Acute Irradiation Research Articles

First Insights Into the M2 Inflammatory Response After Adipose-Tissue-Derived Stem Cell Injections in Radiation-Injured Muscles.

The cutaneous radiation syndrome is the clinical consequence of local high-dose irradiation. It is characterized by extensive inflammation, necrosis, and poor revascularization of the skin, resulting in muscle inflammation and fibrosis. Based on these physiopathological processes, subcutaneous injections of adipose-tissue-derived stem/stromal cells have shown favorable effects on skin-wound healing in a minipig model of cutaneous radiation syndrome, in which muscle fibrosis persisted. Since fibrosis is mainly due to the inflammatory processes that often affect underlying tissues as well, the beneficial effects of intramuscular injections of adipose-tissue-derived stem/stromal cells on tissue recovery were evaluated. The polarization of the inflammatory response of irradiated muscle in a minipig model of cutaneous radiation syndrome was determined after acute local irradiation with 50 Gy gamma rays in a preliminary study (six minipigs). Analysis of the main inflammatory cytokines of the inflammatory response M1 (IL-1-beta and IL-6) and M2 (IL-10 and TGF-beta) by western blotting and in situ hybridization, as well as analysis of CD80/CD206 M1/M2 macrophage-specific markers by immunohistochemistry on minipig muscle samples, was performed 76 d after irradiation. The treatment of irradiated muscles with autologous adipose-tissue-derived stem/stromal cells led to an increase in IL-10 and TGF-beta, being associated with an increase in CD68+/CD206+ cells in this area. This highlights a polarization of M2 in the inflammatory response and indicates that adipose-tissue-derived stem/stromal cells may direct the irradiated tissues' inflammatory response towards a proregenerative outcome.

Abstract 845: Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat

Abstract Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. For instance, patients receiving acute doses of irradiation to the thoracic cavity for Hodgkin's lymphoma or breast cancer are subject to an elevated risk of RIHD. Excessive oxidative stress, at least in part, is responsible for some of the tissue damage. The ability to monitor and mitigate the long-term cardiac effects of radiation exposure in these populations by modulating oxidative stress has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate irradiation-induced heart damage. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at two and four weeks post-irradiation, as well as followed for one year. Four weeks following gamma irradiation, both males and females showed decreased heart mass and decreased whole body mass after exposure to medium and high doses of radiation and these decreases were sustained in the high dose groups after one year. Serum cardiac troponin I and T analysis revealed signs of cardiomyopathy in both the medium and high dose groups at early time points and this signal was sustained in some animals up to one year later. Echocardiography revealed functional changes in cardiac performance including an increase in left ventricular volume at diastole in males and a decrease in left ventricular mass. Low red blood cell count indicated sustained anemic conditions in both males and females receiving the highest dose of irradiation, yet males appeared to be more sensitive. Levels of pro-inflammatory IL-6 were elevated at four weeks in males receiving the high dose. Finally, multiple animals receiving radiation developed spontaneous tumors after one year. We are currently investigating the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage. Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao. Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 845.

Recovery kinetics of micronucleus formation by fractionated X-ray irradiation in various types of human cells.

High-dose ionizing radiation is sufficient for breaking DNA strands, leading to cell death and mutations. By contrast, the effects of fractionated ionizing radiation on human-derived cells remain unclear. To better understand the genotoxic effects of fractionated ionizing radiation, as well as the cellular recovery rate, we investigated the frequency of micronucleus (MN) formation in various types of human cells. We irradiated cells with fractionated X-ray doses of 2 Gy at a rate of 0.0635 Gy/min, separated into two to eight smaller doses. After irradiation, we investigated the frequency of MN formation. In addition, we investigated the rate of decrease in MN frequency after irradiation with 1 or 2 Gy X-rays at various recovery periods. Fractionated irradiation decreased MN frequency in a dose-dependent manner. When the total dose of X-rays was the same, the MN frequencies were lower after fractionated X-ray irradiation than acute irradiation in every cell type examined. The rate of MN decrease was faster in KMST-6 cells, which were derived from a human embryo, than in the other cells. The rate of MN decrease was higher in cells exposed to fractionated X-rays than in those exposed to acute irradiation. Recovery rates were very similar among cell lines, except in KMST-6 cells, which recovered more rapidly than other cell types.

