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Background Radiation therapy used to treat pelvic and abdominal tumors can cause acute or chronic radiation enteropathy. Chronic radiation intestinal fibrosis is one of the most common causes of gastrointestinal complaints. Here, we aimed to clarify that the supplement of dietary fiber inulin can alleviate chronic radiation-induced intestinal fibrosis by altering the gut microbiota, and to elucidate the mechanism. Results Inulin supplements have been shown to elevate the abundances of bacterial that produce short-chain fatty acids (SCFAs) and increased fecal concentrations of microbially derived SCFAs. In validation experiment, transplantation of inulin-derived gut microbiota and metabolite alleviated colonic fibrosis in a mouse model of chronic radiation enteropathy. Treatment with inulin-derived gut microbiota metabolites significantly reduced the expression of fibrosis-related genes and collagen synthesis-related genes in the mouse embryonic fibroblast cell line NIH/3T3. In NIH/3T3 cell lines, the use of inulin-derived metabolites also inhibited the expression of genes related to the extracellular matrix synthesis pathway. Conclusions These evidences highlight that inulin might be employed as a safe and effective supplement to fight against chronic radiation intestinal fibrosis. Our finding also provides a novel insight into targeting changes in gut microbiota to treat radiation enteropathy.

Both immunotherapy checkpoint blocking and radiotherapy used alone in solid tumors show limited anticancer effect, due to the insufficient T cells infiltration and rarely elicited systemic immune responses. Methods: AGuIX has recently been developed for magnetic resonance imaging-guided radiotherapy and proven to act as an efficient radiosensitizer. In order to further improve the efficiency of tumor treatment, a unique synergistic strategy based on Gadolinium-based nanoparticles-AGuIX mediated radiotherapy and immunotherapy checkpoint blocking was developed for B16 tumor therapy in the present study. Clone formation, cell apoptosis and immunofluorescence were performed to detect the radiosensitization effect of AGuIX nanoparticles. The therapeutic effect was validated in both abscopal and metastasis tumor models, and analyzed the synergistic mechanism in vivo. Results: AGuIX as a radiosensitizer exacerbated radiation-induced DNA damage, cell cycle arrest and apoptosis on B16 cells. More importantly, it could efficiently induce the immunogenic cell death (ICD) of irradiated B16 tumor cells, and consequently triggered the maturation of dendritic cells (DCs) and activated systemic T-cell responses. Combining AGuIX-mediated radiotherapy with programmed cell death protein 1 (PD1) blocking demonstrated excellent synergistic therapeutic effects in both abscopal and metastasis tumor models by a significant increase in the infiltration of effector CD8+ T cells and effectively alleviating the immunosuppressive microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in tumors.Conclusion: Our findings indicate that this combination therapy provided a new and powerful immunotherapy model to achieve durable anti-tumor responses, which is likely to be a promising comprehensive treatment strategy for cancer treatment.

OBJECTIVE We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase (PARP) inhibitor, olaparib, and the Bloom syndrome protein (BLM) helicase inhibitor, ML216, in non-small cell lung cancer (NSCLC) cells. METHODS Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays. Mechanistically, the effects of ML216, olaparib, and radiation on cell and tumor proliferation, DNA damage, cell cycle, apoptosis, homologous recombination (HR) repair, and non-homologous end joining (NHEJ) repair activity were determined. RESULTS Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells, which was seen as decreased surviving fractions and Rad51 foci, increased total DNA damage, and γH2AX and 53BP1 foci (P < 0.05). The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation (P < 0.05), while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells. In addition to increases of double strand break (DSB) damage and decreases of Rad51 foci, olaparib combined with ML216 also increased pDNA-PKcs (S2056) foci, abrogated G2 cell cycle arrest, and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo (P < 0.05). Moreover, Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair, promoted NHEJ repair, and inactivated cell cycle checkpoint signals both in vitro and in vivo (P < 0.05). CONCLUSIONS Taken together, these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells, and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization, as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy.

Tertiary lymphoid structures (TLSs) are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions, including infection, autoimmune disease, and cancer. In the tumor microenvironment (TME), the structures of TLSs, including B-cell- and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers. Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients. It was shown that well-developed TLSs characterized by mature B cells synthesized tumor specific antibodies, which were considered as specific markers for a good prognosis. However, there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses. These factors include dysfunctional B cells, regulatory T cells, and T follicular regulatory cells. The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs; it is therefore essential to fully understand the function and influencing factors in TLSs. It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies. In this review, we focused on recent advances in TLSs in human solid tumors, including structural characteristics and classes, antitumor mechanisms, immunosuppressive factors, and TLS-based therapeutic approaches.

Intestinal injury caused by ionizing radiation (IR) is a main clinical issue for patients with cancer receiving abdominal or pelvic radiotherapy. Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that the pineal gland in the brain normally secretes. The study aimed to disclose the potential function of melatonin in intestinal injury induced by IR and its mechanism. Pretreatment with melatonin enhanced the 30-day survival rate of the irradiated mice and promoted the recovery of the intestinal epithelium and hematopoietic function following abdominal irradiation (ABI). Melatonin altered the gene profile of the small intestines from mice following ABI. The enriched biological process terms for melatonin treatment prior to radiation were mainly involved in the immune process. LPS/IL-1-mediated inhibition of RXR Function, TWEAK signaling, and Toll-like receptor signaling were the most activated canonical pathways targeted by melatonin. An upstream analysis network showed that Tripartite motif-containing 24 (TRIM24) was the most significantly inhibited and S100 calcium binding protein A9 (S100A9) activated. TRIM24 activated atherogenesis and cell viability in breast cancer cell lines and S100A9 inhibited the metabolism of amino acids. Melatonin has radioprotective effects on ABI-caused intestinal injury. The mechanisms behind the beneficial effects of melatonin were involved in activation of the immunity. It is necessary to conduct further experiments to explore the underlying mechanisms.

