Using bio-orthogonally catalyzed lethality strategy to generate mitochondria-targeting anti-tumor metallodrugs in vitro and in vivo     

Xuling Xue  Chenggen Qian  Qin Tao  Yuanxin Dai  Mengdi Lv  Jingwen Dong  Zhi Su  Yong Qian  Jing Zhao  Hong-Ke Liu  Zijian Guo 《国家科学评论(英文版)》2021,8(9)

Synthetic lethality was proposed nearly a century ago by geneticists and recently applied to develop precision anti-cancer therapies. To exploit the synthetic lethality concept in the design of chemical anti-cancer agents, we developed a bio-orthogonally catalyzed lethality (BCL) strategy to generate targeting anti-tumor metallodrugs both in vitro and in vivo. Metallodrug Ru-rhein was generated from two non-toxic species Ru-N₃ and rhein-alkyne via exclusive endogenous copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction without the need of an external copper catalyst. The non-toxic species Ru-arene complex Ru-N₃ and rhein-alkyne were designed to perform this strategy, and the mitochondrial targeting product Ru-rhein was generated in high yield (>83%) and showed high anti-tumor efficacy in vitro. This BCL strategy achieved a remarkable tumor suppression effect on the tumor-bearing mice models. It is interesting that the combination of metal-arene complexes with rhein via CuAAC reaction could transform two non-toxic species into a targeting anti-cancer metallodrug both in vitro and in vivo, while the product Ru-rhein was non-toxic towards normal cells. This is the first example that exclusive endogenous copper was used to generate metal-based anti-cancer drugs for cancer treatment. The anti-cancer mechanism of Ru-rhein was studied and autophagy was induced by increased reactive oxygen species and mitochondrial damage. The generality of this BCL strategy was also studied and it could be extended to other metal complexes such as Os-arene and Ir-arene complexes. Compared with the traditional methods for cancer treatment, this work presented a new approach to generating targeting metallodrugs in vivo via the BCL strategy from non-toxic species in metal-based chemotherapy.  相似文献   

运动预处理后内源性阿片肽对大鼠心肌缺血 再灌注损伤早期保护作用          下载免费PDF全文

王强 《河北体育学院学报》2015,29(6):83-88

目的：探讨运动预处理后内源性阿片肽对大鼠心肌缺血再灌注损伤早期保护作用及机制。方法：健康雄性SD大鼠60只,随机分成假手术组（sham组）、缺血再灌注模型组（I/R组）、运动预处理组（EP组）和运动预处理+纳洛酮组（EPN组）。在运动预适应模型基础上,结扎左冠状动脉前降支复制大鼠心肌缺血再灌注模型,采用多道生理记录仪描记血流动力学参数,用酶联免疫法（ELISA）检测血清心肌肌钙蛋白I（cTnI）和血浆β 内啡肽（β End）、强啡肽A（Dyn A）和亮氨酸 脑啡肽（L Enk）含量,用原子分光光度法检测心肌中钙离子（Ca2+）浓度。结果：①与I/R组相比,EP组在再灌注期LVSP、±dp/dtmax降低幅度明显减小（P＜005）;与EP组相比,EPN组在再灌注60分钟后LVSP和 dp/dtmax值下降,且具有显著性差异（P＜005）。②与I/R组相比,EP组血清cTnI漏出明显减少,具有显著性差异（P＜005）;EPN组血清cTnI降低,但差异不显著（P＞005）;与EP组相比,EPN组中血清cTnI值明显升高,有统计学意义（P＜005）。③与I/R组相比,EP组和EPN组血浆中β End、Dyn A、L Enk浓度均明显升高,且有显著性差异（P＜005）;EP组与EPN组各项指标差异不显著（P＞005）。④与I/R组相比,EP组心肌细胞胞浆中Ca2+浓度明显降低,具有显著性差异（P＜005）;EPN组心肌细胞胞浆中Ca2+浓度有降低趋势,但差异不显著（P＞005）;与EP组相比,EPN组中心肌细胞胞浆中Ca2+浓度明显升高,有统计学意义（P＜005）。结论：运动预处理对心肌缺血再灌注损伤有保护作用,内源性阿片肽可能通过对抗交感神经兴奋和经阿片受体后途径维持细胞内钙稳态,保持细胞结构完整和功能正常,维持心脏舒缩功能,发挥早期的保护效应。  相似文献   

不同强度力竭运动大鼠运动后12h肝细胞凋亡的研究   总被引：2，自引：0，他引：2  

陈伟  樊新生  张廷妍  李善妮 《北京体育大学学报》2010,(2)