Targeting PRPK and TOPK for skin cancer prevention and therapy.

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1 and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.

Plant breeding of some tropical fruits in Thailand; durian, mango, rambutan, tangerine, pummelo and papaya

Until recently, most Thai fruit cultivars were improved by chance seedlings and selected by Thai farmers. However, some commercial cultivars were selected and improved by plant breeders. A durian breeding program was commenced by the Department of Agriculture in 1956. Eighteen cultivars were selected to be parent plants for 55 reciprocal crosses and produced 7,634 F1 hybrid seedlings. Three promising lines were selected as commercial cultivars, namely, 'Chanthaburi 1', '2' and '3' in 2006 and characterized by DNA fingerprinting. Subsequently, 253 lines of F2 generation, 4,278 F1 lines from 51 new crosses between 1998 and 2002, 110 interspecific hybrids from 45 crosses between 1988 and 1992 and 21 crosses in 2000 are being investigated for high tolerance to Phytophthora palmivora, high yield and good fruit quality. Between 2006 and 2016, three lines were released namely, 'Chanthaburi 4', '5' and '6' in 2013 and another three will be released namely, 'Chanthaburi 7', '8', '9' in 2016. Exploration, collection, conservation, characterization, documentation and utilization of mango and rambutan species were studied in 2000-2003. Two lines of mango (CB0007 and CB0010) and one line of rambutan (CB0023) 'Thong Muang Trat' with long shelf life were selected. A mango breeding project was conducted on 60 crosses and 2 hybrids namely, 'Chanthaburi 1' and '2' were released with early maturity. In addition, the commercial cultivars 'Nam Dok Mai', 'Nam Dok Mai Si Tong' are exported. From 1974-1983, rambutan cultivar improvement was achieved by reciprocal crossing between five parents and 'Plew#3' was released to farmers. Acute and chronic gamma irradiation for mutation induction in tangerine (C. reliculata) and pummelo (C. grandis) to produce seedless cultivars or those containing fewer seeds were conducted between 2000-2006. Two seedless M1V4 pummelo 'Kao Thong Dee' resulted. Moreover, 8 promising lines were further investigated and one of them, A4V3-22-2 has good eating quality, 0-2 seeds fruit-1 and high yield namely, 'Phare 1'. Pummelo cultivar improvement has been conducted from 2006-2010 for high yield, high quality. Evaluation of 425 F1 hybrid pummelos showed that some have good growth, have started to set fruit and are being evaluated. In addition, 2 citrus species ('Thabtim' and 'Cleopatra') used as rootstocks have good compatiblity and result in good growth of cultivar 'Kao Thong Dee'. DOA papaya breeding was commenced in 1984. The DOA approved 'Khaek Dam Si Sa Ket' was selected as a new cultivar in 1994. 'Khaek Dam' was crossed to 'Coimbatire No. 2' (CO2) and 'Phichit' line was approved in 1997. A cross between the 'Khaek Dam' and the 'Florida Tolerant' cultivar, resulted in new cultivars, 'Khaek Dam Tha Phra' and 'Khon Kaen 80' which were approved in 1997 and 2010, respectively. In addition, genetic engineering was undertaken by the DOA in collaboration with Cornell University. The coat protein gene (CP gene) of PRSV was transferred into Thai papaya, 'Khaek Dam' and 'Khaek Nuan' cultivars. Currently, one cultivar 'Khaek Dam' (R3 300KD) and two 'Khaek Nuan' (R3 319-1KN-180 and R3 319-1KN-181) cultivars were selected for the R3 PRSV resistance. However, GMO research is still limited at the present in Thailand.

