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Development of radiation countermeasure agents for acute radiation syndromes

动物模型与实验医学(英文) 2023年第4期6卷 329-336页

作者： Bowen Guan deguan li Aimin Meng National Human Diseases Animal Model Resource Center NHC Key Laboratory of Human Disease Comparative MedicineBeijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal Sciences Chinese Academy of Medical Sciences(CAMS)Peking Union Medical College(PUMC)National Center of Technology Innovation for Animal ModelBeijingChina Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation MedicineChinese Academy of Medical SciencePeking Union Medical CollegeTianjinChina

The risk of internal and external exposure to ionizing radiation(IR)has increased alongside the development and implementation of nuclear technology.Therefore,serious security issues have emerged globally,and there has been an increase in the number of studies focusing on radiological prevention and medical countermeasures.Radioprotective drugs are particularly important components of emergency medical preparedness strategies for the clinical management of IR-induced injuries.However,a few drugs have been approved to date to treat such injuries,and the related mechanisms are not entirely understood.Thus,the aim of the present review was to provide a brief overview of the World Health Organization's updated list of essential medicines for 2023 for the proper management of national stockpiles and the treatment of radiological emergencies.This review also discusses the types of radiation-induced health injuries and the related mechanisms,as well as the development of various radioprotective agents,including Chinese herbal medicines,for which significant survival benefits have been demonstrated in animal models of acute radiation syndrome.

关键词： Chinese herbal medicines essential medicines list ionizing radiation radiation countermeasure agents radiation injury

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The protective effects of Xuebijing injection on intestinal injuries of mice exposed to irradiation

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Animal Models and Experimental Medicine 2022年第6期5卷 565-574页

作者： Yinping Dong YuanYang Zhang Xinyue Wang Wenxuan li Junling Zhang Lu Lu Hui Dong Saijun Fan Aimin Meng deguan li Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation MedicineChinese Academy of Medical Science&Peking Union Medical CollegeTianjinChina Key Laboratory of Human Disease Comparative Medicine Ministry of HealthBeijing Engineering Research Center for Laboratory Animal Models of Human Critical DiseasesNational Human Diseases Animal Model Resource CenterInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PUMC)BeijingChina

Background:Gastrointestinal(GI)injury is one of the most common side effects of radiotherapy.However,there is no ideal therapy method except for symptomatic treatment in the clinic.Xuebijing(XBJ)is a traditional Chinese medicine,used to treat sepsis by injection.In this study,the protective effects of XBJ on radiation-i nduced intestinal injury(RⅢ)and its mechanism were explored.Methods:The effect of XBJ on survival of irradiated C57BL/6 mice was monitored.Histological changes including the number of crypts and the length of villi were evaluated by H&E.The expression of Lgr5^(+)intestinal stem cells(ISCs),Ki67^(+)cells,villin and lysozymes were examined by immunohistochemistry.The expression of cytokines in the intestinal crypt was detected by RT-PCR.DNA damage and apoptosis rates in the small intestine were also evaluated by immunofluorescence.Results:In the present study,XBJ improved the survival rate of the mice after 8.0and 9.0 Gy total body irradiation(TBI).XBJ attenuated structural damage of the small intestine,maintained regenerative ability and promoted proliferation and differentiation of crypt cells,decreased apoptosis rate and reduced DNA damage in the intestine.Elevation of IL-6 and TNF-α was limited,but IL-1,TNF-β and IL-10 levels were increased in XBJ-treated group after irradiation.The expression of Bax and p53 were decreased after XBJ treatment.Conclusions:Taken together,XBJ provides a protective effect on RⅢby inhibiting inflammation and blocking p53-related apoptosis pathway.

