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1.
AbstractPurpose: Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition. Materials and methods: Athymic nude rats were cranially irradiated (10 Gy) and subjected to intrahippocampal transplantation surgery 2 days later. Human embryonic stem cells (hESC) or human neural stem cells (hNSC) were transplanted, and animals were subjected to cognitive testing on a novel place recognition task 8 months later. Results: Grafting of hNSC was found to provide long lasting cognitive benefits over an 8-month post-irradiation interval. At this protracted time, hNSC grafting improved behavioral performance on a novel place recognition task compared to irradiated animals not receiving stem cells. Engrafted hESC previously shown to be beneficial following a similar task, 1 and 4 months after irradiation, were not found to provide cognitive benefits at 8 months. Conclusions: Our findings suggest that hNSC transplantation promotes the long-term recovery of the irradiated brain, where intrahippocampal stem cell grafting helps to preserve cognitive function. 相似文献
2.
目的研究幼鼠全脑小剂量照射对脑室周围神经干细胞的影响。方法6周Wistar大鼠80只,随机分为对照组4J0只,照射组4J0只,用1Gy X射线全脑照射,照射后30和60d,分别随机取5只处死,测量体重、脑重量。照射后6h、7、14、30和60d,用免疫组织化学方法动态检测脑室周围nestin阳性细胞的表达。结果尽管照射组和对照组大鼠的体重相似,但照射组大鼠脑重量显著减少。在脑室周围,照射6h后,许多凋亡细胞出现,同时,nestin阳性细胞明显减少(对照组的69%),7d恢复到照射前水平,14 d nestin阳性细胞达到最大值(为对照组的182%),30 d nestin阳性细胞恢复到基线水平(为对照组的96%),并且在随后的60d没有变化。结论单次小剂量照射对脑室周围神经干细胞的影响是可逆的,提示在临床治疗上,连续多次X射线照射也许对神经干细胞有一个不可逆的影响,从而导致脑生长迟缓或功能异常。 相似文献
3.
AbstractPurpose: The low dose radiation response of primary human umbilical vein endothelial cells (HUVEC) and its immortalized derivative, the EA.hy926 cell line, was evaluated and compared. Material and methods: DNA damage and repair, cell cycle progression, apoptosis and cellular morphology in HUVEC and EA.hy926 were evaluated after exposure to low (0.05–0.5 Gy) and high doses (2 and 5 Gy) of acute X-rays. Results: Subtle, but significant increases in DNA double-strand breaks (DSB) were observed in HUVEC and EA.hy926 30 min after low dose irradiation (0.05 Gy). Compared to high dose irradiation (2 Gy), relatively more DSB/Gy were formed after low dose irradiation. Also, we observed a dose-dependent increase in apoptotic cells, down to 0.5 Gy in HUVEC and 0.1 Gy in EA.hy926 cells. Furthermore, radiation induced significantly more apoptosis in EA.hy926 compared to HUVEC. Conclusions: We demonstrated for the first time that acute low doses of X-rays induce DNA damage and apoptosis in endothelial cells. Our results point to a non-linear dose-response relationship for DSB formation in endothelial cells. Furthermore, the observed difference in radiation-induced apoptosis points to a higher radiosensitivity of EA.hy926 compared to HUVEC, which should be taken into account when using these cells as models for studying the endothelium radiation response. 相似文献
4.
Purpose: To determine whether changes in oxidative stress could enhance the sensitivity of neural precursor cells to ionizing radiation. Materials and methods: Two strategies were used whereby oxidative stress was modulated endogenously, through manipulation cell culture density, or exogenously, through direct addition of hydrogen peroxide. Results: Cells subjected to increased endogenous oxidative stress through low-density growth routinely exhibited an inhibition of growth following irradiation. However, cells subjected to chronic exogenous oxidative treatments showed increased sensitivity to proton and γ-irradiation compared to untreated controls. Reduced survival of irradiated cultures subjected to oxidizing conditions was corroborated using enzymatic viability assays, and was observed over a range of doses (1 – 5 Gy) and post-irradiation re-seeding densities (20 – 200 K/plate). Conclusions: Collectively our results provide further support for the importance of redox state in the regulation of neural precursor cell function, and suggest that oxidative stress can inhibit the proliferative potential of cells through different mechanisms. This is likely to compromise survival and under conditions where excess exogenous oxidants might predominate, sensitivity to irradiation may be enhanced. 相似文献
5.