Lessons from the accident with 137Cesium in Goiania, Brazil: Contributions to biological dosimetry in case of human exposure to ionizing radiation

Human exposure to ionizing radiation has increased over time, mainly due to medical applications, occupational and environmental exposure, as well as accidents involving radioactive materials. In September 1987, an accident with 137Cesium occurred in Goiânia city, Brazil; the accident started with the removal of a 50.9-TBq 137Cesium source from an abandoned radiotherapy unit. Among the radiation-exposed victims, at least 50 individuals showed symptoms of whole-body and local acute irradiation, and also external or internal contamination. In this report, the purpose was to review and summarize the main results of cytogenetic studies carried out with victims of 137Cesium, for blood collection performed shortly after the accident, and following several years post-exposure. The importance of dose estimates by biological dosimetry is highlighted, and also several lessons that were learned from the initial to follow-up (7–10 years after the accident) studies, mainly by applying the fluorescence in situ hybridization (FISH) method. A relevant aspect discussed on the basis of the results obtained in those studies refers to the incidence of chromosomal translocations, which were directly compared to the initial frequencies of dicentrics that were previously used to estimate the absorbed doses. In general, translocation frequencies were two to three times lower than the dicentric frequencies, and the differences were dose-dependent. Furthermore, regarding attempts to perform retrospective dosimetry (10 years post-accident), the dose estimates using translocation frequencies for victims of 137Cesium indicate the feasibility of this approach only for low level exposure (below 0.5 Gy), while for higher doses there are some limitations, and the requirement to apply appropriate correction factors, which were discussed on the basis of literature data. Apart of this, in general terms, important aspects to be mentioned refer to the need for better care and control of radioactive devices, as well as adequate education programs for professionals and also the population.

Abstract A25: Intestinal tumorigenesis in APCMin/+ mice was higher after acute relative to fractionated proton radiation: Implications for space radiation-induced colorectal carcinogenesis

Abstract Ionizing radiation (IR) is a risk factor for colorectal cancer (CRC) based on epidemiologic studies. With increasing interest in exploring outer space, astronauts on prolonged space missions such as a mission to Mars will be exposed to IR doses that are expected to heighten the risk of CRC. Sources of space radiation beyond Earth's magnetosphere are galactic cosmic radiation (GCR) and solar particle event (SPE) and about 90% of the IR in outer space is energetic protons, which are more damaging than photon radiations such as γ-rays. While astronauts on deep-space missions are estimated to receive ~250 μGy/day of proton, radiation dose during SPE could reach up to ~2 Gy behind shielding. However, the risk of CRC after energetic proton radiation is not yet fully defined due to lack of human or animal model data. Limitations in obtaining adequate human data mandate that in vivo mechanistic data for CRC risk estimates be obtained using animal models and surrogate biologic and molecular end points relevant to human disease process. The purpose of the current study was to quantitatively and qualitatively compare and characterize differences in intestinal tumorigenesis between acute and fractionated proton irradiation in APCMin/+ mice, a well-established mouse model for human CRC. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy x 4). Since proton dose to astronauts is variable based on space environment, in this initial study we chose a high single dose and a low daily dose pattern to assess intestinal tumorigenesis. Intestinal tumor frequency and grade were noted, and tumor and normal tissue samples were collected from irradiated and control mice euthanized 100 to 110 days after radiation exposure. Molecular analysis was focused on DNA damage, genomic instability, specific epigenetic changes and mutation analysis, and cellular proliferative signaling pathways relevant to CRC using immunoblots, immunohistochemistry, and PCR. Relative to control and fractionated protons, there was significantly higher intestinal tumor frequency and grade after acute proton irradiation. At the molecular level our data showed increased DNA damage and DNA double-strand breaks, decreased genomic stability, and upregulation of proliferative β-catenin and Akt signaling after acute proton exposure. Since increased DNA damage was not associated with concomitant increased apoptosis and there was increased microsatellite instability, our data are suggestive of continued proliferation of cells bearing sublethal damages. Mutational analysis showed significantly more tumors had higher overall mutation frequency and increased p53 hot spot mutations after acute relative to fractionated proton exposure. In fractionated proton groups, tumor frequency and grade as well as molecular changes were statistically comparable to control groups. When considered along with higher mutational frequency and altered promoter methylation of key CRC-related genes in tumor adjacent normal tissues, our data are suggestive of marked differences in carcinogenesis of acute vs. fractionated proton radiation with higher tumorigenic effects associated with acute exposures. Citation Format: Shubhankar Suman, Bo-Hyun Moon, Albert J. Fornace, Jr., Kamal Datta. Intestinal tumorigenesis in APCMin/+ mice was higher after acute relative to fractionated proton radiation: Implications for space radiation-induced colorectal carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A25.

