AIMS:Radiation-induced intestinal injury (RIII) significantly impairs the quality of life in patients with abdominal/pelvic cancer undergoing radiotherapy, often necessitating treatment cessation. The ACE2/Ang-(1-7)/MasR axis, a protective pathway within the renin-angiotensin system, represents a potential anti-inflammatory target. This study explored the role of ACE2 activation in mitigating RIII and the underlying mechanisms. RESULTS:Treatment with diminazene aceturate (DIZE), a selective ACE2 agonist, prior to lethal radiation blocked intestinal stem cell (ISC) death, enhanced crypt regeneration, preserved epithelial barrier integrity, and reduced intestinal inflammation, thereby promoting mice survival. Notably, the radioprotective effect of DIZE was reversed by ACE2 or MasR antagonists, and other ACE2 agonists exhibited similar radioprotective efficacy. DIZE treatment improved the survival of ISCs both in vitro and in vivo postradiation. Mechanistically, DIZE directly targeted intestinal epithelial cells (IECs), preventing the activation of radiation-induced MAPK (p38/JNK) and NF-κB pathways. This effect was abolished by ACE2 knockdown in a human intestinal epithelial cell line (HIECs) in vitro. Intriguingly, DIZE failed to inhibit endothelial cell apoptosis or attenuate MAPK/NF-κB pathway activation in irradiated endothelial cells. Preliminary evidence indicates DIZE did not affect the radiosensitivity of colorectal tumor cells or azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumors in mice.Conclusion and Innovation:This study is the first to demonstrate selective ACE2-mediated intestinal protection without compromising tumor radiosensitivity. These findings demonstrate ACE2 activation selectively shields IECs from radiation damage by inhibiting MAPK/NF-κB pathways, offering a novel therapeutic strategy to alleviate RIII without compromising tumor radiosensitivity. Antioxid. Redox Signal. 44, 843-858.

Background and Purpose Radiation-induced ovarian injury (RIOI) compromises the clinical utility of pelvic radiotherapy and reduces fertility in young female patients. Dimethyl sulfoxide (DMSO) exhibits antioxidant property. Hearin, we aimed to explore the protective effect and underlying mechanism of DMSO on RIOI. Materials and Methods C57BL/6J female mice were treated with DMSO prior to undergoing lower abdominal radiation. Intragenerational and transgenerational fertility were assessed by mating experiment. Ovaries were harvested to evaluate follicle count and morphology. Granulosa cells were analyzed by immunohistochemical staining of TUNEL and Ki67. An ovary explant organ culture system was established to evaluate the effect of DMSO. Fluorescent probes were employed to evaluate mitochondrial mass and function. DNA double-strand breaks were detected by immunoblotting of γ-H2AX. Results DMSO preserved the fertility of irradiated mice and even safeguarded the reproductive capacity of their unirradiated female offspring. Histological analyses revealed that DMSO preserves the ovarian follicle reserve, including both primordial and developing follicles. Additionally, DMSO demonstrated radioprotective effects in ex vivo ovarian tissue. Moreover, DMSO reduced apoptosis and enhanced proliferation in granulosa cells. Mechanistically, DMSO alleviated radiation-induced oxidative stress and preserved mitochondrial function, as evidenced by increased mitochondrial mass, reduced oxidant levels, and enhanced mitochondrial membrane potential. Moreover, DMSO reduced the levels of DNA damage accumulation in vivo and in vitro . Conclusion Our data suggest that DMSO may offer a potential pharmacological treatment option for fertility impairment in women undergoing radiotherapy, which warrants further investigation in clinical settings.