AbstractPurpose: The objective of this study was to elucidate the action of α-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating radiation-induced injuries. Material and methods: CD2F1 mice were exposed to a high dose of radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMC) from TS- and AMD3100-injected mice after irradiation. Intestinal and splenic tissues were harvested after irradiation and cells of those tissues were analyzed for markers of apoptosis and mitosis. Bacterial translocation from gut to heart, spleen, and liver in TS-treated and irradiated mice was evaluated by bacterial culture. Results: We observed that the infusion of PBMC from TS- and AMD3100-injected mice significantly inhibited apoptosis, increased cell proliferation in the analyzed tissues of recipient mice, and inhibited bacterial translocation to various organs compared to mice receiving cells from vehicle-mobilized cells. This study further supports our contention that the infusion of TS-mobilized progenitor-containing PBMC acts as a bridging therapy by inhibiting radiation-induced apoptosis, enhancing cell proliferation, and inhibiting bacterial translocation in irradiated mice. Conclusions: We suggest that this novel bridging therapeutic approach that involves the infusion of TS-mobilized hematopoietic progenitors following acute radiation injury might be applicable to humans as well. 相似文献
6.
AbstractPurpose: The aim of this study was to compare levels of apoptosis, necrosis, mitotic cell death and senescence after treatment with both direct radiation and irradiated cell conditioned medium. Materials and methods: Human keratinocytes (HaCaT cell line) were irradiated (0.005, 0.05 and 0.5 Gy) using a cobalt 60 teletherapy unit. For bystander experiments, the medium was harvested from donor HaCaT cells 1 hour after irradiation and transferred to recipient HaCaT cells. Clonogenic assay, apoptosis, necrosis, mitotic cell death, senescence and cell cycle analysis were measured in both directly irradiated cells and bystander cells Results: A reduction in cell survival was observed for both directly irradiated cells and irradiated cell conditioned medium (ICCM)-treated cells. Early apoptosis and necrosis was observed predominantly after direct irradiation. An increase in the number of cells in G2/M phase was observed at 6 and 12 h which led to mitotic cell death after 72 h following direct irradiation and ICCM treatment. No senescence was observed in the HaCaT cell line following either direct irradiation or treatment with ICCM. Conclusion: This study has shown that directly irradiated cells undergo apoptosis, necrosis and mitotic cell death whereas ICCM-treated cells predominantly undergo mitotic cell death. 相似文献
7.
Purpose: To investigate alterations of mitochondria in irradiated endothelial cells to further elucidate the mechanism underlying radiation-induced heart disease. Materials and methods: Experiments were performed using human umbilical vein endothelial cells (HUVECs). HUVECs were irradiated with single gamma ray dose of 0, 5, 10 and 20?Gy, respectively. Apoptosis was assessed by flow cytometry at 24, 48 and 72?h post-irradiation, respectively. The intracellular reactive oxygen species (ROS) was measured with 2′,7′-dichlorofluorescein-diacetate (DCFH-DA) at 24?h post-irradiation. Mitochondrial membrane potential ( ΔΨm) by JC-1 and the opening of mitochondrial permeability transition pore (mPTP) by a calcein-cobalt quenching method were detected at 24?h post-irradiation in order to measure changes of mitochondria induced by gamma ray irradiation. Results: Gamma ray irradiation increased HUVECs apoptosis in a dose-dependent and time-dependent manner. Irradiation also promoted ROS production in HUVECs in a dose-dependent manner. At 24?h post-irradiation, the results showed that irradiation decreases ΔΨm, however, paradoxically, flow cytometry showed green fluorescence instensity higher in irradiated HUVECs than in control HUVECs in an irradiation dose-dependent manner which indicated gamma ray irradiation inhibited mPTP opening in HUVECs. Conclusions: Gamma ray irradiation induces apoptosis and ROS production of endothelial cells, and decreases ΔΨm meanwhile contradictorily inhibiting the opening of mPTP. 相似文献
8.