Особливості клітинного складу кісткового мозку щурів при гострому опроміненні та введенні S-гетерилмодифікованого цистеаміну

Особливості клітинного складу кісткового мозку щурів при гострому опроміненні та введенні S-гетерилмодифікованого цистеаміну

1145 Acute UV irradiation and intrinsic aging modulate various histone deacetylases expression levels in human skin in vivo

Epigenetic regulation is widely considered to play an important role in aging, but experimental evidence to support this hypothesis for skin aging in vivo is scarce. Histone deacetylases(HDACs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. There are 11 HDACs and 7 sirtuins(Sirts) as histone deacetylases that play a critical role in epigenetics. Previously, our group demonstrated the role of histone acetylation in UV-induced inflammation and matrix impairment. Here, to understand the histone acetylation alterations occurring during the aging process, we investigated the changes HDACs and Sirts expressions in UV-irradiated human skin, and the intrinsically aged and photoaged human skin in vivo. We found that acetyl-H3 level was increased and HDAC4, 11, and Sirt4 mRNA were significantly deceased in UV-irradiated skin. In intrinsically aged skin, acetyl-H3 level was increased and HDAC4, 5, 10, 11, and Sirt6, 7 mRNA were significantly deceased. However, histone acetylation and HDACs expressions in photoaged forearm skin were not different from those in intrinsically aged buttock skin in the same individuals. Thus, our results suggested that decreased HDACs expression by acute UV irradiation and intrinsic aging may contribute to increased histone acetylation. Therefore, epigenetic regulation that reduces histone acetylation by increasing the expression of HDACs may prevent skin aging.

Effects of acute gamma irradiation on in vitro culture of Exacum affine Balf.f. ex Regel

Exacam affine Balf. f. ex Regel (Persian Violet) is an ornamental plant with small, purple flowers having yellow pollen in their center and it is mostly cultivated as a houseplant. The effect of acute gamma irradiation on in vitro cultures of E. affine was studied by treatment with gamma radiation using a Mark I Gamma Irradiator at the Nuclear Technology Research Center, Kasetsart University, Thailand with a Cesium-137 source at doses of 0, 10, 20, 30, 40, 50 and 60 Gy and a dose rate of 3.74 Gy/min. After irradiation, subcultures were grown on new Murashige and Skoog (MS) medium; then, after 60 d, the numbers of new branches on surviving plantlets were counted. Samples were subsequently subcultured to new MS medium for morphological study. The median lethal dose was 45 Gy and the 50% decreasing growth rate was 32 Gy. Some variations were observed in irradiated samples in M1V2, such as changes in the number of petals in a flower (four and six petals), flower color (light purple, white), smaller leaves, curled-shaped leaves, variegated leaves, lighter-green leaves and shorter internodes than the control.

Physiological effects of short acute UVB treatments in Chenopodium quinoa Willd

Increased ultraviolet B (UVB) radiation due to global change can affect plant growth and metabolism. Here, we evaluated the capacity of quinoa to resist under short acute UVB irradiation. Quinoa was daily exposed for 30 or 60 min to 1.69 W m−2 UVB. The results showed that 30 min exposure in 9 d-course did not cause severe alterations on photosynthetic pigments and flavonoids, but a significant increase of antioxidant capacity was observed. Otherwise, 60 min UVB in 5 d-course reduced almost all these parameters except for an increase in the de-epoxidation of xanthophyll cycle pigments and led to the death of the plants. Further studies of gas exchange and fluorescence measurements showed that 30 min UVB dramatically decrease stomatal conductance, probably associated to reactive oxygen species (ROS) production. Inhibition of photosynthetic electron transport was also observed, which could be a response to reduce ROS. Otherwise, irreversible damage to the photosynthetic apparatus was found with 60 min UVB probably due to severe ROS overproduction that decompensates the redox balance inducing UVB non-specific signaling. Moreover, 60 min UVB compromised Rubisco carboxylase activity and photosynthetic electron transport. Overall, these data suggest that quinoa modulates different response mechanisms depending on the UVB irradiation dosage.

