实验性脑出血中普遍的基因组损伤：基于机理的碳纳米粒子的治疗潜力。,ACS Nano

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实验性脑出血中普遍的基因组损伤：基于机理的碳纳米粒子的治疗潜力。
ACS Nano ( IF 15.8 ) Pub Date : 2020-02-21 , DOI: 10.1021/acsnano.9b05821
Prakash Dharmalingam ₁ , Girish Talakatta ₁ , Joy Mitra ₁ , Haibo Wang ₁ , Paul J Derry ₂ , Lizanne Greer Nilewski ₃ , Emily A McHugh ₃ , Roderic H Fabian ₄ , Kimberly Mendoza ₃ , Velmarini Vasquez ₁ , Pavana M Hegde ₁ , Eugenia Kakadiaris ₃ , Trenton Roy ₃ , Istvan Boldogh ₅ , Venkatesh L Hegde ₁ , Sankar Mitra _{1,

6} , James M Tour ₇ , Thomas A Kent _{2,

3,

8} , Muralidhar L Hegde _{1,

6,

9}

Affiliation

Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas 77030, United States.
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.
Department of Neurology, Baylor College of Medicine, and Michael E. DeBakey VA Medical Center, Houston, Texas 77030, United States.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
Weill Medical College of Cornell University, New York, New York 10065, United States.
Departments of Chemistry, Computer Science, Materials Science and NanoEngineering, Smalley-Curl Institute and the NanoCarbon Center, Rice University, Houston, Texas 77005, United States.
Stanley H. Appel Department of Neurology, Houston Methodist Hospital and Research Institute, Houston, Texas 77030, United States.
Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Neurological Institute, Houston Methodist, Houston, Texas 77030, United States.

脑出血（ICH）的治疗仍然难以捉摸，部分取决于出血本身的严重程度以及血液及其分解产物（如血红素和游离铁）的多种有害作用。尽管在ICH后发现了氧化性损伤和基因组损伤，但这种损伤的细节及其影响仍不清楚。在这里，我们发现，尽管游离铁主要产生与活性氧（ROS）相关的单链DNA断裂，但血红素却意外地在神经元和内皮细胞基因组以及小鼠中诱导了快速持久的核和线粒体双链断裂（DSB）。实验性ICH后的大脑可与γ射线和DNA复杂化学疗法相比。潜在的持久性DSB和DNA损伤反应的结果，血红素还导致培养的神经元和内皮细胞的衰老表型。在神经元中也观察到了其他衰老细胞类型中随后报道的对铁锈病的抗性。尽管抗氧化剂可以防止衰老，但细胞对铁锈病很敏感。为了解决衰老和对肥大病的抵抗力，我们通过共价键合铁螯合剂去铁胺（DEF）合成了一种修饰的，催化的且快速内在化的碳纳米材料，即聚（乙二醇）共轭的亲水性碳簇（PEG-HCC）。这种多功能纳米粒子DEF-HCC-PEG保护细胞免受衰老和肥大症的侵害，并在体外和体内恢复了核和线粒体基因组的完整性。

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

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.

更新日期：2020-02-12

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