Multiple exposures to low-dose ionizing radiation induced the initiation and progression of pro-atherosclerotic phenotypes in mice and vascular endothelial cell damage.

OBJECTIVE: This study aimed to investigate the effects of low-dose radiation on the abdominal aorta of mice and vascular endothelial cells. METHODS: Wild-type and tumor-bearing mice were exposed to 15 sessions of low-dose irradiation, resulting in cumulative radiation doses of 187.5, 375, and 750 mGy. The effect on the cardiovascular system was assessed. Immunohistochemistry analyzed protein expressions of PAPP-A, CD62, P65, and COX-2 in the abdominal aorta. Microarray technology, Gene Ontology analysis, and pathway enrichment analysis evaluated gene expression changes in endothelial cells exposed to 375 mGy X-ray. Cell viability was assessed using the Cell Counting Kit 8 assay. Immunofluorescence staining measured γ-H2AX levels, and real-time polymerase chain reaction quantified mRNA levels of interleukin-6 (IL-6), ICAM-1, and Cx43. RESULTS: Hematoxylin and eosin staining revealed thickening of the inner membranes and irregular arrangement of smooth muscle cells in the media membrane at 375 and 750 mGy. Inflammation was observed in the inner membranes at 750 mGy, with a clear inflammatory response in the hearts of tumor-bearing mice. Immunohistochemistry indicated increased levels of PAPP-A, P65, and COX-2 post-irradiation. Microarray analysis showed 425 up-regulated and 235 down-regulated genes, associated with processes like endothelial cell-cell adhesion, IL-6, and NF-κB signaling. Cell Counting Kit 8 assay results indicated inhibited viability at 750 mGy in EA.hy926 cells. Immunofluorescence staining demonstrated a dose-dependent increase in γ-H2AX foci. Reverse transcription quantitative PCR results showed increased expression of IL6, ICAM-1, and Cx43 in EA.hy926 cells post 750 mGy X-ray exposure. CONCLUSION: Repeated low-dose ionizing radiation exposures triggered the development of pro-atherosclerotic phenotypes in mice and damage to vascular endothelial cells.

Screening radiation-differentially expressed circular RNAs and establishing dose classification models in the human lymphoblastoid cell line AHH-1.

PURPOSE: In the event of a large-scale radiological accident, rapid and high-throughput biodosimetry is the most vital basis in medical resource allocation for the prompt treatment of victims. However, the current biodosimeter is yet to be rapid and high-throughput. Studies have shown that ionizing radiation modulates expressions of circular RNAs (circRNAs) in healthy human cell lines and tumor tissue. circRNA expressions can be quantified rapidly and high-throughput. However, whether circRNAs are suitable for early radiation dose classification remains unclear. METHODS: We employed transcriptome sequencing and bioinformatics analysis to screen for radiation-differentially expressed circRNAs in the human lymphoblastoid cell line AHH-1 at 4 h following exposure to 0, 2, and 5 Gy 60Co γ-rays. The dose-response relationships between differentially expressed circRNA expressions and absorbed doses were investigated using real-time polymerase chain reaction and linear regression analysis at 4 h, 24 h, and 48 h post-exposure to 0, 2, 4, 6, and 8 Gy. Six distinct dose classification models of circRNA panels were established and validated by receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 11 radiation-differentially expressed circRNAs were identified and validated. Based on dose-response effects, those circRNAs changed in a dose-responsive or dose-dependent manner were combined into panels A through F at 4 h, 24 h, and 48 h post-irradiation. ROC curve analysis showed that panels A through C had the potential to effectively classify exposed and non-exposed conditions, which area under the curve (AUC) of these three panels were all 1.000, and the associate p values were .009. Panels D through F excellently distinguished between different dose groups (AUC = 0.963-1.000, p < .05). The validation assay showed that panels A through F demonstrated consistent excellence in sensitivity and specificity in dose classification. CONCLUSIONS: Ionizing radiation can indeed modulate the circRNA expression profile in the human lymphoblastoid cell line AHH-1. The differentially expressed circRNAs exhibit the potential for rapid and high-throughput dose classification.

Biodosimetry Based on Gamma-H2AX Quantification in Human Peripheral Blood Lymphocytes after Partial-body Irradiation.

