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DNA double-strand breaks (DSBs) are cytotoxic lesions that compromise genomic integrity and trigger cell death. Homologous recombination (HR) is a major pathway for repairing DSBs in cycling cells. However, it remains unclear whether transient modulation of HR could confer protection to adult stem cells against lethal irradiation exposure. In this study, we investigated the radio-protective effect of the RAD51-stimulatory compound RS-1 on adult stem cells and progenitor cells with varying cycling rates in intestinal and hematopoietic tissues. Treatment with RS-1 even at high doses did not induce noticeable cell death or proliferation of intestinal crypt cells in vivo. Pretreatment with RS-1 before irradiation significantly decreased mitotic death, promoted DNA repair and enhanced the survival of intestinal stem cells and progenitor cells and increased the number of regenerative crypt colonies thereby mitigating IR-induced gastrointestinal syndrome. Moreover, RS-1 pretreatment could increase the survival and regeneration of irradiated intestinal organoids in vitro, which can be rescued by RAD51 inhibitor. However, pretreatment with RS-1 in vivo did not elevate nucleated cell count or HSPCs in bone marrow after 6 Gy irradiation. Additionally, there was no impact on mouse survival due to drug treatment observed. Thus, our data suggest that targeting HR as a strategy to prevent tissue damage from acute irradiation exposure may depend on cell cycling rates and intrinsic DNA repair mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Radiation-mediated GI injury (RIGI) is observed in humans either due to accidental or intentional exposures. This can only be managed with supporting care and no approved countermeasures are available till now. Early detection and monitoring of RIGI is important for effective medical management and improve survival chances of exposed individuals., Objective: The present study aims to identify new signatures of RIGI using data mining approach followed by validation of selected hub genes in mice., Methods: Data mining study was performed using microarray datasets from Gene Expression Omnibus database. The differentially expressed genes were identified and further validated in total-body irradiated mice., Results: Based on KEGG pathway analysis, lipid metabolism was found as one of the predominant pathways altered in irradiated intestine. Extensive alteration in lipid profile and lipid modification was observed in this tissue. A protein-protein interaction network revealed top 08 hub genes related to lipid metabolism, namely Fabp1, Fabp2, Fabp6, Npc1l1, Ppar-α, Abcg8, Hnf-4α, and Insig1. qRT-PCR analysis revealed significant up-regulation of Fabp6 and Hnf-4α and down-regulation of Fabp1, Fabp2 and Insig1 transcripts in irradiated intestine. Radiation dose and time kinetics study revealed that the selected 05 genes were altered differentially in response to radiation in intestine., Conclusion: Finding suggests that lipid metabolism is one of the key targets of radiation and its mediators may act as biomarkers in detection and progression of RIGI.

Background: Radiation-induced intestinal injury (RIII) interrupts the scheduled processes of abdominal and pelvic radiotherapy (RT) and compromises the quality of life of cancer survivors. However, the specific regulators and mechanisms underlying the effects of RIII remain unknown. The biological effects of RT are caused primarily by DNA damage, and ataxia telangiectasia mutated (ATM) is a core protein of the DNA damage response (DDR). However, whether ATM is regulated by deubiquitination signaling remains unclear., Methods: We established animal and cellular models of RIII. The effects of ubiquitin-specific protease 15 (USP15) on DNA damage and radion-induced intestinal injury were evaluated. Mass spectrometry analysis, truncation tests, and immunoprecipitation were used to identify USP15 as a binding partner of ATM and to investigate the ubiquitination of ATM. Finally, the relationship between the USP15/ATM axes was further determined via subsequent experiments., Results: In this study, we identified the deubiquitylating enzyme USP15 as a regulator of DNA damage and the pathological progression of RIII. Irradiation upregulates the expression of USP15, whereas pharmacological inhibition of USP15 exacerbates radiation-induced DNA damage and RIII both in vivo and in vitro. Mechanistically, USP15 interacts with, deubiquitinates, and stabilises ATM via K48-linked deubiquitination. Notably, ATM overexpression blocks the effect of USP15 genetic inhibition on DNA damage and RIII progression., Conclusions: These findings describe ATM as a novel deubiquitination target of USP15 upon radiation-induced DNA damage and intestinal injury, and provides experimental support for USP15/ATM axis as a potential target for developing strategies that mitigate RIII., (© 2024. The Author(s).)