PURPOSE:Radiation-induced skin injury is a common complication that seriously affects the follow-up treatment and life quality of tumor patients. Nocardia rubra cell-wall skeleton (N-CWS) has been reported to have pro-angiogenesis effects, and its role on RISI remains unclear. The aim of this study was to investigate its effect on repair of radiation induced skin injury. MATERIALS AND METHODS:After exposure to 45 Gy X-rays, the irradiated areas of SD rats were treated by N-CWS every 3 days. The radioprotective effects of N-CWS were evaluated by body weight changes, skin scores, H&E staining and TUNEL staining. Microvascular monitoring system and immunofluorescence staining of CD31 were performed to assess angiogenic capacity in vivo. In vitro, the activity and apoptosis of HUVECs were measured by CCK8 and flow cytometry. The angiogenic capacity of HUVECs was evaluated by tubule formation assay and Transwell assay. Western blot was performed to verify the possible mechanisms of the protective effect of N-CWS against radiation-induced skin damage. RESULTS:N-CWS was demonstrated to have low toxicity and radioprotective effects, maintained cell activity and attenuated radiation-induced apoptosis. In addition, N-CWS attenuated radiation-induced vascular injury in vivo and in vitro. Furthermore, P38 MAPK was shown to be associated with the radiation protection capability of N-CWS in HUVECs. CONCLUSIONS:N-CWS promoted the repair of radiation-induced skin injury by enhancing angiogenesis, and the mechanism was related to the activation of P38 MAPK.

AIMS:Radiation-induced intestinal injury (RIII) severely compromises the quality of life in patients undergoing abdominal/pelvic radiotherapy and may necessitate treatment discontinuation. To date, there is no approved agent for the prevention or treatment of RIII. This study aims to clarify the protective effects of mannose on RIII and elucidate its mechanisms of action, in order to identify new safe and effective therapeutic agents and potential therapeutic targets for the prevention and treatment of RIII. RESULTS:Here, we report that intraperitoneal administration of mannose, a natural bioactive monosaccharide, at 24, 12, and 2 h prior to lethal irradiation increased the survival rate of mice from 0% to 50%. Specifically, mannose pretreatment significantly blocked crypt cell apoptosis, preserved epithelial barrier integrity, attenuated intestinal inflammation, and enhanced crypt regeneration. Additionally, mannose treatment enhanced the survival of intestinal stem cells both in vitro and in vivo following radiation exposure. We further confirmed that mannose maintains mitochondrial homeostasis and alleviates cellular oxidative stress. Moreover, mannose facilitated the repair of DNA double-strand breaks, thereby inhibiting aberrant mitosis after radiation exposure. Additionally, preliminary evidence indicates that mannose does not affect the radiosensitivity of colorectal tumor cells or azoxymethane/dextran sodium sulfate-induced colorectal tumors in mice.Conclusion and Innovation:Given its low toxicity and wide availability, our findings suggest that mannose represents a promising protective strategy for RIII. Antioxid. Redox Signal. 00, 000-000.

Renal fibrosis is a common mechanism leading to kidney failure in chronic kidney diseases (CKDs), including obstructive nephropathy (ON). Dysregulated inflammation is central to the development of renal fibrosis, but how local immune cells within the tissue microenvironment integrate and coordinate to drive this condition remains largely unknown. Herein, we documented that neutrophils were abundantly recruited and expelled neutrophil extracellular traps (NETs) in human and mouse fibrotic kidneys. Importantly, circulating levels of NETs components displayed a significant correlation with worsened kidney function in ON patients. In the unilateral ureteral obstruction (UUO) mouse model, blocking NETs by protein-arginine deiminase type 4 (PAD4) deletion or DNase treatment significantly impaired NETs formation and inhibited renal fibrosis and inflammation, whereas NETs adoptive transfer exacerbated the fibrotic process. Moreover, NET-mediated renal fibrosis was associated with enhanced infiltration of cytotoxic CD8(+) T cells, which produced granzyme B (GZMB) to drive tubular cell epithelial-mesenchymal transition (EMT) and fibroblast activation. Accordingly, pharmacological inhibition of GZMB resulted in blunted kidney inflammation and fibrosis. Furthermore, NETs profoundly potentiated the production of T-cell chemokines CXCL9/10/11 in macrophages, but not in tubular cells or fibroblasts, thus driving T-cell infiltration and fueling inflammatory cascades in the kidneys. Mechanistically, the NET-macrophage interaction was partially mediated by the TLR2/4 signaling. Thus, our work reveals a previously unexplored role of the collaboration between NETs and macrophages in supporting CD8(+) T cell infiltration, which orchestrates kidney inflammation and fibrosis.

Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.

过氧化物酶体增殖物活化受体(peroxisome proliferator activatived receptors,PPARs)是核受体超家族成员,包括PPARα、PPARδ和PPARγ3种亚型,他们在不同组织中表达,其中PPARγ在脂肪组织、心脏、 肠道和免疫细胞中存在,在脂肪合成过程中起着关键作用.PPARγ具有抗氧化作用,通过调控Nrf2信号通路、 内皮型NOS(eNOS)和诱导型NOS(iNOS)表达以及其他相关信号通路发挥作用.辐射诱导的氧化应激是引起细胞水平和全身水平损伤的主要因素,由于PPARγ具有抗氧化应激的能力,有望成为辐射防护和辐射治疗的有效靶点.

Radiotherapy of abdominal and pelvic tumors almost inevitably injures the intestine by oxidative stress and causes inflammation. Regrettably, traditional radioprotective agents for irradiation (IR) induced intestinal injury suffer from challenges such as poor solubility, unsatisfactory bioactivity and undesired adverse reactions, which significantly limit their usefulness. Polydopamine nanoparticles (PDA-NPs) have shown promising potential in scavenging reactive oxygen species (ROS) and suppressing inflammation. In this study, PDA-NPs were prepared by a simple method and their physical properties were characterized. Mice received two doses of PDA-NPs by oral gavage 22 h apart, and were irradiated with X-rays 2 h after the last gavage. The protective effect of PDA-NPs and possible mechanisms of protection against IR-induced intestinal injury were explored. The results showed that PDA-NPs were spherical and well dispersed, with good shape uniformity, compact structure, good colloid dispersion stability, concentration-dependent light absorption, and accurate quantification. Importantly, PDA-NPs reduced mortality and prolonged the average survival time of mice after IR. Furthermore, PDA-NPs protected mice from IR-induced injury to crypt-villus units and maintained intestinal barrier function in the intestine. In particular, PDA-NPs significantly inhibited the depletion of Lgr5+ intestinal stem cells (ISCs) and promoted cell regeneration after IR, which indicated that the regeneration ability of ISCs was maintained and the repair of intestinal structure and function was promoted. Finally, PDA-NPs significantly suppressed the apoptosis, inflammatory pyroptosis and DNA damage of intestinal cells induced by ionizing radiation. Altogether, our study suggested that PDA-NPs may have great potential in protecting the intestines from ionizing radiation damage.

Recently, Toll-like receptors (TLRs) have been extensively studied in radiation damage, but the inherent defects of high toxicity and low efficacy of most TLR ligands limit their further clinical transformation. CRX-527, as a TLR4 ligand, has rarely been reported to protect against radiation. We demonstrated that CRX-527 was safer than LPS at the same dose in vivo and had almost no toxic effect in vitro. Administration of CRX-527 improved the survival rate of total body irradiation (TBI) to 100% in wild-type mice but not in TLR4-/- mice. After TBI, hematopoietic system damage was significantly alleviated, and the recovery period was accelerated in CRX-527-treated mice. Moreover, CRX-527 induced differentiation of HSCs and the stimulation of CRX-527 significantly increased the proportion and number of LSK cells and promoted their differentiation into macrophages, activating immune defense. Furthermore, we proposed an immune defense role for hematopoietic differentiation in the protection against intestinal radiation damage, and confirmed that macrophages invaded the intestines through peripheral blood to protect them from radiation damage. Meanwhile, CRX-527 maintained intestinal function and homeostasis, promoted the regeneration of intestinal stem cells, and protected intestinal injury from lethal dose irradiation. Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.

