A Current Overview of the Biological Effects of Combined Space Environmental Factors in Mammals.

Distinct from Earth's environment, space environmental factors mainly include space radiation, microgravity, hypomagnetic field, and disrupted light/dark cycles that cause physiological changes in astronauts. Numerous studies have demonstrated that space environmental factors can lead to muscle atrophy, bone loss, carcinogenesis, immune disorders, vascular function and cognitive impairment. Most current ground-based studies focused on single environmental factor biological effects. To promote manned space exploration, a better understanding of the biological effects of the spaceflight environment is necessary. This paper summarizes the latest research progress of the combined biological effects of double or multiple space environmental factors on mammalian cells, and discusses their possible molecular mechanisms, with the hope of providing a scientific theoretical basis to develop appropriate countermeasures for astronauts.

The long noncoding RNA CRYBG3 induces aneuploidy by interfering with spindle assembly checkpoint via direct binding with Bub3.

Aneuploidy is a hallmark of genomic instability that leads to tumor initiation, progression, and metastasis. CDC20, Bub1, and Bub3 form the mitosis checkpoint complex (MCC) that binds the anaphase-promoting complex or cyclosome (APC/C), a crucial factor of the spindle assembly checkpoint (SAC), to ensure the bi-directional attachment and proper segregation of all sister chromosomes. However, just how MCC is regulated to ensure normal mitosis during cellular division remains unclear. In the present study, we demonstrated that LNC CRYBG3, an ionizing radiation-inducible long noncoding RNA, directly binds with Bub3 and interrupts its interaction with CDC20 to result in aneuploidy. The 261-317 (S3) residual of the LNC CRYBG3 sequence is critical for its interaction with Bub3 protein. Overexpression of LNC CRYBG3 leads to aneuploidy and promotes tumorigenesis and metastasis of lung cancer cells, implying that LNC CRYBG3 is a novel oncogene. These findings provide a novel mechanistic basis for the pathogenesis of NSCLC after exposure to ionizing radiation as well as a potential target for the diagnosis, treatment, and prognosis of an often fatal disease.

Additive effects of simulated microgravity and ionizing radiation in cell death, induction of ROS and expression of RAC2 in human bronchial epithelial cells.

Radiation and microgravity are undoubtedly two major factors in space environment that pose a health threat to astronauts. However, the mechanistic study of their interactive biological effects is lacking. In this study, human lung bronchial epithelial Beas-2B cells were used to study the regulation of radiobiological effects by simulated microgravity (using a three-dimensional clinostat). It was found that simulated microgravity together with radiation induced drop of survival fraction, proliferation inhibition, apoptosis, and DNA double-strand break formation of Beas-2B cells additively. They also additively induced Ras-related C3 botulinum toxin substrate 2 (RAC2) upregulation, leading to increased NADPH oxidase activity and increased intracellular reactive oxygen species (ROS) yield. The findings indicated that simulated microgravity and ionizing radiation presented an additive effect on cell death of human bronchial epithelial cells, which was mediated by RAC2 to some extent. The study provides a new perspective for the better understanding of the compound biological effects of the space environmental factors.

Regional biomechanical imaging of liver cancer cells.

Liver cancer is one of the leading cancers, especially in developing countries. Understanding the biomechanical properties of the liver cancer cells can not only help to elucidate the mechanisms behind the cancer progression, but also provide important information for diagnosis and treatment. At the cellular level, we used well-established atomic force microscopy (AFM) techniques to characterize the heterogeneity of mechanical properties of two different types of human liver cancer cells and a normal liver cell line. Stiffness maps with a resolution of 128x128 were acquired for each cell. The distributions of the indentation moduli of the cells showed significant differences between cancerous cells and healthy controls. Significantly, the variability was even greater amongst different types of cancerous cells. Fitting of the histogram of the effective moduli using a normal distribution function showed the Bel7402 cells were stiffer than the normal cells while HepG2 cells were softer. Morphological analysis of the cell structures also showed a higher cytoskeleton content among the cancerous cells. Results provided a foundation for applying knowledge of cell stiffness heterogeneity to search for tissue-level, early-stage indicators of liver cancer.