Background: Radiation-induced lymphopenia (RIL) is closely related to the prognosis of cervical cancer patients and may affect the efficacy of immune checkpoint inhibitors (ICIs). However, the factors influencing RIL are not very clear. In addition to bone marrow (BM) dose-volume, animal studies indicate radiation-induced bowel injury may be a more crucial factor. Further clarification of the correlation between RIL and bowel dose-volume is important for cervical cancer treatment., Methods: Cervical cancer patients treated with postoperative radiotherapy or radical radiotherapy were eligible for this retrospective study. Clinical characteristics, dose parameters of bowel and BM, planning target volume (PTV) size, overall survival (OS) and progression-free survival (PFS) were recorded. The absolute lymphocyte count<0.5×10 9 /L at radiotherapy end was defined as severe RIL (sRIL). Hazard ratio (HR) and 95% confidence interval (Cl)were estimated using Cox regression models. Survival curve was plotted using the Kaplan-Meier method. On this basis, the receiver operating characteristics (ROC) curve was used to calculate the area under the curve (AUC) for radiation parameters with sRIL as the state variable., Result: A total of 118 cervical cancer patients were included in this study, with a median follow-up time of 57.6 months. In multivariable Cox regression analysis, international Federation of Gynecology and obstetrics (FIGO) stage (HR, 11.806; 95% CI, 3.256-42.809; p<0.001), concurrent chemotherapy (HR, 0.200; 95% CI, 0.054-0.748; p=0.017), sRIL after radiotherapy (HR, 6.009; 95% CI, 1.361-26.539; p=0.018), and pathological type (HR, 2.261; 95% CI, 1.043-4.901; p=0.039) were significantly correlated with OS. Patients with sRIL had significantly decreased OS (79.1% vs 94.1%; HR, 3.81; 95%CI, 1.46-9.92; p=0.023). In binary logistic regression analysis, sRIL was significantly correlated with bowel V45 (Odds radio (OR), 1.025; 95%CI, 1.007-1.044; p=0.007), BM V10 (OR, 0.987; 95%CI, 0.978-0.997; p=0.011), BM V20 (OR, 1.017; 95%CI, 1.002-1.031, p=0.027), and PTV size (OR, 0.998; 95%CI, 0.996-1.000; p=0.026). The ROC curve showed, bowel V45 (AUC=0.787, p<0.001) was the best indicator for predicting sRIL., Conclusion: SRIL after radiotherapy could significantly predict decreased OS. In addition, sRIL is associated with higher bowel, BM dose-volume, PTV size, indicating that the bowel may be an important organ leading to an increased risk of sRIL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LZ declared a shared affiliation with the author YX to the handling editor at time of review., (Copyright © 2024 Li, Chen, Liu, Xu and Ji.)

Radiation-induced intestinal injury (RIII) constitutes a challenge in radiotherapy. Ionizing radiation (IR) induces DNA and mitochondrial damage by increasing reactive oxygen species (ROS). Sodium-glucose cotransporter 1 (SGLT1) is abundant in the gastrointestinal tract and the protective effects of inhibited SGLT1 in kidney and cardiovascular disease have been widely reported. However, the function of SGLT1 in RIII remains unclear. Herein, we reported that IR induced intestinal epithelial cell damage along with upregulation of SGLT1 in vivo and in vitro, which was alleviated by inhibition of SGLT1. Specifically, maintaining intestinal cell homeostasis was detected through cellular proliferation, apoptosis, and DNA damage assays, promoting epithelial regeneration and lifespan extension. Considering the importance of mitochondrial function in cell fate, we next confirmed that SGLT inhibition maintains mitochondrial homeostasis through enhanced mitophagy in intestinal epithelial cells. Finally, based on the bioinformatics analysis and cell validation, we demonstrated that inhibition of SGLT1 suppresses the PI3K/AKT/mTOR pathway to enhance mitophagy activation post-irradiation. In addition, we preliminarily demonstrate that SGLT inhibitors do not affect the radiosensitivity of tumors. Hence, our findings suggest that inhibition of SGLT is a promising therapeutic strategy to protect against RIII. To the best of our knowledge, this is the first report on the potential effect of SGLT1 inhibition in RIII., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This study was supported by the National Natural Science Foundation of China (82304082)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiation-induced intestinal injury is one of the most common intestinal complications caused by pelvic and abdominal tumor radiotherapy, severely impacting patients' quality of life. Ionizing radiation, while killing tumor cells, inevitably damages healthy tissue. Radiation-induced enteropathy results from radiation therapy-induced intestinal tissue damage and inflammatory responses. This damage involves various complex molecular mechanisms, including cell apoptosis, oxidative stress, release of inflammatory mediators, disruption of immune responses, and imbalance of intestinal microbiota. A thorough understanding of these molecular mechanisms is crucial for developing effective prevention and treatment strategies.

Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24 h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8 + cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage., (© 2024. The Author(s).)

In mice, intestinal tuft cells have been described as a long-lived, postmitotic cell type. Two distinct subsets have been identified: tuft-1 and tuft-2 (ref. 1 ). By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase on interleukin-4 (IL-4) and IL-13 exposure, as reported previously in mice 2-4 . This occurs through proliferation of pre-existing tuft cells, rather than through increased de novo generation from stem cells. Indeed, proliferative tuft cells occur in vivo both in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans., (© 2024. The Author(s).)

Iron redistribution in the intestine after total body irradiation is an established phenomenon. However, in the literature, there are no reports about the use of X-ray fluorescence microscopy or equivalent techniques to generate semi-quantitative 2D maps of iron in sectioned intestine samples from irradiated mice. In this work, we used X-ray fluorescence microscopy (XFM) to map the elemental content of iron as well as phosphorus, sulfur, calcium, copper and zinc in tissue sections of the small intestine from eight-week-old BALB/c male mice that developed gastrointestinal acute radiation syndrome (GI-ARS) in response to exposure to 8 Gray of gamma rays. Seven days after irradiation, we found that the majority of the iron is localized as hot spots in the intercellular regions of the area surrounding crypts and stretching between the outer perimeter of the intestine and the surface cell layer of villi. In addition, this study represents our current efforts to develop elemental cell classifiers that could be used for the automated generation of regions of interest for analyses of X-ray fluorescence maps. Once developed, such a tool will be instrumental for studies of effects of radiation and other toxicants on the elemental content in cells and tissues. While XFM studies cannot be conducted on living organisms, it is possible to envision future scenarios where XFM imaging of single cells sloughed from the human (or rodent) intestine could be used to follow up on the progression of GI-ARS.

