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As a common serious complication of thoracic radiotherapy, radiation-induced pulmonary fibrosis (RIPF) severely limits radiation therapy approaches. Epithelial–mesenchymal transition (EMT) is a direct contributor to the fibroblast pool during fibrogenesis, and prevention of EMT is considered an effective strategy to inhibit tissue fibrosis. Our previous study revealed that TANK-binding kinase 1 (TBK1) regulates EMT in lung cancer cells. In the present study, we aimed to investigate the therapeutic potential of targeting TBK1 to prevent RIPF and EMT progression. We found radiation-induced EMT and pulmonary fibrosis in normal alveolar epithelial cells and lung tissues. TBK1 knockdown or inhibition significantly reversed EMT in vivo and in vitro and attenuated pulmonary fibrosis and collagen deposition. Moreover, we observed that TBK1 was elevated in a time- and dose-dependent manner by radiation. Meanwhile, radiation also induced time- and dose-dependent activation of AKT and ERK, each of whose inhibitors suppressed radiation-induced EMT. Intriguingly, silencing of TBK1 with shRNA also blocked the radiation-induced activation of AKT and ERK signaling. The ERK inhibitor did not obviously affect the expression of TBK1 or phosphorylated AKT, while AKT inhibition suppressed activation of ERK without changing the expression of TBK1. Finally, we found that a TBK1 inhibitor inhibited inflammatory cytokine expression in a RIPF model and Amlexanox protected normal cells and mice from ionizing radiation. In conclusion, our results indicate that the TBK1–AKT–ERK signaling pathway regulates radiation-induced EMT in normal alveolar epithelial cells, suggesting that TBK1 is a potential target for pulmonary fibrosis prevention during cancer radiotherapy. Lung cancer: Suppressing fibrosis during radiotherapy The risk of scarred tissues and respiratory distress during radiation treatment of lung cancer could be reduced by targeting an enzyme that alters healthy cells. Lung cancer radiotherapy often causes pulmonary fibrosis, excessive growth of fibrous tissues in the lungs, involving the transition of normal epithelial cells into an invasive form of multipotent stem cells. The development of pulmonary fibrosis limits the clinical application of radiotherapy. Hongjin Qu and co-workers at the Second Military University in Shanghai, China, previously demonstrated that the TANK-binding kinase 1 (TBK1) enzyme regulates this transition. Now, the team have shown that levels of TBK1 itself increased during radiation treatment, together with two proteins that would normally suppress alterations in healthy cells. Inhibiting TBK1, both in cell cultures and mouse models, reversed the cell transitions and prevented pulmonary fibrosis.

Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

Identifying new targets for overcoming radioresistance is crucial for improving the efficacy of lung cancer radiotherapy, given that tumor cell resistance is a leading cause of treatment failure. Recent research has spotlighted the significance of Musashi2 (MSI2) in cancer biology. In this study, we first demonstrated that MSI2 plays a key function in regulating the radiosensitivity of lung cancer. The expression of MSI2 is negatively correlated with overall survival in cancer patients, and the knockdown of MSI2 inhibits tumorigenesis and increases radiosensitivity of lung cancer cells. Cellular radiosensitivity, which is closely linked to DNA damage, is influenced by MSI2 interaction with ataxia telangiectasia mutated and Rad3‐related kinase (ATR) and checkpoint kinase 1 (CHK1) post‐irradiation; moreover, knockdown of MSI2 inhibits the ATR‐mediated DNA damage response pathway. RNA‐binding motif protein 17 (RBM17), which is implicated in DNA damage repair, exhibits increased interaction with MSI2 post‐irradiation. We found that knockdown of RBM17 disrupted the interaction between MSI2 and ATR post‐irradiation and increased the radiosensitivity of lung cancer cells. Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy. Scientific hypothesis: After radiation exposure, lung cancer cells undergo DNA damage, triggering RBM17 to sense signals. MSI2, assisted by RBM17, translocates into the nucleus, where it interacts with ATR and CHK1, activating downstream pathways. This activation enhances the DNA damage repair. Upon repair completion, MSI2 and RBM17 dissociate from ATR and exit the nucleus, returning to the initial state.

