IL-37b作用于树突状细胞CD39/ATP轴抑制类风湿性关节炎大鼠炎症反应的作用及机制

目的探讨白细胞介素37b重组蛋白(rmIL-37b)通过调节CD39/ATP轴抑制树突状细胞(DC)诱导类风湿性关节炎(RA)大鼠炎症反应的机制。方法将SD大鼠随机分为空白对照组(CTL)、CIA模型组、rmIL-37b 5μg/kg组、rmIL-37b 10μg/kg组,每组各10只。除了空白对照组外,其余大鼠采用含有卡介苗的完全弗氏佐剂和牛Ⅱ型胶原混合乳液免疫刺激,建立CIA模型。确定建模成功当天(D0),rmIL-37b组分别尾静脉注射5μg/kg、10μg/kg rmIL-37b;CTL组和CIA模型组注射相同体积的(1 ml/kg)生理盐水,连续给药15 d。免疫组化法检测滑膜组织Nod样受体蛋白3(NRPL3)炎症小体的表达,流式细胞术检测DC表型,另外试剂盒检测血清三磷酸腺苷(ATP)和免疫学指标。结果与CIA模型组相比,rmIL-37b 10μg/kg组大鼠足容积、AI值、NLRP3炎症小体表达量、血清ATP、IL-1β、IL-18、肿瘤坏死因子α(TNF-α)、抗Ⅱ型胶原抗体亚型(anti-ColⅡ-IgG、anti-ColⅡ-IgG2a)水平均降低,同时DC表面CD...     

麻黄细辛附子汤对肾阳虚外感小鼠及正常小鼠的效-毒作用研究

目的研究麻黄细辛附子汤(MXF)干预肾阳虚外感小鼠的药效作用及其对正常小鼠的毒性作用差异,并考察其效-毒作用机制。方法BABL/C雄性小鼠随机分为正常组、正常毒性低、中、高剂量组;肾阳虚外感模型组;肾阳虚外感低、中、高剂量组,连续灌胃给药6 d,记录体重、肛温等药理指标并观察小鼠的一般体征,检测生化指标、炎症因子。结果药效实验中,与正常组小鼠相比,肾阳虚外感模型组小鼠生化指标肌酸激酶(CK)、肌酸激酶-同工酶(CK-MB)、羟丁酸脱氢酶(α-HBDH)、乳酸盐脱氢酶(LDH)、丙氨酸氨基转移酶(ALT)、天冬氨酸转移酶(AST)、碱性磷酸酶(ALP)、尿素(urea)含量明显升高(P<0.05),炎症因子白介素-6(IL-6)、单核细胞去化蛋白(MCP-1)、肿瘤坏死因子-α(TNF-α)、白介素-10(IL-10)、干扰素-γ(INF-γ)以及白介素12(IL-12p70)含量升高明显(P<0.05)。经给药治疗后,各给药组CK、ALT、urea等生化指标含量较模型组有所回调,各给药组IL-6、IL-10、IFN-γ等炎症因子含量较模型组有不同程度的回调;毒性研究中,各给药组生化指标CK、urea、半胱氨酸(CYS-C)的含量较正常组显著升高(P<0.05),炎症因子白介素-10(IL-10)含量明显上升、白介素-12(IL-12p70)含量明显下降(P<0.05)。结论经MXF给药治疗后,肾阳虚外感给药组小鼠的一些生化指标均有不同程度的回调,MXF可通过调节IL-6、IL-10、IFN-γ、MCP-1、肿瘤坏死因子-α(TNF-α)等炎症因子改善机体的炎症反应;而正常小鼠给予不同剂量的MXF后心脏、肝脏和肾脏功能出现失调,机体通过细胞转移、打破免疫应答的平衡,从而使正常小鼠出现炎症反应。     

早期电针干预对SAMP8小鼠学习记忆能力和海马磷酸化Tau蛋白水平的影响

目的:探讨早期电针"百会""大椎""肾俞"穴对快速老化小鼠(SAMP8小鼠)学习记忆能力和海马磷酸化Tau蛋白表达的影响,为临床电针治疗阿尔茨海默病(AD)时间点的选择提供参考。方法:将36只3月龄SAMP8小鼠随机分为模型组、3月龄电针组、9月龄电针组,每组12只;以12只同龄正常老化SAMR1小鼠作为空白对照组。3月龄电针组及9月龄电针组分别于小鼠3月龄及9月龄时予电针"百会""大椎""肾俞"穴治疗(连续波,2 Hz,1.5~2 mA),20 min/次,每日1次,8 d为一疗程,疗程间隔2 d,共治疗3个疗程。每组小鼠在水迷宫检测学习记忆能力结束后统一于10月龄取材;免疫组织化学法、免疫蛋白印迹法(Western blot)检测小鼠海马磷酸化Tau蛋白的表达,实时荧光定量PCR法检测小鼠海马Tau mRNA表达。结果:与空白对照组比较,模型组小鼠逃避潜伏期明显延长(P<0.01),原平台象限停留时间较短,跨越平台次数减少(P<0.01),海马磷酸化Tau蛋白及Tau mRNA表达较高(P<0.01);与模型组比较,3月龄电针组及9月龄电针组小鼠逃避潜伏期缩短(P<0.05),原平台象限停留时间延长,跨越平台次数增多(P<0.05),小鼠海马磷酸化Tau蛋白及Tau mRNA表达降低(P<0.05);与9月龄电针组比较,3月龄电针组小鼠逃避潜伏期缩短(P<0.05),原平台象限停留时间延长,跨越平台次数增多(P<0.05),海马磷酸化Tau蛋白及Tau mRNA表达降低(P<0.01)。结论:早期电针干预能更有效地改善SAMP8小鼠学习记忆能力并降低其海马磷酸化Tau蛋白水平。     

