Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit.

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Ionizing radiation-induced altered microRNA expression as biomarkers for assessing acute radiation injury

Expert Review of Molecular Diagnostics ◽

10.1080/14737159.2017.1366316 ◽

2017 ◽

Vol 17 (10) ◽

pp. 871-874 ◽

Cited By ~ 7

Author(s):

Vijay K. Singh ◽

Harvey B. Pollard

Keyword(s):

Ionizing Radiation ◽

Radiation Injury ◽

Microrna Expression ◽

Acute Radiation ◽

Acute Radiation Injury ◽

Radiation Induced

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Evaluation of Gamma Radiation-Induced Biochemical Changes in Skin for Dose Assesment: A Study on Small Experimental Animals

Disaster Medicine and Public Health Preparedness ◽

10.1017/dmp.2018.16 ◽

2018 ◽

Vol 13 (02) ◽

pp. 197-202

Author(s):

Sandeep Kumar Soni ◽

Mitra Basu ◽

Priyanka Agrawal ◽

Aseem Bhatnagar ◽

Neelam Chhillar

Keyword(s):

Radiation Dose ◽

Gamma Radiation ◽

Radiation Injury ◽

Acute Radiation ◽

Dose Assessment ◽

Whole Body ◽

Dependent Manner ◽

Acute Radiation Injury ◽

Radiation Induced ◽

Dose Dependent

AbstractObjectiveResearchers have been evaluating several approaches to assess acute radiation injury/toxicity markers owing to radiation exposure. Keeping in mind this background, we assumed that whole-body irradiation in single fraction in graded doses can affect the antioxidant profile in skin that could be used as an acute radiation injury/toxicity marker.MethodsSprague-Dawley rats were treated with CO-60 gamma radiation (dose: 1-5 Gy; dose rate: 0.85 Gy/minute). Skin samples were collected (before and after radiation up to 72 hours) and analyzed for glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (LPx).ResultsIntra-group comparison showed significant differences in GSH, GPx, SOD, and CAT, and they declined in a dose-dependent manner from 1 to 5 Gy (P value<0.01, r value: 0.3-0.5). LPx value increased (P value<0.01, r value: 0.3-0.5) as the dose increased, except in 1 Gy (P value>0.05).ConclusionsThis study suggests that skin antioxidants were sensitive toward radiation even at a low radiation dose, which can be used as a predictor of radiation injury and altered in a dose-dependent manner. These biochemical parameters may have wider application in the evaluation of radiation-induced skin injury and dose assessment. (Disaster Med Public Health Preparedness. 2019;13:197–202).

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Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury

Blood ◽

10.1182/blood-2021-153206 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2947-2947

Author(s):

Allen Annis ◽

David Sutton ◽

Manuel Aivado ◽

Vojislav Vukovic

Keyword(s):

