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Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle

  • Prakash Dharmalingam
    Prakash Dharmalingam
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
  • Girish Talakatta
    Girish Talakatta
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
  • Joy Mitra
    Joy Mitra
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
    More by Joy Mitra
  • Haibo Wang
    Haibo Wang
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
    More by Haibo Wang
  • Paul J. Derry
    Paul J. Derry
    Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, United States
  • Lizanne Greer Nilewski
    Lizanne Greer Nilewski
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
  • Emily A. McHugh
    Emily A. McHugh
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
  • Roderic H. Fabian
    Roderic H. Fabian
    Department of Neurology, Baylor College of Medicine, and Michael E. DeBakey VA Medical Center, Houston, Texas 77030, United States
  • Kimberly Mendoza
    Kimberly Mendoza
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
  • Velmarini Vasquez
    Velmarini Vasquez
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
  • Pavana M. Hegde
    Pavana M. Hegde
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
  • Eugenia Kakadiaris
    Eugenia Kakadiaris
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
  • Trenton Roy
    Trenton Roy
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
    More by Trenton Roy
  • Istvan Boldogh
    Istvan Boldogh
    Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, United States
  • Venkatesh L. Hegde
    Venkatesh L. Hegde
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
  • Sankar Mitra
    Sankar Mitra
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
    Weill Medical College of Cornell University, New York, New York 10065, United States
    More by Sankar Mitra
  • James M. Tour*
    James M. Tour
    Departments of Chemistry, Computer Science, Materials Science and NanoEngineering, Smalley-Curl Institute and the NanoCarbon Center, Rice University, Houston, Texas 77005, United States
    *Email: [email protected]
  • Thomas A. Kent*
    Thomas A. Kent
    Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030, United States
    Department of Chemistry, Rice University, Houston, Texas 77005, United States
    Stanley H. Appel Department of Neurology, Houston Methodist Hospital and Research Institute, Houston, Texas 77030, United States
    *Email: [email protected]
  • , and 
  • Muralidhar L. Hegde*
    Muralidhar L. Hegde
    Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States
    Weill Medical College of Cornell University, New York, New York 10065, United States
    Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Neurological Institute, Houston Methodist, Houston, Texas 77030, United States
    *Email: [email protected]
Cite this: ACS Nano 2020, 14, 3, 2827–2846
Publication Date (Web):February 12, 2020
https://doi.org/10.1021/acsnano.9b05821
Copyright © 2020 American Chemical Society

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    Abstract

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    Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies. Potentially as a result of persistent DSBs and the DNA damage response, hemin also resulted in senescence phenotype in cultured neurons and endothelial cells. Subsequent resistance to ferroptosis reported in other senescent cell types was also observed here in neurons. While antioxidant therapy prevented senescence, cells became sensitized to ferroptosis. To address both senescence and resistance to ferroptosis, we synthesized a modified, catalytic, and rapidly internalized carbon nanomaterial, poly(ethylene glycol)-conjugated hydrophilic carbon clusters (PEG-HCC) by covalently bonding the iron chelator, deferoxamine (DEF). This multifunctional nanoparticle, DEF-HCC-PEG, protected cells from both senescence and ferroptosis and restored nuclear and mitochondrial genome integrity in vitro and in vivo. We thus describe a potential molecular mechanism of hemin/iron-induced toxicity in ICH that involves a rapid induction of DSBs, senescence, and the consequent resistance to ferroptosis and provide a mechanistic-based combinatorial therapeutic strategy.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.9b05821.

    • List of gene targets and primer sequences used for LA-PCR experiment and additional experimental data for dose and time kinetics of iron (FeSO4 and Fe-NTA)-induced cell death analysis and hemin purity analysis chromatogram; PGC-1α levels and DNA integrity in hemin-treated neurons; PGC-1α levels in ICH mice; DNA strand breaks quantitation in hemin-treated b.End3 cells and its amelioration by PEG-HCC; inhibition of hemin-induced senescence by PEG-HCC in b.End3 cells; GPx4 levels in hemin-treated iPSC-derived neurons together with erastin/ferrostatin controls; in vitro DNA damage by hemin and iron and characterization of nanoparticles via thermogravimetric analysis (PDF)

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