases, Aaron K. Holley, Lu Miao, Yanming Zhao, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

SIGNIFICANCE: Ionizing radiation is a vital component in the oncologist's arsenal for the treatment of cancer. Approximately 50% of all cancer patients will receive some form of radiation therapy as part of their treatment regimen. DNA is considered the major cellular target of ionizing radiation and can be damaged directly by radiation or indirectly through reactive oxygen species (ROS) formed from the radiolysis of water, enzyme-mediated ROS production, and ROS resulting from altered aerobic metabolism.

RECENT ADVANCES: ROS are produced as a byproduct of oxygen metabolism, and superoxide dismutases (SODs) are the chief scavengers. ROS contribute to the radioresponsiveness of …

Nuclear Interaction Between Adr-Induced P65 And P53 Mediates Cardiac Injury In Inos (−/−) Mice, Marsha P. Cole, Jitbanjong Tangpong, Terry D. Oberley, Luksana Chaiswing, Kinsley K. Kiningham, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

Adriamycin (ADR) treatment causes an imbalance in the levels of nitric oxide (^•NO) and superoxide (O₂^•−) production leading to cardiac injury. Previously we demonstrated that mice lacking inducible nitric oxide synthase (iNOS) have increased oxidative stress and mitochondrial injury. The molecular events leading to increased mitochondrial injury in iNOS deficient mice is unknown. ADR in the absence of iNOS preferentially activates a proapoptotic pathway without a concurrent increase in prosurvival pathways. Treatment with ADR leads to an increase in DNA binding activity of nuclear factor kappa B (NFκB) and p53 in wildtype mice. Following ADR …

Ether Bridge Formation In Loline Alkaloid Biosynthesis, Juan Pan, Minakshi Bhardwaj, Jerome Ralph Faulkner, Padmaja Nagabhyru, Nikki D. Charlton, Richard M. Higashi, Anne-Frances Miller, Carolyn A Young, Robert B. Grossman, Christopher L. Schardl

Toxicology and Cancer Biology Faculty Publications

Lolines are potent insecticidal agents produced by endophytic fungi of cool-season grasses. These alkaloids are composed of a pyrrolizidine ring system and an uncommon ether bridge linking carbons 2 and 7. Previous results indicated that 1-aminopyrrolizidine was a pathway intermediate. We used RNA interference to knock down expression of lolO, resulting in the accumulation of an alkaloid identified as exo-1-acetamidopyrrolizidine based on high-resolution MS and NMR. Genomes of endophytes differing in alkaloid profiles were sequenced, revealing that those with mutated lolO accumulated exo-1-acetamidopyrrolizidine but no lolines. Heterologous expression of wild-type lolO complemented a lolO mutant, resulting in …

Repair Of Oxidative Dna Damage And Cancer: Recent Progress In Dna Base Excision Repair, Timothy L. Scott, Suganya Rangaswamy, Christina A. Wicker, Tadahide Izumi

Toxicology and Cancer Biology Faculty Publications

SIGNIFICANCE: Reactive oxygen species (ROS) are generated by exogenous and environmental genotoxins, but also arise from mitochondria as byproducts of respiration in the body. ROS generate DNA damage of which pathological consequence, including cancer is well established. Research efforts are intense to understand the mechanism of DNA base excision repair, the primary mechanism to protect cells from genotoxicity caused by ROS.

RECENT ADVANCES: In addition to the notion that oxidative DNA damage causes transformation of cells, recent studies have revealed how the mitochondrial deficiencies and ROS generation alter cell growth during the cancer transformation.

CRITICAL ISSUES: The emphasis of this …

Intramolecular Telomeric G-Quadruplexes Dramatically Inhibit Dna Synthesis By Replicative And Translesion Polymerases, Revealing Their Potential To Lead To Genetic Change, Deanna N. Edwards, Amrita Machwe, Zhigang Wang, David K. Orren

Toxicology and Cancer Biology Faculty Publications

Recent research indicates that hundreds of thousands of G-rich sequences within the human genome have the potential to form secondary structures known as G-quadruplexes. Telomeric regions, consisting of long arrays of TTAGGG/AATCCC repeats, are among the most likely areas in which these structures might form. Since G-quadruplexes assemble from certain G-rich single-stranded sequences, they might arise when duplex DNA is unwound such as during replication. Coincidentally, these bulky structures when present in the DNA template might also hinder the action of DNA polymerases. In this study, single-stranded telomeric templates with the potential to form G-quadruplexes were examined for their effects …

Paracrine Apoptotic Effect Of P53 Mediated By Tumor Suppressor Par-4, Ravshan Burikhanov, Tripti Shrestha-Bhattarai, Nikhil Hebbar, Shirley Qiu, Yanming Zhao, Gerard P. Zambetti, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53⁻/⁻ or Par-4⁻/⁻ mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 …

