Background:Bone marrow (BM) suppression is the most prevalent dose-limiting side effect of chemotherapy and radiotherapy. Exposure to ionizing radiation (IR) results in acute BM suppression and long-term BM injury. Gasdermin E (GSDME) is crucial for mediating apoptosis and pyroptosis during chemotherapy. However, its role in radiation-induced hematopoietic injury is not well established. Therefore, we aimed to investigate the role of GSDME on radiation-induced hematopoietic injury. Methods:We established hematopoietic radiation injury models in C57BL/6 mice and Gsdme-/- mice. The peripheral blood (PB) counts, phenotypes of BM cells and spleen cells were analyzed. The colony-forming unit-granulocyte and macrophage assays and competitive repopulation assays were measured to evaluate the function of hematopoietic cells. Results:We demonstrated that GSDME regulates the survival and differentiation of hematopoietic stem cells (HSCs). The knockout of GSDME reduced the number and proliferation of HSCs and shortened the survival time of mice post IR. Additionally, GSDME knockout protected LSK (Lin-Sca1+c-kit+) cells, long-term HSCs (LT-HSCs), granulocyte-monocyte progenitors (GMPs), and myeloid cells (M cells) from IR injuries during acute BM suppression. Furthermore, GSDME knockout protected LSK cells, LT-HSCs, GMPs and M cells, alleviated the proliferation inhibition of hematopoietic progenitor cells (HPCs) and exacerbated lymphocyte damage during long-term BM injury. Conclusion:GSDME is vital for the survival and differentiation of HSCs, and its absence promotes myeloid-biased differentiation postirradiation. These findings highlight the critical role of GSDME in radiation-induced hematopoietic injury, particularly in the myeloid differentiation of HSCs.

核和辐射暴露会对受到照射的个人或者公众健康产生危害,建立动物模型对探讨辐射损伤机制、研究和评价防治措施必不可少.由于大剂量急性辐射损伤防护药物难以在临床进行有效性评价,研发与人体对辐射损伤及干预措施反应性一致的动物模型就尤为重要.本文在介绍辐射损伤的基础上,对辐射损伤动物模型研究现状及应用进展进行简要综述.

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.

Objective: Spermidine, a natural polyamine, possesses anti-oxidant, autophagy-regulation, and anti-aging properties. Elevated levels of oxidative stress, which was mediated the senescence of hematopoietic stem cells (HSCs) induced by radiation exposure, may further contribute to long-term myelosuppression. Therefore, this study investigated the protective effect of spermidine on the long-term damage of the hematopoietic system caused by radiation exposure.Methods: In vitro experiments, bone marrow mononuclear cells (BMMNCs) of C57BL/6 mice were isolated and incubated with 5 mM spermidine for 30 min, then irradiated by 2 Gy X ray. The survival rate, proliferation, and differentiation ability of BMMNCs were detected. In vivo experiment, mice received 4 Gy total body irradiation (TBI), 3 mM spermidine were administered in the drinking water every day for 14 days prior to irradiation and then continued for 30 days after irradiation. Peripheral blood, bone marrow cell typing, level of reactive oxygen species (ROS), colony-forming ability of HSC, and transplantation-reconstitution capability were detected.Results: In vitro experiments, spermidine significantly improved the survival rate of BMMNCs as well as the proliferation and differentiation ability of HSCs exposure to ionizing radiation (IR). In vivo, spermidine reduced levels of ROS in HSCs; spermidine attenuated long-term myeloid differentiation deviation induced by TBI. Spermidine promoted the proliferation and differentiation ability of stem cells, but failed to ameliorate the decreased engraftment capacity of bone marrow cells in mice exposed to TBI.Conclusion: This study demonstrated that spermidine could promote the recovery of IR-induced inhibition of proliferation and differentiation ability of HSCs, partly through antioxidant effects. Whether combining spermidine with other radioprotectants could further increase protective efficacy and reduce the long-term bone marrow injury needs further investigation.

Background: Busulfan (BU) is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell (HSC) transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells. The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU. Different susceptibilities were demonstrated in genetically diverse (GD) mice in our preliminary research.Methods: Three strains of GD mice with different susceptibilities to BU-induced HSC injury were used for screening biological markers of HSC injury susceptibility in urine. The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins. Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-linked immunoassay (ELISA).Results: Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence, apoptosis, and angiogenesis; whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways, those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways. Based on protein abundance differences, several urinary proteins that may be indicative of susceptibility were screened, and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.Conclusions: This study indicates that urinary protein levels can reflect differences in susceptibility to BU-induced HSC injury. Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.

