Radiation-induced Injury Research Articles

Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury

Genotoxic therapy triggers reactive oxygen species (ROS) production and oxidative tissue injury. S-nitrosylation is a selective and reversible posttranslational modification of protein thiols by nitric oxide (NO), and 5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. However, the mechanism by which BH4 affects protein S-nitrosylation and ROS generation has not been determined. Here, we showed that ionizing radiation disrupted the structural integrity of BH4 and downregulated GTP cyclohydrolase I (GCH1), which is the rate-limiting enzyme in BH4 biosynthesis, resulting in deficiency in overall protein S-nitrosylation. GCH1-mediated BH4 synthesis significantly reduced radiation-induced ROS production and fueled the global protein S-nitrosylation that was disrupted by radiation. Likewise, GCH1 overexpression or the administration of exogenous BH4 protected against radiation-induced oxidative injury in vitro and in vivo. Conditional pulmonary Gch1 knockout in mice (Gch1fl/fl; Sftpa1-Cre+/− mice) aggravated lung injury following irradiation, whereas Gch1 knock-in mice (Gch1lsl/lsl; Sftpa1-Cre+/− mice) exhibited attenuated radiation-induced pulmonary toxicity. Mechanistically, lactate dehydrogenase (LDHA) mediated ROS generation downstream of the BH4/NO axis, as determined by iodoacetyl tandem mass tag (iodoTMT)-based protein quantification. Notably, S-nitrosylation of LDHA at Cys163 and Cys293 was regulated by BH4 availability and could restrict ROS generation. The loss of S-nitrosylation in LDHA after irradiation increased radiosensitivity. Overall, the results of the present study showed that GCH1-mediated BH4 biosynthesis played a key role in the ROS cascade and radiosensitivity through LDHA S-nitrosylation, identifying novel therapeutic strategies for the treatment of radiation-induced lung injury.

Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial

PurposeTo evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. MethodsIn this phase III, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiotherapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiotherapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiotherapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea; ≥G1 and ≥G2 diarrhea lasting at least 3 days; and damage to the rectal mucosa due to radiotherapy measured by endoscopy. ResultsTwo-hundred-and-eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 140). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs. 14.8 and 4.5 days, respectively; P<0.001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs. 55.7%, P<0.001). Three patients felt intolerable or abdominal pain following rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P=0.061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P<0.001). ConclusionThe results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Targeted Nanoparticles to Mitigate Radiation-Induced Blood-Brain Barrier Disruption and Cognitive Impairment

Background: Damage to neurovascular endothelium contributes to cognitive decline through increased blood-brain barrier (BBB) permeability. In our studies of mice and endothelial cells (ECs) subject to irradiation, we detect increases in mitochondrial reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) damage, and cell-free release of mtDNA. Cell-free mtDNA acts as a damage associated molecular pattern (DAMP), and similarly to bacterial DNA, binds Toll-like receptor 9, triggering a pro-inflammatory and pro-oxidative response. However, these irradiation-induced effects are attenuated with TLR9 inhibition or mtROS scavenging. Our preliminary data implicate TLR9’s critical role in propagating a feedforward mechanism of sustained oxidative endothelial damage and dysfunction following radiation therapy. We hypothesize that specific inhibition of TLR9 in neurovascular ECs during radiation will prevent BBB permeability and cognitive decline. Thus, the purpose of the study is to use a novel nanoparticle (NP)-based tool to examine the sequela of cranial irradiation and provide proof-of-concept for its use as a mitigator. Methods: To target TLR9 in irradiated ECs, poly (lactic-co-glycolic acid)-based NP coated with cyclic Arg-Gly-Asp (cRGD)-peptide were designed and loaded with TLR9 antagonist (aTLR9, ODN-2088, 2.23ug/mg particle). cRGD-peptide is a ligand for integrin αvβ3, which is highly expressed in ECs post-irradiation (IR). C57Bl6 mice were administered NP-ODN-2088 (aTLR9-NP) or empty-NP (3mg injection) and subjected to unilateral cranial Xray IR (dose of 12Gy). 30d post-IR, memory and learning ability were assessed with the Novel Object Recognition (NOR) and Y-maze tests. The functionality of the NPs was assessed in vivo via BBB permeability, neuronal density, mtDNA damage, and serum levels of mtDNA and in vitro via mtROS production levels and inflammatory markers measurement in human brain microvascular endothelial cells (HBMECs) 5 days post-IR (IR dose of 4Gy). Results: In cultured HBMECs, treatment with aTLR9-NP prevented mtROS production 120hours post-IR. This correlated with attenuated inflammatory intermediates (p65, TNFa, IL6, and IL8), as compared to treatment with vehicle. In mice, aTLR9-NP treatment preserved integrity of mtDNA isolated from brain tissue and decreased blood levels of circulating cell-free mtDNA. aTLR9-NP treatment showed protective effects on BBB permeability and neuronal dropout, and these findings corresponded with preserved cognition in both, NOR and Y-maze tests. NP treatment caused no changes in alkaline phosphatase, alanine transaminase, aspartate aminotransferase, or bilirubin levels, indicating no liver injury. Conclusion: Inhibition of TLR9 in ECs was observed to prevent radiation-induced BBB permeability, neuronal dropout, and cognitive decline. Our findings support a pathway through which TLR9 links oxidative endothelial injury to neurological pathology. Currently there are no pharmacological options for treating radiation-induced normal tissue injury and targeting TLR9 poses a promising strategy. American Heart Association 2021CDA 853499. NIH R01 EY 031544-02 Veterans Affairs I01 BX000163-12. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Modeling Radiation-Induced Epithelial Cell Injury in Murine Three-Dimensional Esophageal Organoids.