Food wastage represented by the deterioration of perishable food like fruits and vegetables is a serious global problem with tremendous ethical, financial, and environmental costs. The atmosphere (CO2 and O2) has a crucial role in food storage and can regulate physiological food metabolism and microbial growth. Modified atmosphere packaging (MAP) is a promising method used to extend shelf life and preserve the quality of perishable food; yet, its use depends on the specific gas permeability and selectivity of polymer membranes to generate an atmosphere desirable for storage. In this study, we established and validated a new plant leaf-mimetic shellac-based MAP membrane embedded with chitosan porous microspheres loaded with antimicrobial tannic acid (TA-CPM) as gas "switches" for regulating O2 and CO2 permeability and CO2/O2 selectivity. The effects of different amounts of TA-CPM added into the hybrid membranes were examined for litchi preservation at room temperature. Our results showed that this hybrid TA-CPM/shellac packaging membrane could regulate the internal CO2 and O2 concentrations and the CO2/O2 ratio within the packages containing litchis by adjusting the addition amount of TA-CPM. The 0.05% TA-CPM/shellac and 0.10% TA-CPM/shellac packages, especially 0.05% TA-CPM/shellac, generated a more desirable CO2 and O2 atmosphere for litchi preservation compared with controls, which was reflected by the delaying of browning and rotting, maintaining of the natural color of the litchi pericarp, preservation of pulp quality, inhibition of polyphenol oxidase and guaiacol peroxidase activities, and reduction of oxidative cell damage in litchis. The results suggested that 0.05% TA-CPM/shellac and 0.10% TA-CPM/shellac packaging membranes, especially 0.05% TA-CPM/shellac, could generate an ideal atmosphere for litchi storage at room temperature, demonstrating that this permeation-controlled hybrid membrane has great potential in food preservation and other applications requiring a modified atmosphere.

PURPOSE Intestinal damage induced by radiation exposure is a major clinic concern of radiotherapy for patients with abdominal or pelvic tumor. Melatonin (N-acetyl-5-methoxytryptamine) is likely be an ideal radioprotector to protect individuals from radiation exposure. The study aimed to define the role of melatonin in small intestinal damage caused by abdominal irradiation (ABI). MATERIALS AND METHODS 30-day survival rate and pathological histology of the intestines from melatonin-treated mice after 13 Gy ABI exposure was first detected. Next, quantitative proteomics analysis of the small intestines tissue was examined and GO term and KEGG pathways analysis were performed. RESULTS Melatonin treatment before ABI exposure significantly increased 30-day survival rate to 83% and ameliorated damage to the intestinal epithelial cells. Melatonin significantly altered the proteins profile of the small intestines following irradiation. For the irradiated mice treated with melatonin in comparison with the irradiated mice, the enriched GO terms were mainly involved in defense response to other organism (BP, GO: 0098542), response to other organism (BP, GO: 0051707), anion transmembrane transporter activity (MF, GO: 0008509), and secondary active transmembrane transporter activity (MF, GO: 0015291). In the process of antioxidant activity (MF, GO: 0016209), melatonin treatment prior to radiation exhibited high protein levels of Sod3 and Gpx3. The markedly KEGG pathways for melatonin treatment prior to radiation mainly included protein digestion and absorption (ko 04974) and mineral absorption (ko 04978). p53 signaling pathway and DNA repair pathways were enriched in melatonin treated mice. The amount of radiation-induced DNA damage and the cell apoptosis of the small intestines was decreased in the melatonin-treated mice. CONCLUSIONS Melatonin may protect small intestines from radiation damage through increasing DNA repair and decreasing cell apoptosis of the small intestines. Our data provided perspective for the study of melatonin in mitigating ABI-caused intestinal damage.

Resveratrol (RSV) has broad prospective applications as a radiation protection drug, but its mechanism of action is not yet clear. Here, we found that 5 μM RSV can effectively reduce the cell death caused by irradiation. Irradiation leads to G2/M phase arrest in the cell cycle, whereas RSV treatment increases S-phase cell cycle arrest, which is associated with sirtuin 1 (SIRT1) regulation. Meanwhile, RSV promotes DNA damage repair, mainly by accelerating the efficiency of homologous recombination repair. Under oxidative stress, tyrosyl-tRNA synthetase (TyrRS) is transported to the nucleus to protect against DNA damage. RSV can promote TyrRS acetylation, thus promoting TyrRS to enter the nucleus, where it regulates the relevant signaling proteins and reduces apoptosis and DNA damage. SIRT1 is a deacetylase, and SIRT1 knockdown or inhibition can increase TyrRS acetylation levels, further reducing radiation-induced apoptosis after RSV treatment. Our study revealed a new radiation protection mechanism for RSV, in which the acetylation of TyrRS and its translocation into the nucleus is promoted, and this mechanism may also represent a novel protective target against irradiation.-Gao, P., Li, N., Ji, K., Wang, Y., Xu, C., Liu, Y., Wang, Q., Wang, J., He, N., Sun, Z., Du, L., Liu, Q. Resveratrol targets TyrRS acetylation to protect against radiation-induced damage.

The planting area of macadamia in China accounted for more than one third of the world’s planted area. The lipid compositions, minor components, and antioxidant capacities of fifteen varieties of macadamia oil (MO) in China were comparatively investigated. All varieties of MO were rich in monounsaturated fatty acids, mainly including oleic acid (61.74–66.47%) and palmitoleic acid (13.22–17.63%). The main triacylglycerols of MO were first time reported, including 19.2–26.1% of triolein, 16.4–18.2% of 1-palmitoyl-2,3-dioleoyl-glycerol, and 11.9–13.7% of 1-palmitoleoyl-2-oleoyl-3-stearoyl-glycerol, etc. The polyphenol, α-tocotrienol and squalene content varied among the cultivars, while Fuji (791) contained the highest polyphenols and squalene content. Multiple linear regression analysis indicated the polyphenols and squalene content positively correlated with the antioxidant capacity. This study can provide a crucial directive for the breeding of macadamia and offer an insight into industrial application of MO in China.