ABSTRACT: Quantification of gamma-H2AX foci can estimate exposure to ionizing radiation. Most nuclear and radiation accidents are partial-body irradiation, and the doses estimated using the total-body irradiation dose estimation formula are often lower than the actual dose. To evaluate the dose-response relation of gamma-H2AX foci in human peripheral blood lymphocytes after partial-body irradiation and establish a simple and high throughput model to estimate partial-body irradiation dose, we collected human peripheral blood and irradiated with 0-, 0.5-, 1-, 2-, 3-, 4-, 5-, 6-, and 8-Gy gamma rays to simulate total-body irradiation in vitro. Gamma-H2AX foci were quantitated by flow cytometry at 1 h after irradiation, and a dose-response curve was established for total-body irradiation dose estimation. Then, a partial-body irradiation dose-response calibration curve was established by adding calibration coefficients based on the Dolphin method. To reflect the data distribution of all doses more realistically, the partial-body irradiation dose-response calibration curve was divided into two sections. In addition, partial-body irradiation was simulated in vitro, and the PBI data were substituted into curves to verify the accuracy of the two partial-body irradiation calibration curves. Results showed that the dose estimation variations were all less than 30% except the 25% partial-body irradiation group at 1 Gy, and the partial-body irradiation calibration dose-response curves were YF 1 = - 3.444 x 2 + 18.532 x + 3.109, R 2 = 0.92 (YF ≤ 27.95); YF 2 = - 2.704 x 2 + 37.97 x - 56.45, R 2 = 0.86 (YF > 27.95). Results also suggested that the partial-body irradiation dose-response calibration curve based on the gamma-H2AX foci quantification in human peripheral blood lymphocytes is a simple and high throughput model to assess partial-body irradiation dose.

Effects of cyclophosphamide and mitomycin C on radiation-induced transcriptional biomarkers in human lymphoblastoid cells.

PURPOSE: Ionizing radiation (IR)-induced transcriptional changes are considered a potential biodosimetry for dose evaluation and health risk monitoring of acute or chronic radiation exposure. It is crucial to understand the impact of confounding factors on the radiation-responsive gene expressions for accurate and reproducible dose assessment. This study aims to explore the potential influence of exposures to chemotherapeutic agents such as cyclophosphamide (CP) and mitomycin C (MMC) on IR-induced transcriptional biomarkers. METHODS: The human B lymphoblastoid cells (AHH-1) were exposed to 0, 20, 50, 100, 200 and 500 µg/ml CP or 0, 0.025, 0.05, 0.1 and 1 µg/ml MMC, respectively. The appropriate concentrations of CP and MMC were added for 1 h before irradiation with 0, 2, 4 and 6 Gy of 60Co γ-rays at a dose rate of 1 Gy/min. Cell viability was evaluated by CCK-8 assay. The gene expression responses of 18 radiation-induced transcriptional biomarkers were examined at 24 h after exposures to CP and MMC, respectively. The expression levels of five crucial DNA interstrand crosslinks (ICLs) repair genes were also evaluated. The biodosimetry models were established based on the specific radiation-responsive gene combinations. RESULTS: The baseline transcriptional levels of the 18 selected genes were slightly affected by CP treatment in the absence of IR, while the transcript responses to IR could be inhibited as the concentration of CP up to 50 µg/ml. MMC treatment up-regulated the background levels in most radiation-responsive gene expressions. Of 18 genes, only the relative mRNA expression levels of CDKN1A and BBC3 were repressed after treatment with IR and MMC in combination. The relative mRNA level of RAD51 was significantly up-regulated after exposure to CP, while the expression of FANCD2, RAD51 and BLM showed an overall increase in response to MMC treatment. After irradiation, the relative mRNA expression levels of FANCD2, BRCA2 and RAD51 exhibited dose-dependent increases in IR alone and MMC treatment groups. In addition, the biodosimetry models were established using 2-4 radiation-responsive genes based on different radiation exposure scenarios. CONCLUSION: Our findings suggested that IR-induced gene expression changes were slightly affected after exposure to a relatively low concentration of CP and MMC. Gene expression combinations might improve the broad applicability of transcriptional biodosimetry across diverse radiation exposures.

Low-dose ionizing radiation: Effects on the proliferation and migration of lens epithelial cells via activation of the Wnt/ß-catenin pathway.