Esophageal squamous cell carcinoma (ESCC) is a deadly consequence of radiation exposure to the esophagus. ESCC arises from esophageal epithelial cells that undergo malignant transformation and features a perturbed squamous cell differentiation program. Understanding the dose- and radiation quality-dependence of the esophageal epithelium response to radiation may provide insights into the ability of radiation to promote ESCC. We have explored factors that may play a role in esophageal epithelial radiosensitivity and their potential relationship to ESCC risk. We have utilized a murine three-dimensional (3D) organoid model that recapitulates the morphology and functions of the stratified squamous epithelium of the esophagus to study persistent dose- and radiation quality-dependent changes. Interestingly, although high-linear energy transfer (LET) Fe ion exposure induced a more intense and persistent alteration of squamous differentiation and 53BP1 DNA damage foci levels as compared to Cs, the MAPK/SAPK stress pathway signaling showed similar altered levels for most phospho-proteins with both radiation qualities. In addition, the lower dose of high-LET exposure also revealed nearly the same degree of morphological changes, even though only ~36% of the cells were predicted to be hit at the lower 0.1 Gy dose, suggesting that a bystander effect may be induced. Although p38 and ERK/MAPK revealed the highest levels following high-LET exposure, the findings reveal that even a low dose (0.1 Gy) of both radiation qualities can elicit a persistent stress signaling response that may critically impact the differentiation gradient of the esophageal epithelium, providing novel insights into the pathogenesis of radiation-induced esophageal injury and early stage esophageal carcinogenesis.

PANoptosis induced by inflammatory cytokines promotes salivary glands radiation injury.

Salivary glands are frequently damaged in patients undergoing radiotherapy for head and neck cancer. Whether PANoptosis, which is characterized by pyroptosis, apoptosis, and necroptosis, occurs during radiation injury to the salivary glands and its role remain unclear. Radiation-induced injury models of mouse submandibular gland, as well as primary acinar cells and HSG cell lines were established to determine the presence of radiation-induced PANoptosis. Several programmed cell death inhibitors, PFTα, disulfiram, Nec-1 and zVAD, were used to compare the effects of different cell death pathway on radiation injury. The LEGENDplex™ Human Inflammation Panel was used to characterize the inflammatory landscape secreted by salivary gland cells after radiotherapy. Single 15Gy or 8Gy radiotherapy triggered PANoptosis in mouse submandibular gland or salivary gland cells. Compared to the suppression of pyroptosis, apoptosis, or necroptosis alone, the inhibition of PANoptosis is more effective in preventing radiation injury to the salivary glands (p < 0.0001). The levels of multiple inflammatory cytokines were significantly up-regulated in the supernatants of HSG cells within 48 h after IR. Neutralizing inflammatory cytokines are capable of inhibiting salivary glands PANoptosis. Inhibition of PANoptosis induced by inflammatory cytokines can effectively prevent radiation injury of salivary glands.