Comparison of radiosensitivity response to acute and chronic gamma irradiation in colored wheat

We aimed to investigate the biological responses induced by acute and chronic gamma irradiation in colored wheat seeds rich in natural antioxidants. After acute and chronic irradiation, the phenotypic effects on plant growth, germination rate, seedling height, and root length were examined, and the biochemical changes were investigated by analyzing the expression of antioxidant enzyme-related genes, antioxidant enzyme activities, and total antioxidant capacity. High dosages of chronic radiation reduced plant growth compared with the controls. Electron spin resonance measurement and 2,2-diphenyl-1-picrylhydrazyl activity analysis showed lower amount of free radicals in colored wheat seeds on chronic irradiation with low dosage of gamma rays compared to seeds subjected to acute irradiation. Expression levels of anthocyanin biosynthesis genes, antioxidant-related genes, and antioxidant enzyme activity in seeds and young leaves of seedling showed diverse effects in response to different dosages and types of gamma irradiation. This suggests that phenotype is affected by the dosage and type of gamma radiation, and the phytochemicals in colored wheat seeds involved in antioxidant activity to scavenge free radicals respond differently to irradiation types. This provides evidence that acute and chronic exposure to radiation have different effects on seeds and young leaves after germination.

Effect of acute gamma irradiation on flower, bulb characters and stability of mutants in tuberose (Polianthes tuberosa)

Genetic variability is the prerequisite for any crop to be improved. Mutation breeding is a best method identified to enhance the genetic variability in crops within short time. Knowing the limited variability in tuberose (Polianthes tuberosa), present investigation was undertaken for the improvement in this crop by utilizing the cultivars Phule Rajani and Prajwal. To induce variation, gamma radiation (2.5 - 15 Gy) was applied and the effect on flower and bulb characters were assessed in M1 generation. With increase in doses of gamma irradiation, gradual reduction in number of spikes, flower number, number of bulb, weight of bulb and bulb diameter was observed. In some cases lower dose was found simulative, while higher dose had inhibitory effect on morphological variation. Various macro mutations were scored for uniform flowering, reduced number of bulbs and spike number in M1 population. The mutants of VM1 generation not found stable in VM2 generation. But we could able to find the some more mutants from the maintained gamma irradiated population of VM2 generation related to change in flower shape. In general, freshly harvest tuberose bulbs of cv. Prajwal and Phuel Rajani responded more to gamma irradiation. From this study, it has found that gamma irradiation level, 7.5 Gy and 10.0 Gy were found optimal for mutation induction in these two tuberose cultivars.

Improved survival with higher radiation dose for esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PurposeThe optimal radiation dose for patients with esophageal squamous cell carcinoma (ESCC) has long been debated. We undertook the retrospective study to evaluate the survival impact of high dose vs standard dose in patients with stage II–III esophageal cancer treated with definitive chemoradiotherapy (CRT).ResultsA total of 137 patients were included in our study, 63 patients classified as standard-dose group and 74 as high-dose group. For the 63 patients in the standard-dose group, the median PFS and the 1-, 2-, and 3-year PFS rates were 12.6 months, 58.0%, 26.0% and 12.0%, respectively; for the 74 patients in the high-dose group, they were 20.0 months, 80.1%, 31.0% and 20.0%, respectively (P = 0.013). The median OS of the patients in the standard-dose group and high-dose group groups were 19.0 months and 26.6 months, respectively, and the 1-, 2- and 3-year survival rates were 78.0%, 39.0%, and 24.0% , and 89.0%, 61.0%, and 30.0%, respectively (P = 0.037). Besides the rate of grade ≥ 3 acute irradiation esophagitis in the high-dose group (10.5% versus. 2.2%, P < 0.01), there were no significantly differ of treatment-related toxicities between the two groups.Materials and MethodsAccording to the radiation dose, patients from 2010 to 2014 were allocated into either the standard-dose group (50–50.4 Gy) or the high-dose group (≥ 59.4 Gy). Overall survival (OS), progression-free survival (PFS) and treatment-related toxicities were assessed and compared between the two groups.ConclusionsOur findings suggest that higher radiation dose could perform better outcomes for esophageal squamous cell carcinoma patients.