The testis is susceptible to ionizing radiation, and male infertility and sexual dysfunction are prevalent problems after whole-body or local radiation exposure. Currently, there is no approved agent for the prevention or treatment of radiation-induced testicular injury. Herein, we investigated the radioprotective effect of dimethyl sulfoxide (DMSO), an organosulfur compound that acts as a free radical scavenger, on testicular injury. Treatment of mice with a single dose of DMSO prior to 5 Gy irradiation restored sex hormones and attenuated the reduction in testis weight. Histological analyses revealed that DMSO alleviated the distorted architecture of seminiferous tubules and promoted seminiferous epithelium regeneration following irradiation. Moreover, DMSO provided quantitative and qualitative protection for sperm and preserved spermatogenesis and fertility in male mice. Mechanistically, DMSO treatment enhanced GFRα-1+ spermatogonial stem cell and c-Kit+ spermatogonial survival and regeneration after radiation. DMSO also alleviated radiation-induced oxidative stress and suppressed radiation-induced germ cell apoptosis in vivo and in vitro. Additionally, DMSO efficiently reduced DNA damage accumulation and induced the expression of phosph-BRCA1, BRCA1, and RAD51 proteins, indicating that DMSO facilitates DNA damage repair with a bias toward homologous recombination. In summary, our findings demonstrate the radioprotective efficacy of DMSO on the male reproductive system, which warrants further studies for future application in the preservation of male fertility during conventional radiotherapy and nuclear accidents.

分析当前核应急医学救援人体表面污染控制相关标准,探讨现有标准的不足,提出核应急医学救援人体表面污染控制相关标准应用建议.认为现行标准WS/T 467-2014《核和辐射事故医学响应程序》、GBZ/T 271-2016《核或辐射应急准备与响应通用准则》、T/WSJD 7-2020《核辐射突发事件放射性污染人员洗消流程及技术要求》适用于核应急医学救援人体表面污染控制,其中GBZ/T 271-2016的参考理念较新、可操作性较强,建议任务单位及相关应急力量参考使用.

Radiation-induced intestinal injury (RIII) restricts the therapeutic efficacy of radiotherapy in abdominal or pelvic malignancies. Also, intestinal injury is a major cause of death following exposure to high doses of radiation in nuclear accidents. No safe and effective prophylactics or therapeutics for RIII are currently available. Here, we reported that the apigenin, a natural dietary flavone, prolonged the survival in c57 mice after lethal irradiation. Apigenin pretreatment brought about accelerated restoration of crypt-villus structure, including enhanced regenerated crypts, more differentiated epithelium cells, and increased villus length. In addition, intestinal crypt cells in the apigenin-treated group exhibited more proliferation and less apoptosis. Furthermore, apigenin increased the expression of Nrf2 and its downstream target gene HO-1, and decreased oxidative stress after irradiation. In conclusion, our findings demonstrate the radioprotective efficacy of apigenin. Apigenin has the potential to be used as a radioprotectant in cancer therapy and nuclear accidents.

分析当前核应急医学救援时人体表面污染检测方法存在测不准、测得慢、测得累、表面污染检测设备易污染等不足,提出优化建议.现行人体表面污染检测方法由于费时费力、操作性不强,是整个核应急医学救援的"限速步骤".提出了在核应急医学救援人体表面污染检测时,综合利用高灵敏γ剂量率仪结合表面污染检测仪检测的方法,首先使用高灵敏γ剂量率仪对人员体表进行快速初筛,再使用表面污染检测仪精准测量,可大幅提高人体表面污染检测的效率与精准度.该方法检测效率高、速度快,能降低测量人员体能消耗,且高灵敏γ剂量率仪、表面污染检测仪为核应急医学救援力量常用设备,可直接参考此方法进行人体表面污染快速筛选.