Purpose:?To characterise the radiation response of human hematopoietic stem and progenitor cells (HSPC) with respect to X and carbon ion irradiation. Materials and methods:?HSPC from peripheral blood of healthy donors treated with granulocyte-colony stimulating factor (G-CSF) were enriched for the transmembrane glycoprotein CD34 (cluster of differentiation) and irradiated with X rays or carbon ions (29 keV/μm monoenergetic beam and 60-85 keV/μm spread-out Bragg peak), mimicking radiotherapy conditions. Apoptotic cell death, cell cycle progression and the frequency of chromosomal aberrations were determined. Results:?After radiation exposure no inhibition in the progression of the cell cycle was detected. However, an enhanced frequency of apoptotic cells and an increase in aberrant cells were observed, both effects being more pronounced for carbon ions than X rays, resulting in a relative biological effectiveness (RBE) of 1.4–1.7. The fraction of complex-type aberrations was higher following carbon ion exposure. Conclusions:?RBE values of carbon ions are low, as expected for radiosensitive cells. The observed frequencies of apoptotic cells and chromosome aberrations in HSPC are similar to those reported for human peripheral blood lymphocytes suggesting that at least with respect to apoptosis and chromosomal aberrations mature lymphocytes reflect the respective radiation responses of their proliferating progenitors. 相似文献
9.
AbstractPurpose: A comparative study of the effects of different radiation modalities on cell death was performed. Materials and methods: Radiation modalities included γ-rays, fast neutrons, a mixed energy neutron beam called the modified enhanced thermal neutron beam and the mixed beam including Auger electron irradiation by gadolinium neutron capture. U87 (human brain tumor cells) cell survival curve data were modeled to predict how cells died. Transmission electron microscopy (TEM) images were assembled into a morphology of cell death (MCD) database and used to determine the fraction of necrotic or autophagic cells. Results: Linear energy transfer (LET) differences for the different radiation modalities were revealed by modeling. All radiation modalities induced autophagy but only fast neutrons induced significant levels of necrosis. No necrosis, above control levels, was found in cells irradiated with mixed beam irradiation including Auger electrons. The number of autophagosomes increased with increasing time after exposure to all radiation modalities indicating progression of autophagy but only cells irradiated with the mixed beam plus Auger electrons exhibited extreme autophagy. Conclusions: Mixed neutron beam irradiation plus Auger electron irradiation from gadolinium neutron capture is a moderately high LET modality that kills U87 cells without the induction of necrosis and with progression of autophagy to an extreme state. 相似文献
10.
目的 探讨过表达脑源性神经营养因子(BDNF)的神经干细胞(NSCs)移植入放射性脑损伤大鼠模型后,对海马内神经营养因子水平及小胶质细胞活化的影响。 方法 从胎鼠脑中分离海马神经干细胞并进行培养。选用绿色荧光蛋白(GFP)-慢病毒、GFP-BDNF-慢病毒感染神经干细胞。将SD大鼠按随机数表法分为4组:健康对照组、单纯照射组(R组)、照射后GFP修饰的神经干细胞移植组(R+NSCs组)、照射后GFP-BDNF修饰的神经干细胞移植组(R+BDNF-NSCs组)。全脑单次20 Gy照射后1个月将神经干细胞移植入大鼠双侧海马内。移植后2和8周检测海马组织中BDNF、胶质源性神经营养因子(GDNF)、神经生长因子(NGF)的表达情况;免疫荧光染色观察小胶质细胞活化情况。 结果 移植后2和8周时,与R组相比,R+BDNF-NSCs组海马组织中BDNF、NGF蛋白表达均水平明显增高( P<0.05);移植后8周R+NSCs组和R+BDNF-NSCs组活化的小胶质细胞与R组相比并未显著减少( P>0.05)。 结论 过表达BDNF的神经干细胞移植后促进BDNF、NGF的产生,增加了辐射暴露后的海马内神经营养因子水平。 相似文献
11.