Assessing radiation-induced carotid artery injury using ultrasound in patients with head and neck cancer

Background and purposeRadiotherapy (RT) can damage neck vessels in patients with head and neck cancer (HNC). This study investigated the early effects of RT on carotid artery, including the internal media thickness (IMT) and carotid plaques of the common carotid artery (CCA). Materials and methodsThis study included 69 patients with HNC who underwent RT at the First Hospital of Jilin University from March 2017 to September 2022, and 69 healthy participants as controls. Color Doppler ultrasound (CDUS) of the carotid artery was used to measure the CCA IMT and plaques. ResultsLeft CCA IMT increased from 0.60 mm (0.60, 0.70) before RT to 0.70 mm (0.60, 1.20) after RT (P < 0.0001). Right CCA IMT changed from 0.60 mm (0.60, 0.71) before RT to 0.60 mm (0.60, 1.10) after RT (P = 0.0002). CCA IMT was 0.60 mm (0.60, 0.70) and 0.80 mm (0.60, 1.20) in the ≤40 Gy and >40 Gy groups (P = 0.0004). The CCA plaques number increased significantly after RT on both the left and right sides (Pleft < 0.0001; Pright <0.0001). The CCA plaques volume increased from 0 mm3 (0, 11.35) and 0 mm3 (0, 8.55) before RT to 8.8 mm3 (0, 21.5) and 5.8 mm3 (0, 16.1) on the left and right sides. Correlation analysis revealed a correlation between CCA IMT and age (r = 0.283, P = 0.001), smoking status (r = 0.179, P = 0.020), and radiation dose (r = 0.188, P = 0.028). ConclusionRT significantly increased CCA IMT, and the growth was related to the radiation dose. The number and volume of the CCA plaques also increased after RT.

18β-glycyrrhetinic acid alleviates radiation-induced skin injury by activating the Nrf2/HO-1 signaling pathway.

Radiation-induced skin injury is a common side effect of radiotherapy, but there are few therapeutic drugs available for prevention or treatment. In this study, we demonstrate that 18β-Glycyrrhetinic acid (18β-GA), a bioactive component derived from Glycyrrhiza glabra, substantially reduces the accumulation of reactive oxygen species (ROS) and inhibits apoptosis in HaCaTcells after ionizing radiation (IR), thereby mitigating radiation-induced skin injury. Mechanistically, 18β-GA promotes the nuclear import of Nrf2, leading to activation of the Nrf2/HO-1 signaling pathway in response to IR. Importantly, Nrf2 silencing increases cell apoptosis and reverse the protective effect of 18β-GA on radiation-induced skin injury. Furthermore, 18β-GA preserves skin tissue structure after irradiation, inhibits inflammatory cell infiltration, and alleviates radiation dermatitis. In conclusion, our results suggest that 18β-GA reduces intracellular ROS production and apoptosis by activating the Nrf2/HO-1 signaling pathway, leading to amelioration of radiation dermatitis.

LPA5-Dependent signaling regulates regeneration of the intestinal epithelium following irradiation.

Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.

Asparagine endopeptidase deficiency mitigates radiation-induced brain injury by suppressing microglia-mediated neuronal senescence

Mounting evidence supports the role of neuroinflammation in radiation-induced brain injury (RIBI), a chronic disease characterized by delayed and progressive neurological impairment. Asparagine endopeptidase (AEP), also known as legumain (LGMN), participates in multiple malignancies and neurodegenerative diseases and may potentially be involved in RIBI. Here, we found AEP expression was substantially elevated in the cortex and hippocampus of wild-type (Lgmn+/+) mice following whole-brain irradiation. Lgmn knockout (Lgmn-/-) alleviated neurological impairment caused by whole-brain irradiation by suppressing neuronal senescence. Bulk RNA and metabolomic sequencing revealed AEP's involvement in the antigen processing and presentation pathway and neuroinflammation. This was further confirmed by co-culturing Lgmn+/+ primary neurons with the conditioned media derived from irradiated Lgmn+/+ or Lgmn-/- primary microglia. Furthermore, esomeprazole inhibited the enzymatic activity of AEP and RIBI. These findings identified AEP as a critical factor of neuroinflammation in RIBI, highlighting the prospect of targeting AEP as a therapeutic approach.