Age at exposure is a critical modifier of the risk of radiation-induced cancer. However, the effects of age on radiation-induced carcinogenesis remain poorly understood. In this study, we focused on tissue stem cells using Lgr5-eGFP-ires-Cre ERT2 mice to compare radiation-induced DNA damage responses between Lgr5+ and Lgr5- intestinal stem cells. Three-dimensional immunostaining analyses demonstrated that radiation induced apoptosis and the mitotic index more efficiently in adult Lgr5- stem cells than in adult Lgr5+ stem cells but not in infants, regardless of Lgr5 expression. Supporting this evidence, rapid and transient p53 activation occurred after irradiation in adult intestinal crypts but not in infants. RNA sequencing revealed greater variability in gene expression in adult Lgr5+ stem cells than in infant Lgr5+ stem cells after irradiation. Notably, the cell cycle and DNA repair pathways were more enriched in adult stem cells than in infant stem cells after irradiation. Our findings suggest that radiation-induced DNA damage responses in mouse intestinal crypts differ between infants and adults, potentially contributing to the age-dependent susceptibility to radiation carcinogenesis.

Radiotherapy is a common treatment for abdominal and pelvic tumors, while the radiation-induced intestinal injury (RIII) is one of the major side-effects of radiotherapy, which reduces the life quality and impedes the treatment completion of cancer patients. Previous studies have demonstrated that environmental pollutant microplastics led to various kinds of injury in the gut, but its effects on RIII are still uncovered. In this study, we fed the C57BL/6J mice with distilled water or 50 μg/d polystyrene microplastics (PSMPs) for 17 days and exposed the mice to total abdominal irradiation (TAI) at day 14. Then the severity of RIII was examined by performing histopathological analysis and microbial community analysis. The results demonstrated that PSMPs significantly aggravated RIII in small intestine rather than colon of mice upon TAI. PSMPs increased levels of the histopathological damage and the microbial community disturbance in mice small intestine, shown by the overabundance of Akkermansiaceae and the decrease of microflora including Lactobacillaceae, Muribaculaceae and Bifidobacteriaceae. In conclusion, our results suggested that more microplastics exposure might led to more severe RIII, which should be considered in patients' daily diet adjustment and clinical radiotherapy plan evaluation. Furthermore, this study also called for the further researches to uncover the underlying mechanism and develop novel strategies to attenuate RIII in mice intestine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ionizing radiation (IR), including radiotherapy, can exert lasting harm on living organisms. While liposaccharide (LPS) offers resistance to radiation damage, it also induces toxic responses. Thankfully, an LPS analogue called N-formylmethionine-leucyl-phenylalanine (fMLP) holds the potential to mitigate this toxicity, offering hope for radiation protection., Methods: Survival of C57BL/6 mice exposed to IR after administration with fMLP/LPS/WR-2721 or saline was recorded. Cell viability and apoptosis assay of bone marrow (BMC), spleen and small intestinal epithelial (HIECs) cells were tested by Cell Counting Kit-8 (CCK-8) and flow cytometry assay. Tissue damage was evaluated by Hematoxilin and Eosin (H&E), Ki-67, and TUNEL staining. RNA sequencing was performed to reveal potential mechanisms of fMLP-mediated radiation protection. Flow cytometry and western blot were performed to verify the radiation protection mechanism of fMLP on the cell cycle., Results: The survival rates of C57BL/6 mice exposed to ionizing radiation after administering fMLP increased. fMLP demonstrated low toxicity in vitro and in vivo, maintaining cell viability and mitigating radiation-induced apoptosis. Moreover, it protected against tissue damage in the hematopoietic and intestinal system. RNA sequencing shed light on fMLP's potential mechanism, suggesting its role in modulating innate immunity and cell cycling. This was evidenced by its ability to reverse radiation-induced G2/M phase arrests in HIECs., Conclusion: fMLP serves as a promising radioprotective agent, preserving cells and radiosensitive tissues from IR. Through its influence on the cell cycle, particularly reversing radiation-induced arrest in G2/M phases, fMLP offers protection against IR's detrimental effects., (© 2024. The Author(s).)