Rhein inhibits ATP-triggered inflammatory responses in rheumatoid rat fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder, which may lead to joint disabilities. So far the pathogenesis of RA remains largely undetermined, and there are still no potent drugs for clinical treatment. Rhein, a natural bioactive anthraquinone derivative, exhibited significant anti-inflammatory activities demonstrated by previous studies. Here we aimed to investigate the effects of rhein on ATP-induced inflammation responses in fibroblast-like synoviocytes isolated from a rat model of collagen induced arthritis (CIA). Our results showed that ATP triggered rapid cytosolic calcium concentration ([Ca2+]c) increase depending on extracellular Ca2+ entry. Given the major P2 subtypes expressed in rat synoviocytes were P2X4 and P2Y2 receptors, ATP-elicited calcium entry should be mainly resulted from activating P2X4. Interestingly, rhein could effectively block the ATP-induced [Ca2+]c increases in a dose-dependent manner. Besides, rhein also suppressed the production of intracellular reactive oxygen species (ROS) induced by ATP in synoviocytes that was resulted from P2X4-mediated Ca2+ entry. Brilliant blue G (BBG), which can block P2X4 receptor at high concentration, showed similar suppressive effects on above responses. Furthermore, in lipopolysaccharide-primed cells, application of ATP synergistically promoted the gene expression of cyclooxygenase-2, interleukin-6 and matrix metalloproteinase-9. Both rhein and BBG attenuated these inflammatory gene expressions enhanced by ATP. Above data together suggested a potential anti-arthritic role of rhein by inhibiting ATP-induced [Ca2+]c increase, ROS production and inflammatory gene expression targeting P2X4 in CIA rat synoviocytes, which will provide a novel insight in the therapy of RA.

Current status of space radiobiological studies in China.

After successfully launching two space laboratories, namely, Tiangong-1 and Tiangong-2, China has announced her next plan of constructing the Chinese Space Station (CSS) in 2022. The CSS will provide not only platforms for Chinese scientists to carry out experimental studies in outer space but also opportunities for open international cooperation. In this article, we review the development of China's manned space exploration missions and the preliminary plan for CSS. Additionally, China has initiated space radiation research decades ago with both ground-based simulation research platform and space vehicles and has made noticeable progresses in several aspects. These include studies on human health risk assessment using mammalian cell cultures and animals as models. Furthermore, there have been numerous studies on assessing the space environment in plant breeding.

Overexpression of Ras-Related C3 Botulinum Toxin Substrate 2 Radiosensitizes Melanoma Cells In Vitro and In Vivo.

Radioresistance is the major obstacle in the radiotherapy of the malignant melanoma. Thus, it is of importance to increase the radiosensitivity of melanoma cells. In the present study, the radioresistant melanoma cell line OCM-1 with inducible overexpression of Ras-related C3 botulinum toxin substrate 2 was established based on a radiation-inducible early growth response gene (Egr-1) promoter. The effects of Ras-related C3 botulinum toxin substrate 2 overexpression on the radiosensitivity of melanoma cells exposed to either X-rays or carbon ion beams were evaluated in cultured cells as well as xenograft tumor models. In addition, both reactive oxygen species yield and the NADPH oxidase activity were measured in the irradiated melanoma cells. It was found that the radiation-inducible overexpression of Ras-related C3 botulinum toxin substrate 2 sensitized the melanoma cells to both X-rays and carbon ion irradiation by enhancing the NADPH oxidase activity and the subsequent reactive oxygen species production. Besides, the overexpression of Ras-related C3 botulinum toxin substrate 2 enhanced the tumor-killing effect of radiotherapy in xenograft tumors significantly. The results of this study indicate that Ras-related C3 botulinum toxin substrate 2 is promising in increasing the radiosensitivity of melanoma cells, which provides experimental evidence and theoretical basis for clinical radiosensitization of the malignant melanoma.