CTC1 is a component of the mammalian CST (CTC1–STN1–TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3′-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.

Radiation enteritis is an old but emerging question induced by the application of radiation. However, no effective drugs for radiation enteritis in clinic. In this study, we found that thymoquinone (TQ) could mitigate intestinal damages induced by irradiation. After exposure to irradiation, TQ-treated improved the irradiated mice survival rate, ameliorated intestinal injury and increased the numbers of intestinal crypts. Furthermore, Lgr5

Radiation resistance is an obstacle to the successful treatment of lung cancer. Metformin, a first-line antidiabetic drug, has been studied for its potential use in radiotherapy, as several lines of evidence suggest that metformin enhances radiation sensitivity of cancer cells. However, the underlying mechanisms by which metformin exerts its radiosensitization effects on non-small cell lung cancer (NSCLC) cells remain obscure. Here, we confirmed that metformin increases the radiosensitivity of NSCLC cells and radiation-resistant NSCLC cells. Furthermore, we identified nuclear factor erythroid 2-related factor 2 (NRF2) as a critical target of radiosensitization effect of metformin, as the radiosensitization effect was abolished in NRF2 knockout cells. We also showed that metformin treatment increased the ubiquitination and proteasomal degradation of NRF2 through a KEAP1-independent mechanism. The decrease of NRF2 led to reduced transcription of downstream antioxidant-related proteins, inhibited the initiation of DNA damage repair pathways, and compromised G2/M phase arrest after radiation. In an orthotopic transplanted tumor model in nude mice, metformin treatment reduced NRF2 levels and led to fewer lung tumor nodules. Combination of irradiation further potentiated the antitumor efficacy compared to each of the single treatments. In conclusion, our results suggest that the degradation of NRF2 that is induced by metformin may play a pivotal role in radiosensitizing NSCLC cells and that metformin can be developed as a sensitizer of radiotherapy against lung cancer.

RecQ-mediated genome instability protein 1 (RMI1) is an important component of the BLM-Topo IIIα-RMI1-RMI2 complex and plays a critical role in maintaining genome stability. However, the cellular functions of RMI1 in response to ionizing radiation (IR) are poorly understood. In this study, we found that

This study aimed to investigate the combined effects of a coating based on shellac and the active agent tannic acid (TA) on the storability and physiological variations of mangoes stored at room temperature. Results showed that TA-shellac prolonged shelf life and improved overall quality of mangoes to a higher extent compared with controls, which was reflected in the extension of shelf life for approximately 10 days, maintaining of tissue firmness and weight loss, slowing down of respiration rate, improvement of physical properties and chemical qualities, suppression of browning, reduction of lipid peroxidation, preservation of aromatic volatiles, and regulation of the related enzymes activities. Addition of TA to shellac coating also improved the antifungal effect of the formulation. The results suggest that a synergistic effect took place between TA and shellac, which demonstrates the high potential for shelf life extension and quality improvement of mangoes of this formulation.

Ionizing radiation (IR) can act as a negative factor for human homeostasis, by causing and even aggravating a series of pathological conditions. To protect the intactness of normal tissues, effective anti-radiation drugs are urgently needed for alleviating the outcomes of radioactive damage. In this study, we demonstrate that atractylenolide II (ATR II), a sesquiterpenoid monomer extracted from traditional Chinese medicine atractylodes macrocephala, can markedly suppress IR damage by promoting the expression of antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone oxido-reductase 1 (NQO-1), which are mediated by nuclear factor-erythroid 2-like 2 (Nrf2) signaling pathway. Furthermore, here we reveal that ATR II effectively upregulates the expression of mitogen-activated protein kinase p38 (MAPKp38), which also acts as a regulator of Nrf2 signaling cascade. Indeed, treatment with a MAPKp38 inhibitor can significantly downregulate the expression of Nrf2 and its downstream target genes HO-1 and NQO-1 and, consequently, abolish the protective effect of ATR II against IR. Consistently, ATR II also has a protective function against IR-induced damage in animal models. In conclusion, our study provides an unexpected function of ATR II in preventing IR-induced damage by modulating MAPKp38/Nrf2 signaling pathway.

A comparison study has been performed to analyze the chemical compositions, antioxidant activity, thermal and rheological behaviors of macadamia (Macadamia integrifolia) oils (MOs) obtained by squeezing, solvents extraction and aqueous extraction. MOs were rich in monounsaturated fatty acids (82.73–82.85%), including mainly oleic acid (60.74–61.37%) and palmitoleic acid (18.71–19.39%). The lipid compositions, tocopherol (∼36 mg/kg) and phytosterols (∼1900 mg/kg) were not significantly influenced by processing method. However, the content of squalene (261.88 mg/kg), polyphenols (39.74 mg/kg) and antioxidant capacity of MOs obtained by squeezing were significantly higher than those extracted by solvents and aqueous. Furthermore, different processing method in the thermal and spectral profiles of MOs was similar, and MOs were liquid at room temperature (25 °C). Additionally, all MOs exhibited Newtonian flow behavior. This study indicated that the pressing might be the most suitable process for extracting macadamia oil with a high antioxidant capacity and beneficial minor components.

Radiation enteritis is an old but emerging question induced by the application of radiation. However, no effective drugs for radiation enteritis in clinic. In this study, we found that thymoquinone (TQ) could mitigate intestinal damages induced by irradiation. After exposure to irradiation, TQ-treated improved the irradiated mice survival rate, ameliorated intestinal injury and increased the numbers of intestinal crypts. Furthermore, Lgr5+ ISCs and their daughter cells, including Vil1+ enterocytes, Ki67+ cells and lysozyme+ Paneth cells, were all significantly increased with TQ treatment. In addition, P53, γH2AX, caspase8, caspase9 and caspase3 expression were all reduced by TQ. Our data showed that TQ modulated DNA damages and decreased the apoptosis in the small intestine. TQ might be used for radiation enteritis treatment.

