Medical Toxicology Commons^™

Chemotherapy-Induced Tissue Injury: An Insight Into The Role Of Extracellular Vesicles-Mediated Oxidative Stress Responses, Chontida Yarana, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

The short- and long-term side effects of chemotherapy limit the maximum therapeutic dose and impair quality of life of survivors. Injury to normal tissues, especially chemotherapy-induced cardiomyopathy, is an unintended outcome that presents devastating health impacts. Approximately half of the drugs approved by the Food and Drug Administration for cancer treatment are associated with the generation of reactive oxygen species, and Doxorubicin (Dox) is one of them. Dox undergoes redox cycling by involving its quinone structure in the production of superoxide free radicals, which are thought to be instrumental to the role it plays in cardiomyopathy. Dox-induced protein oxidation changes …

Loss Of Fructose-1,6-Bisphosphatase Induces Glycolysis And Promotes Apoptosis Resistance Of Cancer Stem-Like Cells: An Important Role In Hexavalent Chromium-Induced Carcinogenesis, Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate …

The Role Of Sodium Bicarbonate In The Management Of Some Toxic Ingestions, Aibek E. Mirrakhimov, Taha Ayach, Aram Barbaryan, Goutham Talari, Romil Chadha, Adam Gray

Internal Medicine Faculty Publications

Adverse reactions to commonly prescribed medications and to substances of abuse may result in severe toxicity associated with increased morbidity and mortality. According to the Center for Disease Control, in 2013, at least 2113 human fatalities attributed to poisonings occurred in the United States of America. In this article, we review the data regarding the impact of systemic sodium bicarbonate administration in the management of certain poisonings including sodium channel blocker toxicities, salicylate overdose, and ingestion of some toxic alcohols and in various pharmacological toxicities. Based on the available literature and empiric experience, the administration of sodium bicarbonate appears to …

Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same …

Multiple Path Particle Dosimetry For Prediction Of Mouse Lung Deposition Of Nanoaerosol Particles, Mohammed Ali

Technology Faculty Publications and Presentations

Nanoaerosolized particle (dia.<200 >nm) antibiotic inhalation therapy was tested to treat pneumonic tularemia in mice caused by Francisella novicida infection. Very limited experimental techniques are available to properly estimate inhaled doses and distribution of the drug inside the mouse lungs. To overcome this problem, computational simulation of particle deposition based on the Multiple Path Particle Dosimetry (MPPD) model was employed to simulate in vivo experimental conditions which included nasal breathing with whole body exposure to the antibiotic in the form of nano-aerosolized medicine. The deposition results were compared with several in vivo experimental data reported in literature; and satisfactory agreements …

Injury-Induced Microvesicle Particle Release In Human Skin Explant Tissue, Katherine E. Fahy, Langni Liu, Christine M. Rapp, Eric J. Romer, Christina E. Borchers, Richard Simman, Ji C. Bihl, Jeffrey B. Travers

Pharmacology and Toxicology Faculty Publications

Microvesicle particles (MVP) are 100-1000 nm vesicles that bud from the cell membrane and transmit intercellular signals locally and systemically via their bioactive cargo (e.g. cytokines).

Injury-Induced Microvesicle Particle Release In Human Skin Explant Tissue, Katherine E. Fahy, Langni Liu, Christina E. Borchers, Richard Simman, Ji C. Bihl, Jeffrey B. Travers

Pharmacology and Toxicology Faculty Publications

Microvesicle particles (MVP) are 100-1000 nm vesicles that bud from the cell membrane and transmit intercellular signals locally and systemically via their bioactive cargo (e.g. cytokines). We have previously shown that thermal burn injury or UVB radiation result in the formation Platelet Activating Factor (PAF), and UVB or a PAF agonist (CPAF) can promote MVP formation in keratinocytes. Thermal burn and UVB radiation can result in systemic effects, even though their injury is localized to the skin. We therefore propose that PAF-producing injuries, UVB irradiation or thermal burn injury, result in the formation of MVPs that can potentially transport cytokines …

Characterization Of A Mutant Oncolytic Adenovirus And The Role Of Jnk In Enhancing Virotherapy., Stephen L. Wechman

Electronic Theses and Dissertations

Oncolytic adenoviruses (Ads) have great therapeutic potential for lung cancer treatment. Cancer selective E1b-deleted Ads are safe; however, their clinical cancer therapeutic efficacy remains limited. The limited efficacy of Ad virotherapy is due to many factors including inefficient cancer cell lysis, Ad release and spread. Progress in overcoming these barriers to Ad virotherapy are hampered by limited knowledge of the genes associated with enhanced Ad release and spread and the dearth of understanding of the mechanisms by which E1b-deleted Ads cause cancer cell lysis. The role of c-JNK n- terminal kinase (JNK) phosphorylation in this process remains unknown. …

