Background
Severe ionizing radiation (IR)-induced intestinal injury associates with high mortality, which is a worldwide problem requiring urgent attention. In recent years, studies have found that the PHD-HIF signaling pathway may play key roles in IR-induced intestinal injury, and we found that FG-4592, the PHD inhibitor, has significant radioprotective effects on IR-induced intestinal injury.
Methods
In the presence or absence of FG-4592 treatment, the survival time, pathology, cell viability, cell apoptosis, and organoids of mice after irradiation were compared, and the mechanism was verified after transcriptome sequencing. The data were analyzed using SPSS ver. 19 software.
Results
Our results show that FG-4592 had significant radioprotective effects on the intestine. FG-4592 improved the survival of irradiated mice, inhibited the radiation damage of intestinal tissue, promoted the regeneration of intestinal crypts after IR and reduced the apoptosis of intestinal crypt cells. Through organoid experiments, it is found that FG-4592 promoted the proliferation and differentiation of intestinal stem cells (ISCs). Moreover, the results of RNA sequencing and Western blot showed that FG-4592 significantly upregulated the TLR4 signaling pathway, and FG-4592 had no radioprotection on TLR4 KO mice, suggesting that FG-4592 may play protective role against IR by targeting TLR4.
Conclusion
Our work proves that FG-4592 may promote the proliferation and regeneration of ISCs through the targeted regulation of the TLR4 signaling pathway and ultimately play radioprotective roles in IR-induced injury. These results enrich the molecular mechanism of FG-4592 in protecting cells from IR-induced injury and provide new methods for the radioprotection of intestine.
Accidental radiation exposure is a threat to human health that necessitates effective clinical diagnosis. Suitable biomarkers are urgently needed for early assessment of exposure dose. Existing technologies being used to assess the extent of radiation have notable limitations. As a radiation biomarker, miRNA has the advantages of simple detection and high throughput. In this study, we screened for miRNAs with dose and time dependent responses in peripheral blood leukocytes via miRNA sequencing in establishing the animal model of acute radiation injury. Four radiation-sensitive and stably expressed miRNAs were selected out in the 24 h group of leukocyte miRNAs: mmu-miR-130b-5p, mmu-miR-148b-5p, mmu-miR-184-3p, mmu-miR-26a-2-3p, and five were screened in the 48 h group of leukocyte miRNAs: mmu-miR-130b-5p, mmu-miR-423-5p, mmu-miR-676-3p, mmu-miR-150-5p, mmu-miR-342-3p.The correlation curves between their expression and irradiation dose were plotted. Then, the results were validated by RT-qPCR in mouse peripheral blood. As a result, mmu-miR-150-5p and mmu-miR-342-3p showed the highest correlation at 48h after irradiation, and mmu-miR-130b-5p showed good correlation at both 24 h and 48 h after irradiation. In a conclusion, the miRNAs that are sensitive to ionizing radiation with dose dependent effects were selected out, which have the potential of forming a rapid assessment scheme for acute radiation injury.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.