In patients with high-level radiation exposure, gastrointestinal injury is the main cause of death. Despite the severity of damage to the gastrointestinal tract, no specific therapeutic option is available. Tauroursodeoxycholic acid (TUDCA) is a conjugated form of ursodeoxycholic acid that suppresses endoplasmic reticulum (ER) stress and regulates various cell-signaling pathways. We investigated the effect of TUDCA premedication in alleviating intestinal damage and enhancing the survival of C57BL/6 mice administered a lethal dose (15Gy) of focal abdominal irradiation. TUDCA was administered to mice 1 h before radiation exposure, and reduced apoptosis of the jejunal crypts 12 h after irradiation. At later timepoint (3.5 days), irradiated mice manifested intestinal morphological changes that were detected via histological examination. TUDCA decreased the inflammatory cytokine levels and attenuated the decrease in serum citrulline levels after radiation exposure. Although radiation induced ER stress, TUDCA pretreatment decreased ER stress in the irradiated intestinal cells. The effect of TUDCA indicates the possibility of radiation therapy for cancer in tumor cells. TUDCA did not affect cell proliferation and apoptosis in the intestinal epithelium. TUDCA decreased the invasive ability of the CT26 metastatic colon cancer cell line. Reduced invasion after TUDCA treatment was associated with decreased matrix metalloproteinase (MMP)-7 and MMP-13 expression, which play important roles in invasion and metastasis. This study shows a potential role of TUDCA in protecting against radiation-induced intestinal damage and inhibiting tumor cell migration without any radiation and radiation therapy effect., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joong Sun Kim reports financial support was provided by National Research Foundation of Korea. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The efficacy of Liangxue Guyuan Yishen Decoction (LGYD), a traditional Chinese medicine, has been scientifically proven in the treatment of radiation-induced intestinal injury (RIII) and preservation of intestinal integrity and function following high-dose radiation exposure. However, further investigation is required to comprehensively elucidate the precise mechanisms underlying the therapeutic effects of LGYD in order to provide potential pharmaceutical options for radiation protection., Purpose: This study aims to elucidate the potential mechanism through which LGYD exerts its therapeutic effects on RIII by modulating the gut microbiota (GM)., Methods: 16 s rRNA analysis was employed to assess the impact of varying doses of whole body irradiation (WBI) on GM in order to establish an appropriate model for this study. The effects of LGYD on GM and SCFA were evaluated using 16 s rRNA and Quantification of SCFA. UHPLC-QE-MS was utilized to identify the active components in LGYD as well as LGYD drug containing serum (LGYD-DS). Subsequently, immunofluorescence and immunohistochemical staining were conducted to validate the influence of LGYD and/or characteristic microbiota on RIII recovery in vivo. The effects of LGYD-DS, characteristic flora, and SCFA on intestinal stem cell (ISC) were assessed by measuring organoid surface area in intestinal organoid model., Results: The species composition and abundance of GM were significantly influenced by whole-body irradiation with a dose of 8.5 Gy, which was used as in vivo model. LGYD significantly improves the survival rate and promotes recovery from RIII. Additionally, LGYD exhibited a notable increase in the abundance of Akkermansia muciniphila (AKK) and levels of SCFA, particularly isobutyric acid. LGYD-DS consisted of seven main components derived from herbs of LGYD. In vivo experiments indicated that both LGYD and AKK substantially enhanced the survival rate after radiation and facilitated the recovery process for intestinal structure and function. In the organoid model, treatment with LGYD-DS, AKK supernatant or isobutyric acid significantly increased organoid surface area., Conclusions: LGYD has the potential to enhance RIII by promoting the restoration of intestinal stem cell, which is closely associated with the upregulation of AKK abundance and production of SCFA, particularly isobutyric acid., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed. And all experiments met clinical and animal ethical requirements., (Copyright © 2024. Published by Elsevier GmbH.)

Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor β (CBFβ) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 10 8 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Gastrointestinal-acute radiation syndrome (GI-ARS) caused by moderate to high doses of ionizing radiation exposure contribute to early death in humans. GI injury is also a common adverse effect seen in cancer patients undergoing abdominal/pelvic radiotherapy. Currently, no countermeasure agents have been approved for medical management of GI-ARS. The present study aims to evaluate the mechanism of action of Trichostatin A(TSA), a pan histone deacetylase inhibitor, against radiation-induced GI injury., Methods: TSA (150 ng/kg bw) was administered to mice 1 h and 24 h after 15 Gy abdominal irradiation. Expression of various markers of oxidative stress, mitochondrial dysfunction, and apoptosis were checked in the jejunum, and their possible regulation through the Nrf2 signaling pathway was evaluated., Results: TSA administered post-irradiation (15 Gy + TSA) elevated intestinal total antioxidant and glutathione levels by regulating the expression of Slc7A11 and antioxidant proteins, GCLC, GPX4, and TXNRD1. Improved mitochondrial membrane potential, ATP levels, downregulation of mitochondrial quality control proteins, (PINK1 and PARKIN), and differential regulation of the apoptotic proteins, (BAX, PUMA and BCL2) with reduced intestinal epithelial cell apoptosis in the TSA-adminstered group were observed. TSA also upregulated Nrf2 in the presence of its specific inhibitor, ML385, suggesting its involvement in regulating Nrf2 signaling during oxidative stress induced by radiation in intestine. H & E stained jejunum cross-sections revealed that TSA mitigated radiation-mediated intestinal injury in mice., Conclusions: Present findings indicate that TSA is beneficial in mitigating the damaging effects of ionizing radiation in the intestine., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Intestinal stem cells (ISCs) are pivotal for the maintenance and regeneration of the intestinal epithelium. Berberine (BBR) exhibits diverse biological activities, but it remains unclear whether BBR can modulate ISCs' function. Therefore, we investigated the effects of BBR on ISCs in healthy and radiation-injured mice and explored the potential underlying mechanisms involved. The results showed that BBR significantly increased the length of the small intestines, the height of the villi, and the depth and density of the crypts, promoted the proliferation of cryptal epithelial cells and increased the number of OLFM4 + ISCs and goblet cells. Crypts from the BBR-treated mice were more capable of growing into enteroids than those from untreated mice. BBR alleviated WAI-induced intestinal injury. BBR suppressed the apoptosis of crypt epithelial cells, increased the quantity of goblet cells, and increased the quantity of OLFM4 + ISCs and tdTomato + progenies of ISCs after 8 Gy WAI-induced injury. Mechanistically, BBR treatment caused a significant increase in the quantity of p-S6, p-STAT3 and p-ERK1/2 positive cryptal epithelial cells under physiological conditions and after WAI-induced injury. In conclusion, BBR is capable of enhancing the function of ISCs either physiologically or after radiation-induced injury, indicating that BBR has potential value in the treatment of radiation-induced intestinal injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Research on plant and animal peptides has garnered significant attention, but there is a lack of studies on the functional properties of Tenebrio molitor peptides, particularly in relation to their potential mitigating effect on radiation damage and the underlying mechanisms. This study aims to explore the protective effects of Tenebrio molitor peptides against radiation-induced damage. Mice were divided into five groups: normal, radiation model, and low-, medium-, and high-dose Tenebrio molitor peptide (TMP) groups (0.15 g per kg BW, 0.30 g per kg BW, and 0.60 g per kg BW). Various parameters such as blood cell counts, bone marrow DNA content, immune organ indices, serum levels of D-lactic acid, diamine oxidase (DAO), endotoxin (LPS), and inflammatory factors were assessed at 3 and 15 days post gamma irradiation. Additionally, the intestinal tissue morphology was examined through H&E staining, RT-qPCR experiments were conducted to analyze the expression of inflammatory factors in the intestine, and immunohistochemistry was utilized to evaluate the expression of tight junction proteins ZO-1 and Occludin in the intestine. The findings revealed that high-dose TMP significantly enhanced the hematopoietic system function in mice post radiation exposure, leading to increased spleen index, thymus index, blood cell counts, and bone marrow DNA production ( p < 0.05). Moreover, TMP improved the intestinal barrier integrity and reduced the intestinal permeability. Mechanistic insights suggested that these peptides may safeguard intestinal barrier function by downregulating the gene expression of inflammatory factors TNF-α, IL-1β, and IL-6, while upregulating the expression of tight junction proteins ZO-1 and Occludin ( p < 0.05). Overall, supplementation with TMP mitigates radiation-induced intestinal damage by enhancing the hematopoietic system and the intestinal barrier, offering valuable insights for further investigations into the mechanisms underlying the protective effects of these peptides against ionizing radiation.