Therapeutic Efficacy Of Cerium Oxide Nanoparticles Against Sepsis Induced Multi-Organ Dysfunction Syndrome In Sprague Dawley Rats, Nandini Durga Prasanna Kumar Manne

Theses, Dissertations and Capstones

Sepsis is a generalized term that signifies the presence of a pathogen in the blood stream to which the body responds by eliciting a systemic inflammatory response. Although sepsis is the leading cause of death in non-coronary intensive care units in United States, there are currently no FDA approved therapeutic drugs to treat this disorder. Cerium oxide nanoparticles (CeO₂) have been shown to exhibit anti-oxidant, anti-inflammatory, and anti-bacterial properties both in vitro and in vivo. Whether CeO₂ nanoparticles can be used for the treatment of sepsis is currently unclear.

To investigate whether CeO₂ nanoparticles can …

Synthetic Triterpenoids Can Protect Against Toxicity Without Reducing The Efficacy Of Treatment With Carboplatin And Paclitaxel In Experimental Lung Cancer, Karen T. Liby

Dartmouth Scholarship

Synthetic oleanane triterpenoids are multifunctional drugs being developed for the prevention and treatment of a variety of chronic diseases driven by inflammation and oxidative stress. Low nanomolar concentrations of triterpenoids inhibit the induction of inflammatory cytokines, and these drugs are potent activators of the Nrf2 cytoprotective pathway. In contrast, low micromolar concentrations of triterpenoids increased the production of ROS and induced apoptosis in a dose-dependent manner in malignant MCF10 CA1a breast cancer cells. Because cancer cells respond differently to ROS than normal cells, it should be possible to exploit these differences therapeutically. In an experimental model of lung cancer, the …

Anti-Cancer Effects Of Glypican-3 On Huh-7 Hepatocellular Carcinoma Cells, Jiyu Wen, Xiaojun Wen, Jinju Wang, Yang Shu, Zhidong Qiu, Zhongkao Liu, Ran Li, Guofang Zeng, Shiting Bao, Huilai Miao, Yanfang Chen, Mingyi Li

Pharmacology and Toxicology Faculty Publications

Aim: Previous studies have suggested Glypican-3 (GPC3) could be a valuable diagnostic marker for hepatocellular carcinoma. This study examined the effects of overexpression of GPC3 on Huh-7 hepatoma cells.

Methods: We constructed a recombinant plasmid vector pcDNA3.1 (+)-GPC3 for GPC3 overexpression studies in Huh-7 cells. RT-PCR and Western blotting were used to confirm GPC3 gene expression. Cell proliferation was evaluated by 5-ethynyl-2-deoxyuridine (EdU) incorporation assay. Cell cycle progression and apoptosis were determined by flow cytometry using propidium iodide (PI) and Annexin V-FITC/PI staining, respectively. Cell migration and invasion were examined by Boyden Transewll and Matrigel assays.

Results: GPC3 overexpression effectively …

The Preliminary Study Of Effects Of Tolfenamic Acid On Cell Proliferation, Cell Apoptosis, And Intracellular Collagen Deposition In Keloid Fibroblasts In Vitro, Dan Yi, Mackenzie S. Newman, Yanfang Chen, Richard Simman

Pharmacology and Toxicology Faculty Publications

Keloid scarring is a fibroproliferative disorder due to the accumulation of collagen type I. Tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, has been found to potentially affect the synthesis of collagen in rats. In this preliminary study, we aimed to test the effects of TA on cell proliferation, cell apoptosis, and the deposition of intracellular collagen in keloid fibroblasts. Normal fibroblasts (NFs) and keloid fibroblasts (KFs) were obtained from human dermis tissue. Within the dose range 10−3–10−6 M and exposure times 24 h, 48 h, and 72 h, we found that 0.55 × 10−3 M TA at 48 h exposure …

Strand Exchange Of Telomeric Dna Catalyzed By The Werner Syndrome Protein (Wrn) Is Specifically Stimulated By Trf2, Deanna Edwards, David K. Orren, Amrita Machwe

Toxicology and Cancer Biology Faculty Publications

Werner syndrome (WS), caused by loss of function of the RecQ helicase WRN, is a hereditary disease characterized by premature aging and elevated cancer incidence. WRN has DNA binding, exonuclease, ATPase, helicase and strand annealing activities, suggesting possible roles in recombination-related processes. Evidence indicates that WRN deficiency causes telomeric abnormalities that likely underlie early onset of aging phenotypes in WS. Furthermore, TRF2, a protein essential for telomere protection, interacts with WRN and influences its basic helicase and exonuclease activities. However, these studies provided little insight into WRN's specific function at telomeres. Here, we explored the possibility that WRN and TRF2 …

An Analysis Of Fatty Acid Metabolism’S Role In The Development Of Acute Functional Tolerance To Ethanol In Caenorhabditis Elegans, Richard Raabe