目的 建立国内外首个比较医学大数据平台服务系统,为研究人员获得有效的实验动物和动物模型科学数据提供服务,为决策者提供数据支撑,解决研究中对于数据的获取及分析问题.方法 制定元数据和数据采集相关表格,对实验动物相关数据、比较医学相关数据资源进行整合.集成大规模实验动物、动物模型、表型数据、动物实验数据,构建基于PHP(hypertext preprocessor)的比较医学大数据平台.结果 比较医学大数据平台()基于国内外比较医学相关研究成果,系统梳理了实验动物、动物模型和动物实验数据,形成多维度跨时空数据比较分析结果.以比较医学科学数据为主体内容,提供实验动物、人类疾病、比较医学、动物实验和相关产品数据.结论 本文建立了比较医学大数据平台,实现了科学数据资源的统一保存及比较医学大数据的集成共享.

Objective To explore the effects of interleukin-6 (IL-6) gene knockout on the cognitive function and pathological changes in 5×FAD transgenic mice of Alzheimer's disease.Methods IL-6+/- mice were crossed with 5×FAD mice to establish the 5×FAD;IL-6-/- mouse model,and 3-month-old and 10-month-old mice were selected for experiments.The cognitive function of mice was detected by behavioral tests,and HE staining and β-amyloid (Aβ) immunohistochemical staining were performed to detect the pathological changes of mouse brain tissue.Results The number of 5×FAD;IL-6-/- model mice (3 months old,n=20;10 months old,n=5) and 5×FAD littermate control (3 months old,n=26;10 months old,n=24) conformed to the Mendel's law.Compared with that of the 5×FAD mice at the same age,the discrimination ratio of 3-month-old 5×FAD;IL-6-/- mice increased in the novel object recognition test (q=3.890,P=0.002).Morris water maze test results showed that the 3-month-old 5×FAD;IL-6-/- mice had longer time spent in target quadrant (q=3.797,P=0.012) and more times of crossing platform (q=2.505,P=0.017) than the 5×FAD mice at the same age.The results of immunohistochemical staining showed that IL-6 knockout reduced the Aβ deposition in the hippocampus (q=13.490,P=0.002;q=45.680,P<0.001) and cortex (q=16.830,P=0.001;q=14.180,P=0.001) of 5×FAD mice.Conclusion IL-6 gene knockout can significantly improve the spatial memory and reduce the Aβ deposition in the brain of 5×FAD mice.

Abstract 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‐induced 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 8.0 and 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 RIII by inhibiting inflammation and blocking p53‐related apoptosis pathway.

缺血性脑卒中因其高发病率、致残率和致死率,造成了严重的疾病负担,是医药研发人员关注的重点疾病之一.但脑卒中临床前研究结果向临床转化率低,凸显了对动物模型优化的迫切需要.非人灵长类动物(nonhuman primates,NHPs)在大脑解剖和生理学方面与人类相似性更高,因此,利用NHPs构建模型,有望促进缺血性脑卒中临床前研究向临床治疗的转化.本文对脑卒中NHPs模型的建模方法和评价指标以及模型应用进展进行综述,讨论近期所用模型及评价方法的优势和不足,并对未来NHPs模型研究需要克服的困难和可能的发展方向进行了展望.

Morphine is a widely used analgesic, but its use in clinical precision medicine is limited by the variance in response among individuals. Although previous studies have shown that individual differences in morphine can be explained in terms of pharmacodynamics and pharmacokinetics, genetic polymorphisms also play an important role. However, the genetic basis of different sensitivity and tolerance susceptibility to morphine remains ambiguous. Using 15 strains of inbred Genetic Diversity (GD) mice, a new resource with wide genetic and phenotypic variation, we demonstrated great variance in sensitivity to morphine analgesia and susceptibility to morphine tolerance between different GD strains. Among-individual variance in response to morphine analgesia in the population can be modeled in GD mice. Two loci respectively may be associated with the among-individual variance in morphine sensitivity and tolerance, confirming the role of genetic factors in among-individual different responses to morphine. These results indicate that GD mice may be a potential tool for the identification of new biomarkers to improve the clinical administration of morphine.

Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation in clinic with poor prognosis and limited therapeutic options. Previous results have shown that senescent cells, such as fibroblast and type II airway epithelial cell, are strongly implicated in pathology of RIPF. However, the role of senescent macrophages in the development RIPF is still unknown. In this study, we report that ionizing radiation (IR) increase cellular senescence with higher expression of senescence-associated β-galactosidase (SA-β-Gal) and senescence-specific genes (p16, p21, Bcl-2, and Bcl-xl) in irradiated bone marrow-derived monocytes/macrophages (BMMs). Besides, there’s a significant increase in the expression of pro-fibrogenic factors (TGF-β1 and Arg-1), senescence-associated secretory phenotype (SASP) proinflammatory factors (Il-1α, Il-6, and Tnf-α), SASP chemokines (Ccl2, Cxcl10, and Ccl17), and SASP matrix metalloproteinases (Mmp2, Mmp9 and Mmp12) in BMMs exposed to 10 Gy IR. In addition, the percentages of SA-β-Gal + senescent macrophages are significantly increased in the macrophages of murine irradiated lung tissue. Moreover, robustly elevated expression of p16, SASP chemokines (Ccl2, Cxcl10, and Ccl17) and SASP matrix metalloproteinases (Mmp2, Mmp9, and Mmp12) is observed in the macrophages of irradiated lung, which might stimulate a fibrotic phenotype in pulmonary fibroblasts. In summary, irradiation can induce macrophage senescence, and increase the secretion of SASP in senescent macrophages. Our findings provide important evidence that senescent macrophages might be the target for prevention and treatment of RIPF.

目的 观察白消安(busulfan)对2型糖尿病模型KK/upj-Ay/J(KKAy)小鼠的造血系统功能的损伤作用,并与对照C57BL/6 J(B6)小鼠进行比较.方法 雄性KKAy小鼠,随机分为白消安给药组和溶剂对照组,前者腹腔注射白消安,剂量40 mg/kg,后者注射同等剂量的5％的DMSO,B6小鼠进行相同处理分组.给药后15 d称重、计算免疫脏器系数,检测小鼠的外周血计数和分类,流式细胞术检测骨髓中造血祖细胞(hematopoietic progenitor cell,HPC)、造血干细胞(hematopoietic stem cell,HSC)和长期造血干细胞(long term-hematopoietic stem cell,LT-HSC)的比例.通过粒细胞巨噬细胞集落形成单位(colony-forming unit-granulocyte and macrophage,CFU-GM)测定实验评价小鼠造血祖细胞的功能.结果 白消安给药后15 d,KKAy小鼠的体重、白细胞(white blood cell,WBC)、红细胞(red blood cell,RBC)、血红蛋白(hemoglobin,HGB)、血小板(blood platelet,PLT)、淋巴细胞(lymphocyte,LYM)、中性粒细胞(neutrophil,NEU)、骨髓中HPC、HSC和LT-HSC的比例均显著降低,CFU-GM数目明显降低,脾和胸腺细胞的比例未见明显变化.白消安给药后,KKAy小鼠的WBC、RBC、HGB和LYM明显低于B6小鼠,但PLT和HSC的比例明显高于B6小鼠.KKAy小鼠的PLT和HSC的降低幅度显著低于B6小鼠,而HPC的降低幅度明显高于B6小鼠.结论 40 mg/kg白消安给药能损伤小鼠的造血系统功能.白消安给药后,KKAy小鼠的WBC、RBC、HGB和LYM损伤较重,但PLT和HSC损伤较轻且耐受性更强,而造血祖细胞的耐受性低于B6小鼠.