The small intestine is one of the most sensitive organs to irradiation injury, and the development of high effective radioprotectants especially with low toxicity for intestinal radiation sickness is urgently needed. Monophosphoryl lipid A (MPLA) was found to be radioprotective in our previous study, while its effect against the intestinal radiation injury remained unknown. In the present study, we firstly determined the intestinal apoptosis after irradiation injury according to the TUNEL assay. Subsequently, we adopted the immunofluorescence technique to assess the expression levels of different biomarkers including Ki67, γ-H2AX, and defensin 1 in vivo. Additionally, the inflammatory cytokines were detected by RT-PCR. Our data indicated that MPLA could protect the intestine from ionizing radiation (IR) damage through activating TLR4 signal pathway and regulating the inflammatory cytokines. This research shed new light on the protective effect of the novel TLR4 agonist MPLA against intestine detriment induced by IR.

As natural nanoparticles, exosomes regulate a wide range of biological processes via modulation of its components, including circular RNAs (circRNAs). CircRNAs are a novel class of closed-loop single-stranded RNAs with a wide distribution, and play diverse biological roles. Due to its stability in exosomes, exosomal circRNAs serve as biomarkers, pathogenic regulators and exert therapeutic potentials in some cardiovascular diseases, including atherosclerosis, acute coronary syndrome, ischemia/reperfusion injury, heart failure, and peripheral artery disease. In this review, we detailed the current knowledge on the biogenesis and functions of exosomes, circRNAs, and exosomal circRNAs, as well as their involvement in these cardiovascular diseases, providing novel insights into the diagnosis and treatment of these diseases.

Radiation‐induced lung injury (RILI), divided into early radiation pneumonia (RP) and late radiation‐induced pulmonary fibrosis (RIPF), is a common serious disease after clinical chest radiotherapy or nuclear accident, which seriously threatens the life safety of patients. There has been no effective prevention or treatment strategy till now. Epithelial‐mesenchymal transition (EMT) is a key step in the occurrence and development of RILI. In this study, we demonstrated that emetine dihydrochloride (EDD) alleviated RILI through inhibiting EMT. We found that EDD significantly attenuated EMT‐related markers, reduced Smad3 phosphorylation expression after radiation. Then, for the first time, we observed EDD alleviated lung hyperaemia and reduced collagen deposit induced by irradiation, providing protection against RILI. Finally, it was found that EDD inhibited radiation‐induced EMT in lung tissues. Our study suggested that EDD alleviated RILI through inhibiting EMT by blocking Smad3 signalling pathways. In summary, our results indicated that EDD is a novel potential radioprotector for RILI.

Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase II[alpha] (TOPOII[alpha]) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOII[alpha] interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOII[alpha], inhibition of which provided potential target for overcoming cancer resistance. Keywords: DNA damage repair, Transglutaminase 2 (TG2), DNA double strand breaks (DSBs), Topoisomerase II[alpha] (TOPOII[alpha]), Cancer therapy

Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) is a dose limiting factor in radiotherapy and a great threat for individual nuclear-related military missions. However, there are currently no available strategies to effectively prevent the damage on the intestine induced by IR. In the present study, the protective activity of Heat Killed Salmonella typhimurium (HKST) on intestine against IR was investigated. Through mouse intestinal organoids and whole body irradiation of mice, we found that the pretreatment with HKST significantly preserved the structure of small intestine upon IR exposure and promoted the proliferation of intestinal cells post-IR. Further study revealed that the radioprotective effects of HKST were involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radioprotective effects of HKST. To sum up, our study suggested HKST as a potential radioprotectant used for prevention of IR-induced GI toxicity.

Locked segment-dominated landslides initiate when locked segments are sufficiently damaged to be unlocked. The evolution of such slopes toward instability displays either an exponentially or stepwise accelerated displacement pattern, but the underlying mechanisms of these patterns are elusive. We show that the displacement pattern is governed by mechanical synergy (resistance homogenization) between the ruptured locked segment and the transfixion segment. Using a mechanical model, we demonstrate that rapid and slow resistance homogenizations, which depend mainly on the brittleness of locked segments, cause two unlocking-induced startup mechanisms that lead to loss of slope stability: one occurring at the peak-stress points and the other at the residual-strength points of the locked segments. Accordingly, the evolution toward instability exhibits one of the two abovementioned patterns. External factors, such as rainwater, can deteriorate the strength of geomaterials but hardly alter the inherent mechanical rules that a locked segment adheres to. These findings provide insights into the mechanism of locked segment-dominated landslides and pave the way for reliably predicting their occurrence.