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BackgroundAn increasing number of studies have recently reported that microRNAs packaged in exosomes contribute to multiple biological processes such as cancer progression; however, little is known about their role in the development of radiation-induced bystander effects.MethodsThe exosomes were isolated from the culture medium of BEP2D cells with or without γ-ray irradiation by ultracentrifugation. To monitor DNA damage and repair efficiency, the DNA double-strand break biomarker 53BP1 foci, comet, micronuclei, expression of DNA repair genes and NHEJ repair activity were detected. The miR-1246 targeting sequence of the DNA ligase 4 (LIG4) mRNA 3′UTR was assessed by luciferase reporter vectors.ResultsmiR-1246 was increased in exosomes secreted from 2 Gy-irradiated BEP2D cells and inhibited the proliferation of nonirradiated cells. The miR-1246 mimic, exosomes from irradiated cells, and radiation-conditioned cell culture medium increased the yields of 53BP1 foci, comet tail and micronuclei in nonirradiated cells, and decreased NHEJ efficiency. miR-1246 downregulated LIG4 expression by directly targeting its 3′UTR.ConclusionsOur findings demonstrate that miR-1246 packaged in exosomes could act as a transfer messenger and contribute to DNA damage by directly repressing the LIG4 gene. Exosomal miR-1246 may be a critical predictor of and player in radiation-induced bystander DNA damage.

End resection of DNA double-strand breaks (DSBs) to form 3′ single-strand DNA (ssDNA) is critical to initiate the homologous recombination (HR) pathway of DSB repair. HR pathway is strictly limited in the G1-phase cells because of lack of homologous DNA as the templates. Exonuclease 1 (EXO1) is the key molecule responsible for 3′ ssDNA formation of DSB end resection. We revealed that EXO1 is inactivated in G1-phase cells via ubiquitination-mediated degradation, resulting from an elevated expression level of RING-box protein 1 (RBX1) in G1 phase. The increased RBX1 significantly prompted the neddylation of Cullin1 and contributed to the G1 phase-specific degradation of EXO1. Knockdown of RBX1 remarkedly attenuated the degradation of EXO1 and increased the end resection and HR activity in γ-irradiated G1-phase cells, as demonstrated by the increased formation of RPA32, BrdU, and RAD51 foci. And EXO1 depletion mitigated DNA repair defects due to RBX1 reduction. Moreover, increased autophosphorylation of DNA-PKcs at S2056 was found to be responsible for the higher expression level of the RBX1 in the G1 phase. Inactivation of DNA-PKcs decreased RBX1 expression, and simultaneously increased EXO1 expression and DSB end resection in G1-phase cells. This study demonstrates a new mechanism for restraining the HR pathway of DNA DSB repair in G1 phase via RBX1-prompted inactivation of EXO1.

Radiation-induced bystander effect (RIBE) describes a set of biological effects in non-targeted cells that receive bystander signals from the irradiated cells. RIBE brings potential hazards to adjacent normal tissues in radiotherapy, and imparts a higher risk than previously thought. Excessive release of some substances from irradiated cells into extracellular microenvironment has a deleterious effect. For example, cytokines and reactive oxygen species have been confirmed to be involved in RIBE process via extracellular medium or gap junctions. However, RIBE-mediating signals and intercellular communication pathways are incompletely characterized. Here, we first identified a set of differentially expressed miRNAs in the exosomes collected from 2 Gy irradiated human bronchial epithelial BEP2D cells, from which miR-7-5p was found to induce autophagy in recipient cells. This exosome-mediated autophagy was significantly attenuated by miR-7-5p inhibitor. Moreover, our data demonstrated that autophagy induced by exosomal miR-7-5p was associated with EGFR/Akt/mTOR signaling pathway. Together, our results support the involvement of secretive exosomes in propagation of RIBE signals to bystander cells. The exosomes-containing miR-7-5p is a crucial mediator of bystander autophagy.