研究对象、方法:利用细胞免疫组化的方法研究力竭运动后12 h成年雄性SD大鼠肝细胞凋亡同肝细胞内的自由基水平和钙代谢之间的关系。结果:1)运动组与C组相比,凋亡细胞的数量差异显著(p<0.05);运动组组间差异也具有显著意义(p<0.05)。2)ME、HE组肝细胞内SOD活性与C组相比差异显著(p<0.05),但运动组组间差异不显著。3)ME组肝细胞中MDA含量增加、GSH含量降低,且相对于对照组差异显著(p<0.05);HE组虽有类似变化,但与其它各组相比无显著性差异。4)运动组肝细胞中Ca2+含量较对照组增加,差异显著(ME:p<0.01,HE:p<0.05),运动组组间差异显著(p<0.05)。结论:1)力竭运动可导致肝细胞凋亡,氧化应激及钙离子超载是引起细胞凋亡的重要因素,且前者可能发挥更重要作用。2)中等强度力竭运动更易于导致肝细胞凋亡,其原因可能同长时间力竭运动引起中暑或严重缺水,进而导致恢复期内中性粒细胞发生呼吸爆发有关。  相似文献   

无尾目动物线粒体基因组结构研究最新进展     

张雁  聂刘旺  王晶晶 《巢湖学院学报》2009,11(6):84-88

脊椎动物线粒体DNA(mtDNA)是一个长度约为15-22kb环形结构.mtDNA呈母系遗传,在大部分的脊椎动物中具有相对保守性.但是在两栖纲无尾目动物中,线粒体基因组的基因排列顺序却存在很大变异,这种基因重排现象可以用TDRL模型来解释.本文综述了今年来在无尾目线粒体基因组结构的研究成果,分析了蛙类mtDNA基因重排多样性,结果发现无尾目动物共有8类不同的线粒体基因排列方式,并初步分析了这些不同基因结构的关系.  相似文献   

有氧训练对一次力竭运动小鼠心肌及血清抗氧化酶的影响     

巩清波 《体育科技文献通报》2013,(11):28-29,42

目的：经过16周有氧训练,观察一次性力竭运动后小鼠心肌及血清抗氧化酶活性及过氧化脂质的变化,探讨长期有氧运动对运动应激时机体的抗氧化能力的影响。方法：36只雌性KM小鼠随即分成有氧训练组（E组）、运动应激组（0组）和空白对照组（c组）,E组经过16周有氧训练后与0组进行一次性力竭游泳实验,测定力竭运动后心肌和血清中MDA、SOD、CAT、T—AOC、CK等指标的变化。结果：小鼠经过力竭运动后心肌SOD、CAT、T—AOC含量,E组与0组相比增加非常显著（P〈0．01）。结论：经过16周的有氧训练后,小鼠对运动应激引起的氧化适应能力得到提高,小鼠的心脏组织和血清中脂质过氧化程度都有所下降。  相似文献   

Risk of cardiac rupture after acute myocardial infarction is related to a risk of hemorrhage     

Geng QIAN  Hong-bin LIU  Jin-wen WANG  Chen WU  Yun-dai CHEN 《Journal of Zhejiang University. Science. B》2013,14(8):736-742

Although cardiac rupture (CR) is a fatal mechanical complication of acute myocardial infarction (AMI), to date no predictive model for CR has been described. CR has common pathological characteristics with major bleeding. We aimed to investigate the relationship between the risk factors of major bleeding and CR. A total of 10 202 consecutive AMI patients were recruited, and mechanical complications occurred in 72 patients. AMI patients without CR were chosen as control group. Clinical characteristics including bleeding-related factors were compared between the groups. The incidences of free wall rupture (FWR), ventricular septal rupture (VSR), and papillary muscle rupture (PMR) were 0.39%, 0.21%, and 0.09%, respectively, and the hospital mortalities were 92.5%, 45.5%, and 10.0%, respectively. Female proportion and average age were significantly higher in the groups of FWR and VSR than in the control group (P<0.01); higher white blood cell count and lower hemoglobin were found in all CR groups (P<0.01). Compared to the control group, patients with CR were more likely to receive an administration of thrombolysis [26.39% vs. 13.19%, P<0.05], and were less likely to be treated with primary percutaneous coronary intervention (PCI) [41.67% vs. 81.60%, P<0.05]. The major bleeding scores (integer scores) of FWR, VSR, and PMR were (17.70±7.24), (21.91±8.33), and (18.60±7.88), respectively, and were significantly higher than that of the control group (11.72±7.71) (P<0.05). A regression analysis identified age, increased heart rate, anemia, higher white blood cell count, and thrombolysis as independent risk factors of CR, most of which were major bleeding-related factors. The patients with CR have a significantly higher risk of hemorrhage compared to the group without CR. Risk of CR after AMI is related to the risk of hemorrhage.  相似文献   

铃兰提取液对蟾蜍心肌活动的影响     

宫汝淳  马晓红 《通化师范学院学报》2000,(2)

本文通过化学方法提取的铃兰毒甙(convallataxin)液,铃兰皂甙(convauasaponin)液作用于蟾蜍离体心脏活动,发现铃兰叶、茎、根、全草浸液,水提取液皆有强心作用.  相似文献   