Background/Aims: Circular RNAs (circRNAs) make up a large class of non-coding RNAs and play important roles in a variety of diseases, including nervous system diseases and cancers. The intestinal epithelium is sensitive to ionizing radiation, radiotherapy of abdominal or pelvic tumors or nuclear accident exposure can lead to high radiation toxicity, which can result in radiation-induced intestinal injury. The goal of this present study was to analyze the potential roles of circRNAs in radiation-induced intestinal injury. Methods: Mice were divided into two groups: control group and irradiated group. Irradiated group was 3.5 days after 14Gy abdominal irradiation (ABI) group. We started with RNA-seq of circRNA changes in mouse jejuna after radiation and validated by RT-PCR in the following experimental. miRNAs targeted mRNAs were predicted using proprietary software based on target scan and Miranda. The network of circRNA-miRNA-mRNA was illustrated by cytoscape software. Results: 2751 circRNAs were detected in the two groups. At day 3.5 post-radiation, 42 and 48 circRNAs were found to be significantly upregulated and downregulated, respectively, compared to the control (p≤0.05, Fold Change ≥2). Further, the altered expression of 10 circRNAs (chr18: 35610871-35613502+, chr15: 95864225-95894541+, chr3: 96041338-96042928-, chr5: 64096979-64108263+, chr19: 16705875-16710941-, chr5: 134491893-134500149-, chr19: 42562552-42564341+, chr5: 32640331-32664400+, chr3: 72958113-72960367- and chr8: 79343654-79372364-) were verified by RT-PCR. Compared the miRNA-targeted mRNAs with our mRNAs sequencing data, we found 14 upregulated circRNA-targeted mRNAs were also unregulated and 22 downregulated circRNAs-targeted mRNAs were also downregulated. Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the MAPK signaling pathway. Conclusions: This study reveals that expression of circRNAs was altered in the jejuna of mice post-irradiation and provides a resource for the study of circRNAs in radiation-induced intestinal injury and repair.

In this data article, 146 villagers (exposed group) were randomly selected from the workers who involved in the e-wastes recycling directly as a daily job in Tianjin. Control group, including 121 villagers, came from another town without e-waste disposal sites. Chromosomal aberrations (CA) and cytokinesis blocking micronucleus (CBMN) were performed to detect the cytogenetic effect for each subject. DNA damage was detected using comet assay; the DNA percentage in the comet tail (TDNA%), tail moment (TM), and Olive tail moment (OTM) were recorded to describe DNA damage to lymphocytes and spermatozoa. Routine semen analysis, spermatozoa motility and morphology were analyzed. The RT2Profiler PCR array was used to measure levels of expression of 84 genes related to quality of DNA. It showed significant relationships between CA, CBMN, DNA damage and exposure time in exposure subjects. The alteration of sperm motility rate, abnormality rate and total sperm counts had association with exposure time and age.

RMI1 (RecQ-mediated genome instability protein 1) forms a conserved BTR complex with BLM, Topo IIIα, and RMI2, and its absence causes genome instability. It has been revealed that RMI1 localizes to nuclear foci with BLM and Topo IIIα in response to replication stress, and that RMI1 functions downstream of BLM in promoting replication elongation. However, the precise functions of RMI1 during replication stress are not completely understood. Here we report that RMI1 knockdown cells are hypersensitive to hydroxyurea (HU). Using comet assay, we show that RMI1 knockdown cells exhibit accumulation of broken DNAs after being released from HU treatment. Moreover, we demonstrate that RMI1 facilitates the recovery from activated checkpoint and resuming the cell cycle after replicative stress. Surprisingly, loss of RMI1 results in a failure of RAD51 loading onto DNA damage sites. These findings reveal the importance of RMI1 in response to replication stress, which could explain the molecular basis for its function in maintaining genome integrity.

Mesenchymal stem cells (MSCs) derived from different tissues may aid in the regeneration of radiation-induced organ lesions; however, the radiation responses of human MSCs from different sources are unknown. In our study, a comparison of the results from cell proliferation, apoptosis, cell cycle, DNA damage, and DNA repair assays consistently showed that MSCs derived from adipose tissue possess a significantly stronger radiation resistance capacity than MSCs derived from umbilical cord and gingival, which is accompanied by a higher level of phosphorylated signal transducer and activator of transcription 3 (Stat3) expression. This reminds us Stat3 could be a potential biomarker of radiation resistance. These findings provide a better understanding of radiation-induced biologic responses in MSCs and may lead to the development of better strategies for stem cell treatment and cancer therapy.

Maintenance of genome integrity is critical for faithful propagation of genetic information and the prevention of the mutagenesis induced by various DNA damage events. RecQ-mediated genome instability protein 1 (RMI1), together with Bloom syndrome protein and topoisomerase IIIα, form an evolutionarily conserved complex that is critical for the maintenance of genomic stability. Herein, we report that RMI1 depletion increases cell sensitivity to camptothecin treatment, as shown by an elevation of genotoxic stress-induced DNA double-strand breaks, a stronger activation of the DNA damage response, and a greater G2/M cell cycle delay. Our findings support that, upon DNA damage, RMI1 forms nuclear foci at the damaged regions, interacts with RAD51, and facilitates the recruitment of RAD51 to initiate homologous recombination. Our data reveal the importance of RMI1 in response to DNA double-strand breaks and shed light on the molecular mechanisms by which RMI1 contributes to maintain genome stability.-Fang, L., Sun, X., Wang, Y., Du, L., Ji, K., Wang, J., He, N., Liu, Y., Wang, Q., Zhai, H., Hao, J., Xu, C., Liu, Q. RMI1 contributes to DNA repair and to the tolerance to camptothecin.