Metal-semiconductor heterostructures integrate multiply functionalities beyond those of their individual counterparts. Great efforts have been devoted to synthesize heterostructures with controlled morphologies for the applications ranging from photocatalysis to photonic nanodevices. Beyond the morphologies, the interface between two counterparts also significantly influences the performance of the heterostructures. Here, we synthesize Au/CdSe Janus nanostructures consisting of two half spheres of Au and CdSe separated by a flat and high-quality interface. Au/CdSe with other morphologies could also be prepared by adjusting the overgrowth conditions. The photocatalytic hydrogen generation of the Au/CdSe Janus nanospheres is measured to be 3.9 times higher than that of the controlled samples with CdSe half-shells overgrown on the Au nanospheres. The highly efficient charge transfer across the interface between Au and CdSe contributes to the improved photocatalytic performance. Our studies may find the applications in the design of heterostructures with highly efficient photocatalytic activity.

In higher plants, DREB1/CBF-type transcription factors play an important role in tolerance to low temperatures, drought, and high-salt stress. These transcription factors bind to CRT/DRE elements in promoter regions of target genes, regulating their expression. In this study, we cloned and characterized a novel gene encoding a DREB1 transcription factor from dwarf apple, Malus baccata (GenBank accession number: EF582842). Expression of MbDREB1 was induced by cold, drought, and salt stress, and also in response to exogenous ABA. Subcellular localization analyses revealed that MbDREB1 localizes in the nucleus. A yeast activity assay demonstrated that the MbDREB1 gene encodes a transcription activator, which specifically binds to DRE/CRT elements. Compared with wild-type plants, transgenic Arabidopsis overexpressing MbDREB1 showed increased tolerance to low temperature, drought, and salt stresses. Analysis of the MbDREB1 promoter revealed an ABA-responsive element (ABRE), an inducer of CBF expression 1 (ICE1)-like binding site, two MYB recognition sites, and three stress-inducible GT-1 boxes. GUS activities driven by the MbDREB1 promoter in transgenic Arabidopsis increased in response to ABA, cold temperature, drought, and salt treatments. Interestingly, the expression of both ABA-independent and ABA-dependent stress-induced genes (COR15a and rd29B, respectively) was activated under normal growth conditions in Arabidopsis overexpressing MbDREB1. These results suggest that MbDREB1 functions as a transcription factor and increases plant tolerance to low temperature, drought, and salt stress via both ABA-dependent and ABA-independent pathways.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The central pathogenesis is an explosive cytokine storm characterized by a significant increase in proinflammatory cytokines, including IL-1β, IL-6, IL-18, IFN-γ, and TNF-α. Meanwhile, negative regulatory factors, such as IL-10 and TGF-β, are also related to the production of HLH. Exploring the specific mechanism of cytokine storms could provide ideas regarding targeted therapy, which could be helpful for early treatment to reduce the mortality of HLH. Although some research has focused on the advantages of targeted therapies, there is still a lack of a comprehensive discourse. This article attempts to summarize the mechanisms of action of various cytokines and provide a therapeutic overview of the current targeted therapies for HLH.

We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin-resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain.