Preservation of chromosomal integrity in murine spermatozoa derived from gonocytes and spermatogonial stem cells surviving prenatal and postnatal exposure to γ-rays in mice.

Pre- and postnatal male mice were acutely (659-690 mGy/min) and continuously (0.303 mGy/min) exposed to 2 Gy γ-rays to evaluate spermatogenic potential and chromosome damage in their germ cells as adults. Acute irradiation on Days 15.5, 16.5, and 17.5 post-coitus affected testicular development, as a result of massive quiescent gonocyte loss; the majority of the seminiferous tubules in these testes were devoid of germ cells. Acute irradiation on Days 18.5 and 19.5 post-coitus had less effect on testicular development and spermatogenesis, even though germ cells were quiescent gonocytes on these days. Adverse effects on testicular development and spermatogenesis were observed following continuous irradiation between Days 14.5 and 19.5 post-coitus. Exposure to acute and continuous postnatal irradiation after the differentiation of spermatogonial stem cells and spermatogonia resulted in nearly all of the seminiferous tubules exhibiting spermatogenesis. Neither acute nor continuous irradiation was responsible for the increased number of multivalent chromosomes in primary-spermatocyte descendents of the exposed gonocytes. In contrast, a significant increase in cells with multivalent chromosomes was observed following acute irradiation on Days 4 and 11 post-partum. No significant increases in unstable structural chromosomal aberrations or aneuploidy in spermatozoa were observed, regardless of cell stage at irradiation or the radiation dose-rate. Thus, murine germ cells that survive prenatal and postnatal irradiation can restore spermatogenesis and produce viable spermatozoa without chromosome damage. These findings may provide a better understanding of reproductive potential following accidental, environmental, or therapeutic irradiation during the prenatal and postnatal periods in humans.

740 Serum Amyloid A1 is induced by UV irradiation and detected by toll-like receptor 4 to cause skin inflammation

Cutaneous inflammation induced by UV irradiation has been well documented clinically. However, despite many previous efforts, it is not fully understood which molecules mediate this inflammatory response. Our recent study found that serum amyloid A1 (SAA1) was increased in UV-irradiated human skin. Since SAA1 has been reported to exert proinflammatory effect, this finding implicates SAA1 as a mediator in UV-induced cutaneous inflammation. Here, we demonstrated that the expression of SAA1 was increased by acute UV irradiation in mouse skin in vivo. Intradermal injection of recombinant mouse SAA1 caused inflammation and induced IL-1β and IL-6 in mouse skin in vivo. Correspondingly, treatment of recombinant human SAA1 (rhSAA1) induced IL-1β, IL-6, and IL-8 in primary normal human dermal fibroblasts (NHDFs). In addition, knockdown of Toll-like receptor 4 (TLR4) or blocking of NF-κB signaling pathway attenuated rhSAA1-induced proinflammatory cytokine expressions in NHDFs. Taken together, our data showed that SAA1 was produced by UV irradiation and induced inflammation in mouse skin in vivo and that SAA1 induced proinflammatory cytokines in NHDFs through TLR4/NF-κB signaling pathway. Therefore, our results suggest that SAA1 can be a potential mediator for UV irradiation-induced cutaneous inflammation.

