Interferon regulatory factor 1-triggered free ubiquitin protects the intestines against radiation-induced injury via CXCR4/FGF2 signaling.

Radiation-induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation-induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5-9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor-2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation-induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option.

Pronounced Enhancement in Radiosensitization of Esophagus Cancer Cultivated in Docosahexaenoic Acid via the PPAR -γ Activation.

Docosahexaenoic acid (DHA) has been reported to suppress the tumor growth and improve prognosis and has been used to cooperate with many other chemotherapy medicines. Up to now, surveys focused on the Interaction between DHA and radiation are relatively modest. Our study sought to evaluate the radiosensitivity changes caused by DHA on esophageal cancer cells. We selected TE-1 and TE-10 esophagus cancer cells as models and performed routine cell proliferation assay and cloning assay to detect the impact of DHA combined with X-ray. We used cell cycle assay, lipid peroxidation assay, comet assay, and apoptosis assay to unearth the potential causes. We also launched a mouse transplanted tumor experiment to verify the synergetic effect of DHA and irradiation. Finally, a western blot assay was used to find a novel mechanism. As a result, DHA improved TE-1 and TE-10 radiosensitivity in vivo and in vitro. What's more, PPAR-γ expression increased due to the DHA supplement. Inhibiting PPAR-γ could attenuate benefits brought out by DHA somehow. Due to its explicit usage and convenience, DHA would serve as an adjuvant therapy before radiotherapy if the clinical trials indicated positive.

Targeting USP11 may alleviate radiation-induced pulmonary fibrosis by regulating endothelium tight junction.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a major side effect after radiotherapy for thoracic malignancies. However, rare anti-RIPF therapeutics show definitive effects for treating this disease. Ubiquitin-specific peptidase 11 (USP11) has been reported to promote transforming growth factor ß (TGFß) signaling which plays an essential role underlying RIPF. Herein, we explored the role of USP11 on RIPF. MATERIALS AND METHODS: In the present study, USP11-knockout (Usp11-/-) mice were used to explore the effects of USP11 on RIPF. The lung tissue was obtained after receiving 30 Gy X-ray irradiation. The expression of USP11, TGF-ß1, and a-SMA was determined by immunohistochemical and Western Blot, respectively. γ-H2AX foci and TUNEL positive cells were detected by fluorescent technique to assess DNA damage and apoptosis. High-throughput proteomic analysis was applied to further explore the related mechanisms. The transwell co-culture method was used to investigate bystander effects in HELF cells induced by irradiated HMEC-1 cells in vitro. RESULTS: Here we found that radiation activated USP11 in vivo and in vitro. Our results showed that USP11 deficiency effectively decreased serum TGF-ß1 level, suppressed α-SMA expression, and mitigated pulmonary fibrosis. In addition, fewer γ-H2AX foci and decreased apoptotic cells were identified after irradiation in the primary cells isolated from the lungs of Usp11-/- mice. High-throughput proteomics analysis results showed that 22-upregulated and 158-downregulated proteins were identified in the lung tissues of Usp11-/- mice after irradiation. Furthermore, gene set enrichment analysis (GSEA) revealed that USP11 deficiency affects the tight junction signaling pathway. CONCLUSIONS: We verified that USP11 deficiency remarkably reinforced tight junction in the endothelial cells and alleviated TGF-ß1 to inhibit fibrosis of fibroblast cells. The present study preliminarily showed that USP11-knockout mitigated RIPF via reinforcement endothelial barrier function.

Deoxycholic acid-modified microporous SiO2nanofibers mimicking colorectal microenvironment to optimize radiotherapy-chemotherapy combined therapy.

Radiotherapy and chemotherapy remain the main therapeutics for colorectal cancer. However, due to their inevitable side effects on nomal tissues, it is necessary to evaluate the toxicity of radio-/chemotherapy regimens. The newly developedin vitrohigh throughput strategy is promising for these assessments. Nevertheless, the currently monolayer culture condition adopted in the preclinical screening processesin vitrohas been proved not so efficient asin vivosince its poor physiological similarity toin vivomicroenvironment. Herein, we fabricated microporous SiO2nanofiber mats and further bioactivated with deoxycholic acid (DCA) to mimic the chemical signals in the colorectal cancer microenvironment forin vitroregimen assessment of radiotherapy and chemotherapy. The colorectal cancer cells contacted with the DCA-modified SiO2nanofiber (SiO2-DCA NF) mats spatially, and the human intestinal epithelial cell on SiO2-DCA NF mats exhibited better x-ray and cisplatin tolerance. The distinguishable irradiation and drug tolerance of cells on SiO2-DCA NF mats indicated that the actual microenvironment of intestine might instruct colorectal cancer differently compared with the common biological experiments. The presented DCA-modified microporous SiO2nanofibrous mats endowing a better mimicry of colorectal micro-environment, would provide a promising platform forin vitroassessment of radio-/chemotherapy regimens.