AbstractPurpose: Radioresistance of cancer cells remains a fundamental barrier for maximum efficient radiotherapy. Tumor heterogeneity and the existence of distinct cell subpopulations exhibiting different genotypes and biological behaviors raise difficulties to eradicate all tumorigenic cells. Recent evidence indicates that a distinct population of tumor cells, called cancer stem cells (CSC), is involved in tumor initiation and recurrence and is a putative cause of tumor radioresistance. There is an urgent need to identify the intrinsic molecular mechanisms regulating the generation and maintenance of resistance to radiotherapy, especially within the CSC subset. The chemokine C-X-C motif receptor 4 (CXCR4) has been found to be a prognostic marker in various types of cancer, being involved in chemotaxis, stemness and drug resistance. The interaction of CXCR4 with its ligand, the chemokine C-X-C motif ligand 12 (CXCL12), plays an important role in modulating the tumor microenvironment, angiogenesis and CSC niche. Moreover, the therapeutic inhibition of the CXCR4/CXCL12 signaling pathway is sensitizing the malignant cells to conventional anti-cancer therapy. Content: Within this review we are summarizing the role of the CXCR4/CXCL12 axis in the modulation of CSC properties, the regulation of the tumor microenvironment in response to irradiation, therapy resistance and tumor relapse. Conclusion: In light of recent findings, the inhibition of the CXCR4/CXCL12 signaling pathway is a promising therapeutic option to refine radiotherapy. 相似文献
13.
AbstractPurpose: A study of irradiated (0.25–2 Gy) murine bone marrow has investigated the relationships between apoptotic responses of cells exposed in vivo and in vitro and between in vivo apoptosis and tissue cytotoxicity. Materials and methods: The time course of reduction in bone marrow cellularity in vivo was determined by femoral cell counts and apoptosis measurements obtained using three commonly used assays. Inflammatory pro-apoptotic cytokine production at 24 h post-exposure in vivo was investigated using a bystander protocol. Results: In vivo, there is a dose- and time-dependent non-linear reduction in bone marrow cellularity up to 24 h post- irradiation not directly represented by apoptosis measurements. The majority of cells are killed within 6 h but there is on-going cell loss in vivo up to 24 h post-irradiation in the absence of elevated levels of apoptosis and associated with the induction of cytokines produced in response to the initial tumor protein 53 (p53)-dependent apoptosis. Conclusion: The results demonstrate that small increases in measured apoptosis can reflect significant intramedullary cell death and with apoptotic processes being responsible for pro-inflammatory mechanisms that can contribute to additional on-going cell death. The findings demonstrate the importance of studying tissue responses when considering the mechanisms underlying the consequences of radiation exposures. 相似文献
14.
Purpose:?To analyse short term and long term X-ray irradiation effects on proliferation, viability, glucose and amino acid uptake of murine melanoma cells in vitro and metastasis in vivo. Materials and methods:?B16-F10 melanoma cells were irradiated with different doses of X-ray irradiation (200?kV) in the range from 1–20?Gy. One, two and three days respectively 7, 14 and 21 days after treatment cells were analysed concerning cell growth, viability, proliferation, cell cycle distribution, glucose and amino acid transport. Moreover the capability of the cells for in vivo metastasis was examined. Results:?As short term response on irradiation we detected decreased cell growth, viability and arrest in the G2/M phase of the cell cycle. Long term response involves re-start of proliferation, increased cell growth and glucose uptake but still decreased viability and amino acid transport. In vivo metastasis is lost immediately after irradiation and regained to a low extent beyond two weeks time for recurrence of cells before injection. Conclusions:?In vitro data suggest that surviving melanoma cells compensate the initial irradiation-dependent damage of proliferation within three weeks possibly by increase in glucose uptake. For metastasis in vivo the role of additional mechanisms is strongly suggested. 相似文献
15.