关键词： Xuebijing injection Intestinal injury Total body irradiation Inflammation Apoptosis

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Discovery of the radio-protecting effect of Ecliptae Herba,its constituents and targeting p53-mediated apoptosis in vitro and in vivo

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1216-1230页

作者： Jiang Wu Wenfeng Gou Zhiyun Wang Huajie Chang deguan li Wenbin Hou Changxiao liu Department of Pharmaceutical Engineering School of Chemical Engineering and TechnologyTianjin UniversityTianjin 300072China Institute of Radiation Medicine Chinese Academy of Medical SciencesTianjin 300192China School of Chinese Materia Medica Tianjin University of Traditional Chinese MedicineTianjin 301617China Research Center for New Drug Evaluation the State Laboratory of Drug Delivery Technology and PharmacokineticsTianjin Institute of Pharmaceutical ResearchTianjin 300193China

Radiation protection drugs are often accompanied by toxicity,even amifostine,which has been the dominant radio-protecting drug for nearly 30 years.Furthermore,there is no therapeutic drug for radiation-induced intestinal injury(RⅢ).This paper intends to find a safe and effective radioprotecting ingredient from natural sources.The radio-protecting effect of Ecliptae Herba(EHE) was discovered preliminarily by antioxidant experiments and the mouse survival rate after137Cs irradiation.EHE components and blood substances in vivo were identified through UPLC-Q-TOF.The correlation network of “natural components in EHE-constituents migrating to blood-targets-pathways” was established to predict the active components and pathways.The binding force between potential active components and targets was studied by molecular docking,and the mechanism was further analyzed by Western blotting,cellular thermal shift assay(CETSA),and Ch IP.Additionally,the expression levels of Lgr5,Axin2,Ki67,lysozyme,caspase-3,caspase-8,8-OHd G,and p53 in the small intestine of mice were detected.It was found for the first time that EHE is active in radiation protection and that luteolin is the material basis of this protection.Luteolin is a promising candidate for RⅢ.Luteolin can inhibit the p53 signaling pathway and regulate the BAX/BCL2 ratio in the process of apoptosis.Luteolin could also regulate the expression of multitarget proteins related to the same cell cycle.

关键词： p53 Apoptosis Luteolin Eclipta prostrata L. Radio-protecting Radiation-induced intestinal injury Radiation protection

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Evaluating a novel protective agent against radiation-induced acute intestinal injury

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Radiation Medicine and Protection 2023年第4期4卷 221-226页

作者： Xin He Jing Wu Yinping Dong Wenxuan li Xinyue Wang Qidong Huo Tongpeng Yue Yiliang li Bin Wu deguan li Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine Institute of Radiation MedicineChinese Academy of Medical Science&Peking Union Medical CollegeTianjin 300192China Department of Bioengineering Shandong PolytechnicJinan 250104China

Objective:To develop and synthesize a novel derivative of ethyl pyruvate,named TZC02,and investigate its radioprotective effects against ionizing radiation(IR)-induced intestinal injury in mice.Methods:Male C57BL/6J mice weighing(20±2)g in the survival experiment were randomly divided into five groups(n=10 in each):control group,IR group,IR+TZC02(50 mg/kg)group,IR+TZC02(100 mg/kg)group,and IR+TZC02(200 mg/kg)group.Mice's survival rates were monitored for 7 d.In other experiments,the male mice were randomly divided into three groups(n=5 per group):control group,IR group,and IR+TZC02(100 mg/kg)group.TZC02 was intragastrically administered 1 h before 12 Gy abdominalγ-ray irradiation(ABI)and 24 h,48 h after irradiation,respectively.Three days after IR exposure,small intestinal tissues were collected and the number of small intestinal crypts was determined using hematoxylin&eosin(H&E)staining.Immunohistochemical analysis was used to assess the regenerative capacity of the small intestine(SI)and radiation-induced damage,stemness markers or DNA repair surrogates,including Ki67,lysozyme,and villus.The expressions of histone H2AX phosphorylation(γH2AX)and caspase-3 were evaluated through immunofluorescence analyses.Additionally,in vitro cultured small intestinal organoids were employed to investigate the effects of TZC02 on SI regeneration after irradiation.Results:The administration of TZC02 significantly improved the 7 d-survival rate of mice exposed to 12 Gy ABI(P<0.05).Compared to the IR group,TZC02 treatment attenuated the decrease of SI Ki67-positive cells[(59.60±6.33)vs.(37.70±7.82),t=11.89,P<0.0001]and Paneth cells[(9.90±1.37)vs.(5.50±1.71),t=6.02,P<0.001]in five crypts,and reduced structural damage to the SI[villus height,(349.49±60.17)μm vs.(294.72±40.09)μm;t=3.39;P<0.05].TZC02 also significantly decreased the crypt apoptosis detected by caspase-3[(10.75±1.26)vs.(29.83±2.56),t=13.39,P<0.0001]and DNA damage detected by gH2AX[(10.40±1.14)vs.(29.60±2.70),t=10.13,P<0.0001].The organoid survival 7 d post-irradiation