The Effects Of Moderate Alcohol Consumption And Inflammation On The Hepatic Matrisome And The Renal Cortex Proteome., Christine E. Dolin

Electronic Theses and Dissertations

Background. The association of chronic ethanol (EtOH) consumption with extracellular matrix (ECM) changes in alcoholic liver disease (ALD) is well established in the context of hepatic fibrosis. However, it is becoming increasingly understood that the hepatic ECM responds dynamically to stress well before fibrosis. The term “transitional tissue remodeling” describes qualitative and quantitative ECM changes in response to injury that do not alter the overall architecture of the organ; these ECM changes may contribute to early disease initiation and/or progression. The nature and magnitude of these changes to the ECM are currently poorly understood. In contrast to the liver, EtOH …

The Interaction Of Homoserine Lactones And Paraoxonase 2 Modulates Cell Death Signaling And Cell Proliferation., Aaron Mackallan Neely

Electronic Theses and Dissertations

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule that functions to facilitate bacteria-bacteria communication. C12 has also been reported to affect many aspects of human host cell physiology, including evoking cell death in various types of cells. However, the signaling pathway(s) leading to C12-triggerred cell death remains unclear. To clarify cell death signaling induced by C12, we examined mouse embryonic fibroblasts (MEFs) deficient in one or more caspases. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in cells, probably through the direct induction of mitochondrial membrane permeabilization. Importantly, C12 induces apoptosis …

Melatonin And Its Metabolites Protect Human Melanocytes Against Uvb-Induced Damage: Involvement Of Nrf2-Mediated Pathways, Zorica Janjetovic, Stuart G. Jarrett, Elizabeth F. Lee, Cory Duprey, Russel J. Reiter, Andrzej T. Slominski

Toxicology and Cancer Biology Faculty Publications

Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing …

Lkb1 Inactivation Drives Lung Cancer Lineage Switching Governed By Polycomb Repressive Complex 2, Haikuo Zhang, Christine Fillmore Brainson, Shohei Koyama, Amanda J. Redig, Ting Chen, Shuai Li, Manav Gupta, Carolina Garcia-De-Alba, Margherita Paschini, Grit S. Herter-Sprie, Gang Lu, Xin Zhang, Bryan P. Marsh, Stephanie J. Tuminello, Chunxiao Xu, Zhao Chen, Xiaoen Wang, Esra A. Akbay, Mei Zheng, Sangeetha Palakurthi, Lynette M. Sholl, Anil K. Rustgi, David J. Kwiatkowski, J. Alan Diehl, Adam J. Bass, Norman E. Sharpless, Glenn Dranoff, Peter S. Hammerman, Hongbin Ji, Nabeel Bardeesy, Dieter Saur, Hideo Watanabe, Carla F. Kim, Kwok-Kin Wong

Toxicology and Cancer Biology Faculty Publications

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but …

Glioma Stem Cells-Derived Exosomes Promote The Angiogenic Ability Of Endothelial Cells Through Mir-21/Vegf Signal, Xu Sun, Xiaotang Ma, Jinju Wang, Yuhui Zhao, Yue Wang, Ji C. Bihl, Yanfang Chen, Chuanlu Jiang

Pharmacology and Toxicology Faculty Publications

Glioma stem cells (GSCs) play an important role in glioblastoma prognosis. Exosomes (EXs) mediate cell communication by delivering microRNAs (miRs). Glioblastoma has a high level of miR-21 which could upregulate vascular endothelial growth factor (VEGF) expression. We hypothesized GSC-EXs can promote the angiogenic ability of endothelial cells (ECs) through miR-21/VEGF signal. GSCs were isolated from U-251 cells with stem cell marker CD133. GSCs transfected without or with scramble or miR-21 mimics were used to produce GSC-^EXscon, GSC-EXs^sc and GSC-EXs^miR-21. Human brain ECs were co-cultured with vehicle, GSC-EXs^con, GSC-EXs^sc or GSC-EXs^miR-21 plus …

Effects Of Storage Time On Glycolysis In Donated Human Blood Units, Zhen Qi, John D. Roback, Eberhard O. Voit

Toxicology and Cancer Biology Faculty Publications

Background: Donated blood is typically stored before transfusions. During storage, the metabolism of red blood cells changes, possibly causing storage lesions. The changes are storage time dependent and exhibit donor-specific variations. It is necessary to uncover and characterize the responsible molecular mechanisms accounting for such biochemical changes, qualitatively and quantitatively; Study Design and Methods: Based on the integration of metabolic time series data, kinetic models, and a stoichiometric model of the glycolytic pathway, a customized inference method was developed and used to quantify the dynamic changes in glycolytic fluxes during the storage of donated blood units. The method provides a …