目的 比较老年SD大鼠和青年SD大鼠外周血和免疫细胞分型指标差异.方法 12月龄和8周龄的SD大鼠进行外周血细胞计数、白细胞分类、免疫脏器系数、外周血免疫细胞分型、脾免疫细胞分型和脾T细胞P16表达量的检测.结果 与青年大鼠相比,老年大鼠外周血白细胞计数,淋巴细胞百分比下降;红细胞,血红蛋白,中性粒细胞百分比,嗜酸性粒细胞百分比和嗜碱性粒细胞百分比升高;血小板和单核细胞百分比未见差异.胸腺系数、脾系数,老年大鼠与青年大鼠未见差异.外周血免疫细胞分型中,老年大鼠辅助T细胞、调节性T细胞、自然杀伤细胞和单核细胞比例升高,B细胞比例降低;脾淋巴细胞分型检测结果显示,老年组大鼠B细胞(CD45RA)低于青年组大鼠(P<0.01),两组CD3未见差异.老年雄性大鼠脾T细胞P16 mRNA表达量与青年雄性大鼠相比有明显升高(P<0.05).结论 老年大鼠外周血细胞及免疫细胞分型改变.脾T细胞P16表达可能作为免疫衰老的生物学标志.文中对检测结果进行了比较分析,将为研究老年疾病及衰老动物模型提供基础数据.

目的 比较分析不同月龄SD大鼠外周血和免疫器官的免疫细胞分型指标性别差异.方法 选用12月龄SD大鼠和2月龄SD大鼠,雌雄各半,检测外周血细胞计数及分类、脏器指数、外周血和脾免疫细胞分型、脾T细胞P16表达量,并对结果进行性别差异比较.结果 年轻大鼠的各项检测指标未见性别差异.外周血计数与分类结果显示,与青年大鼠比较,老年雌性大鼠白细胞下降;老年雄性大鼠和老年雌性大鼠红细胞上升,两项指标均具有性别差异;老年雄性大鼠和老年雌性大鼠均表现为中性粒百分比上升、淋巴细胞百分比下降、嗜酸性粒细胞百分比升高,未见性别差异;外周血其他指标未见明显改变.老年雌性大鼠胸腺指数低于老年雄性大鼠;老年雄性大鼠脾指数升高,并高于老年雌性大鼠.外周血免疫细胞流式分析结果显示,老年雌性大鼠辅助T细胞、调节T细胞和细胞毒性T细胞上升;老年雌性大鼠B细胞下降;老年雄性大鼠自然杀伤细胞升高;这几项指标均具有性别差异.脾淋巴细胞分型结果显示,老年雌性大鼠CD3+升高,CD45RA+下降.脾T细胞P16表达量老年大鼠P16均升高,未见性别差异.结论 本研究各项指标在青年组大鼠未见性别差异,老年大鼠在外周血白细胞、红细胞计数,中性粒、单核细胞百分比;免疫脏器指数;免疫细胞分型分析中调节T细胞,细胞毒T细胞,自然杀伤细胞,B细胞,CD3阳性细胞等指标改变均存在性别差异.提示老年大鼠的免疫系统的内稳态(homeostasis)平衡失调,在老年性改变中的一些指标出现性别差异.本研究结果为研究老年疾病及衰老动物模型提供了性别对老龄化影响的基础数据.

Sitagliptin, an inhibitor of the dipeptidyl peptidase IV (DPP4), has been implicated in the regulation of type 2 diabetes. However, the role and mechanism of sitagliptin administration in total body irradiation (TBI)- induced hematopoietic cells injury are unclear. In this study, we demonstrated that sitagliptin had therapeutic effects on hematopoietic damage, which protected mice from 7.5 Gy TBI-induced death, increased the numbers and colony formation ability of hematopoietic cells. These therapeutic effects might be attributed to the inhibition of NOX4-mediated oxidative stress in hematopoietic cells, and the alleviation of inflammation was also helpful. Therefore, sitagliptin has potential as an effective radiotherapeutic agent for ameliorating TBI-induced hematopoietic injury.

目的 建立大鼠星形胶质细胞衰老模型,模拟老年大鼠体内星形胶质细胞衰老,探讨衰老的星形胶质细胞条件培养基对神经干细胞增殖能力的影响.方法 采用胰酶消化法分离新生1 d大鼠皮层星形胶质细胞和15 d胎鼠端脑神经干细胞,200μmol/L H2 O2诱导星型胶质细胞4 h建立衰老模型;收取培养3 d和7d衰老细胞上清作为条件培养基,以1:3或1:2的比例加入神经干细胞增殖培养基中,通过神经干细胞及神经球计数观察对增殖功能的影响,以正常星型胶质细胞条件培养基作为对照.结果 3 d正常条件培养基对神经干细胞短期增殖无影响,对长期增殖有抑制作用;3d衰老条件培养基抑制神经干细胞的增殖;7d正常条件培养基促进神经干细胞短期增殖,对长期增殖有抑制作用;7d衰老条件培养基抑制神经干细胞的增殖,抑制作用大于正常条件培养基.结论 H2 O2诱导衰老的星形胶质细胞抑制神经干细胞的增殖,对长期增殖的抑制作用大于正常星形胶质细胞.

