scholarly journals Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome

2019 ◽  
Vol 60 (3) ◽  
pp. 308-317 ◽  
Author(s):  
Michael R Landauer ◽  
Adam J Harvey ◽  
Michael D Kaytor ◽  
Regina M Day
Keyword(s):  
Estrogen Receptor ◽  
Mechanism Of Action ◽  
Total Body Irradiation ◽  
Intramuscular Injection ◽  
Acute Radiation ◽  
Beta Agonist ◽  
Therapeutic Window ◽  
Acute Radiation Syndrome ◽  
Single Intramuscular Injection ◽  
Total Body

Abstract There are no FDA-approved drugs that can be administered prior to ionizing radiation exposure to prevent hematopoietic–acute radiation syndrome (H-ARS). A suspension of synthetic genistein nanoparticles was previously shown to be an effective radioprotectant against H-ARS when administered prior to exposure to a lethal dose of total body radiation. Here we aimed to determine the time to protection and the duration of protection when the genistein nanosuspension was administered by intramuscular injection, and we also investigated the drug’s mechanism of action. A single intramuscular injection of the genistein nanosuspension was an effective radioprotectant when given prophylactically 48 h to 12 h before irradiation, with maximum effectiveness occurring when administered 24 h before. No survival advantage was observed in animals administered only a single dose of drug after irradiation. The dose reduction factor of the genistein nanosuspension was determined by comparing the survival of treated and untreated animals following different doses of total body irradiation. As genistein is a selective estrogen receptor beta agonist, we also explored whether this was a central component of its radioprotective mechanism of action. Mice that received an intramuscular injection of an estrogen receptor antagonist (ICI 182,780) prior to administration of the genistein nanosuspension had significantly lower survival following total body irradiation compared with animals only receiving the nanosuspension (P < 0.01). These data define the time to and duration of radioprotection following a single intramuscular injection of the genistein nanosuspension and identify its likely mechanism of action.

scholarly journals Proteomic Evaluation of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Murine Total-body Irradiation Model

2019 ◽  
Vol 116 (4) ◽  
pp. 516-528 ◽  
Author(s):  
Weiliang Huang ◽  
Jianshi Yu ◽  
Jace W. Jones ◽  
Claire L. Carter ◽  
Keely Pierzchalski ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Total Body Irradiation ◽  
Acute Radiation ◽  
Acute Radiation Syndrome ◽  
Total Body

Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model

2016 ◽  
Vol 111 (2) ◽  
pp. 134-144 ◽  
Author(s):  
Natalia I. Ossetrova ◽  
Patrick H. Ney ◽  
Donald P. Condliffe ◽  
Katya Krasnopolsky ◽  
Kevin P. Hieber
Keyword(s):  
Total Body Irradiation ◽  
Severity Score ◽  
Acute Radiation ◽  
Score System ◽  
Acute Radiation Syndrome ◽  
Total Body

scholarly journals Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

2018 ◽  
Vol 190 (6) ◽  
pp. 576 ◽  
Author(s):  
Evan L. Pannkuk ◽  
Evagelia C. Laiakis ◽  
Melissa Garcia ◽  
Albert J. Fornace ◽  
Vijay K. Singh
Keyword(s):  
Total Body Irradiation ◽  
Nonhuman Primates ◽  
Acute Radiation ◽  
Acute Radiation Syndrome ◽  
Metabolomics Study ◽  
Total Body ◽  
Serum Metabolomics

scholarly journals Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256208
Author(s):  
W. Bradley Rittase ◽  
Elizabeth A. McCart ◽  
Jeannie M. Muir ◽  
Roxane M. Bouten ◽  
John E. Slaven ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Blood Cells ◽  
Acute Radiation ◽  
Radiation Injuries ◽  
Induced Expression ◽  
Acute Radiation Syndrome ◽  
Radiation Induced ◽  
Total Body ◽  
Captopril Treatment

Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42–0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32–35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model.

scholarly journals Mitigating Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on Hematopoietic Acute Radiation Syndrome after Total-Body Ionizing Irradiation in Mice

2019 ◽  
Vol 192 (6) ◽  
pp. 602 ◽  
Author(s):  
Yong-Jae Kim ◽  
Jinseon Jeong ◽  
Su-Hyun Shin ◽  
Do Young Lee ◽  
Ki-Young Sohn ◽  
...  
Keyword(s):  
Acute Radiation ◽  
Ionizing Irradiation ◽  
Acute Radiation Syndrome ◽  
Total Body

scholarly journals Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome

2018 ◽  
Vol 96 (5) ◽  
pp. 442-458
Author(s):  
Shereen Mohamed Galal ◽  
Mohamed Khairy Abdel-Rafei ◽  
Hesham Farouk Hasan
Keyword(s):  
White Blood Cells ◽  
Acute Radiation ◽  
Janus Kinase ◽  
Sublethal Dose ◽  
Related Factor ◽  
Acute Radiation Syndrome ◽  
Signal Transducers ◽  
Human Erythropoietin ◽  
Radiation Induced ◽  
Total Body