Eye lens opacification (cataract) induced by ionizing radiation is an important concern for radiation protection. Human lens epithelial cells (HLE-B3) were irradiated with γ-rays and radiation effects, including cell proliferation, cell migration, cell cycle distribution, and other changes related to the ß-catenin pathway, were determined after 8-72 h and 7 d. In an in vivo model, mice were irradiated; DNA damage (γH2AX foci) in the cell nucleus of the anterior capsule of the lens was detected within 1 h, and radiation effects on the anterior and posterior lens capsules were observed after 3 months. Low-dose ionizing radiation promoted cell proliferation and migration. The expression levels of ß-catenin, cyclin D1, and c-Myc were significantly increased in HLE-B3 cells after irradiation and ß-catenin was translocated into the cell nucleus (activation of the Wnt/ß-catenin pathway). In C57BL/6 J mouse lens, even a very low irradiation dose (0.05 Gy) induced the formation of γH2AX foci, 1 h after irradiation. At 3 months, migratory cells were found in the posterior capsule; expression of ß-catenin was increased and it was clustered at the nucleus in the epithelial cells of the lens anterior capsule. The Wnt/ß-catenin signaling pathway may an important role in promoting abnormal proliferation and migration of lens epithelial cells after low-dose irradiation.

Melatonin inhibits senescence-associated melanin pigmentation through the p53-TYR pathway in human primary melanocytes and the skin of C57BL/6 J mice after UVB irradiation.

UVB exposure accelerates skin aging and pigmentation. Melatonin effectively regulates tyrosinase (TYR) activity and aging. The purpose of this study was to determine the association between premature senescence and pigmentation, and the mechanism of melanin synthesis effected by melatonin. Primary melanocytes were extracted and identified from the male foreskin. To inhibit TYR expression, primary melanocytes were transduced with the lentivirus pLKD-CMV-EGFP-2A-Puro-U6-TYR. The wild-type TYR(+/+) and TYR(-/-) or TYR(+/-) knockout C57BL/6 J mice were used to determine the role of TYR on melanin synthesis in vivo. Results showed that UVB-induced melanin synthesis is dependent on TYR in primary melanocytes and mice. Furthermore, in primary melanocytes pretreated with Nutlin-3 or PFT-α to up or downregulate p53, results showed that premature senescence and melanin synthesis increased in primary melanocytes after UVB irradiation at 80 mJ/cm2, and further increased after being treated with Nutlin-3, while significantly decreased with PFT-α. In addition, melatonin inhibited UVB-induced premature senescence associated with inactivation of p53 and phosphorylation of p53 on Ser15 (ser-15), a decrease of melanin synthesis accompanied by reduced TYR expression. Moreover, skin erythema and pigmentation induced by UVB were reduced in the dorsal and ear skin of mice topically pretreated with 2.5% melatonin. These indicate that melatonin inhibits UVB-induced senescence-associated pigmentation via the p53-TYR pathway in primary melanocytes and prevents pigmentation obviously in the dorsal and ear skin of C57BL/6 J mice after UVB irradiation. KEY MESSAGES: P53 links UVB irradiation-induced senescence and senescence-associated pigmentation and regulates TYR in primary melanocytes after UVB irradiation. Melatonin inhibits senescence-associated pigmentation through the p53-TYR pathway in primary melanocytes. Melatonin prevents skin erythema and melanin pigmentation induced by UVB irradiation in the dorsal and ear skin of C57BL/6J mice.

Genome-Wide Identification and Evolutionary Analyses of SrfA Operon Genes in Bacillus.

A variety of secondary metabolites contributing to plant growth are synthesized by bacterial nonribosomal peptide synthases (NRPSs). Among them, the NRPS biosynthesis of surfactin is regulated by the SrfA operon. To explore the molecular mechanism for the diversity of surfactins produced by bacteria within the genus Bacillus, we performed a genome-wide identification study focused on three critical genes of the SrfA operon-SrfAA, SrfAB and SrfAC-from 999 Bacillus genomes (belonging to 47 species). Gene family clustering indicated the three genes can be divided into 66 orthologous groups (gene families), of which a majority comprised members of multiple genes (e.g., OG0000009 had members of all three SrfAA, SrfAB and SrfAC genes), indicating high sequence similarity among the three genes. Phylogenetic analyses also found that none of the three genes formed monophyletic groups, but were usually arranged in a mixed manner, suggesting the close evolutionary relationship among the three genes. Considering the module structure of the three genes, we propose that self-duplication, especially tandem duplications, might have contributed to the initial establishment of the entire SrfA operon, and further gene fusion and recombination as well as accumulated mutations might have continuously shaped the different functional roles of SrfAA, SrfAB and SrfAC. Overall, this study provides novel insight into metabolic gene clusters and operon evolution in bacteria.

