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Articles 1 - 10 of 10
Full-Text Articles in Medical Toxicology
Mechanisms Of Cigarette Smoke-Induced Mitochondrial Dysfunction In Striated Muscle And Aorta, Stephen T. Decker
Mechanisms Of Cigarette Smoke-Induced Mitochondrial Dysfunction In Striated Muscle And Aorta, Stephen T. Decker
Doctoral Dissertations
Cigarette Smoke is a significant cause of morbidity and mortality in the United States, accounting for over 480,000 annual deaths. Of these deaths, the most common cause of mortality in chronic smokers is cardiometabolic diseases. Likewise, a significant portion of smokers experience some form of cardiac, vascular, or metabolic dysfunction throughout their lifetime. More specifically, smoking is shown to induce mitochondrial dysfunction in these tissues, causing an increase in oxidative damage and poor overall health. However, despite the advances in the health outcomes related to cigarette smoke exposure, the mechanisms underlying mitochondrial dysfunction in striated muscle and the vasculature remain …
Redox Proteomic Identification Of Hne-Bound Mitochondrial Proteins In Cardiac Tissues Reveals A Systemic Effect On Energy Metabolism After Doxorubicin Treatment, Y. Zhao, Sumitra Miriyala, L. Miao, Mihail I. Mitov, David M. Schnell, Sanjit Kumar Dhar, J. Cai, J. B. Klein, Rukhsana Sultana, D. Allan Butterfield, Mary Vore, I. Batinic-Haberle, Subbarao Bondada, Daret K. St. Clair
Redox Proteomic Identification Of Hne-Bound Mitochondrial Proteins In Cardiac Tissues Reveals A Systemic Effect On Energy Metabolism After Doxorubicin Treatment, Y. Zhao, Sumitra Miriyala, L. Miao, Mihail I. Mitov, David M. Schnell, Sanjit Kumar Dhar, J. Cai, J. B. Klein, Rukhsana Sultana, D. Allan Butterfield, Mary Vore, I. Batinic-Haberle, Subbarao Bondada, Daret K. St. Clair
Toxicology and Cancer Biology Faculty Publications
Doxorubicin (DOX), one of the most effective anticancer drugs, is known to generate progressive cardiac damage, which is due, in part, to DOX-induced reactive oxygen species (ROS). The elevated ROS often induce oxidative protein modifications that result in alteration of protein functions. This study demonstrates that the level of proteins adducted by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, is significantly increased in mouse heart mitochondria after DOX treatment. A redox proteomics method involving two-dimensional electrophoresis followed by mass spectrometry and investigation of protein databases identified several HNE-modified mitochondrial proteins, which were verified by HNE-specific immunoprecipitation in cardiac mitochondria from the …
Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis And Tumor Progression In Mouse Models Of Lung Cancer And Impacts Tumor-Initiating Cells, Han Xie, Jun-Ichi Hanai, Jian-Guo Ren, Lev Kats, Kerri Burgess, Parul Bhargava, Sabina Signoretti, Julia Billiard, Kevin J. Duffy, Aaron Grant, Xiaoen Wang, Pawel Lorkiewicz, Sabrina Schatzman, Michael Bousamra, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan, Pier Paolo Pandolfi, Vikas P. Sukhatme, Pankaj Seth
Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis And Tumor Progression In Mouse Models Of Lung Cancer And Impacts Tumor-Initiating Cells, Han Xie, Jun-Ichi Hanai, Jian-Guo Ren, Lev Kats, Kerri Burgess, Parul Bhargava, Sabina Signoretti, Julia Billiard, Kevin J. Duffy, Aaron Grant, Xiaoen Wang, Pawel Lorkiewicz, Sabrina Schatzman, Michael Bousamra, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan, Pier Paolo Pandolfi, Vikas P. Sukhatme, Pankaj Seth
Toxicology and Cancer Biology Faculty Publications
The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo …
Mnsod And Autophagy In Prevention Of Oxidative Mitochondrial Injuries Induced By Uvb In Murine Skin, Vasudevan Bakthavatchalu
Mnsod And Autophagy In Prevention Of Oxidative Mitochondrial Injuries Induced By Uvb In Murine Skin, Vasudevan Bakthavatchalu
Theses and Dissertations--Toxicology and Cancer Biology