Background/aim: The aim of this study was to develop an enhanced intestinal toxicity assay with three outputs assessing proliferation, villi morphology and DNA damage after irradiation., Materials and Methods: Whole 5 cm jejunal lengths were collected from mice following total body x-ray irradiation (0-15 Gy) at 0-84 h. Tissues were wrapped into swirls for cryopreservation and immunohistochemically stained for EdU, CD31, and γH2AX. A semi-automated image analysis was developed for the proliferation, villi morphology, and DNA damage models., Results: Proliferation assessed via EdU staining varied with cycles of damage repair, hyperproliferation, and homeostasis after radiation, with the time to onset of each cycle variable based on radiation dose. An analysis model evaluating the amount of proliferation per unit length of jejunum analyzed was developed, with a dose-response curve identified at 48 h post treatment. The villi length model measured the length of intact and healthy CD31-stained capillary beds between the crypts and villi tips at 3.5 days post treatment within a 0-10 Gy dose range. The DNA damage model evaluated the intensity of γH2AX staining within cellular nuclei, with a useful dose-response identified at 1 h post-radiation treatment., Conclusion: This assay demonstrates flexibility for assessing radiation-induced damage, with analysis of proliferation, villi length, or direct DNA damage achievable at defined time points and within useful radiation dose curves. The software-assisted image analysis allows for rapid, comprehensive, and objective data generation with an assay turnover time of days instead of weeks on samples that are representative of most of the treated jejunum., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Ultrahigh-dose-rate (FLASH) irradiation has been reported to reduce normal tissue damage compared with conventional dose rate (CONV) irradiation without compromising tumor control. This proof-of-concept study aims to develop a deep learning (DL) approach to quantify the FLASH isoeffective dose (dose of CONV that would be required to produce the same effect as the given physical FLASH dose) with postirradiation mouse intestinal histology images., Methods and Materials: Eighty-four healthy C57BL/6J female mice underwent 16 MeV electron CONV (0.12 Gy/s; n = 41) or FLASH (200 Gy/s; n = 43) single fraction whole abdominal irradiation. Physical dose ranged from 12 to 16 Gy for FLASH and 11 to 15 Gy for CONV in 1 Gy increments. Four days after irradiation, 9 jejunum cross-sections from each mouse were hematoxylin and eosin stained and digitized for histological analysis. CONV data set was randomly split into training (n = 33) and testing (n = 8) data sets. ResNet101-based DL models were retrained using the CONV training data set to estimate the dose based on histological features. The classical manual crypt counting (CC) approach was implemented for model comparison. Cross-section-wise mean squared error was computed to evaluate the dose estimation accuracy of both approaches. The validated DL model was applied to the FLASH data set to map the physical FLASH dose into the isoeffective dose., Results: The DL model achieved a cross-section-wise mean squared error of 0.20 Gy 2 on the CONV testing data set compared with 0.40 Gy 2 of the CC approach. Isoeffective doses estimated by the DL model for FLASH doses of 12, 13, 14, 15, and 16 Gy were 12.19 ± 0.46, 12.54 ± 0.37, 12.69 ± 0.26, 12.84 ± 0.26, and 13.03 ± 0.28 Gy, respectively., Conclusions: Our proposed DL model achieved accurate CONV dose estimation. The DL model results indicate that in the physical dose range of 13 to 16 Gy, the biologic dose response of small intestinal tissue to FLASH irradiation is represented by a lower isoeffective dose compared with the physical dose. Our DL approach can be a tool for studying isoeffective doses of other radiation dose modifying interventions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Perturbations produced by ionizing radiation on intestinal tissue are considered one of highly drastic challenges in radiotherapy. Animals were randomized into five groups. The first group was allocated as control, and the second was subjected to whole body γ-irradiation (10 Gy). The third was administered HA NP (17.6 mg/kg/day; i.p.) and then irradiated. The fourth one received MitoQ (2 mg/kg/day; i.p.) and then irradiated. The last group received MitoQ/HA NP (2 mg/kg/day; i.p.) for 5 days prior to irradiation. Mice were sacrificed a week post-γ-irradiation for evaluation. MitoQ/HA NP ameliorated mitochondrial oxidative stress as indicated by rising (TAC) and glutathione peroxidase and decreasing malondialdehyde, showing its distinguished antioxidant yield. That impacted the attenuation of apoptosis, which was revealed by the restoration of the anti-apoptotic marker and lessening proapoptotic caspase-3. Inflammatory parameters dwindled via treatment with MitoQ/HA NP. Moreover, this new NP exerts its therapeutic action through a distinguished radioprotective pathway (Hmgb1/TLR-4.) Subsequently, these antioxidants and their nanoparticles conferred protection to intestinal tissue as manifested by histopathological examination. These findings would be associated with its eminent antioxidant potential through high mitochondria targeting, enhanced cellular uptake, and ROS scavenging. This research underlines MitoQ/HA NP as a new treatment for the modulation of intestinal damage caused by radiotherapy modalities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: The small intestine is one of the organs most vulnerable to ionizing radiation (IR) damage. However, methods to protect against IR-induced intestinal injury are limited. CBLB502, a Toll-like receptor 5 (TLR5) agonist from Salmonella flagellin, exerts radioprotective effects on various tissues and organs. However, the molecular mechanisms by which CBLB502 protects against IR-induced intestinal injury remain unclear. Thus, this study aimed to elucidate the mechanisms underlying IR-induced intestinal injury and the protective effects of CBLB502 against this condition in mice., Materials and Methods: Mice were administered 0.2 mg/kg CBLB502 before IR at different doses for different time points, and then the survival rate, body weight, hemogram, and histopathology of the mice were analyzed., Results: CBLB502 reduced IR-induced intestinal injury. RNA-seq analysis revealed that different doses and durations of IR induced different regulatory patterns. CBLB502 protected against intestinal injury mainly after IR by reversing the expression of IR-induced genes and regulating immune processes and metabolic pathways., Conclusion: This study preliminarily describes the regulatory mechanism of IR-induced intestinal injury and the potential molecular protective mechanism of CBLB502, providing a basis for identifying the functional genes and molecular mechanisms that mediate protection against IR-induced injury., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although there are several types of radiation exposure, it is debated whether low‑dose‑rate (LDR) irradiation (IR) affects the body. Since the small intestine is a radiation‑sensitive organ, the present study aimed to evaluate how it changes when exposed to LDR IR and identify the genes sensitive to these doses. After undergoing LDR (6.0 mGy/h) γ radiation exposure, intestinal RNA from BALB/c mice was extracted 1 and 24 h later. Mouse whole genome microarrays were used to explore radiation‑induced transcriptional alterations. Reverse transcription‑quantitative (RT‑q) PCR was used to examine time‑ and dose‑dependent radiation responses. The histopathological status of the jejunum in the radiated mouse was not changed by 10 mGy of LDR IR; however, 23 genes were upregulated in response to LDR IR of the jejunum in mice after 1 and 24 h of exposure. Upregulated genes were selected to validate the results of the RNA sequencing analysis for RT‑qPCR detection and results showed that only Na + /K + transporting subunit α4, glucose‑6‑phosphatase catalytic subunit 2 (G6PC2), mucin 6 (MUC6) and transient receptor potential cation channel subfamily V member 6 levels significantly increased after 24 h of LDR IR. Furthermore, G6PC2 and MUC6 were notable genes induced by LDR IR exposure according to protein expression via western blot analysis. The mRNA levels of G6PC2 and MUC6 were significantly elevated within 24 h under three conditions: i) Exposure to LDR IR, ii) repeated exposure to LDR IR and iii) exposure to LDR IR in the presence of inflammatory bowel disease. These results could contribute to an improved understanding of immediate radiation reactions and biomarker development to identify radiation‑susceptible individuals before histopathological changes become noticeable. However, further investigation into the specific mechanisms involving G6PC2 and MUC6 is required to accomplish this.

Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients' quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection., (© 2024. The Author(s).)

Background: The gut microbiota is strongly associated with radiation-induced gut damage. This study aimed to assess the effectiveness and safety of intestinal microecological transplantation for treating patients with chronic radiation enteritis., Case Summary: A 64-year-old female with cervical cancer developed abdominal pain, diarrhea, and blood in the stool 1 year after radiotherapy. An electronic colonoscopy was performed to diagnose chronic radiation enteritis. Two courses of intestinal microecological transplantation and full-length 16S rRNA microbiological analysis were performed. The patient experienced short- and long-term relief from symptoms without adverse effects. Whole 16S rRNA sequencing revealed significant differences in the intestinal flora's composition between patient and healthy donors. Pathogenic bacteria, such as Escherichia fergusonii and Romboutsia timonensis , were more in the patient. Beneficial bacteria such as Faecalibacterium prausnitzii , Fusicatenibacter saccharivorans , Ruminococcus bromii , and Bifidobacterium longum were more in the healthy donors. Intestinal microbiota transplantation resulted in a significant change in the patient's intestinal flora composition. The composition converged with the donor's flora, with an increase in core beneficial intestinal bacteria, such as Eubacterium rectale , and a decrease in pathogenic bacteria. Changes in the intestinal flora corresponded with the patients' alleviating clinical symptoms., Conclusion: Intestinal microecological transplantation is an effective treatment for relieving the clinical symptoms of chronic radiation enteritis by altering the composition of the intestinal flora. This study provides a new approach for treating patients with chronic radiation enteritis., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts., Result: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8 + cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles., Conclusion: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. Video Abstract., (© 2024. The Author(s).)

CUL4B, a crucial scaffolding protein in the largest E3 ubiquitin ligase complex CRL4B, is involved in a broad range of physiological and pathological processes. While previous research has shown that CUL4B participates in maintaining intestinal homeostasis and function, its involvement in facilitating intestinal recovery following ionizing radiation (IR) damage has not been fully elucidated. Here, we utilized in vivo and in vitro models to decipher the role of CUL4B in intestinal repair after IR-injury. Our findings demonstrated that prior to radiation exposure, CUL4B inhibited the ubiquitination modification of PSME3, which led to the accumulation of PSME3 and subsequent negative regulation of p53-mediated apoptosis. In contrast, after radiation, CUL4B dissociated from PSME3 and translocated into the nucleus at phosphorylated histones H2A (γH2AX) foci, thereby impeding DNA damage repair and augmenting p53-mediated apoptosis through inhibition of BRCA1 phosphorylation and RAD51. Our study elucidated the dynamic role of CUL4B in the repair of radiation-induced intestinal damage and uncovered novel molecular mechanisms underlying the repair process, suggesting a potential therapeutic strategy of intestinal damage after radiation therapy for cancers., (© 2024. The Author(s).)

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI ( 60 Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B , TNFA , CCL2, IL18 , and CXCL8 , and the inflammasome component NLRP3 . Captopril suppressed radiation-induced IL1B and TNFA . Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Scope: Naringenin (NAR) possesses unique anti-inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation-induced intestinal injury and the underlying mechanisms., Methods and Results: C57BL/6J mice are exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation-induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR-mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2-APB, indicating that TRPV6 inhibition is essential for NAR activity., Conclusion: NAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII., (© 2024 The Authors. Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

The intestine is prone to radiation damage in patients undergoing radiotherapy for pelvic tumors. However, there are currently no effective drugs available for the prevention or treatment of radiation-induced enteropathy (RIE). In this study, we aimed at investigating the impact of indole-3-carboxaldehyde (I3A) derived from the intestinal microbiota on RIE. Intestinal organoids were isolated and cultivated for screening radioprotective tryptophan metabolites. A RIE model was established using 13 Gy whole-abdominal irradiation in male C57BL/6J mice. After oral administration of I3A, its radioprotective ability was assessed through the observation of survival rates, clinical scores, and pathological analysis. Intestinal stem cell survival and changes in the intestinal barrier were observed through immunofluorescence and immunohistochemistry. Subsequently, the radioprotective mechanisms of I3A was investigated through 16S rRNA and transcriptome sequencing, respectively. Finally, human colon cancer cells and organoids were cultured to assess the influence of I3A on tumor radiotherapy. I3A exhibited the most potent radioprotective effect on intestinal organoids. Oral administration of I3A treatment significantly increased the survival rate in irradiated mice, improved clinical and histological scores, mitigated mucosal damage, enhanced the proliferation and differentiation of Lgr5 + intestinal stem cells, and maintained intestinal barrier integrity. Furthermore, I3A enhanced the abundance of probiotics, and activated the AhR/IL-10/Wnt signaling pathway to promote intestinal epithelial proliferation. As a crucial tryptophan metabolite, I3A promotes intestinal epithelial cell proliferation through the AhR/IL-10/Wnt signaling pathway and upregulates the abundance of probiotics to treat RIE. Microbiota-derived I3A demonstrates potential clinical application value for the treatment of RIE.