AbstractPurpose: Silymarin has been widely exploited for its hepatoprotective activities. This study aimed to evaluate the protective efficacy of silymarin against γ-radiation. Materials and methods: The radioprotective properties of silymarin were studied using different assays. Cytotoxicity of silymarin on Human embryonic kidney (HEK) cells was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Protective efficacy against γ-radiation was assessed by studying reduction in micronuclei frequency and free radical generation using 2′,7′-dichlorodihydroflurescin diacetate (H 2DCFDA). Radiation-induced apoptosis was estimated by Annexin V-PI (propidium iodide) analysis and cell cycle analysis. γ-radiation induced changes in mitochondrial membrane potential (MMP) and DNA damage was estimated employing flow-cytometry and comet assay respectively. Results: MTT assay and Annexin V-PI studies showed that pre-incubation of HEK cells with silymarin protected them from γ-irradiation. Significant reduction in apoptosis (76.36%) was observed. Silymarin also decreased the percentage of radiation-induced micronuclei (> 69%) ( p < 0.05 ). Measurement of intracellular reactive oxygen species (ROS) by H 2DCFDA revealed a reduction in ROS (21%) at 0.5 h. Cell cycle analysis revealed G 1 block in the unirradiated control, which declined in the silymarin pretreated irradiated group (0.5 h). Silymarin treatment resulted in a significant increase in MMP (2 h) against the radiation control. Moreover, the presence of silymarin during irradiation significantly decreased the DNA damage (as measured by comet assay). Conclusions: Protection against radiation-induced cell-death and DNA damage by silymarin could be attributed to a reduction in ROS induced by γ-radiation. In vitro experiments on HEK cells explicitly prove that silymarin is a promising, effective and safe radiation countermeasure agent. 相似文献
16.
AbstractPurpose: In the months following radiotherapy, a rapid recurrence of glioblastoma multiforme occurs in the periphery of the resection cavity. The aim of this study was to assess the contribution of irradiation of the brain in the infiltration profile of glioma cells. Material and methods: Using the F98/Fischer rat glioma model, we either irradiated the brain, the F98 cancer cells, or both to separately investigate the effects of radiation. Inflammatory cytokines and pro-infiltration molecules were measured in irradiated brain. Results: A stimulation of interleukin-1β and transforming growth factor β1 expression 4 h after brain irradiation supported induction of inflammation. Early elevated expression of phospholipase A 2 was also measured and was followed by a stimulation of cyclooxygenase-2 from day 5 to 20 after irradiation. This resulted in a biphasic increase of prostaglandins E 2 and D 2 biosynthesis with maximum at 4 h and 15 days post-irradiation. An important enhancement of F98 cells infiltration was observed when brain was irradiated, which took place at the expense of the growth of the primary tumour and resulted in a decreased median survival of the Fischer rats. This stimulation of F98 cells infiltration was associated with the pro-infiltration molecule, matrix metalloproteinase-2. Conclusion: In the animal model proposed, we demonstrated that irradiation of brain increased the infiltration capacity of F98 cells to the brain, resulting in a reduction of media survival of rats bearing this tumour. This animal model has also allowed identifying inflammatory cytokines and pro-infiltration molecules induced by radiation that can be targeted to prevent this adverse effect of radiation. 相似文献
17.
Purpose: Exposure to proton irradiation during missions in deep space can lead to bone marrow injury. The acute effects of proton irradiation on hematopoietic stem and progenitor cells remain undefined and thus were investigated. Materials and methods: We exposed male C57BL/6 mice to 0.5 and 1.0?Gy proton total body irradiation (proton-TBI, 150?MeV) and examined changes in peripheral blood cells and bone marrow (BM) progenitors and LSK cells 2 weeks after exposure. Results: 1.0?Gy proton-TBI significantly reduced the numbers of peripheral blood cells compared to 0.5?Gy proton-TBI and unirradiated animals, while the numbers of peripheral blood cell counts were comparable between 0.5?Gy proton-TBI and unirradiated mice. The frequencies and numbers of LSK cells and CMPs in BM of 0.5 and 1.0?Gy irradiated mice were decreased in comparison to those of normal controls. LSK cells and CMPs and their progeny exhibited a radiation-induced impairment in clonogenic function. Exposure to 1.0?Gy increased cellular apoptosis but not the production of reactive oxygen species (ROS) in CMPs two weeks after irradiation. LSK cells from irradiated mice exhibited an increase in ROS production and apoptosis. Conclusion: Exposure to proton-TBI can induce acute damage to BM progenitors and LSK cells. 相似文献
18.