关键词： Abdominal irradiation Small intestine Apoptosis DNA damage Radiation-induced intestinal injury

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无线电能传输系统电磁辐射抑制研究

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中国测试 2024年第4期50卷 173-179页

作者：车凯郁金星刘松涛陈传敏宫云茜李德管国网河北省电力有限公司电力科学研究院河北石家庄050021 华北电力大学环境科学与工程学院河北保定071000

无线电能传输技术使消费电子或电动汽车可以实现非接触式充电,但较为严重的电磁辐射限制其进一步的应用和推广。为在不使用复杂耦合器结构的前提下有效降低无线电能传输系统的电磁辐射问题,该文提出基于扩频调制的无线电能传输系统电磁... 详细信息

无线电能传输技术使消费电子或电动汽车可以实现非接触式充电,但较为严重的电磁辐射限制其进一步的应用和推广。为在不使用复杂耦合器结构的前提下有效降低无线电能传输系统的电磁辐射问题,该文提出基于扩频调制的无线电能传输系统电磁辐射抑制方法,以降低无线电能传输系统的电磁辐射问题。首先,介绍周期性扩频调制技术和复数频调制技术的基本原理,并对两种扩频调制技术的参数进行设计与分析;然后,分析扩频调制技术的电磁辐射抑制效果和其对系统效率的影响;最后,通过搭建样机的形式对所提出的方案进行验证。实验结果表明:周期性扩频调制技术可以降低8.71~16.7 dB不等的辐射强度衰减,而复数频调制技术可以降低6.67~13.4 dB不等的辐射强度衰减,所提的扩频调制方案可以有效降低无线电能传输系统存在的电磁辐射问题。

关键词：无线电能传输电磁辐射抑制周期性扩频调制复数频调制

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微残清颗粒逆转白血病干细胞耐药的机制研究

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山西大学学报(自然科学版) 2024年第1期47卷 238-247页

作者：闫理想姜静冯全管杨向东何敬杨曦李德冠史哲新天津中医药大学第一附属医院国家中医针灸临床医学研究中心天津市中医药研究院附属医院山西省中西医结合医院中国医学科学院放射医学研究所

本文探讨了微残清颗粒在逆转白血病干细胞对柔红霉素（DNR）耐药中的作用机制。采用微残清颗粒兔含药血清干预CD34+CD38-KG1a白血病干细胞的方法，将免疫磁珠分选后的CD34+CD38-KG1a细胞分为对照组、DNR组、微残清颗粒组、微残清颗粒+DN... 详细信息