Radiation-induced intestinal injury is one the most common adverse events of radiotherapy, which can severely affect quality of life. There are currently no effective preventive and therapeutic options for this disorder. Quercetin is a natural flavonoid found in common food species, with the characteristics of antioxidative, anti-inflammatory, and anti-cancerous activity. However, the role of quercetin on radiation-induced intestinal injury and the underlying mechanism remains poorly understood. In this study, we found quercetin treatment can improve the survival rate of mice after a single-dose (10 Gy) abdominal irradiation. Quercetin-pretreated mice significantly reduced radiation-induced DNA damage and intestinal epithelium cell apoptosis. In addition, quercetin also improved the proliferation activity of intestinal stem cells and promoted intestine epithelium repair after irradiation. Further studies demonstrated that quercetin treatment curtailed radiation-induced reactive oxygen species generation via regulating Nrf2 signaling in intestinal epithelium cells. Furthermore, treatment with Nrf2 inhibitor, could reverse the above effects. Altogether, quercetin can ameliorate radiation-induced intestine injury via regulating Nrf2 signaling, scavenging free radicals, and promoting intestinal epithelium repair., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

The gastrointestinal (GI) system is highly susceptible to irradiation. Currently, there is no Food and Drug Administration (FDA)-approved medical countermeasures for GI radiation injury. The vitamin E analog gamma-tocotrienol (GT3) is a promising radioprotector in mice and nonhuman primates (NHP). We evaluated GT3-mediated GI recovery in total-body irradiated (TBI) NHPs. Sixteen rhesus macaques were divided into two groups; eight received vehicle and eight GT3 24 h prior to 12 Gy TBI. Proximal jejunum was assessed for structural injuries and crypt survival on day 4 and 7. Apoptotic cell death and crypt cell proliferation were assessed with TUNEL and Ki-67 immunostaining. Irradiation induced significant shortening of the villi and reduced mucosal surface area. GT3 induced an increase in crypt depth at day 7, suggesting that more stem cells survived and proliferated after irradiation. GT3 did not influence crypt survival after irradiation. GT3 treatment caused a significant decline in TUNEL-positive cells at both day 4 (p < 0.03) and 7 (p < 0.0003). Importantly, GT3 induced a significant increase in Ki-67-positive cells at day 7 (p < 0.05). These data suggest that GT3 has radioprotective function in intestinal epithelial and crypt cells. GT3 should be further explored as a prophylactic medical countermeasure for radiation-induced GI injury.

The intestinal tract is an essential component of the body's immune system, and is extremely sensitive to exposure of ionizing radiation. While ionizing radiation can effectively induce multiple forms of cell death, whether it can also promote ferroptosis in intestinal cells and the possible interrelationship between ferroptosis and intestinal immune function has not been reported so far. Here, we found that radiation-induced major ultrastructural changes in mitochondria of small intestinal epithelial cells and the changes induced in iron content and MDA levels in the small intestine were consistent with that observed during cellular ferroptosis, thus suggesting occurrence of ferroptosis in radiation-induced intestinal damage. Moreover, radiation caused a substantial increase in the expression of ferroptosis-related factors such as LPCAT3 and ALOX15 mRNA, augmented the levels of immune-related factors INF-γ and TGF-β mRNA, and decreased the levels of IL-17 mRNA thereby indicating that ionizing radiation induced ferroptosis and impairment of intestinal immune function. Liproxstatin-1 is a ferroptosis inhibitor that was found to ameliorate radiation-induced ferroptosis and promote the recovery from immune imbalances. These findings supported the role of ferroptosis in radiation-induced intestinal immune injury and provide novel strategies for protection against radiation injury through regulation of the ferroptosis pathway., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study explored the radioprotective effects and possible underlying mechanisms of KR-31831 against radiation-induced injury in a mouse model. KR-31831 (30 and 50 mg/kg) was administered to mice 24 h and 30 min before exposure to a single lethal or sublethal dose of whole-body irradiation (WBI) (7 or 4 Gy, respectively). These animals were then evaluated for changes in mortality, various hematological and biochemical parameters, and histological features in response to these treatments. In addition, RNA sequencing was used to profile the radiation-induced transcriptomic response in the bone marrow cells. The results showed that KR-31831 dose-dependently prolonged the 30-day survival period and prevented damage to radiation-sensitive organs, such as the intestine and testis, in response to WBI. Damage to the hematopoietic system was also notably improved in the KR-31831-treated mice, as evidenced by an increase in bone marrow and peripheral blood cells, as well as recovery of the histopathological characteristics of the bone marrow. These protective effects were achieved, at least in part, via the suppression of radiation-induced increases in apoptotic cell death and erythropoietin levels in the plasma. Furthermore, the gene expression profiles of the bone marrow cells of the WBI-treated mice suggested that KR-31831 upregulates the expression of the genes involved in regulating apoptosis and modulating the immune response, both of which are required for protecting the bone marrow. These results suggest the potential therapeutic efficacy of KR-31831 for protection against radiation-induced injury., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)