P53 promotes revival stem cells in the regenerating intestine after severe radiation injury

Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. Together, our findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells.

Repetitive transcranial magnetic stimulation ameliorates cognitive deficits in mice with radiation-induced brain injury by attenuating microglial pyroptosis and promoting neurogenesis via BDNF pathway

BackgroundRadiation-induced brain injury (RIBI) is a common and severe complication during radiotherapy for head and neck tumor. Repetitive transcranial magnetic stimulation (rTMS) is a novel and non-invasive method of brain stimulation, which has been applied in various neurological diseases. rTMS has been proved to be effective for treatment of RIBI, while its mechanisms have not been well understood.MethodsRIBI mouse model was established by cranial irradiation, K252a was daily injected intraperitoneally to block BDNF pathway. Immunofluorescence staining, immunohistochemistry and western blotting were performed to examine the microglial pyroptosis and hippocampal neurogenesis. Behavioral tests were used to assess the cognitive function and emotionality of mice. Golgi staining was applied to observe the structure of dendritic spine in hippocampus.ResultsrTMS significantly promoted hippocampal neurogenesis and mitigated neuroinflammation, with ameliorating pyroptosis in microglia, as well as downregulation of the protein expression level of NLRP3 inflammasome and key pyroptosis factor Gasdermin D (GSDMD). BDNF signaling pathway might be involved in it. After blocking BDNF pathway by K252a, a specific BDNF pathway inhibitor, the neuroprotective effect of rTMS was markedly reversed. Evaluated by behavioral tests, the cognitive dysfunction and anxiety-like behavior were found aggravated with the comparison of mice in rTMS intervention group. Moreover, the level of hippocampal neurogenesis was found to be attenuated, the pyroptosis of microglia as well as the levels of GSDMD, NLRP3 inflammasome and IL-1β were upregulated.ConclusionOur study indicated that rTMS notably ameliorated RIBI-induced cognitive disorders, by mitigating pyroptosis in microglia and promoting hippocampal neurogenesis via mediating BDNF pathway.

Naringenin Alleviates Radiation-Induced Intestinal Injury by Inhibiting TRPV6 in Mice.

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. C57BL/6J mice are exposed to a single dose of 13Gy 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. 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.

The non-targeted effect increases the risk of the radiation-induced myocardial injury

The non-targeted effect increases the risk of the radiation-induced myocardial injury

Impact of Radiotherapy on Radiation-Induced Brain Injury in Patients with Nasopharyngeal Carcinoma Using Nano-Magnetic Resonance Imaging

This study investigate the changes of white matter injury induced by radiation after radiotherapy in patients with nasopharyngeal carcinoma (NPC) and its association with cognitive dysfunction using multiple MRI methods. A total of 42 patients with NPC who underwent radiotherapy at xxx Hospital between December 2018 and June 2021 were included. The patients were randomly divided into 4 groups based on the timing of radiotherapy. Superparamagnetic iron oxide nanoparticles were used as MRI contrast agents. DTI and MRS scans were conducted to measure FA, ADC, NAA/Cho, Cho/Cr, and NAA/Cr ratios in the hippocampus of both temporal lobes. A cognitive assessment was performed using the MoCA and MMSE scales. After radiotherapy, patients experienced a decline in cognitive scores, which stabilized after 6 months. White matter changes were observed in the hippocampus, with decreased FA and increased ADC values that gradually returned to normal levels. Cho value increased and NAA value decreased initially but eventually returned to pre-treatment levels. No significant changes occurred in the Cr value. Metabolite ratios decreased within 3 months post-radiotherapy but gradually increased thereafter, remaining lower than pre-treatment levels at 6 months. Higher radiation doses did not significantly affect FA and ADC values but decreased white matter metabolite ratios. In conclusion, we reveal that the dosage and duration of radiotherapy can influence the degree of brain injury in patients with NPC and highlights the cognitive decline, white matter changes, and changes in metabolite ratios after radiotherapy for NPC, providing insights into the effects of radiation on brain structure and function.