CPT1 Mediated Ionizing Radiation-Induced Intestinal Injury Proliferation via Shifting FAO Metabolism Pathway and Activating the ERK1/2 and JNK Pathway.

The intestinal compensatory proliferative potential is a key influencing factor for susceptibility to radiation-induced intestinal injury. Studies indicated that the carnitine palmitoyltransferase 1 (CPT1) mediated fatty acid ß-oxidation (FAO) plays a crucial role in promoting the survival and proliferation of tumor cells. Here, we aimed to explore the effect of 60Co gamma rays on CPT1 mediated FAO in the radiation-induced intestinal injury models, and investigate the role of CPT1 mediated FAO in the survival and proliferation of intestinal cells after irradiation. We detected the changed of FAO in the plasma and small intestine of Sprague Dawley (SD) rats at 24 h after 60Co gamma irradiation (0, 5 and 10 Gy), using target metabolomics, qRT-PCR, immunohistochemistry (IHC), western blot (WB) and related enzymatic activity kits. We then analyzed the FAO changes in radiation-induced intestinal injury models regardless of ex vivo (mice enteroids), or in vitro (normal human intestinal epithelial cell lines, HIEC-6). HIEC-6 cells were transduced with lentivirus vector GV392 and treated with puromycin for obtaining CPT1 stable knockout cell lines, named CPT1 KO. CPT1 enzymatic activities of HIEC-6 cells and mice enteroids were also inhibited by pharmaceutical inhibitor ST1326 and Etomoxir (ETO), to study the function of CPT1 in the survival and proliferation of HIEC-6 cells after 60Co gamma irradiation. We found that CPT1 mediated FAO was altered in the small intestine of the SD rats after irradiation, especially, the expression level and enzymatic activity of CPT1 were significantly increased. Similarly, the expression levels of CPT1 were also remarkably enhanced in mice enteroids and HIEC-6 cells after irradiation. CPT1 inhibition decreased the proliferation of the HIEC-6 cells and mice enteroids after irradiation partially by reducing the extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways activation, CPT1 inhibition also reduced the proliferation of mice enteroids after irradiation partially by down-regulating the Wnt/ß-catenin signaling activity. In conclusion, our study indicated that CPT1 plays a crucial role in promoting intestinal epithelial cell proliferation after irradiation.

CPT1 Mediated Ionizing Radiation-Induced Intestinal Injury Proliferation via Shifting FAO Metabolism Pathway and Activating the ERK1/2 and JNK Pathway.

The intestinal compensatory proliferative potential is a key influencing factor for susceptibility to radiation-induced intestinal injury. Studies indicated that the carnitine palmitoyltransferase 1 (CPT1) mediated fatty acid ß-oxidation (FAO) plays a crucial role in promoting the survival and proliferation of tumor cells. Here, we aimed to explore the effect of 60Co gamma rays on CPT1 mediated FAO in the radiation-induced intestinal injury models, and investigate the role of CPT1 mediated FAO in the survival and proliferation of intestinal cells after irradiation. We detected the changed of FAO in the plasma and small intestine of Sprague Dawley (SD) rats at 24 h after 60Co gamma irradiation (0, 5 and 10 Gy), using target metabolomics, qRT-PCR, immunohistochemistry (IHC), western blot (WB) and related enzymatic activity kits. We then analyzed the FAO changes in radiation-induced intestinal injury models regardless of ex vivo (mice enteroids), or in vitro (normal human intestinal epithelial cell lines, HIEC-6). HIEC-6 cells were transduced with lentivirus vector GV392 and treated with puromycin for obtaining CPT1 stable knockout cell lines, named CPT1 KO. CPT1 enzymatic activities of HIEC-6 cells and mice enteroids were also inhibited by pharmaceutical inhibitor ST1326 and Etomoxir (ETO), to study the function of CPT1 in the survival and proliferation of HIEC-6 cells after 60Co gamma irradiation. We found that CPT1 mediated FAO was altered in the small intestine of the SD rats after irradiation, especially, the expression level and enzymatic activity of CPT1 were significantly increased. Similarly, the expression levels of CPT1 were also remarkably enhanced in mice enteroids and HIEC-6 cells after irradiation. CPT1 inhibition decreased the proliferation of the HIEC-6 cells and mice enteroids after irradiation partially by reducing the extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways activation, CPT1 inhibition also reduced the proliferation of mice enteroids after irradiation partially by down-regulating the Wnt/ß-catenin signaling activity. In conclusion, our study indicated that CPT1 plays a crucial role in promoting intestinal epithelial cell proliferation after irradiation.

Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration.

PURPOSE: With the development of radiation metabolomics, a large number of radiation-related metabolic biomarkers have been identified and validated. The L-carnitine and acylcarnitines have the potential to be the new promising candidate indicators of radiation exposure. This review summarizes the effect of carnitine shuttle system on the profile of acylcarnitines and correlates the radiation effects on upstream regulators of carnitine shuttle system with the change characteristics of L-carnitine and acylcarnitines after irradiation across different animal models as well as a few humans. CONCLUSIONS: Studies report that acylcarnitines were ubiquitously elevated after irradiation, especially the free L-carnitine and short-chain acylcarnitines (C2-C5). However, the molecular mechanism underlying acylcarnitine alterations after irradiation is not fully investigated, and further studies are needed to explore the biological effect and its mechanism. The activity of the carnitine shuttle system plays a key role in the alteration of L-carnitine and acylcarnitines, and the upstream regulators of the system are known to be affected by irradiation. These evidences indicate that that there is a logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration.

Autophagy regulates X-ray radiation-induced premature senescence through STAT3-Beclin1-p62 pathway in lung adenocarcinoma cells.

PURPOSE: Ionizing radiation (IR) can induce autophagy and premature senescence; however, the link between them has not been clarified. Our research has shown that X-ray irradiation induces premature senescence in lung adenocarcinoma cells, and its occurrence partially depends on the signal transducer and activator of transcription 3 (STAT3). STAT3 can bind to the promoter region of Beclin1 and regulate its expression. Therefore, it is speculated that there may be a close link between premature senescence and autophagy induced by ionizing radiation in lung adenocarcinoma cells. p62 plays a regulatory role in both autophagy and premature senescence, and it is also an irreplaceable molecule that causes the senescence -associated secretory phenotype (SASP) and a substrate for selective autophagy. This study focused on STAT3, Beclin1 and p62 to clarify the regulatory relationship between IR-induced autophagy and premature senescence. MATERIALS AND METHODS: After exposure to 4 Gy X-rays, a ß-galactosidase staining kit was used to detect the positive rate of premature senescence. STAT3 was overexpressed by pcDNA3.0-STAT3 transfection, and was inhibited by AG490 and rapamycin. Lung adenocarcinoma cells were transduced with the adenovirus vector GV119-Beclin1 to knockdown the expression of Beclin1, or treated with ATM and ATR inhibitors to inhibit premature senescence. Western blotting was used to examine alterations in the radiation response proteins STAT3 and p-STAT3, senescence-related proteins p62 and GATA4, autophagy-related proteins Beclin1, and LC3-II/LC3-I. The mRNA expression levels of SASP factors, including IL-6 and IL-8, were examined by real-time polymerase chain reaction. RESULTS: The activity of SA-ß-gal increased significantly (p < .05), and the expression of p62 decreased significantly at 72 h after 4 Gy X-ray irradiation, accompanied by the increased expression of STAT3, p-STAT3, Beclin1, and the LC3-II/LC3-I ratio. Up- or down-regulation of STAT3 expression was followed by an increase or decrease in Beclin1 expression. After treatment with ATM and ATR inhibitors, there were no significant changes in Beclin1 expression or LC3-II/LC3-I ratio in A549 cells after 4 Gy X-ray irradiation. The p62 expression, the percentage of the SA-ß-gal-positive staining cells, and the expression of IL-6 and IL-8 mRNA in cells transduced with GV119-Beclin1 were also decreased significantly after 4 Gy X-ray irradiation compared with that of the 0 Gy group. CONCLUSION: Radiation induces premature senescence and autophagy in lung adenocarcinoma cells. Autophagy regulates X-ray radiation-induced premature senescence through the STAT3-Beclin1-p62 pathway in lung adenocarcinoma cells.

Screening of radiation gastrointestinal injury biomarkers in rat plasma by high-coverage targeted lipidomics.