A flexible split prime editor using truncated reverse transcriptase improves dual-AAV delivery in mouse liver

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Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment

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Insights into the regeneration of skin from Acomys,the spiny mouse

Members of the Acomys genus, known as spiny mice, are unique among mammals in being perfectly capable of regenerating large areas of skin that have been removed. During this regenerative process hairs, sebaceous glands, erector pili muscles, adipocytes and the panniculus carnosus all regenerate and the dermis does not scar. We review here the processes that the epidermis and the individual components of the dermis undergo during spiny mouse regeneration as well as the molecules that have been identified as potentially important in regeneration. We then relate this to what has been proposed as playing a role in studies from the laboratory mouse, Mus musculus. Differences in the immune systems of spiny mice and laboratory mice are also highlighted as this is suggested to play a part not only in the perfect wound healing that embryos display but also in regeneration in lower vertebrates.     

益气逐瘀方对缺氧诱导乳鼠心肌细胞凋亡及miR-24/Bim通路的影响

目的研究益气逐瘀方(参元丹)对缺氧诱导乳鼠心肌细胞凋亡及miR-24/Bim通路的影响。方法分离并培养乳鼠心肌细胞,建立心肌细胞缺氧模型,Lipofectamine2000转染miR-24 mimic/inhibitor至心肌细胞,实验分为正常组、缺氧组、参元丹组、参元丹+miR-24 mimic组、参元丹+miR-24 inhibitor组,治疗组予参元丹含药血清干预。比色法检测心肌细胞培养基上清液LDH、CPK活性,MTT法检测心肌细胞存活率,Annexin V/PI双染流式细胞术检测心肌细胞凋亡,qRT-PCR检测心肌细胞miR-24、Bim mRNA表达。结果与低氧组相比,参元丹组、参元丹+miR-24 mimic组、参元丹+miR-24 inhibitor组均能显著降低细胞培养基上清液LDH、CPK活性(P<0.05),提高心肌细胞存活率(P<0.05),降低心肌细胞凋亡(P<0.05),升高心肌细胞miR-24 mRNA表达(P<0.05),降低Bim mRNA表达(P<0.05);治疗组之间比较,参元丹+miR-24 mimic组作用更显著(P<0.05)。结论益气逐瘀方参元丹能够减轻缺氧诱导乳鼠心肌细胞损伤及细胞凋亡,其作用机制可能与其上调miR-24表达,同时抑制其靶基因Bim mRNA表达有关。     

FGF13 promotes metastasis of triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents 10–20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes, due to the high propensity to develop distant metastases. Hence, new molecular targets for therapeutic intervention are needed for TNBC. We recently conducted a rigorous phenotypic and genomic characterization of four isogenic populations of MDA-MB-231 human triple-negative breast cancer cells that possess a range of intrinsic spontaneous metastatic capacities in vivo, ranging from nonmetastatic (MDA-MB-231_ATCC) to highly metastatic to lung, liver, spleen and spine (MDA-MB-231_HM). Gene expression profiling of primary tumours by RNA-Seq identified the fibroblast growth factor homologous factor, FGF13, as highly upregulated in aggressively metastatic MDA-MB-231_HM tumours. Clinically, higher FGF13 mRNA expression was associated with significantly worse relapse free survival in both luminal A and basal-like human breast cancers but was not associated with other clinical variables and was not upregulated in primary tumours relative to normal mammary gland. Stable FGF13 depletion restricted in vitro colony forming ability in MDA-MB-231_HM TNBC cells but not in oestrogen receptor (ER)-positive MCF-7 or MDA-MB-361 cells. However, despite augmenting MDA-MB-231_HM cell migration and invasion in vitro, FGF13 suppression almost completely blocked the spontaneous metastasis of MDA-MB-231_HM orthotopic xenografts to both lung and liver while having negligible impact on primary tumour growth. Together, these data indicate that FGF13 may represent a therapeutic target for blocking metastatic outgrowth of certain TNBCs. Further evaluation of the roles of individual FGF13 protein isoforms in progression of the different subtypes of breast cancer is warranted.