Electrophysiological Changes on Laryngeal Motor Neuropathways Cause Voice Disorders for Postradiotherapy Patients with Nasopharyngeal Carcinoma

ObjectiveThis study explored electrophysiological changes in the laryngeal motor neuropathway and determined whether lesions in the laryngeal motor cortex (LMC) and its descending tract contribute to voice deterioration and peripheral nerve palsy in patients with nasopharyngeal carcinoma (NPC) post-radiotherapy (RT). Study DesignsProspective cohort study MethodsTwenty-two patients with NPC at 2 to 4 years post-RT (8 female and 14 male), 22 patients with NPC at 8 to 10 years post-RT (8 female and 14 male), and 22 healthy individuals (9 female and 13 male) were selected to test their magnetic evoked potentials (MEP), motor nerve conduction (MNC), and voice quality using transcranial magnetic stimulation (TMS), laryngeal electromyography (LEMG), and the XION DiVAS acoustic analysis software. Three groups were matched according to approximate age. Multiple comparisons were performed among the three groups. ResultsThe voice quality of post-RT patients with NPC deteriorated compared to that of healthy individuals. Bilateral LMC and their corticonuclear tracts to the bilateral ambiguous nuclei of post-RT patients with NPC were impaired according to multi-group comparisons of MEP amplitudes, latencies, and resting motor thresholds (RMT). The vagus and recurrent laryngeal nerves (RLN) of post-RT patients with NPC were impaired according to multi-group comparisons of the amplitude and latencies of the compound muscle action potential (CMAP) and latencies of f-waves. ConclusionsThe voice quality of patients with NPC deteriorated after RT. The pathogenesis of post-RT voice deterioration may involve radiation-induced injuries to the vagus, RLN, and bilateral LMC. Furthermore, radiation-induced injuries to the bilateral LMC may contribute to vagus and RLN palsies. These findings support the use of transcranial approaches to treating voice disorders and peripheral nerve palsies in post-RT patients with NPC.

IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury.

Radiotherapy for treating breast cancer is associated with cardiac damage. This study aimed to investigate the role of the interleukin (IL)-33/soluble receptor ST2 (sST2) axis in radiation-induced cardiac injury. Expressions of IL-33 and sST2 were detected in breast cancer patients following radiotherapy, radiation-induced cardiac damaged mice model, and cardiomyocytes using quantitative real-time PCR (qRT-PCR) and immunohistochemical assay. Cardiac injury was evaluated through an ultrasound imaging system and hematoxylin & eosin staining. The transcriptional factor was assessed using dual-luciferase reporter assay and chromatin immunoprecipitation. The results indicated that IL-33 and sST2 were highly expressed in breast cancer patients, which further elevated post-6 months but reduced after 12 months of radiotherapy. Radiation induces cardiac dysfunction and elevated IL-33 and sST2 levels in a time-dependent manner. However, silencing of IL-33 decreased sST2 expression to alleviate radiation-induced cardiac dysfunction. The IL-33 could be transcriptional activated by TCF7L2 by binding to IL33 promoter sites, which mutation alleviated cardiomyocyte injury caused by radiation. Additionally, radiation treatment resulted in higher levels of TCF7L2, IL-33, and sST2 in cardiomyocytes, and TCF7L2 knockdown reduced IL-33 and sST2 expression. In conclusion, TCF7L2 transcriptional-activated IL-33 mediated sST2 to regulate radiation-induced cardiac damage, providing novel insights into radiotherapy-induced cardiac damage.

Oral Curcumin-Thioketal-Inulin Conjugate Micelles against Radiation-Induced Enteritis.

Radiation-induced enteritis is an unavoidable complication associated with pelvic tumor radiotherapy, significantly influencing the prognosis of cancer patients. The limited availability of commercial gastrointestinal radioprotectors in clinical settings poses a substantial challenge in preventing radiation enteritis. Despite the inherent radioprotective characteristics of Cur in vitro, its poor solubility in water, instability, and low bioavailability lead to inferior therapeutic effects in vivo. Herein, we developed novel ROS-responsive micelles (CTI) from inulin and curcumin, aimed at mitigating radiation enteritis. CTI micelles had excellent solubility and stability. Importantly, CTI improved the cytotoxicity and bioavailability of curcumin, thereby showing enhanced effectiveness in neutralizing ROS induced by radiation, safeguarding against DNA damage, and reducing radiation-induced cellular mortality. Moreover, in a radiation enteritis mice model, CTI not only alleviated severe radiation-induced intestinal injury but also improved redox-related indicators and reduced inflammatory cytokine expression. Furthermore, CTI effectively increased gut microbiota abundance and maintained gut homeostasis. In conclusion, CTI could be a promising candidate for the clinical management of radiation enteritis. Our study provides a new perspective for radioprotection using natural antioxidants.

