Blockade of CD47 increases survival of mice exposed to lethal total body irradiation.
Ontology highlight
ABSTRACT:
SUBMITTER: Soto-Pantoja DR
PROVIDER: S-EPMC3539147 | biostudies-other | 2013
REPOSITORIES: biostudies-other
Similar Datasets
Project description:The details of the dose-dependent response of serum proteins exposed to ionizing radiation, especially the oxidative modification response in amino acid sequences of albumin, the most abundant protein, are unknown. Thus, a proteomic analysis of the serum components from mice exposed to total body X-irradiation (TBI) ranging from 0.5 Gy to 3.0 Gy was conducted using LC-MS/MS. The analysis of oxidative modification sequences of albumin (mOMSA) in TBI mouse serum revealed significant moderate or strong correlations between the X-irradiation exposure dose and modification of 11 mOMSAs (especially the 97th, 267th and 499th lysine residues, 159th methionine residue and 287th tyrosine residues). In the case of X-irradiation of serum alone, significant correlations were also found in the 14 mOMSAs. In addition, a dose-dependent variation in six proteins (Angiotensinogen, Odorant-binding protein 1a, Serine protease inhibitor A3K, Serum paraoxonase/arylesterase 1, Prothrombin and Epidermal growth factor receptor) was detected in the serum of mice exposed to TBI. These findings suggest the possibility that the protein variation and serum albumin oxidative modification responses found in exposed individuals are important indicators for considering the effects of radiation on living organisms, along with DNA damage, and suggests their possible application as biomarkers of radiation dose estimation.
| S-EPMC9495380 | biostudies-literature
Project description:The focus of radiation biodosimetry has changed recently, and a paradigm shift for using molecular technologies of omic platforms in addition to cytogenetic techniques has been observed. In our study, we have used a nonhuman primate model to investigate the impact of a supralethal dose of 12 Gy radiation on alterations in the lung transcriptome. We used 6 healthy and 32 irradiated animal samples to delineate radiation-induced changes. We also used a medical countermeasure, γ-tocotrienol (GT3), to observe any changes. We demonstrate significant radiation-induced changes in the lung transcriptome for total-body irradiation (TBI) and partial-body irradiation (PBI). However, no major influence of GT3 on radiation was noted in either comparison. Several common signaling pathways, including PI3K/AKT, GADD45, and p53, were upregulated in both exposures. TBI activated DNA-damage-related pathways in the lungs, whereas PTEN signaling was activated after PBI. Our study highlights the various transcriptional profiles associated with γ- and X-ray exposures, and the associated pathways include LXR/RXR activation in TBI, whereas pulmonary wound-healing and pulmonary fibrosis signaling was repressed in PBI. Our study provides important insights into the molecular pathways associated with irradiation that can be further investigated for biomarker discovery.
| S-EPMC9418744 | biostudies-literature
Project description:Exposure to ionizing radiation leads to severe damages in radiosensitive organs and induces acute radiation syndrome, including effects on the hematopoietic system and gastrointestinal system. In this study, the radioprotective ability of KMRC011, a novel toll-like receptor 5 (TLR5) agonist, was investigated in C57BL6/N mice exposed to lethal total-body gamma-irradiation. In a 30-day survival study, KMRC011-treated mice had a significantly improved survival rate compared with control after 11 Gy total-body irradiation (TBI), and it was found that the radioprotective activity of KMRC011 depended on its dosage and repeated treatment. In a 5-day short-term study, we demonstrated that KMRC011 treatment stimulated cell proliferation and had an anti-apoptotic effect. Furthermore, KMRC011 increased the expressions of genes related to DNA repair, such as Rad21, Gadd45b, Sod2 and Irg1, in the small intestine of lethally irradiated mice. Interestingly, downregulation of NF-κB p65 in the mouse intestine by KMRC011 treatment was observed. This data indicated that KMRC011 exerted a radioprotective activity partially by regulating NF-κB signaling. Finally, peak expression levels of G-CSF, IL-6, IFN-γ, TNF-α and IP-10 induced by KMRC011 treatment were different depending on the route of administration and type of cytokine. These cytokines could be used as candidate biomarkers for the evaluation of KMRC011 clinical efficacy. Our data indicated that KMRC011 has radioprotective activity in lethally irradiated mice and may be developed as a therapeutic agent for radioprotection.
| S-EPMC6640901 | biostudies-literature
Project description:Hong Shan Capsule (HSC), a crude drug of 11 medicinal herbs, was used in clinical practice for the treatment of radiation injuries in China. In this study, we investigated its protection in rats against acute lethal total-body irradiation (TBI). Pre-administration of HSC reduced the radiation sickness characteristics, while increasing the 30-day survival of the irradiated rats. Administration of HSC also reduced the radiation sickness characteristics and increased the 30-day survival of mice after exposure to lethal TBI. Ultrastructural observation illustrated that the pretreatment of rats with HSC significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed the dramatic effect of HSC on alterations of gene expression caused by lethal TBI. Pretreatment with HSC prevented differential expression of 66% (1398 genes) of 2126 genes differentially expressed in response to TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 32 pathways, such as pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway. Our analysis indicated that the pretreatment of rats with HSC modulated these pathways induced by lethal TBI, such as multiple MAPK pathways, suggesting that pretreatment with HSC might provide protective effects on lethal TBI mainly or partially through the modulation of these pathways. Our data suggest that HSC has the potential to be used as an effective therapeutic or radio-protective agent to minimize irradiation damage.
| S-EPMC4581280 | biostudies-literature
Project description:Duplicate hybridizations with fluorochrome switching were performed following the first two fractions of total body irradiation for accumulated doses of 1.5 Gy and 3.0 Gy. Control samples for all hybridizations were from the same patient before the beginning of treatment.