三种训练对大鼠心肌细胞超微结构的影响     

洪长青  邓树勋 《浙江体育科学》2000,22(3):55-58,64

以大鼠为对象建立持续训练、间歇训练及静力训练３种实验动物模型,研究持续６周的上述３种训练对大鼠心脏系数及心肌细胞超微结构的影响。结果：持续训练组心脏系数增加（ｐ〈０．０５）,光镜下心肌组织毛细血管管径增大、密度增加,电镜下心肌细胞线粒体体积大、融合、肌节变长;间歇训练组心系数增加（ｐ〈０．０５）,心股细胞节缩短,局部可见肌丝断裂、Ｚ线紊乱;静力训练组心脏系数增大仁无显著性意义,心肌细胞线粒体破裂、  相似文献   

长时间游泳对大鼠心肌线粒体渗透性转运的影响     

毛丽娟宋文民  许豪文 《上海体育学院学报》2000,24(4):43-45

采用实验对比研究方法,探讨长时间游泳对大鼠心肌线粒体渗透性的影响。结果表明,90min运动组与对照组相比．心肌线粒体的还原型谷胱甘肽(GSH)的含量无显著性差异,游离钙(FCa^2 )升高;长时间力竭运动组与对照组相比,心肌线粒体的丙二醛(MDA)显著升高,巯基(SH)和还原型谷胱甘Pak(GSH)显著减少,游离钙(FCa^2 )含量也明显降低。  相似文献   

抗阻运动通过刺激骨骼肌FSTL1分泌抑制心梗大鼠心肌细胞凋亡及其机制探讨     

郝美丽  席悦  田振军 《体育科学》2020,(1):67-78

目的:探讨抗阻运动通过刺激骨骼肌卵泡抑素样蛋白1(Follistatin-like protein 1,FSTL1)分泌,抑制心梗(Myocardial Infarction,MI)大鼠心肌细胞凋亡及其机制。方法:动物实验:结扎SD大鼠左冠状动脉前降支制备MI模型,术后随机分为5组,分别为假手术组(S)、心梗安静对照组(MI)、心梗+抗阻运动组(MR)、心梗+腺相关病毒空载体组(MV)、心梗+FSTL1腺相关病毒载体组(MF),每组10只,其中S组只穿线不结扎。术后1周,MR组进行为期4周的爬梯抗阻运动,MV组和MF组于左后肢胫骨前肌分别注射腺相关病毒空载体和FSTL1腺相关病毒载体。训练结束后次日,腹腔麻醉,测定心功能,摘取心脏和左后肢胫骨前肌。Masson染色观察并计算心肌胶原容积百分比(CVF%);TUNEL检测分析心肌细胞凋亡;Western Blotting实验测定骨骼肌和血清FSTL1蛋白含量,心肌FSTL1、DIP2A、p-Akt/Akt、p-mTOR/mTOR、Bcl2/Bax蛋白表达。细胞实验:H9C2细胞分为8组,即H9C2对照组、H9C2+LPS(脂多糖:Lipopolysaccharide,LPS)组、H9C2+LPS+AICAR(AMPK激动剂AICAR)组、H9C2+LPS+LY294002(PI3K抑制剂LY294002)组、H9C2+LPS+AICAR+LY294002组、H9C2+LPS+rhFSTL1组、H9C2+LPS+rhFSTL1+AICAR组、H9C2+LPS+rhFSTL1+LY294002组。TUNEL检测H9C2细胞凋亡,CCK8检测H9C2细胞存活率,Western Blotting实验检测细胞FSTL1、DIP2A、p-Akt/Akt、p-mTOR/mTOR、Bcl2/Bax蛋白表达。结果:MI后大鼠骨骼肌FSTL1基因和蛋白表达降低,心肌FSTL1基因表达无显著变化,心肌和血清FSTL1蛋白水平显著升高,心肌细胞凋亡和心肌纤维化显著增加,心功能下降。抗阻运动或胫骨前肌注射FSTL1腺相关病毒载体后,骨骼肌、血清和心肌FSTL1蛋白水平均显著升高,心肌FSTL1受体DIP2A、p-Akt、p-mTOR、Bcl2/Bax蛋白表达均显著上调,心肌细胞凋亡和心肌纤维化减少,心功能显著改善,且抗阻运动显著上调骨骼肌FSTL1基因表达,但心肌FSTL1基因表达无显著性差异。FSTL1和AICAR干预均显著抑制LPS诱导的H9C2细胞凋亡,增加FSTL1、DIP2A、p-Akt、p-mTOR、Bcl2/Bax蛋白表达水平和细胞存活率,LY294002干预与上述作用相反。结论:在抗阻运动上调MI大鼠心肌FSTL1表达抑制心肌细胞凋亡过程中,骨骼肌源性FSTL1发挥重要作用,骨骼肌源性FSTL1可通过血液循环到达心脏,与其受体DIP2A结合,激活下游Akt-mTOR信号通路,抑制心肌细胞凋亡,降低心肌纤维化,改善MI大鼠心功能。  相似文献