Latexin Inactivation Enhances Survival And Long-Term Engraftment Of Hematopoietic Stem Cells And Expands The Entire Hematopoietic System In Mice, Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard C. Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret K. St. Clair, Jinze Liu, Chang-Guo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang

Toxicology and Cancer Biology Faculty Publications

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 …

Relb Expression Determines The Differential Effects Of Ascorbic Acid In Normal And Cancer Cells, Xiaowei Wei, Yong Xu, Fang Fang Xu, Luksana Chaiswing, David M. Schnell, Teresa Noel, Chi Wang, Jinfei Chen, Daret K. St. Clair, William H. St. Clair

Toxicology and Cancer Biology Faculty Publications

Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced …

A Novel Redox Regulator, Mntnbuoe-2-Pyp5+, Enhances Normal Hematopoietic Stem/Progenitor Cell Function, Yanming Zhao, Dustin W. Carroll, Y. You, Luksana Chaiswing, R. Wen, I. Batinic-Haberle, Subbarao Bondada, Ying Liang, Daret K. St Clair

Toxicology and Cancer Biology Faculty Publications

The signaling of reactive oxygen species (ROS) is essential for the maintenance of normal cellular function. However, whether and how ROS regulate stem cells are unclear. Here, we demonstrate that, in transgenic mice expressing the human manganese superoxide dismutase (MnSOD) gene, a scavenger of ROS in mitochondria, the number and function of mouse hematopoietic stem/progenitor cells (HSPC) under physiological conditions are enhanced. Importantly, giving MnTnBuOE-2-PyP⁵⁺(MnP), a redox- active MnSOD mimetic, to mouse primary bone marrow cells or to C57B/L6 mice significantly enhances the number of HSPCs. Mechanistically, MnP reduces superoxide to hydrogen peroxide, which activates intracellular Nrf2 signaling …

Polyubiquitination Of Apurinic/Apyrimidinic Endonuclease 1 By Parkin, Timothy L. Scott, Christina A. Wicker, Rangaswamy Suganya, Bithika Dhar, Thomas A. Pittman, Craig Horbinski, Tadahide Izumi

Toxicology and Cancer Biology Faculty Publications

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein crucial for repair of oxidized DNA damage not only in genomic DNA but also in mitochondrial DNA. Parkin, a tumor suppressor and Parkinson's disease (PD) associated gene, is an E3 ubiquitin ligase crucial for mitophagy. Although DNA damage is known to induce mitochondrial stress, Parkin's role in regulating DNA repair proteins has not been elucidated. In this study, we examined the possibility of Parkin‐dependent ubiquitination of APE1. Ectopically expressed APE1 was degraded by Parkin and PINK1 via polyubiquitination in mouse embryonic fibroblast cells. PD‐causing mutations in Parkin and PINK1 abrogated APE1 ubiquitination. …

Doxorubicin Cytotoxicity In A Human Proximal Tubular Epithelial Cell Line Was Attenuated By The Natural Product Resveratrol, Morghan Schuyler Getty

Theses, Dissertations and Capstones

The cancer chemotherapeutic agent doxorubicin (DOX), Adriamycin, is part of the treatment regimen for breast, ovarian, small cell lung cancer and acute/chronic lymphoid leukemia. Adverse effects associated with DOX are cardiotoxicity and nephrotoxicity. Interventions are needed to reduce DOX nephrotoxicity. Resveratrol (RES) is a phytochemical contained in grapes, berries and nuts, which possesses antioxidant and anticancer properties. This study tested the hypothesis that RES will attenuate DOX renal cytotoxicity in human noncancerous renal proximal tubular epithelial (HK-2) cells and that RES will reduce DOX mediated changes in mitochondrial function. HK-2 cells were plated and grown for 48 hours (h). Cells …

Uvb Induces Mvp Release In A Paf Dependent Manner In Skin-Dervied Epithelial Cell Line, Langni Liu, Katherine E. Fahy, Christine M. Rapp, Eric J. Romer, Christina E. Borchers, Ji C. Bihl, Jeffrey B. Travers

Pharmacology and Toxicology Faculty Publications

Ultraviolet-B (UVB) irradiation of the skin can result in both acute inflammation and systemic immunosuppression. These effects are mediated by the release of bioactive molecules (e.g. cytokines and lipids) from resident skin epithelial and immune cells. Our lab has previously determined that UVB exposure stimulates the production of an inflammatory phospholipid activator, platelet-activating factor (PAF) and its oxidized analogs, which are involved in mediating the UVB responses. Due to the fact that UVB radiation is absorbed by the epidermis but causes systemic effects, we are interested in examining the PAF-mediated mechanisms of systemic intercellular communication. Microvesicle particles (MVP) are small …