Radioprotective efficacy of Astilbin in mitigating radiation-induced lung injury through inhibition of p53 acetylation.

Radiation-induced lung injury (RILI) is a common side effect in thoracic tumor patients undergoing radiotherapy. At present, there is no ideal radio-protective agent which is widely used in RILI treatment. Astilbin (AST), a bioactive flavonoid, exhibits various biological effects, including anti-inflammatory, antioxidant, and anti-fibrotic activities, which partly result from reducing oxidative stress and inflammation in various pathogenic conditions. However, the protective efficacy of AST to ameliorate RILI has not been reported. In this study, we employed network pharmacology, RNA sequencing, and experimental evaluation to reveal the effects and pharmacological mechanism of AST to treat RILI in vivo and in vitro. We observed that AST reduced radiation-induced apoptosis, DNA damage, inflammatory reactions, and the reactive oxygen species (ROS) level in human normal lung epithelial cells BEAS-2B. Further study showed that AST treatment significantly ameliorated RILI by reducing the radiation-induced pathology changes and inflammatory reaction of lung tissue in C57BL/6J mice. Mechanistically, the expression of epithelial-mesenchymal transition (EMT) markers and radiation-triggered acetylation of the p53 protein were alleviated by AST treatment. Furthermore, AST alleviated the acetylation of p53 after intervention of Trichostatin A (TSA). Our data indicate that AST can alleviate RILI by inhibiting inflammatory reactions and the EMT process through decreasing the expression of p53 acetylation. In conclusion, our study suggests that AST has great potential to be a new protective and therapeutic compound for RILI.

Potential Functions of the tRNA-Derived Fragment tRF-Gly-GCC Associated With Oxidative Stress in Radiation-Induced Lung Injury.

Objective: Transfer RNA-derived small RNAs (tsRNAs) are a novel type of non-coding RNA with various regulatory functions. They are associated with oxidative stress in various diseases, but their potential functions in radiation-induced lung injury (RILI) remain uncertain. Methods: To explore the role of tsRNAs in RILI, we used X-rays to irradiate human bronchial epithelial cells and examined the expression profile of altered tsRNAs by RNA sequencing and bioinformatics analysis. Sequencing results were verified by qRT-PCR. tsRNA functions were explored using several methods, including CCK-8, reactive oxygen species (ROS) assays, cell transfection, and western blotting. Results: Eighty-six differentially expressed tRNA-derived fragments (tRFs) were identified: 64 were upregulated, and 22 were downregulated. Among them, the regulation of tRF-Gly-GCC, associated with oxidative stress, may be mediated by the inhibition of cell proliferation, promotion of ROS production, and apoptosis in the occurrence and development of RILI. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the underlying molecular mechanism may involve the PI3K/AKT and the FOXO1 signaling pathways. Conclusion: Our findings provide new insights into the molecular mechanisms underpinning RILI, advancing the clinical prevention and treatment of this disease.

Construction of MicroRNA-mRNA Regulatory Network in the Molecular Mechanisms of Bleomycin-Induced Pulmonary Fibrosis.

Bleomycin is a common antitumor agent used to treat many different types of malignancies; however, its main side effect is pulmonary fibrosis. The mechanism of bleomycin-induced pulmonary fibrosis (BIPF) has not been fully elucidated. Therefore, to further explore the molecular mechanisms of BIPF, we screened for microRNA (miRNA) and mRNA expression obtained from BIPF samples from the Gene Expression Omnibus database. Subsequently, we identified the differentially expressed miRNAs and genes that overlapped with the differentially expressed miRNAs target genes, predicted by using the miRWalk database selected as a candidate. The candidate genes were visualized based on Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses. A protein-protein interaction network was constructed. Hub differentially expressed genes were selected and corresponding miRNAs to construct a miRNA-mRNA regulation network. Then, we chose three key miRNAs to study their regulatory relationship in bleomycin-induced pulmonary fibrosis. Finally, mouse lung epithelial cells TC-1 and MLE-12 were treated with bleomycin with qPCR to validate the results of three important hub genes and all key miRNAs. And dual-luciferase report experiment was carried out to verify the interaction of mmu-miR-1946a and serpina3n. The results revealed that the imbalance of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a pivotal role in the occurrence and development of BIPF. In addition, Serpina3n and mmu-miR-1946a were proved interaction and may be involved in the regulation of the balance between MMP-9 and TIMP-1. The experimental results also verify the analysis. Our findings provide new insights into the key mediators and pathways related to the molecular mechanisms of BIPF.

Predicting Nomogram for Severe Oral Mucositis in Patients with Nasopharyngeal Carcinoma during Intensity-Modulated Radiation Therapy: A Retrospective Cohort Study.

BACKGROUND: Oral mucositis is an acute adverse reaction with high incidence during radiotherapy. Severe oral mucositis can seriously affect patients' quality of life and compliance with radiotherapy. The aim of this study was to identify the risk factors for severe oral mucositis and to develop a nomogram for predicting severe oral mucositis in patients with nasopharyngeal carcinoma. METHODS: One hundred and ninety patients with nasopharyngeal carcinoma were retrospectively screened in this study. Least absolute shrinkage and selection operator regression and multivariate logistic regression analyses were performed to identify the best predictors of severe oral mucositis. A nomogram was constructed based on the factors. Finally, the discriminative ability of the nomogram was evaluated. RESULTS: Four independent factors predicting severe oral mucositis were identified: age, N stage, the cycle of induction chemotherapy, and dose-volumetric parameter V40 (%) of oral cavity. The area under the receiver of operating characteristic curve of the nomogram was 0.759 (95% confidence interval: 0.691-0.827). CONCLUSIONS: A predictive nomogram for severe oral mucositis was established and validated in this study. The nomogram provides a reliable and practical model for clinically predicting the probability of severe oral mucositis in patients with nasopharyngeal carcinoma before intensity-modulated radiation therapy.

Prognostic Value of CT Imaging-Based Tumor Volume in Patients With Non-Surgical Esophageal Squamous Cell Carcinoma.

BACKGROUND: The American Joint Committee on Cancer-Tumor (AJCC-T) staging system for esophageal carcinoma patients, which is based on the depth of tumor invasion, is not applicable in some cases. This study aims to assess the prognostic value of CT imaging-based tumor volume and its usefulness for T staging in patients with non-surgical esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed the records of 158 ESCC patients undergoing definitive (chemo) radiotherapy from two hospitals. Tumor volume based on the CT imaging was calculated using the formula: V = πabc / 6. Three cutoff points for tumor volume were obtained with the X-tile software. Overall survival (OS) was analyzed using the Kaplan-Meier method. The -2 log-likelihood ratio and Akaike Information Criterion (AIC) value were evaluated to compare the AJCC-T staging system with the proposed T staging method. RESULTS: The median tumor volume was 19.8 cm³ (range from 1.0 to 319.5 cm³). The three optimal cutoff points of tumor volume were 12.7, 22.8, and 51.9 cm³, and the patients were divided into four groups named as proposed T1-T4 stages. The 3-year OS rates in patients with proposed T1 to T4 stages were 67.9%, 30.6%, 21.3%, and 5.3%, respectively. The -2 log-likelihood ratios of the AJCC-T stage and proposed T stage were 1,068.060 and 1,047.418, respectively. The difference in the AIC value between the two T staging systems was 18.642. CONCLUSION: CT imaging-based tumor volume was superior to the depth of tumor invasion for T staging in predicting the prognosis of non-surgical ESCC patient.