Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart
Space travel is associated with an exposure to low-dose rate ionizing radiation and the microgravity environment, both of which may lead to impairments in cardiac function. We used a mouse model to determine short- and long-term cardiac effects to simulated microgravity (hindlimb unloading; HU), con...
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| Veröffentlicht in: | PloS one 2017-07, Vol.12 (7), p.e0180594-e0180594 |
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| creator | Seawright, John W Samman, Yusra Sridharan, Vijayalakshmi Mao, Xiao Wen Cao, Maohua Singh, Preeti Melnyk, Stepan Koturbash, Igor Nelson, Gregory A Hauer-Jensen, Martin Boerma, Marjan |
| description | Space travel is associated with an exposure to low-dose rate ionizing radiation and the microgravity environment, both of which may lead to impairments in cardiac function. We used a mouse model to determine short- and long-term cardiac effects to simulated microgravity (hindlimb unloading; HU), continuous low-dose rate γ-irradiation, or a combination of HU and low-dose rate γ-irradiation.
Cardiac tissue was obtained from female, C57BL/6J mice 7 days, 1 month, 4 months, and 9 months following the completion of a 21 day exposure to HU or a 21 day exposure to low-dose rate γ-irradiation (average dose rate of 0.01 cGy/h to a total of 0.04 Gy), or a 21 day simultaneous exposure to HU and low-dose rate γ-irradiation. Immunoblot analysis, rt-PCR, high-performance liquid chromatography, and histology were used to assess inflammatory cell infiltration, cardiac remodeling, oxidative stress, and the methylation potential of cardiac tissue in 3 to 6 animals per group.
The combination of HU and γ-irradiation demonstrated the strongest increase in reduced to oxidized glutathione ratios 7 days and 1 month after treatment, but a difference was no longer apparent after 9 months. On the other hand, no significant changes in 4-hydroxynonenal adducts was seen in any of the groups, at the measured endpoints. While manganese superoxide dismutase protein levels decreased 9 months after low-dose γ-radiation, no changes were observed in expression of catalase or Nrf2, a transcription factor that determines the expression of several antioxidant enzymes, at the measured endpoints. Inflammatory marker, CD-2 protein content was significantly decreased in all groups 4 months after treatment. No significant differences were observed in α-smooth muscle cell actin protein content, collagen type III protein content or % total collagen.
This study has provided the first and relatively broad analysis of small molecule and protein markers of oxidative stress, T-lymphocyte infiltration, and cardiac remodeling in response to HU with simultaneous exposure to low-dose rate γ-radiation. Results from the late observation time points suggest that the hearts had mostly recovered from these two experimental conditions. However, further research is needed with larger numbers of animals for a more robust statistical power to fully characterize the early and late effects of simulated microgravity combined with exposure to low-dose rate ionizing radiation on the heart. |
| doi_str_mv | 10.1371/journal.pone.0180594 |
| format | Article |
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Cardiac tissue was obtained from female, C57BL/6J mice 7 days, 1 month, 4 months, and 9 months following the completion of a 21 day exposure to HU or a 21 day exposure to low-dose rate γ-irradiation (average dose rate of 0.01 cGy/h to a total of 0.04 Gy), or a 21 day simultaneous exposure to HU and low-dose rate γ-irradiation. Immunoblot analysis, rt-PCR, high-performance liquid chromatography, and histology were used to assess inflammatory cell infiltration, cardiac remodeling, oxidative stress, and the methylation potential of cardiac tissue in 3 to 6 animals per group.
The combination of HU and γ-irradiation demonstrated the strongest increase in reduced to oxidized glutathione ratios 7 days and 1 month after treatment, but a difference was no longer apparent after 9 months. On the other hand, no significant changes in 4-hydroxynonenal adducts was seen in any of the groups, at the measured endpoints. While manganese superoxide dismutase protein levels decreased 9 months after low-dose γ-radiation, no changes were observed in expression of catalase or Nrf2, a transcription factor that determines the expression of several antioxidant enzymes, at the measured endpoints. Inflammatory marker, CD-2 protein content was significantly decreased in all groups 4 months after treatment. No significant differences were observed in α-smooth muscle cell actin protein content, collagen type III protein content or % total collagen.