Microarray Profiling of TGF-ß1-Induced Long Non-Coding RNA Expression Patterns in Human Lung Bronchial Epithelial BEAS-2B Cells.

BACKGROUND/AIMS: TGF-ß1 mediated radiation-induced bystander effects (RIBE) have been linked with malignant transformation and tumorigenesis. However, the underlying mechanisms are not fully understood. METHODS: To reveal new molecules of regulatory functions in this process, lncRNA microarray was performed to profile both lncRNA and mRNA expression patterns in human lung bronchial epithelial BEAS-2B cells treated with TGF-ß1 at a concentration measured in the medium conditioned by directly irradiated BEAS-2B cells. The potential functions of the differentially expressed lncRNAs were predicted by GO and KEGG pathway analyses of their co-expressed mRNAs. Cis- and trans-regulation of the lncRNAs were analyzed and the interaction networks were constructed using Cytoscape. qRT-PCR was conducted to validate the results of microarray profiling. CCK-8 assay was employed for functional validation of 3 identified lncRNAs. RESULTS: 224 lncRNAs were found to be dysregulated, among which 6 lncRNAs were chosen for expression validation by qRT-PCR assay. Pathway analyses showed that differentially expressed lncRNAs are highly correlated with cell proliferation, transformation, migration, etc. Trans-regulation analyses showed that the differentially expressed lncRNAs most likely participate in the pathways regulated by four transcriptional factors, FOS, STAT3, RAD21 and E2F1, which have been identified to be involved in the modulation of oncogenic transformation, cell cycle progression, genomic instability, etc. lnc-THEMIS-2 and lnc-ITGB6-4, predicted to be regulated by STAT3 and E2F1 respectively, were found to rescue the decrease of cell viability induced by TGF-ß1 treatment. CONCLUSION: Our findings suggest that the differentially expressed lncRNAs induced by TGF-ß1 play crucial roles in the oncogenic transformation and tumorigenesis, which provide a better understanding of the underlying mechanisms related to tumorigensis induced by LD/LDR radiations.

Design of two isoreticular Cd-biphenyltetracarboxylate frameworks for dye adsorption, separation and photocatalytic degradation.

Two novel isoreticular cadmium metal-organic frameworks (MOFs) with the framework formula of [Cd2(BPTC)(solvent)3] (H4BPTC = 3,3',5,5'-biphenyltetracarboxylic acid) have been constructed under diverse reaction conditions and characterized by single crystal X-ray diffraction, PXRD, IR and TGA. The neutral 3D frameworks of 1 and 2 with one-dimensional (1D) rhombic channels exhibit both distinct uptake and good selectivity for cationic methylene blue (MB) dye molecules. The adsorption capacity and adsorption kinetic constant of 2 are greater than those of 1, showing the importance of porosity and pore size during the adsorption. Moreover, both MOFs show effective degradation of rhodamine B (RhB) and methyl orange (MO) dyes under UV light irradiation.

Circular RNA profiles in mouse lung tissue induced by radon.

BACKGROUND: Radon is a known human lung carcinogen, whose underlying carcinogenic mechanism remains unclear. Recently, circular RNA (circRNA), a class of endogenous non-protein coding RNAs that contain a circular loop, was found to exhibit multiple biological effects. In this study, circRNA profiles in mouse lung tissues between control and radon exposure were analyzed. METHODS: Six mice were exposed to radon at concentration of 100,000 Bq/m3, 12 h/d, for up to cumulative doses of 60 working level months (WLM). H&E staining and immunohistochemistry of caspase-3 were used to detect the damages in lung tissue. The lung tissue of control and exposed group were selected for circRNA microarray study. The circRNA/microRNA interaction was analyzed by starBase prediction software. 5 highest expressing circRNAs were selected by real-time PCR to validate the consistency in mouse lung tissue exposed to radon. RESULTS: Inflammatory reaction was found in mouse lung tissue exposed to radon, and caspase-3 expression was significantly increased. Microarray screening revealed 107 up-regulated and 83 down-regulated circRNAs, among which top 30 circRNAs with the highest fold changes were chosen for further analysis, with 5 microRNAs binding sites listed for each circRNA. Consistency of the top 5 circRNAs with the highest expressions were confirmed in mice exposed with 60WLM of radon. CONCLUSION: Mouse lung tissue was severely injured when exposed to radon through pathological diagnosis and immunohistochemical analysis. A series of differentially expressed circRNAs demonstrated that they may play an important role in pulmonary toxicity induced by radon.