INTRODUCTION: In the event of radiological accidents and cancer radiotherapies in the clinic, the gastrointestinal (GI) system is vulnerable to ionizing radiation and shows GI injury. Accessible biomarkers may provide means to predict, evaluate, and treat GI tissue damage. The current study investigated radiation GI injury biomarkers in rat plasma. MATERIAL AND METHODS: High-coverage targeted lipidomics was employed to profile lipidome perturbations at 72 h after 0, 1, 2, 3, 5, and 8 Gy (60Co γ-rays at 1 Gy/min) total-body irradiation in male rat jejunum. The results were correlated with previous plasma screening outcomes. RESULTS: In total, 93 differential metabolites and 28 linear dose-responsive metabolites were screened in the jejunum. Moreover, 52 lipid species with significant differences both in jejunum and plasma were obtained. Three lipid species with linear dose-response relationship both in jejunum and plasma were put forth, which exhibited good to excellent sensitivity and specificity in triaging different exposure levels. DISCUSSION: The linear dose-effect relationship of lipid metabolites in the jejunum and the triage performance of radiation GI injury biomarkers in plasma were studied for the first time. CONCLUSION: The present study can provide insights into expanded biomarkers of IR-mediated GI injury and minimally invasive assays for evaluation.

Analysis of Red Blood Cells and their Components in Medical Workers with Occupational Exposure to Low-Dose Ionizing Radiation.

Plenty of reports focus on the effects of low-dose radiation (LDR) on peripheral blood lymphocytes in radiation workers. However, studies on red blood cells (RBCs) in radiation workers are rarely reported. Many studies focused on investigate the hemogram of radiation staffs without detecting other components of RBCs. To explore the potential effect of LDR on RBCs, we detected the level of RBC count, hemoglobin, 2,3-disphosphoglycerate (2,3-DPG), and glutathione (GSH), and then analyzed the factors on these indices in 106 medical radiation workers. As a result, RBC count was affected by sex, age, type of work, length of service (only for females), and annual effective dose (only for males). Hemoglobin status was affected by sex, type of work, and annual effective dose (only for males). Sex, age, and type of work had no effects on the concentration of 2,3-DPG and GSH. Length of service affected 2,3-DPG concentration, and annual effective dose affected GSH level. In conclusion, chronic occupational LDR exposure may have an effect on RBC count, hemoglobin status, and the concentration of 2,3-DPG and GSH in radiation workers to some extent. However, it is still unknown how this kind of influence affects the health of radiation workers.

Effect of Ultraviolet B Irradiation on Melanin Content Accompanied by the Activation of p62/GATA4-Mediated Premature Senescence in HaCaT Cells.

OBJECTIVE: To explore the effect and mechanism of ultraviolet B (UVB) on melanin synthesis and premature senescence in human immortalized keratinocytes (HaCaT) cells. METHODS: HaCaT cells were irradiated with 0, 20, 50, 80, 100, 150, and 200 mJ/cm2 of UVB. NaOH method was used for melanin content assay, cellular tyrosinase (TYR) activity was determined by 3,4-Dihydroxy-L-phenylalanine (L-DOPA) oxidation to dopachrome, premature senescence was analyzed by senescence-associated beta-galactosidase (SA-ß-gal) staining kit, and the levels of p21, p16, p62, and GATA4 proteins were detected by Western blotting. Premature senescence was inhibited by the inhibitors of ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), and the p53 signaling pathway was activated by Nutlin-3. The mRNA levels of senescence-associated secretory phenotype (SASP) factors including tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor A (VEGF-A), and interleukin-8 (IL-8) were measured by real-time quantitative polymerase chain reaction in HaCaT cells after 80 mJ/cm2 of UVB irradiation. RESULTS: The melanin level increased significantly with the elevation of irradiation dose (F = 28.19, 43.82, 143.60, P < .05), reaching the peak at the dose of 80 mJ/cm2. The tyrosinase activity increased significantly (F = 84.50, P < .05), the percentage of premature senescence increased (F = 16.31, P < .05), the levels of p62 decreased, and the level of GATA4 increased obviously with the increase of UVB dose after irradiation. The UVB-induced promotion of GATA4 level was significantly inhibited by being treated with ATM or ATR inhibitor. However, this did not occur in the Nutlin-3-treated group. The mRNA and protein expression of TNF-α increased significantly at 72 h at 80 mJ/cm2 of UVB irradiation. CONCLUSIONS: Melanin contents increased first and decreased afterward with the increasing of UVB irradiation. The decrease of p62-mediated selective autophagy was accompanied by the accumulation of GATA4 after different doses of UVB irradiation. Activation of this p62/GATA4 pathway depends on the ATM and ATR but is independent of p53, and the SASP factor was activated in HaCaT cells at 80 mJ/cm2 of UVB irradiation.