This study has provided the first and relatively broad analysis of small molecule and protein markers of oxidative stress, T-lymphocyte infiltration, and cardiac remodeling in response to HU with simultaneous exposure to low-dose rate γ-radiation. Results from the late observation time points suggest that the hearts had mostly recovered from these two experimental conditions. However, further research is needed with larger numbers of animals for a more robust statistical power to fully characterize the early and late effects of simulated microgravity combined with exposure to low-dose rate ionizing radiation on the heart.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0180594</identifier><identifier>PMID: 28678877</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>4-Hydroxynonenal ; Adducts ; Animals ; Antioxidants - metabolism ; Atherosclerosis ; Biology ; Biology and Life Sciences ; Breast cancer ; Cadmium ; Cardiovascular disease ; Catalase ; Chromatography ; Collagen (type III) ; Collagen - metabolism ; Computer simulation ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - radiation effects ; Dose-Response Relationship, Radiation ; Drug dosages ; Economic conditions ; Enzymes ; Enzymes - metabolism ; Exposure ; Female ; Gamma irradiation ; Gamma Rays ; Glutathione ; Heart - anatomy & histology ; Heart - radiation effects ; Heart diseases ; Heart failure ; Heart rate ; High performance liquid chromatography ; Histology ; Homocysteine ; Immune system ; Infiltration ; Inflammation ; Ionizing radiation ; Irradiation ; Liquid chromatography ; Lymphocytes T ; Manganese ; Markers ; Medical research ; Medicine and Health Sciences ; Metabolism ; Mice ; Mice, Inbred C57BL ; Microgravity ; Myocardium - enzymology ; Myocardium - metabolism ; Oxidative stress ; Oxidative Stress - radiation effects ; Pharmaceutical sciences ; Pharmaceuticals ; Physical Sciences ; Polymerase chain reaction ; Radiation ; Radiation dosage ; Radiation therapy ; Rodents ; Smooth muscle ; Space flight ; Superoxide dismutase ; Travel ; Weightlessness Simulation ; γ Radiation</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0180594-e0180594</ispartof><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-a3ab0c0dfd98f8a48505a2a3ed698c4408de4d8a7f72f9477c1cc4a8bfc158d13</citedby><cites>FETCH-LOGICAL-c526t-a3ab0c0dfd98f8a48505a2a3ed698c4408de4d8a7f72f9477c1cc4a8bfc158d13</cites><orcidid>0000-0002-3230-7547</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28678877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Woloschak, Gayle E.</contributor><creatorcontrib>Seawright, John W</creatorcontrib><creatorcontrib>Samman, Yusra</creatorcontrib><creatorcontrib>Sridharan, Vijayalakshmi</creatorcontrib><creatorcontrib>Mao, Xiao Wen</creatorcontrib><creatorcontrib>Cao, Maohua</creatorcontrib><creatorcontrib>Singh, Preeti</creatorcontrib><creatorcontrib>Melnyk, Stepan</creatorcontrib><creatorcontrib>Koturbash, Igor</creatorcontrib><creatorcontrib>Nelson, Gregory A</creatorcontrib><creatorcontrib>Hauer-Jensen, Martin</creatorcontrib><creatorcontrib>Boerma, Marjan</creatorcontrib><title>Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Space travel is associated with an exposure to low-dose rate ionizing radiation and the microgravity environment, both of which may lead to impairments in cardiac function. We used a mouse model to determine short- and long-term cardiac effects to simulated microgravity (hindlimb unloading; HU), continuous low-dose rate γ-irradiation, or a combination of HU and low-dose rate γ-irradiation.
Cardiac tissue was obtained from female, C57BL/6J mice 7 days, 1 month, 4 months, and 9 months following the completion of a 21 day exposure to HU or a 21 day exposure to low-dose rate γ-irradiation (average dose rate of 0.01 cGy/h to a total of 0.04 Gy), or a 21 day simultaneous exposure to HU and low-dose rate γ-irradiation. Immunoblot analysis, rt-PCR, high-performance liquid chromatography, and histology were used to assess inflammatory cell infiltration, cardiac remodeling, oxidative stress, and the methylation potential of cardiac tissue in 3 to 6 animals per group.
The combination of HU and γ-irradiation demonstrated the strongest increase in reduced to oxidized glutathione ratios 7 days and 1 month after treatment, but a difference was no longer apparent after 9 months. On the other hand, no significant changes in 4-hydroxynonenal adducts was seen in any of the groups, at the measured endpoints. While manganese superoxide dismutase protein levels decreased 9 months after low-dose γ-radiation, no changes were observed in expression of catalase or Nrf2, a transcription factor that determines the expression of several antioxidant enzymes, at the measured endpoints. Inflammatory marker, CD-2 protein content was significantly decreased in all groups 4 months after treatment. No significant differences were observed in α-smooth muscle cell actin protein content, collagen type III protein content or % total collagen.
