Medical Toxicology Commons^™

Sirt1 Deletion Leads To Enhanced Inflammation And Aggravates Endotoxin-Induced Acute Kidney Injury, Rong Gao, Jiao Chen, Yuxin Hu, Zhenyu Li, Shuxia Wang, Sreerama Shetty, Jian Fu

Toxicology and Cancer Biology Faculty Publications

Bacterial endotoxin has been known to induce excessive inflammatory responses and acute kidney injury. In the present study, we used a mouse model of endotoxemia to investigate the role of Sirt1 in inflammatory kidney injury. We examined molecular and cellular responses in inducible Sirt1 knockout (Sirt1-/-) mice and wild type littermates (Sirt1+/+) in lipopolysaccharide (LPS)-induced kidney injury. Our studies demonstrated that Sirt1 deletion caused aggravated kidney injury, which was associated with increased inflammatory responses including elevated pro-inflammatory cytokine production, and increased ICAM-1 and VCAM-1 expression. Inflammatory signaling such as STAT3/ERK phosphorylation and NF-κB activation was markedly elevated in kidney tissues …

Characterizing The Chronic Toxicity Of Ion Mixtures To Ceriodaphnia Dubia Using Two Experimental Designs, Katherine Johnson

All Theses

Total Dissolved Solids, commonly referred to as TDS, is a measure of all organic and inorganic substances that pass through a 2-um filter and are naturally found in aquatic environments. Anthropogenic activities such as agricultural irrigation, road salt runoff, hydraulic fracturing, and coal-fired power plant effluents can increase TDS concentrations of freshwater ecosystems ultimately increasing salinity. Aquatic organisms actively manage the ion balance between their external and internal environments. Freshwater organisms use energy to pump sodium in from the environment, while losing it through passive diffusion. If the external ion concentration changes significantly, these organisms must allocate more energy towards …

Assessing The Relationship Between The Blood-Air Partition Coefficient And Fractional Uptake Of Inspired Halothane, Acetone, And Ethanol Vapors In The Airways Of The C57bl/6j Mouse, Joshua Baruch Baldino

Honors Scholar Theses

The following series of studies investigates the elimination and uptake trends of halothane, acetone, and ethanol vapors in the airways of C57BL/6J mice. These vapors were chosen because they span a wide range of solubilities, as indicated by their blood-air partition coefficients, and are not associated with any significant airway metabolism or reactivity with tissue substrates in vivo. Mice were exposed to a homogeneous vapor mixture containing a 1:1:1 ratio of halothane, acetone, and ethanol at relative concentrations of approximately 10 ppm. Exposure studies were performed with mice in two states, conscious and deceased, in order to provide control …

Effects Of Creosote-Contaminated Sediment Extracts On Mouse Macrophage Physiology And Function, Rayna Silva

All Theses

The southern branch of the Elizabeth River, at Portsmouth Virginia is one of the most polluted systems in North America. This harbor estuary system is also home to the Atlantic Wood Superfund site, which is heavily contaminated with creosote from the Atlantic Wood (AW) preservative company that ceased production in the later 1990s. Creosote is a mixture of polyaromatic hydrocarbons (PAHs), metals, and numerous aliphatic hydrocarbons, and well known to be carcinogenic. The toxicity of sediments and pore waters from the AW site has been studied extensively using Fundulus heteroclitus, also known as the mummichog, or Atlantic killifish. Most adult …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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

Selected Works Temporary Series

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 …