2010-06-09 | E-GEOD-1366 | biostudies-arrayexpress
Project description:During large-scale acute radiation exposure, rapidly distinguishing exposed individuals from nonexposed individuals is necessary. Identifying those exposed to high and potentially lethal radiation doses, and in need of immediate treatment, is especially important. To address this and find plasma biomarkers to assess ionizing radiation-induced mortality in the early stages, mice were administered a whole-body lethal dose of γ radiation, and radiation-induced damage was evaluated. Multiple blood biomarkers were screened using an antibody array, followed by validation using enzyme-linked immunoassay. The results revealed that irradiation (IR)-induced mortality in mice and caused body weight and blood platelet losses in deceased mice compared to surviving mice. The levels of certain proteins differed after IR between these 2 groups. Specific proteins in preirradiated mice were also found to potentiate radiosensitivity. Plasma levels of interleukin (IL)-22, urokinase, resistin, and IL-6 were associated with radiation-induced mortality in irradiated mice and may be useful as potential mortality predictors. Our results suggest that estimating the levels of certain plasma proteins is a promising alternative to conventional cytogenetic biodosimetry to accurately identify individuals exposed to high radiation doses and those at risk of death due to exposure. This strategy would facilitate the rapid triage of individuals requiring immediate and intensive medical treatment.
| S-EPMC7171989 | biostudies-literature
Project description:Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg-1·d-1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.
| S-EPMC8209125 | biostudies-literature
Project description:The purpose of this study was to compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia who underwent a myeloablative allogeneic stem cell transplant with and without total body irradiation (TBI).Adult patients with acute myelogenous leukemia undergoing myeloablative allogeneic stem cell transplant at Duke University Medical Center between 1995 and 2012 were included. The primary endpoint was LFS. Secondary outcomes included overall survival (OS), nonrelapse mortality, and the risk of pulmonary toxicity. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed.A total of 206 patients were evaluated: 90 received TBI-based conditioning regimens and 116 received chemotherapy alone. Median follow-up was 36 months. For all patients, 2-year LFS and OS were 36% (95% confidence interval [CI], 29-43) and 39% (95% CI, 32-46), respectively. After adjusting for known prognostic factors using a multivariate analysis, TBI was associated with improved LFS (hazard ratio: 0.63; 95% CI: 0.44-0.91) and OS (hazard ratio: 0.63; 95% CI, 0.43-0.91). There was no difference in nonrelapse mortality between cohorts, but pulmonary toxicity was significantly more common with TBI (2-year incidence 42% vs 12%, P < .001). High-grade pulmonary toxicity predominated with both conditioning strategies (70% and 93% of cases were grade 3-5 with TBI and chemotherapy alone, respectively).TBI-based regimens were associated with superior LFS and OS but at the cost of increased pulmonary toxicity.
| S-EPMC5514157 | biostudies-other
Project description:Duplicate hybridizations with fluorochrome switching were performed following the first two fractions of total body irradiation for accumulated doses of 1.5 Gy and 3.0 Gy. Control samples for all hybridizations were from the same patient before the beginning of treatment. Keywords: dose response
2004-06-17 | GSE1366 | GEO
Project description:Antibodies targeting the T-cell immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA4) enhance the effectiveness of radiotherapy for melanoma patients, but many remain resistant. To further improve response rates, we explored combining anti-CTLA4 blockade with antisense suppression of CD47, an inhibitory receptor on T cells that limit T-cell receptor signaling and killing of irradiated target cells. Human melanoma data from The Cancer Genome Atlas revealed positive correlations between CD47 mRNA expression and expression of T-cell regulators including CTLA4 and its counter receptors CD80 and CD86. Antisense suppression of CD47 on human T cells in vitro using a translational blocking morpholino (CD47 m) alone or combined with anti-CTLA4 enhanced antigen-dependent killing of irradiated melanoma cells. Correspondingly, the treatment of locally irradiated B16F10 melanomas in C57BL/6 mice using combined blockade of CD47 and CTLA4 significantly increased the survival of mice relative to either treatment alone. CD47 m alone or in combination with anti-CTLA4 increased CD3+ T-cell infiltration in irradiated tumors. Anti-CTLA4 also increased CD3+ and CD8+ T-cell infiltration as well as markers of NK cells in non-irradiated tumors. Anti-CTLA4 combined with CD47 m resulted in the greatest increase in intratumoral granzyme B, interferon-γ, and NK-cell marker mRNA expression. These data suggest that combining CTLA4 and CD47 blockade could provide a survival benefit by enhancing adaptive T- and NK-cell immunity in irradiated tumors.
| S-EPMC7416244 | biostudies-literature