This study has provided the first and relatively broad analysis of small molecule and protein markers of oxidative stress, T-lymphocyte infiltration, and cardiac remodeling in response to HU with simultaneous exposure to low-dose rate γ-radiation. Results from the late observation time points suggest that the hearts had mostly recovered from these two experimental conditions. However, further research is needed with larger numbers of animals for a more robust statistical power to fully characterize the early and late effects of simulated microgravity combined with exposure to low-dose rate ionizing radiation on the heart.</description><subject>4-Hydroxynonenal</subject><subject>Adducts</subject><subject>Animals</subject><subject>Antioxidants - metabolism</subject><subject>Atherosclerosis</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cadmium</subject><subject>Cardiovascular disease</subject><subject>Catalase</subject><subject>Chromatography</subject><subject>Collagen (type III)</subject><subject>Collagen - metabolism</subject><subject>Computer simulation</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - radiation effects</subject><subject>Dose-Response Relationship, Radiation</subject><subject>Drug dosages</subject><subject>Economic conditions</subject><subject>Enzymes</subject><subject>Enzymes - metabolism</subject><subject>Exposure</subject><subject>Female</subject><subject>Gamma irradiation</subject><subject>Gamma Rays</subject><subject>Glutathione</subject><subject>Heart - anatomy & histology</subject><subject>Heart - radiation effects</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Heart rate</subject><subject>High performance liquid chromatography</subject><subject>Histology</subject><subject>Homocysteine</subject><subject>Immune system</subject><subject>Infiltration</subject><subject>Inflammation</subject><subject>Ionizing radiation</subject><subject>Irradiation</subject><subject>Liquid chromatography</subject><subject>Lymphocytes T</subject><subject>Manganese</subject><subject>Markers</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microgravity</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - metabolism</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - radiation effects</subject><subject>Pharmaceutical sciences</subject><subject>Pharmaceuticals</subject><subject>Physical Sciences</subject><subject>Polymerase chain reaction</subject><subject>Radiation</subject><subject>Radiation dosage</subject><subject>Radiation therapy</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Space flight</subject><subject>Superoxide dismutase</subject><subject>Travel</subject><subject>Weightlessness Simulation</subject><subject>γ Radiation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUsFuEzEUXCEQLYU_QGCJC4em2Lter32pVJUClSq4wNl6sd8mDt51sJ2UfBJn_oNvwk3SqkWcbNkz43njqaqXjJ6wpmPvFmEVR_AnyzDiCWWStoo_qg6ZauqJqGnz-N7-oHqW0oLStpFCPK0Oaik6KbvusPp10fdociKhJz5cT2xISCJkJH9-T1yMYB1kF0ZiwjB1I1py7fKcJDesfEFZMjgTwyzC2uUNKbgB4neMW73w09lCXiNJOWJKx-T95zMyYJ5v_E50GTKO2YE_JjBaEnEIFr0bZ8SNJM-RDGFV_MwRYn5ePenBJ3yxX4-qbx8uvp5_mlx9-Xh5fnY1MW0t8gQamFJDbW-V7CVw2dIWamjQCiUN51Ra5FZC13d1r3jXGWYMBzntDWulZc1R9Xqnu_Qh6X3KSTPFRMuElKIgLncIG2Chl9GVmTc6gNPbgxBnuvh1xqNujeiFYtgogxxMIzuwjVEgrFG1rWXROt2_tpoOaE2JI4J_IPrwZnRzPQtr3XIladMVgbd7gRh-rDBlPbhk0HsYsYS39d1RxXlboG_-gf5_Or5DlX9NKWJ_Z4ZRfdO8W5a-aZ7eN6_QXt0f5I50W7XmL7sp3Qs</recordid><startdate>20170705</startdate><enddate>20170705</enddate><creator>Seawright, John W</creator><creator>Samman, Yusra</creator><creator>Sridharan, Vijayalakshmi</creator><creator>Mao, Xiao Wen</creator><creator>Cao, Maohua</creator><creator>Singh, Preeti</creator><creator>Melnyk, Stepan</creator><creator>Koturbash, Igor</creator><creator>Nelson, Gregory A</creator><creator>Hauer-Jensen, Martin</creator><creator>Boerma, Marjan</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-3230-7547</orcidid></search><sort><creationdate>20170705</creationdate><title>Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart</title><author>Seawright, John W ; Samman, Yusra ; Sridharan, Vijayalakshmi ; Mao, Xiao Wen ; Cao, Maohua ; Singh, Preeti ; Melnyk, Stepan ; Koturbash, Igor ; Nelson, Gregory A ; Hauer-Jensen, Martin ; Boerma, Marjan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-a3ab0c0dfd98f8a48505a2a3ed698c4408de4d8a7f72f9477c1cc4a8bfc158d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>4-Hydroxynonenal</topic><topic>Adducts</topic><topic>Animals</topic><topic>Antioxidants - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seawright, John W</au><au>Samman, Yusra</au><au>Sridharan, Vijayalakshmi</au><au>Mao, Xiao Wen</au><au>Cao, Maohua</au><au>Singh, Preeti</au><au>Melnyk, Stepan</au><au>Koturbash, Igor</au><au>Nelson, Gregory A</au><au>Hauer-Jensen, Martin</au><au>Boerma, Marjan</au><au>Woloschak, Gayle E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-05</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0180594</spage><epage>e0180594</epage><pages>e0180594-e0180594</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Space travel is associated with an exposure to low-dose rate ionizing radiation and the microgravity environment, both of which may lead to impairments in cardiac function. We used a mouse model to determine short- and long-term cardiac effects to simulated microgravity (hindlimb unloading; HU), continuous low-dose rate γ-irradiation, or a combination of HU and low-dose rate γ-irradiation.