UVB radiation is a known environmental carcinogen that causes DNA damage and increase ROS generation in mitochondria. Accumulating evidence suggests that mtDNA damage and increased ROS generation trigger mitochondrial translocation of p53. Within mitochondria, p53 interacts with nucleoid macromolecular complexes such as mitochondrial antioxidant MnSOD, mitochondrial DNA polymerase Polγ, and mtDNA. Mitochondria are considered to be a potential source for damage-associated molecular patterns (DAMPs) such as mtDNA, cytochrome C, ATP, and formyl peptides. Intracytoplasmic release of DAMPs can trigger inflammasome formation and programmed cell death processes. Autophagic clearance of mitochondria with compromised integrity can inhibit inflammatory and cell death processes. …
Manganese Superoxide Dismutase: Guardian Of The Powerhouse, Aaron K. Holley, Vasudevan Bakthavatchalu, Joyce M. Velez-Roman, Daret K. St. Clair
Manganese Superoxide Dismutase: Guardian Of The Powerhouse, Aaron K. Holley, Vasudevan Bakthavatchalu, Joyce M. Velez-Roman, Daret K. St. Clair
Toxicology and Cancer Biology Faculty Publications
The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese …
P53 Regulates Oxidative Stress-Mediated Retrograde Signaling: A Novel Mechanism For Chemotherapy-Induced Cardiac Injury, Joyce M. Velez, Sumitra Miriyala, Ramaneeya Nithipongvanitch, Teresa Noel, Chotiros D. Plabplueng, Terry Oberley, Paiboon Jungsuwadee, Holly Van Remmen, Mary Vore, Daret K. St Clair
P53 Regulates Oxidative Stress-Mediated Retrograde Signaling: A Novel Mechanism For Chemotherapy-Induced Cardiac Injury, Joyce M. Velez, Sumitra Miriyala, Ramaneeya Nithipongvanitch, Teresa Noel, Chotiros D. Plabplueng, Terry Oberley, Paiboon Jungsuwadee, Holly Van Remmen, Mary Vore, Daret K. St Clair
Toxicology and Cancer Biology Faculty Publications
The side effects of cancer therapy on normal tissues limit the success of therapy. Generation of reactive oxygen species (ROS) has been implicated for numerous chemotherapeutic agents including doxorubicin (DOX), a potent cancer chemotherapeutic drug. The production of ROS by DOX has been linked to DNA damage, nuclear translocation of p53, and mitochondrial injury; however, the causal relationship and molecular mechanisms underlying these events are unknown. The present study used wild-type (WT) and p53 homozygous knock-out (p53(-/-)) mice to investigate the role of p53 in the crosstalk between mitochondria and nucleus. Injecting mice with DOX (20 mg/kg) causes oxidative stress …
Mir-17* Suppresses Tumorigenicity Of Prostate Cancer By Inhibiting Mitochondrial Antioxidant Enzymes, Yong Xu, Fang Fang, Jiayou Zhang, Sajni Josson, William H. St. Clair, Daret K. St. Clair
Mir-17* Suppresses Tumorigenicity Of Prostate Cancer By Inhibiting Mitochondrial Antioxidant Enzymes, Yong Xu, Fang Fang, Jiayou Zhang, Sajni Josson, William H. St. Clair, Daret K. St. Clair
Toxicology and Cancer Biology Faculty Publications
Aberrant micro RNA (miRNA) expression has been implicated in the pathogenesis of cancer. Recent studies have shown that the miR-17-92 cluster is overexpressed in many types of cancer. The oncogenic function of mature miRNAs encoded by the miR-17-92 cluster has been identified from the 5' arm of six precursors. However, the function of the miRNAs produced from the 3' arm of these precursors remains unknown. The present study demonstrates that miR-17* is able to suppress critical primary mitochondrial antioxidant enzymes, such as manganese superoxide dismutase (MnSOD), glutathione peroxidase-2 (GPX2) and thioredoxin reductase-2 (TrxR2). Transfection of miR-17* into prostate cancer PC-3 …
Nitration And Inactivation Of Manganese Superoxide Dismutase Plays A Critical Role In Metabolic Switch, Muthuswamy Anantharaman
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 …
Effects Of Tamoxifen On Mitochondrial Nos Activity: Alteration In The Intramitochondrial Ca2+ Homeostasis, Sandeep S. Joshi
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.
The Protective Role Of Manganese Superoxide Dismutase Against Adriamycin-Induced Acute Cardiac Toxicity In Transgenic Mice, Hsiu-Chuan Yen, Terry D. Oberley, Satit Vichitbandha, Ye-Shih Ho, Daret K. St. Clair
The Protective Role Of Manganese Superoxide Dismutase Against Adriamycin-Induced Acute Cardiac Toxicity In Transgenic Mice, Hsiu-Chuan Yen, Terry D. Oberley, Satit Vichitbandha, Ye-Shih Ho, Daret K. St. Clair
Toxicology and Cancer Biology Faculty Publications
Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and …