Acute Impacts of Ionizing Radiation Exposure on the Gastrointestinal Tract and Gut Microbiome in Mice.

Radiation therapy for abdominopelvic malignancies often results in damage to the gastrointestinal tract (GIT) and permanent changes in bowel function. An overlooked component of the pathophysiology of radiation-induced bowel injury is the role of the gut microbiome. The goal of this research was to identify the impacts of acute radiation exposure on the GIT and gut microbiome. C57BL/6 mice exposed to whole-body X-rays (0.1-3 Gy) were assessed for histological and microbiome changes 48 h post-radiation exposure. Within the ileum, a dose of 3 Gy significantly decreased crypt depth as well as the number of goblet cells, but increased overall goblet cell size. Overall, radiation altered the microbial distribution within each of the main phyla in a dose- and tissue-dependent manner. Within the Firmicutes phylum, high dose irradiation resulted in significant alterations in bacteria from the class Bacilli within the small bowels, and from the class Clostridia in the large bowels. The 3 Gy radiation also significantly increased the abundance of bacterial families from the Bacteroidetes phylum in the colon and feces. Overall, we identified various alterations in microbiome composition following acute radiation exposure, which could potentially lead to novel biomarkers for tracking patient toxicities or could be used as targets for mitigation strategies against radiation damage.

Radiation Dermatitis: Radiation-Induced Effects on the Structural and Immunological Barrier Function of the Epidermis.

An important hallmark of radiation dermatitis is the impairment of the mitotic ability of the stem/progenitor cells in the basal cell layers due to radiation-induced DNA damage, leading to suppressed cell renewal in the epidermis. However, this mechanism alone does not adequately explain the complex pathogenesis of radiation-induced skin injury. In this review, we summarize the latest findings on the complex pathogenesis of radiation dermatitis and correlate these with the clinical features of radiation-induced skin reactions. The current studies show that skin exposure to ionizing radiation induces cellular senescence in the epidermal keratinocytes. As part of their epithelial stress response, these senescent keratinocytes secrete pro-inflammatory mediators, thereby triggering skin inflammation. Keratinocyte-derived cytokines and chemokines modulate intercellular communication with the immune cells, activating skin-resident and recruiting skin-infiltrating immune cells within the epidermis and dermis, thereby orchestrating the inflammatory response to radiation-induced tissue damage. The increased expression of specific chemoattractant chemokines leads to increased recruitment of neutrophils into the irradiated skin, where they release cytotoxic granules that are responsible for the exacerbation of an inflammatory state. Moreover, the importance of IL-17-expressing γδ-T cells to the radiation-induced hyperproliferation of keratinocytes was demonstrated, leading to reactive hyperplasia of the epidermis. Radiation-induced, reactive hyperproliferation of the keratinocytes disturbs the fine-tuned keratinization and cornification processes, leading to structural dysfunction of the epidermal barrier. In summary, in response to ionizing radiation, epidermal keratinocytes have important structural and immunoregulatory barrier functions in the skin, coordinating interacting immune responses to eliminate radiation-induced damage and to initiate the healing process.

The effect of myeloablative radiation on urinary bladder mast cells

Radiation-induced cystitis is an inflammatory condition affecting the urinary bladder, which can develop as a side effect of abdominopelvic radiotherapy, specifically external-beam radiation therapy or myeloablative radiotherapy. A possible involvement of mast cells in the pathophysiology of radiation-induced cystitis has been indicated in cases of external-beam radiation therapy; however, there is no evidence that these findings apply to the myeloablative aetiology. As such, this study investigated potential changes to urinary bladder mast cell prevalence when exposed to myeloablative radiation. Lethally irradiated C57BL/6J mice that received donor rescue bone marrow cells exhibited an increased mast cell frequency amongst host leukocytes 1 week following irradiation. By 4 weeks, no significant difference in either frequency or cell density was observed. However mast cell diameter was smaller, and a significant increase in mast cell number in the adventitia was observed. This study highlights that mast cells constitute a significant portion of the remaining host leukocyte population following radiation exposure, with changes to mast cell distribution and decreased cell diameter four weeks following radiation-induced injury.