Cardiac tissue was obtained from female, C57BL/6J mice 7 days, 1 month, 4 months, and 9 months following the completion of a 21 day exposure to HU or a 21 day exposure to low-dose rate γ-irradiation (average dose rate of 0.01 cGy/h to a total of 0.04 Gy), or a 21 day simultaneous exposure to HU and low-dose rate γ-irradiation. Immunoblot analysis, rt-PCR, high-performance liquid chromatography, and histology were used to assess inflammatory cell infiltration, cardiac remodeling, oxidative stress, and the methylation potential of cardiac tissue in 3 to 6 animals per group.
The combination of HU and γ-irradiation demonstrated the strongest increase in reduced to oxidized glutathione ratios 7 days and 1 month after treatment, but a difference was no longer apparent after 9 months. On the other hand, no significant changes in 4-hydroxynonenal adducts was seen in any of the groups, at the measured endpoints. While manganese superoxide dismutase protein levels decreased 9 months after low-dose γ-radiation, no changes were observed in expression of catalase or Nrf2, a transcription factor that determines the expression of several antioxidant enzymes, at the measured endpoints. Inflammatory marker, CD-2 protein content was significantly decreased in all groups 4 months after treatment. No significant differences were observed in α-smooth muscle cell actin protein content, collagen type III protein content or % total collagen.
This study has provided the first and relatively broad analysis of small molecule and protein markers of oxidative stress, T-lymphocyte infiltration, and cardiac remodeling in response to HU with simultaneous exposure to low-dose rate γ-radiation. Results from the late observation time points suggest that the hearts had mostly recovered from these two experimental conditions. However, further research is needed with larger numbers of animals for a more robust statistical power to fully characterize the early and late effects of simulated microgravity combined with exposure to low-dose rate ionizing radiation on the heart.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28678877</pmid><doi>10.1371/journal.pone.0180594</doi><orcidid>https://orcid.org/0000-0002-3230-7547</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-07, Vol.12 (7), p.e0180594-e0180594 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1916516886 |
| source | Public Library of Science (PLoS) Journals Open Access; Elektronische Zeitschriftenbibliothek (Open access); MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 4-Hydroxynonenal Adducts Animals Antioxidants - metabolism Atherosclerosis Biology Biology and Life Sciences Breast cancer Cadmium Cardiovascular disease Catalase Chromatography Collagen (type III) Collagen - metabolism Computer simulation Deoxyribonucleic acid DNA DNA methylation DNA Methylation - radiation effects Dose-Response Relationship, Radiation Drug dosages Economic conditions Enzymes Enzymes - metabolism Exposure Female Gamma irradiation Gamma Rays Glutathione Heart - anatomy & histology Heart - radiation effects Heart diseases Heart failure Heart rate High performance liquid chromatography Histology Homocysteine Immune system Infiltration Inflammation Ionizing radiation Irradiation Liquid chromatography Lymphocytes T Manganese Markers Medical research Medicine and Health Sciences Metabolism Mice Mice, Inbred C57BL Microgravity Myocardium - enzymology Myocardium - metabolism Oxidative stress Oxidative Stress - radiation effects Pharmaceutical sciences Pharmaceuticals Physical Sciences Polymerase chain reaction Radiation Radiation dosage Radiation therapy Rodents Smooth muscle Space flight Superoxide dismutase Travel Weightlessness Simulation γ Radiation |
| title | Effects of low-dose rate γ-irradiation combined with simulated microgravity on markers of oxidative stress, DNA methylation potential, and remodeling in the mouse heart |
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