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Title: MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation

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Journal Article: Published Article
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Journal Volume: 11; Journal Issue: 8; Related Information: CHORUS Timestamp: 2017-06-24 16:12:01; Journal ID: ISSN 1932-6203
Public Library of Science (PLoS)
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United States

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Gupta, Paridhi, Gayen, Manoshi, Smith, Joan T., Gaidamakova, Elena K., Matrosova, Vera Y., Grichenko, Olga, Knollmann-Ritschel, Barbara, Daly, Michael J., Kiang, Juliann G., Maheshwari, Radha K., and Fornace, ed., Albert J. MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0160575.
Gupta, Paridhi, Gayen, Manoshi, Smith, Joan T., Gaidamakova, Elena K., Matrosova, Vera Y., Grichenko, Olga, Knollmann-Ritschel, Barbara, Daly, Michael J., Kiang, Juliann G., Maheshwari, Radha K., & Fornace, ed., Albert J. MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation. United States. doi:10.1371/journal.pone.0160575.
Gupta, Paridhi, Gayen, Manoshi, Smith, Joan T., Gaidamakova, Elena K., Matrosova, Vera Y., Grichenko, Olga, Knollmann-Ritschel, Barbara, Daly, Michael J., Kiang, Juliann G., Maheshwari, Radha K., and Fornace, ed., Albert J. Mon . "MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation". United States. doi:10.1371/journal.pone.0160575.
title = {MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation},
author = {Gupta, Paridhi and Gayen, Manoshi and Smith, Joan T. and Gaidamakova, Elena K. and Matrosova, Vera Y. and Grichenko, Olga and Knollmann-Ritschel, Barbara and Daly, Michael J. and Kiang, Juliann G. and Maheshwari, Radha K. and Fornace, ed., Albert J.},
abstractNote = {},
doi = {10.1371/journal.pone.0160575},
journal = {PLoS ONE},
number = 8,
volume = 11,
place = {United States},
year = {Mon Aug 08 00:00:00 EDT 2016},
month = {Mon Aug 08 00:00:00 EDT 2016}

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Publisher's Version of Record at 10.1371/journal.pone.0160575

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Cited by: 6works
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  • Although the protective effect of the polyhydroxylated fullerene derivative C{sub 60}(OH){sub n} against ionizing radiation is an area of much interest, the mechanisms relating to how polyhydroxylated fullerene derivatives improve mitochondrial dysfunction remain unknown. In order to find new and effective radioprotective agents, we synthesized a new polyhydroxylated fullerene molecule with 24 hydroxyl groups of known positions on C{sub 60} and studied its protective effects in mice subjected to irradiation. Mice were pretreated with C{sub 60}(OH){sub 24} for 2 weeks (daily, 40 mg/kg i. p.), then subjected to a lethal dose of whole body gamma-irradiation (from a {sup 60}Co source).more » Survival was observed for 30 days after irradiation. Immune and mitochondrial dysfunction and oxidative damage were analyzed in mice with the same C{sub 60}(OH){sub 24} pretreatment and irradiation except that the animals were euthanized at day 5 after the irradiation. It was found that 2-week C{sub 60}(OH){sub 24} pretreatment effectively reduced whole body irradiation-induced mortality without apparent toxicity. C{sub 60}(OH){sub 24} pretreatment also showed significant protective effects against ionizing-radiation-induced decreases in immune and mitochondrial function and antioxidant defense in the liver and spleen. These results suggest that the polyhydroxylated fullerene derivative C{sub 60}(OH){sub 24} protects against ionizing-radiation-induced mortality, possibly by enhancing immune function, decreasing oxidative damage and improving mitochondrial function.« less
  • Highlights: • A bidentate HQ derivative, AS-2, suppresses p53-dependent apoptosis by DNA damage. • AS-2 does not significantly affect nuclear p53 response. • UV-excited blue emission of AS-2 clearly showed its extranuclear localization. • AS-2 prevents mitochondrial dysfunction despite the increase of mitochondrial p53. • AS-2 protects mice from a radiation dose that causes lethal hematopoietic syndrome. - Abstract: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated micemore » because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo.« less
  • PUBLICATION CLEARED AFTER THE FACT. 2003. Proc. Natl. Acad. Sci. USA 100(7): 4191-4196
  • IL-12, a potent stimulator of hemopoietic progenitor cells, was evaluated as a potential protector against {sup 60}Co-gamma radiation-induced lethal hemopoietic syndrome in mice. Administration of IL-12 before lethal irradiation of genetically distinct strains of mice, B6D2F{sub 1} and C3H/HeJ, protected a significant fraction of both strains of mice from death. Radioprotection was associated with a fivefold increase in the number of bone marrow cells at 6 days after irradiation. Even at supralethal doses of radiation (1200 cGy), the number of c-kit{sup +} bone marrow cells 3 days after irradiation was twofold greater in IL-12-treated mice than in saline-treated mice. However,more » mice that received IL-12 and 1200 cGy (B6D2F{sub 1}) or 900 cGy (C3H/HeJ) died of the gastrointestinal syndrome, as was evident by gross necroscopy and histologic evaluation, within 4 to 6 days after irradiation. Induction of the gastrointestinal syndrome in mice not treated with IL-12 required radiation doses of 1500 cGy or greater in both strains. Thus, at doses of radiation at which IL-12 still protects c-kit{sup +} hemopoietic cells, it sensitizes the intestinal tract to damage. Radioprotection with IL-12 was abrogated by anti-IL-1R or anti-stem cell factor Ab. Anti-IFN-{gamma} Ab did not affect IL-12-induced hemopoietic radioprotection, but abrogated sensitization of the intestinal tract by IL-12. The sensitizing effect of IL-12 may be related to its ability to prime mice to subsequent inflammatory challenge, as demonstrated by an almost 100-fold increase in circulating TNF and IL-6 levels in normal B6D2F{sub 1} mice challenged with IL-12 and LPS. This priming effect of IL-12 also was abrogated by anti-IFN-{gamma} Ab. 34 refs., 6 figs., 5 tabs.« less
  • Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA andmore » reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2′-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage. - Highlights: • Repeated treatment with sulforaphane protects fibroblasts from ionizing radiation • Repeated sulforaphane treatment attenuates radiation induced ROS and DNA damage • Sulforaphane mediated protection is Nrf2 dependent.« less