Enhancement of Acylcarnitine Levels in Small Intestine of Abdominal Irradiation Rats Might Relate to Fatty Acid ß-Oxidation Pathway Disequilibration.

OBJECTIVE: This study aims to analyze the alteration of carnitine profile in the small intestine of abdominal irradiation-induced intestinal injury rats and explore the possible reason for the altered carnitine profile. METHODS: The abdomens of 15 male Sprague Dawley (SD) rats were irradiated with 0, 10, and 15 Gy of 60Co gamma rays. The carnitine profile in the small intestine and plasma samples of SD rats at 72 h after abdominal irradiated with 0 Gy or 10 Gy of 60Co gamma rays were measured by targeted metabolomics. The changes of fatty acid ß-oxidation (FAO), including the expression of carnitine palmitoyltransferase 1 (CPT1) and acyl-CoA dehydrogenases, were analyzed in the small intestine samples of SD rats after exposed to 0, 10, and 15 Gy groups. RESULTS: There were eleven acylcarnitines in the small intestine and fourteen acylcarnitines in the plasma of the rat model significantly enhanced, respectively (P < .05). The expression level and activity of CPT1 in the small intestine were remarkably increased (P < .05), and the activity of acyl-CoA dehydrogenase in the small intestine was noticeably reduced (P < .01) after abdominal irradiation. CONCLUSION: The enhanced acylcarnitine levels in the small intestine of abdominal irradiation rats might relate to the FAO pathway disequilibration.

ATM and TP53 polymorphisms modified susceptibility to radiation-induced lens opacity in natural high background radiation area, China.

Purpose: A population-based case-control study was conducted in Yangjiang and Enping areas in South China to assess whether the risk of lens opacity induced by natural high background radiation exposure is modulated by polymorphisms of ATM and TP53.Materials and methods: A total of 133 cases who were diagnosed with cortical and posterior subcapsular (PSC) opacity were recruited, and 419 healthy controls were selected through counter-matching in terms of radiation status. Genomic DNA from all the participants was genotyped with the Illumina platform for four single nucleotide polymorphisms of ATM (rs189037, rs373759, and rs4585) and TP53 (rs1042522). The cumulative lens dose received during the entire life was estimated based on annual indoor and outdoor radiation doses and gender- and age-specific occupancy factors. Non-conditional logistic regression was performed to calculate odds ratio (OR) and 95% confidence intervals (95% CI).Results:ATM rs189037 and TP53 rs1042522 were significantly related to cortical and PSC opacity. The risk of opacity was higher when individuals carried the A allele of ATM rs189037 and C allele of TP53 rs1042522, compared with GG genotype. ATM rs189037 A allele carriers (AG/AA) and TP53 rs1042522 C allele carriers (CG/CC) combined with a cumulative lens dose of 100 mGy or higher showed statistically significant opacity risks (OR = 5.51, 95% CI: 1.47-20.66; OR = 2.69, 95% CI: 1.10-6.60).Conclusion: The A allele of ATM rs189037 and C allele of TP53 rs1042522 increased the risk of lens opacity induced by radiation. These polymorphisms in ATM and TP53 might modify the risk of cortical and PSC opacity induced by chronic and prolonged low-dose radiation.

Cytogenetic monitoring of peripheral blood lymphocytes from medical radiation professionals occupationally exposed to low-dose ionizing radiation.

In order to assess the health risk of low-dose radiation to radiation professionals, monitoring is performed through chromosomal aberration analysis and micronuclei (MN) analysis. MN formation has drawbacks for monitoring in the low-dose range. Nucleoplasmic bridge (NPB) analysis, with a lower background level, has good dose-response relationships at both high and relatively low dose ranges. Dicentric and ring chromosomes were analyzed in 199 medical radiation professionals, and NPB/MN yields were analyzed in 205 radiation professionals. The effects of sex, age of donor, types of work, and length of service on these cytogenetic endpoints were also analyzed. The yields of the three cytogenetic endpoints were significantly higher in radiation professionals versus controls. Frequencies of dicentric plus ring chromosomes were affected by length of service. NPB frequencies were influenced by type of work and length of service. MN yields were affected not only by types of work and length of service but also by donor sex and age. In conclusion, dicentric plus ring chromosomes, NPB, and MN can be induced by low-dose radiation in radiation professionals. NPB is a potential biomarker to assess the health risk of occupational low-dose radiation exposure.

System and capability of public health response to nuclear or radiological emergencies in China.