Abstract Objective This study aimed to reveal the protective effect of hydrogen storage nanomaterial MgH2 on radiation-induced male fertility impairment. Methods The characterization of MgH2 were analyzed by scanning electron microscopy (SEM) and particle size analyzer. The safety of MgH2 were evaluated in vivo and in vitro. The radioprotective effect of MgH2 on the reproductive system were analyzed in mice, including sperm quality, genetic effect, spermatogenesis, and hormone secretion. ESR, flow cytometry and western blotting assay were used to reveal the underlying mechanisms. Results MgH2 had an irregular spherical morphology and a particle size of approximately 463.2 nm, and the content of Mg reached 71.46%. MgH2 was safe and nontoxic in mice and cells. After irradiation, MgH2 treatment significantly protected testicular structure, increased sperm density, improved sperm motility, reduced deformity rates, and reduced the genetic toxicity. Particularly, the sperm motility were consistent with those in MH mice and human semen samples. Furthermore, MgH2 treatment could maintain hormone secretion and testicular spermatogenesis, especially the generation of Sertoli cells, spermatogonia and round sperm cells. In vitro, MgH2 eliminated the [·OH], suppressed the irradiation-induced increase in ROS production, and effectively alleviated the increase in MDA contents. Moreover, MgH2 significantly ameliorated apoptosis in testes and cells and reversed the G2/M phase cell cycle arrest induced by irradiation. In addition, MgH2 inhibited the activation of radiation-induced inflammation and pyroptosis. Conclusion MgH2 improved irradiation-induced male fertility impairment by eliminating hydroxyl free radicals. Graphical abstract Mice fertility and function were evaluated with or without MgH2 treatment after 5 Gy irradiation. MgH2 had the ability of hydroxyl radicals scavenging and MDA suppressing in testicular tissue induced by irradiation. Further, MgH2 could participate in spermatogenesis and protect sperm development in three stages: the generation of Sertoli cells (Sox-9+), spermatogonia (Stra8+) and round sperm cells (Crem+). Moreover, MgH2 alleviated the decrease of testosterone secreted by interstitial cells after irradiation. In addition, MgH2 suppressed apoptosis, pyroptosis and inflammatory response and alleviated cell cycle arrest by mediating IR-induced ROS.

目的:设计火箭军核应急专用个人防护背囊内容物.方法:该背囊内容物包括个人剂量监测、个人防护、抗放、自助去污、通信、污物收容等6个功能模块,各装具按穿戴取用的顺序组合包装放置.结果:该背囊内容物可满足火箭军核武器核事故医学救援的个人防护需求.结论:该背囊内容物针对性强、功能全面、取用方便,可在承担核武器核事故医学救援任务的部队推广使用.