In this study, macadamia peptides were produced by ultrasonic-assisted alkaline protease, and five components were separated by ultrafiltration centrifuge with different molecular weight (1kDa, 3kDa, 10kDa, 30kDa). The amino acid composition, solubility, water absorption capacity and emulsifying properties of five components were compared. Results showed that all macadamia peptide components were rich in amino acid species, the contents of essential and hydrophobic amino acids ranged from 189.59 to 281.10mg/g and 204.26 to 258.78mg/g, respectively. Meanwhile, the small molecular weight components (MP-1) showed the best solubility and water absorption capacity, large molecular weight components (MP-5) had the best emulsifying properties. This result indicated that the distribution of molecular weight had significant effects on the amino acid composition and functional properties of macadamia peptide components. This study provides a theoretical basis for the further development of macadamia peptide products.

The anti-fatigue effect of macadamia (Macadamia integrifolia) protein and hydrolysate prepared with basic protease were investigated. Random mice grouping was carried out to create 4 groups including the control group and protein hydrolysate groups at low (150 mg/kg·d), medium (500 mg/kg·d) and high (1500 mg/kg·d) doses. All groups were treated by gavage for 28 consecutive days. Weight-loaded swimming test, serum urea nitrogen, serum creatine kinase activity, blood lactic acid and liver glycogen assays were performed to assess its anti-fatigue effect. The results showed that macadamia protein hydrolysate could significantly prolong weight-loaded swimming time, promote synthesis of liver glycogen and decrease blood urea nitrogen and lactic acid. Moreover, it can also significantly reduce serum creatine kinase activity. Therefore, macadamia protein hydrolysate had significant anti-fatigue function.

The growth of biomedical research over the previous decades has been accompanied by an increase in the number, complexity and diversity of experimental animals developed as research tools, and inbred mice are some of the most widely used. However, thus far, no inbred mice have exhibited strong radioresistance for use in radiation-damage research. To develop a radioresistant mouse model, a female Japanese outbreeding strain ICR/JCL mouse was mated with a male Chinese inbred strain 615 mouse. From the F1 generation, the mouse line was maintained by brother-to-sister mating. A novel mouse strain was established over >20 continuous generations and designated the Institute of Radiation Medicine-2 (IRM-2) mouse. The biological characteristics, genetic characteristics and susceptibility to radiation of these mice were determined. The IRM-2 mice inherited traits from the parents, including strong reproductive capacity, stable physiological and biochemical indices and few differences among individuals. According to the genetic results, the IRM-2 mice exhibited homozygosity, isogenicity and consistency, in agreement with international standards for inbred strains. Radiosensitivity studies have previously suggested that the lethal dose (LD)50 values for IRM-2 mice were 7.17 Gy (male) and 7.5 Gy (female), resulting in a dose reduction factor value of 1.39 (male) and 1.37 (female). The mortality of IRM-2 mice irradiated with 8 Gy total body irradiation was 15% at day 9 and 90% at day 15 after radiation. The number of nucleated cells in bone marrow, DNA content and colony-forming unit-spleen counts in IRM-2 mice after exposure to γ-ray irradiation were markedly higher than the corresponding values for the parental strains, suggesting that the IRM-2 mice exhibit high resistance to ionizing radiation. Thus, it is suggested that this novel inbred mouse strain may be developed as an animal model of radioresistance for future use in radiation research.

Radiation-induced intestinal injury is a complex disease for which there is no effective treatment. Apoptosis of intestinal stem cells (ISCs) is the major cause of tissue damage, and replacing those ISCs with an alternative source of stem cells is gaining increasing interest as a potential therapeutic strategy for this condition. In the present study, we examined the protective effects of human umbilical cord mesenchymal stem cells (hMSCs) against ISC death and intestinal damage in a mouse model of radiation injury. hMSCs were introduced via tail vein injection in male C57BL/6J mice two hours after abdominal irradiation (AIR), and survival rates and weight changes were monitored over time. Cellular apoptosis in intestinal tissue was evaluated 6 h after AIR. Histological changes and survival of Lgr5+ ISCs were evaluated at days 3.5 and 5 post-AIR. Intestinal crypts were cultured ex vivo to further characterize the protective effects of hMSCs on ISCs. Ki67+ cells, vill+ enterocytes, lysozymes, CD31 vascular endothelial cells and α-smooth muscle actin were also examined by immunohistochemistry. Compared to mice treated with PBS after AIR, hMSC-treated mice exhibited improved survival, diminished weight loss, reduced radiation-induced apoptosis, attenuated structural damage of the small intestine, enhanced Lgr5+ ISC and Paneth cell survival, as well as increased Ki67+ transient amplifying cells and vill+ enterocytes. The distribution of CD31 vascular endothelial cells and α-smooth muscle actin demonstrated no significant difference between treatment groups. Our results demonstrate that hMSCs promote survival and attenuate intestinal damage by protecting Lgr5+ ISCs in a mouse model of radiation-induced injury.

In order to determine the optimization of test conditions for TPA texture properties of avocado flesh, the method of TPA was used to explore the effect of different compression locations and test parameters on the texture properties. The results showed that the middle part of the avocado flesh was the best part for testing the texture properties. through the correlation analysis of the measured values of texture properties by the avocado flesh, the hardness, springiness and cohesiveness were determined as the key investigation indications. The compressed speed had a significant effect on hardness and cohesiveness, and the compression distance had a significant effect on hardness and springiness. The optimization test parameters of avocado flesh were compression speed of 1mm/s and compression distance of 8 mm.

With the extensive application of radiotherapy in various cancers, its side effects in tissues adjacent to cancers are garnering much attention. Intestines are sensitive to irradiation due to its rapid proliferation, and irradiation-induced enteric inflammation is common in patients with pelvic peritoneal tumors. Sirt1, class III protein deacetylase, could lead to transcriptional repression of various inflammation-associated genes, and our previous study has proved its relationship with interleukin (IL)-1β. Here we show that resveratrol, the activator of Sirt1, could alleviate the bowel inflammation induced by irradiation and the expression of Sirt1 is consistent with the inflammation level. We further identified in vivo that Sirt1 repress the expression of IL-1β by the repression of NLR Family, Pyrin Domain Containing protein 3 (NLRP3) expression. In conclusion, this study confirms resveratrol acts against radiation-induced inflammatory bowel disease via NLRP-3 inflammasome repression in mice and supports Sirt1 as a potential biomarker and therapy target in intestinal radiation protection.