Analysis of the miRNA-mRNA networks in malignant transformation BEAS-2B cells induced by alpha-particles.

The aim of this study was to determine the toxicity induced by irradiation with alpha-particles on malignant transformation of immortalized human bronchial epithelial cells (BEAS-2B) using miRNA-mRNA networks. The expression of BEAS-2B cells was determined by measuring colony formation, mtDNA, mitochondrial membrane potential (MMP), and ROS levels. Changes in BEAS-2B cell gene expression were observed and quantified using microarrays that included an increase in 157 mRNA and 20 miRNA expression and a decrease in 77 mRNA and 48 miRNA. Bioinformatic software was used to analyze these different mRNA and miRNA, which indicated that miR-107 and miR-494 play an important role in alpha-particles-mediated cellular malignant transformation processes. The pathways related to systemic lupus erythematosus, cytokine-cytokine receptor interaction, MAPK signaling pathway, regulation of actin cytoskeleton, and cell adhesion molecules (CAMs) were stimulated, while those of ribosome, transforming growth factor (TGF)-beta signaling pathway, and metabolic pathways were inhibited. Data suggest that miRNA and mRNA play a crucial role in alpha-particles-mediated malignant transformation processes. It is worth noting that three target genes associated with lung cancer were identified and upregulated PEG 10 (paternally expressed gene 10), ARHGAP26, and IRS1.

A novel role of long non-coding RNAs in response to X-ray irradiation.

In the present study, the role of lncRNAs in response to radiation-induced DNA damage and oxidative stress were explored to improve our understanding of the biological pathways activated upon radiation-induced toxicity. The toxicity of X-ray radiation on human bronchial epithelial cell lines (HBE) was determined through a dose-dependent increase in ROS production and γ-H2AX formation and changes to lncRNA expression was observed and quantified using lncRNA-specific microarrays. 115 lncRNAs expression was increased in a dose-dependent manner following X-ray irradiation. Bioinformatic prediction algorithms determined that these lncRNAs significantly affect the p53 signaling pathway, and, more specifically, the BRCA 1 transcription factor and coding genes adjacent to BRCA 1. Our results highlight a previously uncharacterized role for lncRNAs to act via the p53-pathway in response to X-ray-induced DNA damage, and suggest lncRNAs may serve as novel indicators for radiation toxicity.

Down-regulation of let-7 microRNA increased K-ras expression in lung damage induced by radon.

Radon has long been recognized as a human carcinogen leading to lung cancer, but the underlying mechanisms remain obscure. Recent studies have shown that the let-7 microRNA and K-ras play an important role in the development of various cancers. However, the exact role between let-7 and K-ras in radon induced lung damage has not been explored so far. In the present study, wistar rats and human bronchial epithelial (HBE) cells were long-term exposed to radon, and then alterations in histological pathology of rat lung tissue, ROS, antioxidant enzymes activities and clonogenic formation in HBE cells, as well as changes in let-7 and K-ras expression were determined to observe the adverse effects induced by radon. The results showed that long-term exposure to radon produced severe lung damage in rats, significantly increased ROS production and clonogenic formation ratios and decreased SOD activities in HBE cells. In addition, an obvious down-regulation of let-7 and up-regulation of K-ras were also revealed both in mRNA and in protein level in lung tissue of rats and HBE cells exposed to radon. Furthermore, a significant down-regulation of K-ras was then confirmed in both let-7b-3p and let-7a-2-3p transfected HBE cells. Taken together, the present results propose an involvement of let-7 microRNA and K-ras in radon induced lung damage both in vivo and in vitro, which may thus be of potential value in early diagnosis and therapy of radon-induced lung tumorgenesis.

