Modulation of Radiation Injury

Coleman, C. Norman; Stone, Helen B.; Moulder, John E.; Pellmar, Terry C.

doi:10.1126/science.1095956

Cited by 126 publications

(86 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This medical concern is heightened due to the risk of radiological terrorism or radiation accidents (1,3,6,8). Protection or reconstitution of the hematopoietic and immune systems is a critical area of research in the development of radioprotectors and therapeutic agents (2,(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

et al. 2008

View full text Add to dashboard Cite

The purpose of this study was to determine whether a dietary supplement consisting of Lselenomethionine, vitamin C, vitamin E succinate, α-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-β1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.

show abstract

Section: Introductionmentioning

confidence: 99%

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The risk of radiological terrorism resulting in mass casualties heightens these medical concerns [1]. In this regard, the haematopoietic system represents one of the major dose-limiting tissues owing to its high radiation sensitivity, characterised by persistent decreases in endcells, compromised immune function, and increased susceptibility to infections and haemorrhage [2]. Several classes of compounds have been investigated for potential radiation countermeasure activity, including immunomodulators, free radical scavengers, haematopoietic cytokines, modulators of signal transduction and antiapoptotic agents [3][4].…”

mentioning

confidence: 99%

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Satyamitra

Ney²,

Graves³

et al. 2012

The British Journal of Radiology

View full text Add to dashboard Cite

Objective: The objective of this study was to investigate the correlation between in vivo d-tocotrienol (DT3) pharmacokinetics, pharmacodynamics and radiation protection, and to evaluate the effect of DT3 pre-treatment on radiation-induced alterations in apoptotic and autophagic pathways. Methods: We evaluated pharmacokinetics (plasma, 0.5 to 12 h) and pharmacodynamics (peripheral blood indices; day 3, 7, 10 and 14) after a single subcutaneous injection of 300 mg kg -1 DT3 in unirradiated CD2F1 mice. Next, we monitored 30-day post-irradiation survival (9.25 Gy) and haematopoietic recovery of DT3-treated mice (7 Gy) exposed to cobalt-60 c-irradiation. The effects of DT3 on irradiated bone marrow apoptosis and autophagy were determined by analyses of key caspases (3, 7, 9 and 8), beclin-1 and light chain 3 conversion. Results: Plasma concentration of DT3 reached ,195 mM (Cmax) 1 h after injection (Tmax), and DT3 was eliminated from plasma 12 h later. In unirradiated mice, DT3 significantly increased white blood cells (WBCs), neutrophils, lymphocytes (day 3 post DT3 injection) and platelets (day 7) by 1.5-to 2-fold, over vehicle-treated control. DT3 pre-treatment improved 30-day survival to 100% (,15% in control) and accelerated recovery of reticulocytes, platelets, WBCs, neutrophils, lymphocytes and monocytes in peripheral blood. DT3 reduced activation of caspase-8, caspase-3 and caspase-7, inherent to apoptosis, while increasing autophagy-related beclin-1 expression in irradiated bone marrow. Conclusion: These data indicate that DT3 stimulates multilineage haematopoiesis, protects against radiation-induced apoptosis downstream of the mitochondria and stimulates cytoprotective autophagy. Apart from a potent antioxidant activity, DT3 may elicit survival advantage following irradiation by enhancing haematopoiesis and modulating signalling pathways.

show abstract

“…Indeed, knockdown of Ku70 expression sensitizes embryos to a 50 cGy dose of ionizing radiation by increasing cell death in the brain and spinal cord. The consequences of radiation exposure during brain development are well-documented [35] and further study of NHEJ protein function during embryogenesis may provide new insights to the protective mechanisms and consequences of low dose radiation exposure, particularly in sensitive populations such as children and pregnant women [36,37]. Expression of Ku70 is required for radioprotection.…”

mentioning

confidence: 99%

Expression of the Ku70 subunit (XRCC6) and protection from low dose ionizing radiation during zebrafish embryogenesis

Bladen

Navarre

Dynan

et al. 2007

Neuroscience Letters

View full text Add to dashboard Cite

The Ku70 protein, a product of the XRCC6 gene, is a component of the nonhomologous end-joining (NHEJ) pathway of DNA repair, which protects cells from the effects of radiation-induced DNA damage. Although the spatial expression of Ku70 during vertebrate embryogenesis has not been described, DNA repair proteins are generally considered to be "housekeeping" genes, which are required for radioprotection in all cells. Here, we report the cloning and characterization of the zebrafish Ku70 ortholog. In situ hybridization and RT-PCR analyses demonstrate that Ku70 mRNA is maternally provided and expressed uniformly among embryonic blastomeres. Later during embryogenesis, zygotically transcribed Ku70 mRNA specifically accumulates in neural tissue, including the retina and proliferative regions of the developing brain. In the absence of genotoxic stress, morpholino-mediated knockdown of Ku70 expression does not affect zebrafish embryogenesis. However, exposure of Ku70 morpholino-injected embryos to low doses of ionizing radiation leads to marked cell death throughout the developing brain, spinal cord, and tail. These results suggest that Ku70 protein plays a crucial role in protecting the developing nervous system from radiation-induced DNA damage during embryogenesis. KeywordsKu protein; Ku70; XRCC6; embryo; ionizing radiation; nonhomologous end-joining; DNA repair; TUNEL; apoptosis; zebrafish The physical interaction of ionizing radiation with duplex DNA results in double-strand breaks (DSBs), which are one of the most potent types of DNA lesion. In proliferating cells, the cytotoxic effects of DSBs can be acute or latently manifest as chromosomal translocations and other genomic aberrations [1]. Natural sources of DSBs include ionizing radiation and, to a lesser extent, byproducts of normal metabolic processes, such as reactive oxygen species. To mitigate the biological effects of DSBs, organisms have developed protective strategies that sense and rapidly repair this type of DNA damage. Following DSB induction, chromosomal integrity is typically reestablished either by the nonhomologous end-joining (NHEJ) or homologous recombination pathways of DNA repair (reviewed in [2,3]).The NHEJ pathway of DSB repair requires the function of at least five genes: XRCC5, which encodes the Ku80 protein [4][5][6], XRCC6, which encodes the Ku70 protein [7][8][9], LIG4 *Corresponding author: IMMAG, CB-2803, Medical College of Georgia,1120 15th Street, Augusta, GA 30912. Phone: (706) 721-8760. Fax: (706) 721-8752. E-mail: dkozlowski@mcg.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ...

show abstract

Modulation of Radiation Injury

Cited by 126 publications

References 10 publications

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Expression of the Ku70 subunit (XRCC6) and protection from low dose ionizing radiation during zebrafish embryogenesis

Contact Info

Product

Resources

About