本文探讨了微残清颗粒在逆转白血病干细胞对柔红霉素（DNR）耐药中的作用机制。采用微残清颗粒兔含药血清干预CD34+CD38-KG1a白血病干细胞的方法，将免疫磁珠分选后的CD34+CD38-KG1a细胞分为对照组、DNR组、微残清颗粒组、微残清颗粒+DNR组，并应用siRNA法沉默磷酸酯酶与张力蛋白同源物（PTEN）表达，检测各组细胞增殖率、细胞周期/凋亡比例、胞内磷脂酰肌醇激酶（PI3K）/磷酸化蛋白激酶B(p-AKT)/磷酸化雷帕霉素靶蛋白（p-mTOR） mRNA及蛋白量。结果显示，微残清颗粒含药血清联合DNR可明显提高CD34+CD38-KG1a细胞的增殖抑制率、G2/M期比例、总凋亡和早期凋亡率。同时，微残清颗粒含药血清协同DNR提高PTEN mRNA及蛋白表达，降低PI3K、p-AKT、p-m TOR mRNA及蛋白表达。以上结果提示微残清颗粒具有逆转LSCs对DNR耐药的作用，作用机制可能与PTEN负调控PI3K/AKT/mTOR通路相关。

关键词：微残清颗粒白血病干细胞耐药 PTEN PI3K/AKT/mTOR通路

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The effects of Xuebijing Injection on the hematopoietic injury induced by irradiation in mice

The effects of Xuebijing Injection on the hematopoietic inju...

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第四届泛环渤海生物化学与分子生物学会学术交流会

作者： deguan li Xiao Chai Chengchengli Hongying Wu Lu Lu Xiaochun Wang Mingfeng Zhao Aimin Meng Institute of Radiation Medicine Chinese Academy of Medical Science and Peking Union Medical Collage Department of Hematology Tianjin First Central Hospital

Objective:Xuebijing injection(XBJ)is a traditional Chinese herbal prescription widely used in the treatment of sepsis.In this study the protective effects of Xuebijing Injection(XBJ)on the hematopoietic system damage in the radiated mice were observed.Methods:45 ICR mice were divided into three equal groups and designated as non-irradiated mice(Ctl),total body irradiated mice(IR)and IR mice administered XBJ(0.4ml/kg)by ip injection every day for 7 successive

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Expression of Nox4 in the hematopoietic cells of ATM-/- and Terc-/-mice

Expression of Nox4 in the hematopoietic cells of ATM-/- and ...

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第四届泛环渤海生物化学与分子生物学会学术交流会

作者： deguan li Yingying Wang Chengcheng li Hongying Wu Lu Lu Junling Zhang Xiaochun Wang Daohong Zhou Aimin Meng Institute of Radiation Medicine Chinese Academy of Medical Science and Peking Union Medical Collage

Non-phagocytic cell oxidase family of nicotinamide adenine dinucleotide phosphate(NADPH)oxidase is the major sources of reactive oxygen species(ROS)in a number of non-phygocyfic cells.Irradiation might enhance ROS level of hematopoietic stem cells(HSC)by up-regulation of Nox4(NADPH oxidase 4),the ROS levels in HSC of ataxia-telangiectasia mutated(ATM)mice and telomerase knockout(Terc)micewere also

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To investigate the role of macrophages in the development of murine pulmonary fibrosis induced irradiation exposure

To investigate the role of macrophages in the development of...

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第十四届中国实验动物科学年会

作者： Lulu Su deguan li Yinping Dong Yueying Wang Yuquan Wang Bowen Guan Yanhua Lu Feiyue Fan Aimin Meng Institute of Laboratory Animal Science Chinese Academy of Medical Science (CAMS) and Comparative Medicine Center Peking Union Medical College (PUMC) Key Laboratory of Human Diseases Comparative Medicine Ministry of Health Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases Beijing Engineering Research Center for Laboratory Animal Models of Human Critical Diseases Institute of Radiation Medicine Chinese Academy of Medical Science and Peking Union Medical College Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine

Purpose:Radiation induced pulmonary fibrosis(RIPF) is one of the severe injuries induced by irradiation exposure. The pathogenesis of RIPF is very complicated. The present study was to investigate the changes of phenotype of macrophages and genes expression, and explore the effect of irradiation on the function of macrophages in the development of RIPF. Methods: The C57 BL/6 male mice were exposed to 17 Gy X ray irradiation(IR) on the right side of the chest to establish lung fibrosis model. ABT-263 was a BCL-2 inhibitor and found to attenuate RIPF in our previous work. ABT-263 was administered at 16 weeks post IR exposure. The right lung tissues were collected at 4, 8, 16 and 23 weeks post IR to detect the alternation of phenotype of macrophages by flow cytometry. RT-PCR was used to detect genes expression level of sorted macrophages in the right lung at various time-points. Results:(1) During the development of RIPF, the ratio of macrophages in the right lung tissue had no changes between control group and IR group.(2) Compared with the control group, the MFI of M2 macrophages of IR group was significantly decreased at 8 weeks, and increased at 16 weeks and 23 weeks post IR. However, there were no significant differences in the MFI of M1 macrophages between control group and IR group at various time-points.(3) The expression level of P16 in sorted macrophages from irradiated mice significantly increased but the expression level of P21 didn’t change during lung fibrosis. As to the genes related to the function of M1 and M2 macrophage, the expression levels of TGF-α,IL-1α,IL-10, Arg-1 and Mmp14 significantly increased, especially in the late stage of fibrosis development. However, the expression level of TGF-β had no change during fibrosis, which was the most common pro-fibrotic factor.(4) ABT-263 had no function on the ratio of macrophage, macrophage polarization and genes expression at 23 weeks post IR. Discussion:In this study, we found macrophage polarization was changed after pulmonary irradiation exposure.

关键词： Radiation induced pulmonary fibrosis Irradiation Macrophages ABT-263

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Lasso-Cox回归构建直肠癌预后模型并验证

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安徽医科大学学报 2023年第12期58卷 2129-2134,2138页

作者：李德关汪圣毅刘虎张震李永翔安徽医科大学第一附属医院普外胃肠外科合肥230022 中国科学技术大学附属第一医院西区(安徽省肿瘤医院)肿瘤内科合肥230031

目的用Lasso-Cox回归建立直肠癌预后模型并进行验证。方法分析599例行直肠癌根治术患者的临床、病理数据;t检验、曼惠特尼检验、卡方检验进行组间比较;Lasso和Cox回归筛选变量,建立模型;受试者工作特征曲线(ROC)、校准曲线和决策曲线分... 详细信息

目的用Lasso-Cox回归建立直肠癌预后模型并进行验证。方法分析599例行直肠癌根治术患者的临床、病理数据;t检验、曼惠特尼检验、卡方检验进行组间比较;Lasso和Cox回归筛选变量,建立模型;受试者工作特征曲线(ROC)、校准曲线和决策曲线分析(DCA)评估模型的区分度、一致性和临床获益。结果组间比较发现:年龄、身体质量指数(BMI)、术前营养评分、CA199、新辅助治疗、术中输血、血管神经侵犯、癌结节、T分期、N分期、TNM分期、复发转移、放疗、生存时间与术后死亡有关(均P<0.05);Lasso回归筛选出的8个变量纳入Cox回归,年龄(HR=1.04,P<0.05)、BMI(HR=0.89,P<0.05)、输血(HR=2.29,P<0.05)、术后化疗(HR=0.16,P<0.01)、复发(HR=43.67,P<0.01)、转移(HR=2.75,P<0.05)被确定为影响直肠癌预后的独立因素;预测模型的ROC曲线下面积为0.95(95%CI:0.91~0.99),P<0.01;1年、3年生存的预测概率和实际概率接近;DCA曲线远离平行于X轴的决策线和另一条斜率为负数的线。结论该研究构建的列线图具有较好的区分度、一致性和临床获益,有助于预测直肠癌的预后情况。

关键词：直肠肿瘤 Lasso回归 Cox回归列线图校准曲线决策曲线分析

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