Oxidative DNA damage is involved in cigarette smoke-induced lung injury in rats.

OBJECTIVE: Reactive oxygen species (ROS) induced by exogenous toxicants are suggested to be involved in carcinogenesis by oxidative modification of DNA. 8-Hydroxyl-2-deoxyguanosine (8-OHdG) has been considered as a reliable biomarker for oxidative DNA damage both in vivo and in vitro studies. But the effect of smoking on oxidative damage has not yet been fully elucidated. METHODS: Wistar rats were exposed to cigarette smoke at concentrations of 20 and 60 % for 30 min, twice/day for 45 weeks. Then the histopathology of lung tissues, levels of ROS, 8-OHdG, and total antioxidant (T-AOC), expression of DNA repair enzymes, e.g. 8-oxyguaine DNA glycosylase (OGG1), and MutThomolog 1 (Oxidized Purine Nucleoside Triphosphatase, MTH1) were determined in urine, peripheral blood lymphocytes, and lung tissue. RESULTS: The results showed that long-term cigarette smoke exposure can cause obvious damages of lung tissue in rats. In addition, a significant and cigarette smoke concentration-dependent increase in ROS and 8-OHdG were observed compared with the non-exposed control rats. In contrast, the expression of OGG1 and MTH1, and T-AOC levels were obviously decreased after long-term exposure to cigarette smoke. CONCLUSION: These findings indicate that long-term exposure to cigarette smoker increases ROS levels, decreases total antioxidant capacity, and interferes DNA repair capacity that eventually induces oxidative DNA damage, which appears to play an important role in cigarette smoke-induced lung injury in rats, and determination of 8-OHdG levels might be a useful method for monitoring oxidative damage in cigarette smokers.

Does whole-body vibration with alternative tilting increase bone mineral density and change bone metabolism in senior people?

BACKGROUND AND AIMS: Whole-body vibration (WBV) presents as osteogenic in animal models and young patients, but the effect remains unclear in senior people. The use of alternative tilting during WBV to ameliorate bone mass and bone metabolism, particularly in senior people, has not previously been reported. This study assessed changes in bone mineral density (BMD) and bone metabolism in senior people after six-month treatment of whole-body vibration with alternative tilting (WBVAT). METHODS: Fifty-three senior people (11M/42F, >65 yrs, mean age 77) and 15 adults (4M/11F, 50-60 yrs, mean age 53) were enrolled and assigned randomly to WBVAT (senior: n=27; adult: n=7) and control groups (senior: n=26; adult: n=7), respectively. The WBVAT groups were subjected to vertical vibration (0.5-0.8 g, 45-55 Hz) and alternative tilting (2° tilting angle or 8 mm displacement at 0.4 Hz) 20 minutes per day, 3 days a week, for 6 months. BMD in the lumbar spine and femoral neck was measured at 0, 3 and 6 months, respectively, as well as biochemical markers of bone metabolism, including serum calcium, phosphorus, alkaline phosphatase (ALP), osteocalcin and tartrate resistance acid phosphatase at 0, 1, 3 and 6 months, respectively. RESULTS: After 6-month WBVAT treatment, BMD in the lumbar spine and femoral neck increased significantly by 2.52% and 3.22% for senior people, and 1.63% and 2.05% for adults, respectively. The 6-month WBVAT treatment increased BMD in the senior people, both with and without osteoporosis (OP) and in both men and women, but led to a BMD gain greater in people with OP (p<0.01) and women (p<0.01), respectively. The serum ALP level increased significantly by a net 24.4% in seniors after WBVAT treatment at 3 months; other biochemical markers showed non-significant differences between the WBVAT and control groups. CONCLUSIONS: WBVAT treatment may increase BMD in senior people, particularly those with OP and women. Changes in bone metabolism after WBVAT treatment were not observed in most cases.