Theses and Dissertations

An individual’s naïve level of response (LR) to ethanol is predictive of their lifetime likelihood to abuse alcohol. LR is heavily genetically influenced, suggesting that the genes responsible for LR may also be central to the development of abuse disorders. Our laboratory uses the model organism C. elegans to investigate the genetic influences on responses to acute ethanol exposure. We recently found that changes in TAG levels can alter LR. From this result we investigated the role of long-chain polyunsaturated fatty acids (LC-PUFAs) as well enzymes involved in lipid modifications of proteins. We found that LC-PUFAs are necessary for acute …

Hypoxia/Aglycemia-Induced Endothelial Barrier Dysfunction And Tight Junction Protein Downregulation Can Be Ameliorated By Citicoline, Xiaotang Ma, Huiting Zhang, Qunwen Pan, Yuhui Zhao, Ji Chen, Yanfang Chen

Pharmacology and Toxicology Faculty Publications

This study explores the effect of citicoline on the permeability and expression of tight junction proteins (TJPs) in endothelial cells under hypoxia/aglycemia conditions. Hypoxia or oxygen and glucose deprivation (OGD) was utilized to induce endothelial barrier breakdown model on human umbilical vein endothelial cells (HUVECs) and mouse brain microvascular endothelial cells (bEnd.3s). The effect of citicoline on endothelial barrier breakdown models was determined at either low or high concentrations. FITC-Dextran flux was used to examine the endothelial permeability. The expression of TJPs was measured by immunofluorescence, Real-time PCR and Western Blot methods. Results showed that hypoxia or OGD increased the …

Early Chronic Low-Level Lead Exposure Produces Glomerular Hypertrophy In Young C57bl/6j Mice, Christina Sobin, John Basgen

Christina Sobin, Ph.D.

Early chronic lead exposure continues to pose serious health risks for children, particularly those living in lower socioeconomic environments. This study examined effects on developing glomeruli in young C57BL/6J mice exposed to low (30 ppm), higher (330 ppm) or no lead via dams’ drinking water from birth to sacrifice on post-natal day 28. Low-level lead exposed mice [BLL mean (SD); 3.19 (0.70) µg/dL] had an increase in glomerular volume but no change in podocyte number compared to control mice [0.03 (0.01) µg/dL]. Higher-level lead exposed mice [14.68 (2.74) µg/dL] had no change in either glomerular volume or podocyte number. The …

A Characterization Of Gold Nanoparticle Uptake By Mammalian Cells, Thomas Garner

All Dissertations

Over the past decade, there has been an exponential growth in products and applications that utilize nanotechnology, as these materials present exciting opportunities for the development of new products, enhancement of existing products, and the evolution of innovative procedures. However, this recent growth has occurred in the absence of detailed knowledge concerning the interactions of nanoparticles with biological systems. Nanoparticles must usually be bioavailable in order to elicit a biological response, and to reach an active site they must usually cross a membrane. As a result, cell culture studies have proven to be beneficial and are generally one of the …

Diet And Toenail Arsenic Concentrations In A New Hampshire Population With Arsenic-Containing Water, Kathryn L. Cottingham, Roxanne Karimi, Joann F. Gruber, M Scot Zens, Vicki Sayarath, Carol L. Folt, Tracy Punshon, J. Steven Morris, Margaret R. Karagas

Dartmouth Scholarship

Background: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest.

Methods: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) …

Mismatch Repair Genes Mlh1 And Mlh3 Modify Cag Instability In Huntington's Disease Mice: Genome-Wide And Candidate Approaches, Ricardo Mouro Pinto, Ella Dragileva, Andrew Kirby, Alejandro Lloret, Edith Lopez, Jason St. Claire, Gagan B. Panigrahi, Caixia Hou, Kim Holloway, Tammy Gillis, Jolene R. Guide, Paula E. Cohen, Guo-Min Li, Christopher E. Pearson, Mark J. Daly, Vanessa C. Wheeler

Toxicology and Cancer Biology Faculty Publications

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease Hdh(Q111) mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.Hdh(Q111) ) than on a 129 background (129.Hdh(Q111) ). Linkage mapping in (B6x129).Hdh(Q111) F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. …

Cutaneous Manifestations Of Giant Cell Arteritis, Christina E. Borchers, Ronald E. Warwar

Pharmacology and Toxicology Faculty Publications

A 68 year old woman with advanced giant cell arteritis presented with progressive tongue, lip, and scalp necrosis. She was initially misdiagnosed and treated for oral thrush by her primary care physician and emergency department personnel. She was ultimately correctly diagnosed with giant cell arteritis after she developed a left central retinal artery occlusion, ischemic optic neuropathy, and third cranial nerve palsy. She was treated with corticosteroids and the vasculitis was arrested. She was left with permanent defects in her tongue and lip as well as blindness in the left eye.