The volatile components in Gui Qi Mango fruit wine analyzed by headspace solid-phase microextraction-gas chromatography-mass spectrometry. Results showed that 32 kinds of volatile components were detected in Gui Qi Mango fruit wine, including 7 kinds of alcohols (65.69%), 17 kinds of esters (28.92%), 4 kinds of alkanes (2.16%), 3 kinds of aldehydes (0.36%), 2 kinds of olefins (0.32%), 1 kinds of ketones (0.41%), 1 kinds of phenols (0.2%). In the all of the volatile components, the relative content of alcohols and esters were 94.61%. The fermentation process had an effect on the Gui Qi Mango fruit wine, and alcohols and esters played a positive role in the aroma of Gui Qi Mango fruit wine.

Human are exposed to ionizing radiation from natural and artificial sources, which consequently poses a possible risk to human health. However, accumulating evidence indicates that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation (HDR). Low-dose radiation–induced hormesis has been extensively observed in different biological systems, including immunological and hematopoietic systems. Adaptive responses in response to LDR that can induce cellular resistance to genotoxic effects from subsequent exposure to HDR have also been described and researched. Bystander effects, another type of biological effect induced by LDR, have been shown to widely occur in many cell types. Furthermore, the influence of LDR-induced biological effects on certain diseases, such as cancer and diabetes, has also attracted the interest of researchers. Many studies have suggested that LDR has the potential antitumor and antidiabetic complications effects. In addition, the researches on whether LDR could induce stochastic effects were also debated. Studies on the biological effects of LDR in China started in 1970s and considerable progress has been made since. In the present article, we provide an overview of the research progress on the biological effects of LDR in China.

LncRNAs have been reported to play an important role in various diseases. However, their role in the radiation‐induced intestinal injury is unknown. The goal of the present study was to analyse the potential mechanistic role of lncRNAs in the radiation‐induced intestinal injury. Mice were divided into two groups: Control (non‐irradiated) and irradiated. Irradiated mice were administered 14 Gy of abdominal irradiation (ABI) and were assessed 3.5 days after irradiation. Changes to the jejuna of ABI mice were analysed using RNA‐Seq for alterations to both lncRNA and mRNA. These results were validated using qRT‐PCR. LncRNAs targets were predicted based on analysis of lncRNAs‐miRNAs‐mRNAs interaction. 29 007 lncRNAs and 17 142 mRNAs were detected in the two groups. At 3.5 days post‐irradiation, 91 lncRNAs and 57 lncRNAs were significantly up‐ and downregulated respectively. Similarly, 752 mRNAs and 400 mRNAs were significantly up‐ and downregulated respectively. qRT‐PCR was used to verify the altered expression of four lncRNAs (ENSMUST00000173070, AK157361, AK083183, AK038898) and four mRNAs (Mboat1, Nek10, Ccl24, Cyp2c55). Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the VEGF signalling pathway. This study reveals that the expression of lncRNAs was altered in the jejuna of mice post‐irradiation. Moreover, it provides a resource for the study of lncRNAs in the radiation‐induced intestinal injury.

Background Cytokine-based cancer therapies have attracted a great deal of attention in recent years. Unfortunately, resistance to treatment limits the efficacy of these therapeutics. Therefore, the aim of our study was to explore the mechanism of IL-2-based therapy for hepatocellular carcinoma in an attempt to increase the efficiency of this treatment option. Methods HepG2 cells were treated with IL-2. Then, siRNA against TZA was used to transfected into HepG2 cells. Cellular apoptosis was measured via MTT assay, TUNEL assay and caspase-3 activity. Cellular proliferation was evaluated via EdU assay and western blotting. Cellular migration was detected via Transwell assay. Mitochondrial function was monitored by mitochondrial potential analysis, ROS staining, immunofluorescence and western blotting. Pathway blocker and activator were used to establish the role of JNK/F-actin/mitochondrial fission signaling pathway in HepG2 cells stress response. Results Our study found that IL-2 treatment significantly reduced the viability, mobility and proliferation of HepG2 cells in vitro. We also demonstrated that IL-2 treatment was accompanied by an increase in the expression of transcriptional co-activator with PDZ-binding motif (TAZ). Interestingly, genetic ablation of TAZ in the presence of IL-2 further promoted apoptosis, inhibited mobility, and arrested proliferation in HepG2 cells. At the molecular level, IL-2 administration activated excessive mitochondrial fission via the JNK/F-actin pathway; these effects were further enhanced by TAZ deletion. Mechanistically, TAZ knockdown further increased the expression of mitochondrial fission-related proteins such as Drp1, Mff and Fis. The augmented mitochondrial fission stimulated ROS overproduction, mediated redox imbalance, interrupted mitochondrial energy generation, reduced mitochondrial membrane potential, promoted leakage of the pro-apoptotic molecule cyt-c into the nucleus, and initiated caspase-9-related mitochondrial death. Further, we demonstrated that the anti-proliferative and anti-metastatic effects of IL-2 in HepG2 cells were enhanced by TAZ deletion, suggesting that IL-2 sensitizes HepG2 cells to IL-2-based cytokine therapy. However, JNK/F-actin pathway blockade could abrogate the inhibitory effects of TAZ deletion on HepG2 migration, proliferation and survival. Conclusions Taken together, our data indicate that the anti-tumor effects of IL-2-based therapies may be enhanced by TAZ deletion in a JNK/F-actin pathway-dependent manner. This finding provides a novel combinatorial therapeutic approach for treating hepatocellular carcinoma that might significantly increase the efficacy of cytokine-based therapies in a clinical setting. Electronic supplementary material The online version of this article (10.1186/s12935-018-0615-y) contains supplementary material, which is available to authorized users.