Abstract #919: Normal Spermatogenesis 32 Years Later Despite Chemotherapy for Acute Lymphoblastic Leukemia and Total Body Irradiation for Bone Marrow Transplant

Abstract #919: Normal Spermatogenesis 32 Years Later Despite Chemotherapy for Acute Lymphoblastic Leukemia and Total Body Irradiation for Bone Marrow Transplant

Radioprotective effect of ursolic acid in radiation-induced impairment of neurogenesis, learning and memory in adolescent BALB/c mouse

The effect of acute irradiation with 5Gy or fractionated exposure with 0.5Gy continuously for 10days (a total dose of 5Gy) was evaluated in an immature BALB/c mouse model. Radioprotective effect of ursolic acid (at 25mg/kg/daily administered 1h after acute or each of fractionated irradiations, and continuously for 30days) was also investigated. We found that both acute and fractionated irradiation at a total dose of 5Gy did not induce any mortality within 30days after exposure to postnatal day 26 (P26) BALB/c mice, but reduced animal weigh gain in the first few weeks. At 90days after irradiation, the weight of animals with acute irradiation was still significantly lower than the control group; no significant difference though was observed for those fractionatedly exposed mice compared to the control group. Behavioral tests indicated that acute irradiation at 5Gy induced deficits in learning and memory in the contextual fear conditioning test. The memory for novel object recognition was also impaired. Similar changes were not observed in mice with fractionated irradiation. Immunohistochemical study demonstrated clearly that acute and fractionated irradiations induced impairment of neurogenesis in the subgranular zone (SGZ) of the dentate gyrus although fractionated exposure induced much lesser loss of newly generated neurons. Ursolic acid administered at 25mg/kg/daily for 30days after irradiation greatly improved acute irradiation-induced deficits in contextual learning and memory and in novel object recognition memory although it exacerbated radiation-induced reduction of neurogenesis in SGZ.

Influence of a pre-stimulation with chronic low-dose UVB on stress response mechanisms in human skin fibroblasts.

Exposure to solar ultraviolet type B (UVB), through the induction of cyclobutane pyrimidine dimer (CPD), is the major risk factor for cutaneous cancer. Cells respond to UV-induced CPD by triggering the DNA damage response (DDR) responsible for signaling DNA repair, programmed cell death and cell cycle arrest. Underlying mechanisms implicated in the DDR have been extensively studied using single acute UVB irradiation. However, little is known concerning the consequences of chronic low-dose of UVB (CLUV) on the DDR. Thus, we have investigated the effect of a CLUV pre-stimulation on the different stress response pathways. We found that CLUV pre-stimulation enhances CPD repair capacity and leads to a cell cycle delay but leave residual unrepaired CPD. We further analyzed the consequence of the CLUV regimen on general gene and protein expression. We found that CLUV treatment influences biological processes related to the response to stress at the transcriptomic and proteomic levels. This overview study represents the first demonstration that human cells respond to chronic UV irradiation by modulating their genotoxic stress response mechanisms.

Effect of Low-Dose Selenium Supplementation on the Genotoxicity, Tissue Injury and Survival of Mice Exposed to Acute Whole-Body Irradiation.

The aim of the present study is to evaluate the radioprotective effect of low-dose selenium supplementation (multiple administrations) on radiation toxicities and mortality induced by lethal dose of whole-body irradiation (WBI). For this, BALB/c mice received sodium selenite (4μg/kg body wt) intraperitoneally for five consecutive days and subjected to WBI at an absorbed dose of 8Gy (60Co, 1Gy/min). Administration of sodium selenite was continued even during the post irradiation days three times a week till the end of the experiment. The radioprotective effect was evaluated in terms of the improvement in 30days post irradiation survival, protection from DNA damage, and biochemical and histological changes in radiosensitive organs. The results indicated that low-dose sodium selenite administration did not protect the mice from radiation-induced hematopoietic and gastrointestinal injuries and subsequent mortality. However, it significantly prevented the radiation-induced genotoxicity or DNA damage in peripheral leukocytes. Further sodium selenite administration modulated the messenger RNA (mRNA) expression of GPx1, GPx2, and GPx4 in the spleen and intestine differentially and led to a significant increase in GPx activity (∼1.5 to 2-folds) in these organs. In line with this observation, sodium selenite administration reduced the level of lipid peroxidation in the intestine. In conclusion, our study shows that low-dose sodium selenite supplementation can be an effective strategy to prevent WBI-induced genotoxicity but may not have an advantage against mortality sustained during nuclear emergencies.