In order to respond to nuclear or radiological emergencies effectively and protect the physical and mental health of the public, the national-, provincial-, municipal- and county-level public health response systems for nuclear or radiological emergencies had been established in China by the end of twentieth century. The health administrative departments at all levels have established professional emergency response teams, continue to improve their own level of emergency response systems and operating mechanisms, enhance the capabilities of radiation injury treatment, radiation monitoring and protection through training and exercises and also pay attention to the logistical support for emergency response. In this article the organizations, management system and capabilities of public health response to nuclear or radiological emergencies in China are briefly introduced. We try to strengthen information exchange and cooperation with foreign counterparts in this field in the future, so as to jointly promote the development of preparedness and response for nuclear or radiological emergencies.

Effects of radiation quality and dose rate on radiation-induced nucleoplasmic bridges in human peripheral blood lymphocytes.

Previous studies showed that the yield of cobalt-60 γ-rays-induced nucleoplasmic bridges (NPB) in human peripheral blood lymphocytes is dose dependent. However, the influence of the radiation quality and dose rates on NPB frequencies has not been investigated. The present study aimed to investigate NPB frequencies in human peripheral blood lymphocytes induced by carbon ions and explore the dose rate effect on cobalt-60 γ-rays-induced NPB. To establish dose-response curves, human peripheral blood samples were irradiated with 0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 and 8.0 Gy of carbon ions at a dose rate of 3.0 Gy/min in vitro. To explore the dose rate effect, human peripheral blood samples were irradiated with 2.0 and 5.0 Gy of cobalt-60 γ-rays at dose rates of 0.2, 0.5, 1.0, 3.0, 5.0 and 10.0 Gy/min in vitro. NPB and micronuclei (MN) in binucleated cells were analyzed with the cytokinesis-block micronucleus cytome assay. Results showed that the dose-response curve of carbon ion-induced NPB frequencies follow a linear-quadratic model (R2 = 0.934). The relative biological effectiveness (RBE) values of carbon ions to cobalt-60 γ-rays decreased with increased NPB frequencies (ranging from 2.47 to 5.86). Compared with group 1.0 Gy/min, the NPB frequencies in groups 10.0 Gy/min (2.0 Gy), 5.0 and 10.0 Gy/min (5.0 Gy) were decreased significantly (P < 0.05). Carbon ion-induced NPB in human peripheral blood lymphocytes have a good dose-response relationship. Cobalt-60 γ-rays-induced NPB frequencies are affected by the specific dose rate.

Dose-effect relationships of 12C6+ ions-induced dicentric plus ring chromosomes, micronucleus and nucleoplasmic bridges in human lymphocytes in vitro.

PURPOSE: The objective of this research was to explore the dose-effect relationships of dicentric plus ring (dic + r), micronucleus (MN) and nucleoplasmic bridges (NPB) induced by carbon ions in human lymphocytes. MATERIALS AND METHODS: Venous blood samples were collected from three healthy donors. 12C6+ ions beam was used to irradiate the blood samples at the energy of 330 MeV and linear energy transfer (LET) of 50 keV/µm with a dose rate of 1 Gy/min in the spread-out Bragg peak. The irradiated doses were 0 (sham irradiation), 1, 2, 3, 4, 5 and 6 Gy. Dic + r chromosomes aberrations were scored in metaphases. The cytokinesis-block micronucleus cytome (CBMN) was conducted to analyze MN and NPB. The maximum low-dose relative biological effectiveness (RBEM) values of the induction of dic + r, MN and NPB in human lymphocytes for 12C6+ ions irradiation was calculated relative to 60Co γ-rays. RESULTS: The frequencies of dic + r, MN and NPB showed significantly increases in a dose-depended manner after exposure to 12C6+ ions. The distributions of dic + r and MN exhibited overdispersion, while the distribution of NPB agreed with Poisson distribution at all doses. Linear-quadratic equations were established based on the frequencies of dic + r and MN. The dose-response curves of NPB frequencies followed a linear model. The derived RBEM values for dic + r, MN and NPB in human lymphocytes irradiated with 12C6+ ions were 8.07 ± 2.73, 2.69 ± 0.20 and 4.00 ± 2.69 in comparison with 60Co γ-rays. CONCLUSION: The dose-response curves of carbon ions-induced dic + r, MN and NPB were constructed. These results could be helpful to improve radiation risk assessment and dose estimation after exposed to carbon ions irradiation.