目的 探讨硫酸镁对大鼠神经干细胞辐射损伤的保护作用。 方法 取新生大鼠神经干细胞进行培养,用免疫荧光法进行神经干细胞的鉴定后,用含有不同浓度硫酸镁的培养基培养神经干细胞,选择出硫酸镁的合适浓度为1.25 mg/ml。将神经干细胞分为空白对照组、单纯照射组及照射+硫酸镁组,照射+硫酸镁组神经干细胞加入1.25 mg/ml的硫酸镁培养24 h后,分别用2和4 Gy 60Co γ射线对单纯照射组及照射+硫酸镁组进行照射,分别于照射后24、48和72 h用CCK-8对各组进行神经干细胞增殖情况的检测,同时用流式细胞仪对各组神经干细胞凋亡率进行检测。 结果 与空白对照组比较,单纯照射组各时间点反映神经干细胞增殖情况的吸光度值明显降低( t=5.33~8.44, P<0.05),神经干细胞的凋亡率明显升高( t=30.60~71.22, P<0.05)。与单纯照射组比较,照射+硫酸镁组除24 h时间点外余各时间反映神经干细胞增殖的吸光度值有所上升( t=2.45~4.71, P<0.05),各时间点神经干细胞的凋亡率明显降低( t=6.73~41.12, P<0.05)。 结论 硫酸镁具有减轻电离辐射后神经干细胞增殖损伤,降低电离辐射所致的细胞凋亡率。 相似文献
19.
AbstractPurpose: Radiation therapy is an integral part of current treatment modality for colorectal cancer. Recent studies have revealed the presence of cancer stem-like cells (CSCs) population, in different tumors are responsible for therapeutic resistance and disease relapse, including colorectal cancer with poorer survival rate. Hence, characterization of the effect of Ionizing Radiation (IR) in colorectal cancer may serve to explain possible mechanisms. Material and methods: Parental HCT116 and HCT-15 cells and derived colonospheres were irradiated and dose was optimized based on cell survival assay and cell cycle analysis. DNA damage response (DDR) was elucidated by γH2AX foci formation, COMET assay, and ATM, p-ATM, ERCC1 expression post-treatment. The expression level of developmental marker (β-catenin), CSC markers (CD44, KLF4) and telomeric components (TRF2, RAP1, hTERT) were evaluated. Results: We observed cell survival was more in colonospheres post-irradiation and also exhibited decreased γH2AX foci, olive tail moment, increased ERCC1, and p-ATM expression than its parental counterpart which corresponds to efficient DDR. Differential expression of developmental marker, CSC markers, and telomeric components were observed after irradiation. Conclusion: This study highlighted the presence of CSC phenotype in colonospheres having increased DNA repair capacity. Differential expression of developmental marker, CSC markers and telomeric components between parental and colonospheres may contribute in radio-resistance property of CSCs. 相似文献
20.
Purpose: A proof of principle for cell killing by Gadolinium (Gd) neutron capture in Magnevist® preloaded Glioblastoma multiforme (GBM) cells is provided. Materials and methods: U87cells were pre-loaded with 5 mg/ml Magnevist® (Gd containing compound) and irradiated using an enhanced neutron beam developed at NIU Institute for Neutron Therapy at Fermilab. These experiments were possible because of an enhanced fast neutron therapy assembly designed to use the fast neutron beam at Fermilab to deliver a neutron beam containing a greater fraction of thermal neutrons and because of the development of improved calculations for dose for the enhanced neutron beam. Clonogenic response was determined. Results: U87 cell survival after γ irradiation, fast neutron irradiation and irradiation with the enhanced neutron beam in the presence or absence of Magnevist® were determined. Conclusions: U87 cells were the least sensitive to γ radiation, and increasingly sensitive to fast neutron irradiation, irradiation with the enhanced neutron beam and finally a significant enhancement in cell killing was observed for U87 cells preloaded with Magnevist®. The sensitivity of U87 cells pre-loaded with Magnevist® and then irradiated with the enhanced neutron beam can at least in part be attributed to the Auger electrons emitted by the neutron capture event. 相似文献
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