The proteasome inhibitor is a target therapy for multiple myeloma (MM) patients, which has increased the overall survival rate of multiple myeloma in clinic. However, relapse and toxicity are major challenges for almost all MM patients. Thus, there is an urgent need for an effective and less toxic combination therapy. Here, we demonstrated that a natural compound, resveratrol (RSV) displayed anti-proliferative activity in a dose- and time-dependent manner in a panel of MM cell lines. More importantly, a low concentration of RSV was synergistic with a low dose of the proteasome inhibitor carfilzomib (CFZ) to induce apoptosis in myeloma cells. Further studies showed that mitochondria was a key regulatory site after RSV/CFZ combination treatment. RSV induced the release of second mitochondria-derived activator of caspase (Smac) in a dose-dependent manner and kept the Smac in a high level after combination with CFZ. Also, RSV was additive with CFZ to increase reactive oxygen species (ROS) production. Moreover, a stress sensor SIRT1, with deacetylase enzyme activity, was remarkably downregulated after RSV/CFZ combination, thereby significantly decreasing its target protein, survivin in MM cells. Simultaneously, autophagy was invoked after RSV/CFZ combination treatment in myeloma cells. Further inhibition of autophagy could increase more ROS production and apoptosis, indicating a close linkage between autophagy and proteasome to modulate the oxidative stress. Together, these findings suggest that induction of multiple stress responses after RSV/CFZ combination is a major mechanism to synergistically inhibit MM cell growth and reduce the toxicity of CFZ in MM cells. This study also provides an important rationale for the clinic to consider an autophagy inhibitor for the combination therapy in MM patients.

Radiotherapy resistance in patient with non‑small cell lung cancer (NSCLC) reduces patient survival and remains a significant challenge for the treatment of NSCLC. Radiation resistance has been demonstrated to be affected by secreted factors, yet it remains unclear how autocrine secretions affect the radioresistance of NSCLC cells. In the present study, the NSCLC cell line, NCI‑H460, was irradiated with γ‑rays (4 Gy) and then cultured in medium from H460 cells or normal medium to examine the potential influence of cell secretions on the radiation resistance of H460 cells. Cell viability, accumulation of reactive oxygen species and DNA repair capacity were all markedly improved in the irradiated H460 cells that were cultured in conditioned medium (CM), compared with those cells cultured in normal medium. In addition, G2/M cell cycle arrest and upregulation of homologous recombination repair proteins were observed in the CM‑treated cells, while exosomes secreted by H460 cells had no influence on the radiation resistance of H460 cells. Taken together, these results indicate that autocrine secretions enhance the radiation resistance of γ‑irradiated H460 cells and that these secretions mainly affect the DNA repair process.

The acquisition of radioresistance by breast cancer cells during radiotherapy may lead to cancer recurrence and poor survival. Signal transducer and activator of transcription 3 (Stat3) is activated in breast cancer cells and, therefore, may be an effective target for overcoming therapeutic resistance. Mesenchymal stem cells (MSCs) have been investigated for use in cancer treatment. Here, we investigated the potential of MSC conditioned medium (MSC-CM) in sensitizing breast cancer to radiotherapy. It was found that MSC-CM could inhibit the level of activated Stat3, suppress cancer growth, and exhibit synergetic effects with radiation treatment in vitro and in vivo. Furthermore, MSC-CM reduced the ALDH-positive cancer stem cells (CSCs) population, modulated several potential stem cell markers, and decreased tumor migration, as well as metastasis. These results demonstrate that MSC-CM suppresses breast cancer cells growth and sensitizes cancer cells to radiotherapy through inhibition of the Stat3 signaling pathway, thus, providing a novel strategy for breast cancer therapy by overcoming radioresistance.

Background/Aims: SirT1, a conserved NAD+-dependent deacetylase, has been implicated in modulating cell survival and stress responses, and it appears to play an important role in tumorigenesis and cancer resistance to chemoradiotherapy. The mechanism of SirT1 in cancer chemoradiotherapy remains to be further elucidated, which could provide potential targets for cancer therapy. Methods: We performed colony formation, immunofluorescence microscopy, flow cytometry, RNA interference, and western blotting assays to determine whether SirT1 regulates radiation sensitization and which mechanisms and/or pathways it takes in lung cancer cell lines A549 and H460. Results: Initially, the expression of SirT1 was found to be negatively correlated with radiosensitivity in lung cancer cell lines A549 and H460. RNA interference with siSirT1 against SirT1 specifically reduced SirT1 expression and induced radiosensitivity both in A549 and H460 cell lines. In contrast, the radiosensitivity was significantly reduced once SirT1 was activated by resveratrol. Immunofluorescence assay and apoptosis analysis indicated that the effect of SirT1 on the radiosensitivity observed in the A549 and H460 cell lines was mainly achieved by regulating DNA damage repair and apoptosis processes. Furthermore, the expression of SirT1 negatively modulated the expression of apoptosis-related protein NF-κB and its downstream regulator of Smac. Conclusion: Our results indicate that SirT1 regulates apoptosis and radiation sensitization in lung cancer cell lines A549 and H460 via the SirT1/NF-κB/Smac pathway.

The objective of the present work was to study the preparation, optimization and characteristic of nanostructured lipid carriers(NLCs) based on macadamia nut oil. NLC with various macadamia nut oil content were successfully prepared by an optimized microfluidization method using stearic acid as solid lipid and pluronic F68 as surfactant. As a result, NLC with particle size about 286nm were obtained, and the polydispersity index(PI) of all developed NLC were below 0.2 which indicate a narrow size distribution. Furthermore, the encapsulation efficiency and loading capability were investigated as well. Physical stability of NLC demonstrated that particles of system were stable at room temperature and low temperature. Differential scanning calorimetry(DSC) investigation show that the inner structure and recrystallinity of lipid matrix within NLC were greatly influenced by the content of macadamia nut oil.

