Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle
| Autor: | Muralidhar L. Hegde, Velmarini Vasquez, Trenton Roy, Thomas A. Kent, Istvan Boldogh, Prakash Dharmalingam, Emily A. McHugh, Kimberly Mendoza, Joy Mitra, James M. Tour, Roderic H. Fabian, Girish Talakatta, Lizanne G. Nilewski, Haibo Wang, Sankar Mitra, Venkatesh L. Hegde, Paul J. Derry, Pavana M. Hegde, Eugenia Kakadiaris |
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| Rok vydání: | 2020 |
| Předmět: |
Senescence
DNA damage Iron General Physics and Astronomy 02 engineering and technology Deferoxamine 010402 general chemistry 01 natural sciences Article Polyethylene Glycols Mice chemistry.chemical_compound In vivo medicine Animals Humans General Materials Science DNA Breaks Single-Stranded Cells Cultured Cellular Senescence Cerebral Hemorrhage chemistry.chemical_classification Reactive oxygen species General Engineering Cell Differentiation 021001 nanoscience & nanotechnology Carbon In vitro Mitochondria 0104 chemical sciences Cell biology Endothelial stem cell chemistry Hemin Nanoparticles Reactive Oxygen Species 0210 nano-technology DNA Damage medicine.drug |
| Zdroj: | ACS Nano |
| ISSN: | 1936-086X 1936-0851 |
| DOI: | 10.1021/acsnano.9b05821 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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