目的 观察X线全身照射对2型糖尿病模型KKAy小鼠的造血免疫系统功能的损伤作用,并与对照C57小鼠进行比较.方法 KKAy小鼠,分为对照组和照射组,照射组小鼠经X线全身照射,剂量4 Gy,C57小鼠作为对照.照射后15 d检测小鼠的外周血常规,流式细胞术检测骨髓中造血祖细胞、造血干细胞和长期造血干细胞的比例,脾中B细胞和T细胞的比例,胸腺中CD4CD8双阳性T细胞、CD4单阳性T细胞和CD8单阳性T细胞的比例.通过粒细胞集落形成能力实验评价小鼠造血祖细胞的功能.结果 照射前KKAy小鼠的HSC和LT-HSC的比例低于C57小鼠.4 Gy全身照射后,KKAy小鼠的外周血WBC、RBC、PLT、HGB和LYM％分别下降了68.42％、12.17％、8.78％、30.12％、70.84％;骨髓中HPC、HSC和LT-HSC的比例分别下降了34.02％、29.49％、35.74％;脾B细胞和T细胞的比例分别下降了57.85％、58.81％;胸腺CD4CD8双阳性细胞的比例下降了51.70％.KKAy小鼠的骨髓HSC、LT-HSC、外周血RBC和HGB的降低幅度显著低于C57小鼠.结论 4 Gy全身照射损伤KKAy小鼠的造血免疫系统功能,KKAy小鼠可能比C57小鼠表现出对电离辐射较强的耐受性.

细胞衰老是指细胞增殖分化能力和生理功能逐渐发生衰退的过程.众多疾病与细胞衰老有关,衰老机制的研究对相关疾病致病机制的认识和治疗具有重要意义.近年来对于细胞衰老分子机制的研究主要包括氧化自由基学说、DNA损伤积累和端粒缩短等.线粒体的质量、活性改变与细胞衰老密切相关.线粒体功能障碍导致活性氧类代谢紊乱,造成DNA损伤,激活DNA损伤应答,导致细胞衰老.线粒体自噬能够选择性清除衰老、损伤的线粒体,促进线粒体更新,维持线粒体功能,缓解细胞衰老.

目的 利用FOXO3A基因敲除小鼠探讨FOXO3A在造血系统电离辐射(ionizing radiation,IR)损伤中的影响.方法 FOXO3A-/-小鼠和WT小鼠(FVB/N)分为野生型小鼠对照组(WT组),FOXO3A-/-小鼠对照组(FOXO3A-/-组),野生型小鼠照射组(WT+IR),FOXO3A-/-小鼠照射组(FOXO3A-/-+IR)四组,分别接受假照射和4 Gy X射线全身照射(total body irradiation,TBI),剂量率为0.9 Gy/min.接受TBI后14 d检测FOXO3A-/-小鼠和WT小鼠脏器指数、外周血和骨髓细胞计数,骨髓细胞分型,造血祖细胞(HPCs)粒细胞巨噬细胞集落形成单位(colony forming unit-granulocyte and macrophage,CFU-GM)形成能力,观察FOXO3A基因敲除对造血系统辐射损伤的影响.结果 生理情况下,FOXO3A-/-小鼠骨髓有核细胞计数下降,HPCs比例升高(P<0.05);小鼠接受4 Gy X射线TBI后14 d,FOXO3A基因敲除会加重电离辐射诱导的HPCs和造血干细胞(HSCs)比例下降,但也会抑制辐射诱导的骨髓有核细胞数下降和造血祖细胞CFU-GM形成能力减退.结论 FOXO3A基因敲除破坏造血系统稳态维持,加重TBI小鼠HPCs和HSCs的辐射损伤,对造血细胞辐射敏感性产生一定的影响.FOXO3A在造血系统电离辐射损伤中的调节作用以及能否作为防治损伤的靶点还有待进一步研究.