Additional file 1: Fig. S1. Cellular energy metabolism is regulated by TAZ. A ATP production was measured in HepG2 cell transfected with TAZ siRNA or control siRNA in the presence of IL-2. B–F Following IL-2 treatment and siRNA-mediated knockdown of TAZ, western blotting was used to analyze the components of the mitochondrial respiratory complex. G, H Glucose content and lactate production were measured in medium from HepG2 cell treated with TAZ siRNA in the presence of IL-2. *P

We assessed dose levels and the persistence of chromosomal aberrations and micronuclei in three individuals in the 8 year following accidental (60)Co radiation exposure. Venous blood samples were collected and used for analyses: traditional chromosome aberration (CA) measurement, G-banding, and the cytokinesis-block micronucleus (CBMN) assay. For CA analysis, we scored dicentric chromosomes (dic) and rings (r) in peripheral blood lymphocytes. The radiation doses (Gy) suffered by the individuals were estimated as: 1.79-2.43 (A), 2.36-2.86 (B), 1.58-1.82 (C), based on CA analysis; and 1.8-2.34 (A), 2.52-2.98 (B), 1.53-1.77 (C), based on CBMN frequencies. G-banding analysis was used to record translocations (t), inversions (inv), and deletions (del). Following the accident, unstable CAs reduced gradually, but stable aberrations persisted. Unstable CAs and CBMN may be valuable biomarkers for dose estimation shortly after high-dose radiation accidents, while stable aberrations may be more useful for assessing long-term effects.

Introduction Fanconi anemia (FA), as one of the congenital bone marrow failure syndromes, is characterized by severe bone marrow hypocellularity and pancytopenia which is similar with acquired aplastic anemia (AAA). However, patients with FA or AAA need an accurate diagnose, as the two syndromes differ significantly in both treatment and prognosis. FA results from gene mutations of the FA pathway genes specifically required for DNA repair, and the mutation of these genes contributes to the genome instability of FA cells. Based on this feature, chromosome aberration (CA) has been used as a "golden standard" to the auxiliary diagnosis of FA from AAA. However, CA diagnose calls for more technical requirements and a long time for the subsequent statistical analysis. Methods In our study, another two genome instability examination tools, cytokinesis-block micronucleus (CBMN) and single-cell gel electrophoresis (SCGE), were used to distinguish FA patients from AAA patients, compared with CA. Results The results suggested that significant differences were observed in the FA patients compared with the AAA patients and the controls using all of the three genomic instability examination tools. However, CBMN is the most cost-effective method to distinguish FA patients from AAA patients among the three genome instability examination tools, when the time costs, instrument costs, and technical costs were compared. Conclusion In areas with economic and technical limitations, CBMN is an alternative assay to help distinguish FA patients from AAA patients.

Purpose- Ionizing radiation has been associated with adverse effects on the immune system. Currently, there are no effective treatment options to ameliorate these effects. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced long term immunosuppression in mice. Materials and methods- Mice were exposed to total body irradiation, and treated with resveratrol or vehicle. Several immune parameters were measured, including thymus and spleen weights, T lymphocyte and B lymphocyte count in peripheral blood, concanavalin A and lipopolysaccharide induced lymphocyte proliferation. To explore the mechanism, we investigated intracellular ROS level of lymphocytes and mice plasma cytokine levels. Results- Treatment with resveratrol ameliorated TBI-induced atrophy of the thymus and spleen, reduction of lymphocyte count, and decline of lymphocyte proliferation. TBI exhibited significantly reduced level of IL-2, IL-4, IL-7, and IFN-γ compared with the control mice, and treatment with resveratrol attenuated the reduction. Conclusion- The results of the present study suggest that treatment with resveratrol could ameliorate irradiation induced long term immune malfunction at least partly via modulation of plasma cytokine.

In this data article, 146 villagers (exposed group) were randomly selected from the workers who involved in the e-wastes recycling directly as a daily job in Tianjin. Control group, including 121 villagers, came from another town without e-waste disposal sites. Chromosomal aberrations (CA) and cytokinesis blocking micronucleus (CBMN) were performed to detect the cytogenetic effect for each subject. DNA damage was detected using comet assay; the DNA percentage in the comet tail (TDNA%), tail moment (TM), and Olive tail moment (OTM) were recorded to describe DNA damage to lymphocytes and spermatozoa. Routine semen analysis, spermatozoa motility and morphology were analyzed. The RT 2 Profiler PCR array was used to measure levels of expression of 84 genes related to quality of DNA. It showed significant relationships between CA, CBMN, DNA damage and exposure time in exposure subjects. The alteration of sperm motility rate, abnormality rate and total sperm counts had association with exposure time and age.

A synthetic polypeptide ANTP- SmacN7 is a possible radiosensitizing agent derived from N terminal 7 amino acid sequence of Smac protein, which antagonizes a caspase inhibitor XIAP. To investigate the underlying mechanisms behind radiosensitization, we analyzed cellular responses of two non-small cell lung carcinomas (NSCLC) cell lines, H460 and A549, to low- and high-LET ionizing radiation (IR) and ANTP-smacN7. Western analysis revealed that expression of XIAP was higher in A549 than in H460. Sensitivities of these cells to iron (LET=200 kev/μm), carbon (LET=70 kev/μm) and photon (200 kvp X-rays) beams were determined by clonogenic assay. A549 cells were 1.6-2.0-fold more resistant to these IRs than H460, based on the doses required to reduce the cell survival to 50% (LD50). Flow cytometry assay.0s revealed that radio-induced cellular apoptosis emerged at 6 h and reached a peak level at 24 after IR at LD50. Notably, administration of ANTP-SmacN7 reduced the cell survival of A549 and H460 cell by 56% and 30%, respectively, after the iron irradiation at each LD50. These results suggested that ANTP-SmacN7 promotes apoptotic response to IR by antagonizing inhibitory effect of XIAP on caspase and thus being effective for cells particularly with high XIAP expression., H28年度HIMAC共同利用研究成果発表会