目的 探讨δ-生育三烯酚(δ-T3H)诱导小鼠体内粒细胞集落刺激因子(G-CSF)生成的作用,评价δ-T3H促健康小鼠造血活性作用.方法 雄性C57BL/6J小鼠分别单次sc给予δ-T3H 12.5,25,50,100和200 mg·kg-1,于药后24 h采血,酶联免疫吸附法(ELISA)检测血清中G-CSF水平,分析δ-T3H诱导小鼠体内生成G-CSF的剂量效应.小鼠单次sc给予δ-T3H 100 mg·kg-1,于给药后3,6,12,24,36,48,72和96 h采血,ELISA检测血清中G-CSF水平和细胞趋化因子1(CXCL1)、粒巨噬细胞集落刺激因子(GM-CSF),白细胞介素6(IL-6),IL-10,IL-12和肿瘤坏死因子α(TNF-α)水平.雄性小鼠单次sc给予δ-T3H 100 mg·kg-1,于给药后24 h取材分析组织匀浆中G-CSF水平.雄性小鼠连续sc给予δ-T3H 100 mg·kg-15 d,于给药后利用ELISA检测血清中G-CSF、红细胞生成素(EPO)、血小板生成素(TPO)和基质细胞衍生因子1β(SDF-1β)的含量,利用血细胞分析仪检测外周血常规参数.δ-T3H按照100 mg·kg-1分为单次sc给药组和连续2 d sc给药组,于给药24 h后利用流式细胞术分析外周血造血干细胞数量.结果 δ-T3H单次给药升高G-CSF的作用呈给药剂量效应,最低有效剂量≤12.5 mg·kg-1,100 mg·kg-1给药后升高G-CSF的作用达到饱和;δ-T3H单次给药后48 h内以及连续给药期间小鼠血清G-CSF浓度均可维持在较高水平(36±12)μg·L-1;细胞因子检测发现,δ-T3H对CXCL1生成有显著促进作用(P<0.05),不影响血清中其他炎症细胞因子(GM-CSF,IL-6,IL-10,IL-12和TNF-α)的生成;δ-T3H显著升高小鼠淋巴-造血组织如胸腺、脾、淋巴结和骨髓组织液中G-CSF水平(P<0.05),对其他组织器官匀浆中G-CSF含量无显著影响;δ-T3H诱导小鼠血清中TPO和EPO略有升高;血常规检测发现,δ-T3H连续给药可显著增加小鼠外周血白细胞数量(主要为中性粒细胞和单核细胞的升高),血小板小幅升高,而淋巴细胞和红细胞则有一过性降低(P<0.05,P<0.01);流式细胞术分析发现,δ-T3H连续2 d sc给药组小鼠外周血造血干细胞数量显著升高(P<0.01).结论 δ-T3H促进小鼠体内G-CSF生成具有专一性以及组织特异性,同时δ-T3H通过刺激体内G-CSF的生成升高小鼠外周血粒细胞数,并促进外周血造血干细胞数量的增加,具有一定的促造血活性.

In mass casualty events involving radiation exposure, there is a substantial unmet need for identifying and developing an orally bioavailable agent that can be used to protect the hematopoietic stem cell pool and regenerate hematopoiesis after radiation injury. Dimethyl sulfoxide (DMSO), a free-radical scavenger, has shown therapeutic benefits in many preclinical and clinical studies. This study investigates the radioprotective effects of DMSO on oral administration. Single dose of oral DMSO administrated before irradiation conferred 100% survival of C57BL6/J mice receiving otherwise lethal as well as super-lethal radiation dose, with wide radioprotective time frame (from 15min to 4h). Oral DMSO not only protected radiation-induced acute hematopoietic stem and progenitor cell (HSPC) injury, but also ameliorated long-term BM suppression following irradiation in mice. Mechanistically, DMSO directly protected HSPC survival after irradiation in vitro and in vivo, whereas no radioprotective effect was seen in MLL-AF9-induced leukemia cells. Unexpectedly, DMSO treatment did not inhibit radiation-induced HSPC apoptosis, and the HSPC survival from Trp53-and PUMA-deficient mice after irradiation was also protected by DMSO. In conclusion, our findings demonstrate the radioprotective efficacy of oral DMSO. Given its oral efficacy and little toxicity, DMSO is an attractive candidate for human use in a wide variety of settings, including nuclear accidents and medical radiation.

目的 合成新型鞘氨醇-1-磷酸1(S1P1)受体激动剂西帕莫德(siponimod,BAF312).方法 以3′-溴-4′-甲基苯乙酮为原料,经过溴化、醇化、还原氢化等反应,得到化合物(4);另4-氯-3-三氟甲基溴经溴原子取代,得到N-(4-环己基-3-三氟甲基-苄氧基)-乙酰亚氨酸乙酯(5),经Friedel-Crafts酰化反应后得到中间体(6),继而中间体(5)和(6)在酸性条件下生成中间体(7),最后与二氧化锰、氰基硼氢化钠等作用制得西帕莫德.结果 经过一系列反应,合成出西帕莫德,其最终产率为19.2％.结论 用廉价易得的3′-溴-4′-甲基苯乙酮为原料制得西帕莫德,成本经济,操作简便且产率理想.