The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (EPO) against acute radiation syndrome (ARS) in a rat model. Rats were irradiated with a single sublethal dose of γ-radiation (7 Gy; total body irradiation; TBI) on the 1st day of experimental course, then received EPO (5000 IU/kg; i.p.) 24 h after irradiation, and rats were observed for 30 days of survival analysis. Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored. EPO post-exposure treatment alleviated hepatotoxicity biomarkers and restored splenic function. EPO abrogated radiation-induced oxidative stress through the upregulation of the cholinergic anti-inflammatory nicotinic acetylcholine receptor (α-7-nAChR) and the pro-survival Janus kinase-2 and signal transducers and activators of transcription JAK-2/STAT-3 signaling mediated via enhancing nuclear factor erythroid-2 related factor-2 (Nrf-2) cytoprotective machinery in liver and spleen of irradiated rats. Moreover, EPO treatment prevented hepatic and splenic apoptosis. The present study establishes the implication of α-7-nAChR–JAK-2/STAT-3–Nrf-2 signaling cascade in the radiomitigative potential of EPO against ARS.

The Acute Radiation Syndrome in Dogs after Total-Body Exposure to a Supralethal Dose of Ionizing Radiation (Co 60 LD 100/88 hours )

1960 ◽  
Vol 13 (5) ◽  
pp. 712 ◽  
Author(s):  
Stanley Wing Handford ◽  
Paul J. Stonestreet ◽  
Paul W. Johnson ◽  
Leonard A. Freedman ◽  
John H. Flint ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Acute Radiation ◽  
Acute Radiation Syndrome ◽  
Total Body

Administration of an HE2100 Depot Preparation after 60Co Total Body Irradiation (400 cGy) Reduces the Duration of Severe Neutropenia, Thrombocytopenia and Anemia in Rhesus Macaques.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1461-1461 ◽  
Author(s):  
Charles Dowding ◽  
James Frincke ◽  
Armando Garsd ◽  
Dwight R. Stickney ◽  
Christopher L. Reading
Keyword(s):  
Estrogen Receptor ◽  
Total Body Irradiation ◽  
Rhesus Macaques ◽  
Cost Effective ◽  
Estrogen Receptor Α ◽  
Severe Neutropenia ◽  
Vehicle Group ◽  
Major Morbidity ◽  
Adrenal Steroid ◽  
Total Body

Abstract HE2100 (androst-5-ene-3β,17β-diol) is a naturally occuring adrenal steroid hormone that exhibits a relatively weak interaction with the androgen receptor, estrogen receptor-α and estrogen receptor-β but not the glucocorticoid receptor. We previously reported (Blood [2003] 1002;20) that subcutaneous HE2100 administration (daily for 10 days) eliminated severe neutropenia in rhesus macaques exposed to 400 cGy 60Co total body irradiation (TBI). The current study utilized the same model of myelosuppression in rhesus macaques and evaluated the activity of HE2100 when administered as a depot-type preparation on duration of Grade 4 neutropenia (<500/μL, G4 Neut), at least Grade 3 thrombocytopenia (<50,000/μL, G3 Thromb) and Grade 4 anemia (<6.5 g/dL, G4 Anemia). Blood was analysed daily during the cytopenic phase and approximately every three days at other times through Day 35 (irradiation Day 1) to minimize the effect of phlebotomy. HE2100 (15 mg/kg) was administered by daily intramuscular injection for 5 days (Regimen 5d-IM), by four once-weekly intramuscular injections (Regimen 1w-IM) or by four once-weekly subcutaneous injections (Regimen 1w-SQ). The first dose for all regimens was administered 2 to 4 hours after TBI. All groups comprised of 2 male and 1 female young adult rhesus macaques with the exception of the vehicle group (2 males and 2 females). Vehicle-treated animals experienced on average G4 Neut, G3 Thromb and G4 Anemia for 11.8, 3.5 and 4.0 days, respectively. Animals treated by 5d-IM experienced on average 2.7 days of G4 Neut, 0 days of G3 Thromb and 0 days of G4 Anemia. The values for Regimens 1w-IM and 1w-SQ were 6.0 and 4.5 days (G4 Neut), 0.3 and 0.3 days (G3 Thromb) 0 and 0 days (G4 Anemia), respectively. These results indicate that HE2100 depot-type preparations delivered by either 4 or 5 SQ or IM injections substantially reduced the duration of severe neutropenia following 400 cGy TBI. Major morbidity or mortality associated with acute Hematopoietic Syndrome is believed to result from sepsis associated with severe neutropenia. Hence it is possible that HE2100 would protect against acute Hematopoietic Syndrome-related major morbidy or mortality. The contribution of thrombocytopenia or severe anemia to Hematopoietic Syndrome-related major morbidity or mortality is unknown but it is possible that HE2100-mediated protection of these blood elements might be beneficial by, for example, reducing tissue hypoxia. In conclusion, HE2100 affords significant protection as a countermeasure to TBI in rhesus macaques. There is an umet medical need for a cost-effective countermeasure for acute Hematopoietic Syndrome that may result from exposure to a nuclear event. It is possible that the protection seen in rhesus macaques may extend to man.

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