Background Multisystem childhood Langerhans cell histiocytosis (LCH) patients, especially those with risk organ (RO) involved, had not been satisfactorily treated under the international traditional schemes as high incidences of reactivation with late sequelae were largely reported. Over years, we have observed that LCH patients with varied clinical symptoms responded differently to different drugs, suggesting the current grouping strategies based only on the number of organs involved might be inadequate. LCH has been defined as an inflammatory myeloid tumor, thus this study has innovatively divided LCH pediatric patients into inflammatory or malignant symptoms group, and given different intensity treatment regimens to different groups. Aim This clinical study aimed to explore a more appropriate patient grouping system according to the LCH symptom presentations and examine the clinical outcomes of treatment strategies in different groups. Methods According to the clinical manifestations, 37 cases of children were divided into Group A (only inflammatory symptoms) and Group B (malignant symptoms with or without inflammatory symptoms). Patients in Group A and B were initially treated with vindesine (VDS) and methylprednisolone (PSL), and VDS, PSL, pirarubicin (THP) and cyclophosphamide (CTX), respectively. Treatment responses were evaluated six weeks after the induction therapy in all patients, and the criteria were disease status and clinical scores of symptoms. Results Pre- and post-treatment scores were 1.22 ± 0.547 and 0.00 ± 0.00 in Group A, and 14.79 ± 1.686 and 1.00 ± 1.563 in Group B, respectively. All patients had subsequentlly received maintenance therapy without progressive disease. The 4-year overall survival (OS) rate was 100% in both groups and the 4-year event-free survival (EFS) was 94.4% in Group A and 89.5% in Group B, respectively. There were no obvious adverse events (AE) in Group A, whereas the main AE in Group B were alopecia and non-lethal hematological toxicity. Conclusion Stratification according to patients’ clinical symptoms, with low-intensity treatment for inflammatory symptoms (mild manifestations) and intensive treatment with multiple drugs for malignant symptoms (severe manifestations), is a positive exploration that simplifies stratification method, achieves good long-term remission of the disease, and obtains a higher survival rate and quality of life, which seemed to be more appropriate for LCH patients.

Abstract Medulloblastomas (MBs) are currently divided into 4 molecular subgroups: WNT, SHH, Group 3, and Group 4. Among them, Group 3 MB has the worst prognosis, and 40%–50% of Group 3 cases are already metastatic at the time of diagnosis. Emerging evidence indicates that exosomes drive tumor invasion, but very little is known about exosomes in MBs. In this study, we initially discovered that exosomes isolated from Group 3 MB cell lines altered in vitro behaviors of a less invasive SHH MB cell line and yielded a much more aggressive phenotype. RNA-sequencing analysis revealed 7 exosomal miRNAs with markedly different expression levels between the SHH and Group 3 MB cell lines. They were all predicted to be related to the Ras/MAPK pathway according to the Kyoto Encyclopedia of Genes and Genomes data analysis. Increased expression of miR-181a-5p, miR-125b-5p, and let-7b-5p was further confirmed in Group 3 MB cells with real-time PCR and was shown to increase in vitro invasion and migratory abilities of tumor cells through the activation of ERK in Ras/MAPK pathway. Collectively, our findings suggest that exosomal miRNAs have a critical role in MB progression in vitro and might serve as diagnostic biomarkers and therapeutic targets.

Objectives. As an epigenetic player, long noncoding RNAs (LncRNAs) have been reported to participate in multiple biological processes; however, their biological functions in silica-induced pulmonary fibrosis (SIPF) occurrence and development remain incompletely understood. Methods. Five case/control pairs were used to perform integrated transcriptomes analysis of lncRNA and mRNA. Prediction of lncRNA and mRNA functions was aided by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Additionally, we constructed a coexpression network of lncRNAs and mRNAs to identify targets of regulation. Results. In total, 1069 differentially expressed mRNAs and 366 lncRNAs were identified with the changes more than 2 times (p<0.05), of which 351 downregulated mRNA and 31 downregulated lncRNA were <0.5 (p<0.05) and those of 718 upregulated mRNAs and 335 upregulated lncRNA were >2 (p<0.05). The levels of 10 lncRNAs were measured via qRT-PCR; the results were consistent with the microarray data. Four genes named of FEM1B, TRIM39, TRIM32, and KLHL15 were enriched significantly with ubiquitination and immune response. Cytokine-cytokine receptor interaction was the most significantly enriched KEGG pathway in both mRNAs and lncRNAs. The coexpression network revealed that a single lncRNA can interact with multiple mRNAs, and vice versa. Conclusions. lncRNA and mRNA expression were aberrant in patients with SIPF compared to controls, indicating that differentially expressed lncRNAs and mRNAs may play critical roles in SIPF development. Our study affords new insights into the molecular mechanisms of SIPF and identifies potential biomarkers and targets for SIPF diagnosis and treatment.