Purpose: The risk of radiation exposure is considered to have increased in recent years. For convenience and simple administration, development of an effective orally administered radioprotective agent is highly desirable. The steroid 5-androstene-3 beta, 17 beta-diol (5-AED) has been evaluated as both a radioprotector and a radiomitigator in mice and nonhuman primates; however, poor oral bioavailability has limited its development. A variant compound-17 alpha-ethinyl-androst-5-ene-3 beta, 17 beta-diol (EAD) dexhibits significant oral bioavailability. We investigated the radioprotective effects of EAD via oral administration in mice. Methods and Materials: Survival assays were performed in lethally (9.0-10.0 Gy) irradiated mice. Peripheral blood cell counts were monitored in lethally (9.5 Gy) or sublethally (6.5 Gy) irradiated mice. We performed histologic analysis of bone marrow (BM) and frequency and functional analysis of hematopoietic stem and progenitor cells in mice irradiated with 6.5 Gy. To investigate multilineage engraftment of irradiated hematopoietic stem cells after BM transplantation, competitive repopulation assays were conducted. Plasma granulocyte colony-stimulating factor was measured by enzyme-linked immunosorbent assay. Results: Oral administration of EAD on 3 consecutive days before irradiation conferred 100% survival in mice, against otherwise 100% death, at a 9.5-Gy lethal dose of total body irradiation. EAD ameliorated radiation-induced pancytopenia at the same dose. EAD augmented BM cellular recovery and colony-forming ability, promoted hematopoietic stem and progenitor cell recovery, and expanded the pool of functionally superior hematopoietic stem cells in the BM of sublethally irradiated mice. Unlike 5-AED, EAD did not increase granulocyte colony-stimulating factor levels in mice and exhibited no therapeutic effects on hematologic recovery after irradiation; nevertheless, its radioprotective efficacy was superior to that of 5-AED. Conclusions: Our findings demonstrate the radioprotective efficacy of EAD and reveal that the 17 alpha-ethinyl group is essential for its oral activity. Given its oral efficacy and low toxicity, EAD has potential as an optimal radioprotector for use by first responders, as well as at-risk civilian populations. (C) 2018 The Authors. Published by Elsevier Inc.

Purpose: Oral mucositis is one of the most prevalent side effects in patients undergoing radiation therapy for head and neck cancers. Current therapeutic agents such as palifermin recombinant human keratinocyte growth factor and amifostine do not efficiently or fully prevent mucositis. Dimethyl sulfoxide (DMSO), a free-radical scavenger, has shown therapeutic benefits in many preclinical and clinical studies. This study aimed to investigate the efficacy of DMSO in a clinically relevant mouse model of acute, radiation-induced oral mucositis. Methods and Materials: Oral mucositis was induced by a high single and fractioned irradiation of the head and neck area in C57BL/6J mice, and the effects of DMSO(by intraperitoneal injection) were assessed by macroscopic and histopathological examination. Epithelial stem and progenitor cells were analyzed by immunohistochemical staining of p63 and Ki-67, and DNA double-strand breaks (DSBs) were visualized by immunofluorescence detection of gamma-H2AX. Tumor xenograft was obtained using CAL-27 cells. Results: Pretreatment with DMSO protected the oral mucosa from severe acute radiation injury, reduced the extent of radiation-induced weight loss, and had no significant effects on tumor weight in irradiated or nonirradiated xenograft mice. Furthermore, the efficacy of DMSO was superior to that of recombinant human keratinocyte growth factor and amifostine. DMSO treatment prevented the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation. More interestingly, the average levels of gamma-H2AX foci were significantly decreased in p63-positive epithelial stem cells at 6 hours, but not at 2 hours, after irradiation, indicating that DMSO facilitated DNA DSB repair rather than suppressing the indirect action of irradiation. Conclusions: DMSO prevents the loss of proliferative lingual epithelial stem and progenitor cells upon irradiation by facilitating DNA DSB repair, thereby protecting against radiation-induced mucositis without tumor protection. Given its high efficacy and low toxicity, DMSO could be a potential treatment option to prevent radiation-induced oral mucositis. (C) 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).