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Background: It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.
Methods: We assessed the clinical dosage administration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival study evaluated by the log-rank test. Bone marrow and splenic cells were collected on the 21st day, when 1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assay using sera was performed for cell senescence and inflammation status analyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.
Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kg RP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers.
Conclusions: This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.
Keywords
Acute radiation syndrome, Approved pharmaceutical drugs,Granulocyte colony-stimulating factor, Romiplostim, Radiation medical countermeasure
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CURRENT STATUS: Published
View the published article at Stem Cell Research & Therapy.
Version 2
Posted 16 Jul, 2020
No community comments so far
Editorial decision: Accept
On 27 Jul, 2020
Review #2 received
Received 25 Jul, 2020
Review #1 received
Received 23 Jul, 2020
Reviewer #2 agreed
On 15 Jul, 2020
Reviewers invited
Invitations sent on 15 Jul, 2020
Reviewer #1 agreed
On 15 Jul, 2020
Editor assigned
On 13 Jul, 2020
Submission checks complete
On 12 Jul, 2020
Editor invited
On 12 Jul, 2020
No comments provided
Editorial decision: Major Revision
On 03 Jul, 2020
Review #1 received
Received 01 Jul, 2020
Review #3 received
Received 29 Jun, 2020
Review #2 received
Received 29 Jun, 2020
Reviewer #3 agreed
On 19 Jun, 2020
Reviewer #2 agreed
On 17 Jun, 2020
Editor assigned
On 17 Jun, 2020
Reviewers invited
Invitations sent on 17 Jun, 2020
Reviewer #1 agreed
On 17 Jun, 2020
Editor invited
On 16 Jun, 2020
Submission checks complete
On 11 Jun, 2020
First submitted
On 09 Jun, 2020
Metrics
Comments: 0
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A new preprint design is coming!
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See the published version of this preprint at Stem Cell Research & Therapy.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Stem Cell Research & Therapy.
Version 2
Posted 16 Jul, 2020
No community comments so far
Editorial decision: Accept
On 27 Jul, 2020
Review #2 received
Received 25 Jul, 2020
Review #1 received
Received 23 Jul, 2020
Reviewer #2 agreed
On 15 Jul, 2020
Reviewers invited
Invitations sent on 15 Jul, 2020
Reviewer #1 agreed
On 15 Jul, 2020
Editor assigned
On 13 Jul, 2020
Submission checks complete
On 12 Jul, 2020
Editor invited
On 12 Jul, 2020
No comments provided
Editorial decision: Major Revision
On 03 Jul, 2020
Review #1 received
Received 01 Jul, 2020
Review #3 received
Received 29 Jun, 2020
Review #2 received
Received 29 Jun, 2020
Reviewer #3 agreed
On 19 Jun, 2020
Reviewer #2 agreed
On 17 Jun, 2020
Editor assigned
On 17 Jun, 2020
Reviewers invited
Invitations sent on 17 Jun, 2020
Reviewer #1 agreed
On 17 Jun, 2020
Editor invited
On 16 Jun, 2020
Submission checks complete
On 11 Jun, 2020
First submitted
On 09 Jun, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Health Policy
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Stem Cell Research & Therapy.
Background: It has been reported that the high-dosage administration of domestically approved pharmaceutical drugs, especially granulocyte colony-stimulating factor (G-CSF) and romiplostim (RP), is a rapid and appropriate medical treatment for preventing severe acute radiation syndrome (ARS) of victims exposed to lethal total-body irradiation (TBI). However, it remains unclear whether or not the clinical dosage administration of these drugs can ameliorate TBI-induced ARS and related high mortality in order to find various drug treatment options and less toxic optimum protocol depending on the situation surrounding the radiological accidents.
Methods: We assessed the clinical dosage administration in combination with G-CSF and RP as intraperitoneal injection in C57BL/6J mice exposed to more than 7-Gy lethal dose of X-ray TBI for the survival study evaluated by the log-rank test. Bone marrow and splenic cells were collected on the 21st day, when 1 week have passed from last administration, to detect the level of cell apoptosis, intracellular reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (Nrf2)-related anti-oxidative gene expressions, and enzyme-linked immune sorbent assay using sera was performed for cell senescence and inflammation status analyzed with one-way ANOVA and Tukey-Kramer or Bonferroni/Dunn multiple comparison tests.
Results: The combined once-daily administration of 10 μg/kg G-CSF for 4 times and 10 μg/kg RP once a week for 3 times improve the 30-day survival rate of lethal TBI mice compared with untreated TBI mice, accompanied by a gradual increase in the body weight and hematopoietic cell numbers. The radio-mitigative effect is probably attributed to the scavenging of ROS and the reduction in cell apoptosis. These changes were associated with the upregulation of Nrf2 and its downstream anti-oxidative targets in TBI mice. Furthermore, this combination modulated TBI-induced cell senescence and inflammation markers.
Conclusions: This study suggested that the clinical dosage administration in combination with G-CSF and RP may also have radio-mitigative effects on mice exposed to lethal TBI and may be a potent therapeutic agent for mitigating radiation-induced severe ARS.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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