Cell Cycle ◽

Bone Marrow ◽

Cell Cycle Arrest ◽

Mouse Models ◽

Radiation Injury ◽

Acute Radiation ◽

Mouse Bone Marrow ◽

Acute Radiation Injury ◽

Cycle Arrest ◽

Radiation Induced

Abstract Background: Myelosuppression is a common sequela of acute radiation injury due to sensitivity of proliferating bone marrow cells to ionizing radiation. ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide drug that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2, to induce transient, dose-dependent cell cycle arrest in p53-wild-type tissues. ALRN-6924 is being evaluated in clinical trials as a selective chemoprotection agent for patients with p53-mutant cancers to protect healthy normal cells from chemotherapy while not protecting p53-mutant cancer cells. We tested whether ALRN-6924 may similarly protect against radiation-induced toxicity in mouse models of acute radiation injury. Materials and methods: Activation of p21 (CDKN1A), a cell cycle regulator under transcriptional control of p53, was measured in formalin-fixed mouse bone marrow by immunohistochemistry analysis (IHC). Proliferation and apoptosis in bone marrow were measured by IHC of Ki67 and cleaved PARP, respectively. Cell cycle arrest was measured in the bone marrow of ALRN-6924-treated C57BL/6 mice by flow cytometry using EdU incorporation. Serum levels of macrophage inhibitory cytokine-1 (MIC-1), a biomarker of p53 activation, were measured by ELISA. As a model of radiation-induced toxicity, C57BL/6 mice (n=7/group) were treated with one or more intravenous 2.4 mg/kg doses of ALRN-6924 at 24, 16, 8, or 1 hour (or combinations thereof) or placebo prior to a 15 Gy shielded-body radiation dose and then monitored for body weight (BW) changes. Results: ALRN-6924 induced cell cycle arrest in mouse bone marrow with a maximum effect at 8 hrs post-dose. Repeated doses of ALRN-6924 every 8 hrs elevated p21 levels in bone marrow that correlated with reduced Ki67 positivity and increased serum MIC-1 levels. Treatment-dependent changes in cPARP expression in bone marrow were evident, but minimal in magnitude. In a nonlethal radiation exposure model, ALRN-6924 yielded significant protection from radiation-induced BW loss in a schedule-dependent manner. Placebo-treated mice showed 10% to 15% BW loss five days after irradiation, while mice receiving one or more ALRN-6924 doses 8 hrs prior to irradiation had an average of 4% BW loss (p=0.008, two-sided t test). Conclusions: ALRN-6924 mitigated toxicity in a mouse model of acute radiation injury. The observed radioprotection effect was correlated with cell cycle arrest in bone marrow after one or more doses of ALRN-6924. These results support further investigation of ALRN-6924 as a radioprotective agent. Disclosures Annis: Aileron Therapeutics, Inc.: Current Employment. Sutton: Aileron Therapeutics, Inc.: Consultancy; Kriya Therapeutics: Consultancy; First Light Pharmaceuticals: Consultancy; Cygnal Therapeutics: Consultancy. Aivado: Aileron Therapeutics, Inc.: Current Employment. Vukovic: Aileron Therapeutics, Inc.: Current Employment.

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HemaMax™, a Recombinant Human Interleukin-12, Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates

PLoS ONE ◽

10.1371/journal.pone.0030434 ◽

2012 ◽

Vol 7 (2) ◽

pp. e30434 ◽

Cited By ~ 36

Author(s):

Lena A. Basile ◽

Dolph Ellefson ◽

Zoya Gluzman-Poltorak ◽

Katiana Junes-Gill ◽

Vernon Mar ◽

...

Keyword(s):

Radiation Injury ◽

Acute Radiation ◽

Interleukin 12 ◽

Acute Radiation Injury

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Early Biomarkers Associated with P53 Signaling for Acute Radiation Injury

Life ◽

10.3390/life12010099 ◽

2022 ◽

Vol 12 (1) ◽

pp. 99

Author(s):

Weihong Li ◽

Shixiang Zhou ◽

Meng Jia ◽

Xiaoxin Li ◽

Lin Li ◽

...

Keyword(s):

Ionizing Radiation ◽

Candidate Genes ◽

Radiation Injury ◽

Acute Radiation ◽

Dose Assessment ◽

Healthy Population ◽

P53 Signaling ◽

Acute Radiation Injury ◽

Effective Combination ◽

Accurate Dose

Accurate dose assessment within 1 day or even 12 h after exposure through current methods of dose estimation remains a challenge, in response to a large number of casualties caused by nuclear or radiation accidents. P53 signaling pathway plays an important role in DNA damage repair and cell apoptosis induced by ionizing radiation. The changes of radiation-induced P53 related genes in the early stage of ionizing radiation should compensate for the deficiency of lymphocyte decline and γ-H2AX analysis as novel biomarkers of radiation damage. Bioinformatic analysis was performed on previous data to find candidate genes from human peripheral blood irradiated in vitro. The expression levels of candidate genes were detected by RT-PCR. The expressions of screened DDB2, AEN, TRIAP1, and TRAF4 were stable in healthy population, but significantly up-regulated by radiation, with time specificity and dose dependence in 2–24 h after irradiation. They are early indicators for medical treatment in acute radiation injury. Their effective combination could achieve a more accurate dose assessment for large-scale wounded patients within 24 h post exposure. The effective combination of p53-related genes DDB2, AEN, TRIAP1, and TRAF4 is a novel biodosimetry for a large number of people exposed to acute nuclear accidents.

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