Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.Howeve...Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.However,tumor cells can counteract this damage through repair pathways,particularly MutT homolog 1(MTH1)protein attenuation of oxidative DNA damage.Suppression of MTH1 can enhance CDT efficacy,therefore,orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness.Carrier-free CuTH@CD,self-assembled through the supramolecular orchestration ofγ-cyclodextrin(γ-CD)with Cu^(2+)and the MTH1 inhibitor TH588,effectively overcoming tumor resistance by greatly amplifying oxidative damage capability.Without additional carriers and mediated by multiple supramolecular regulatory effects,CuTH@CD enables high drug loading content,stability,and uniform size distribution.Upon internalization by tumor cells,CuTH@CD invalidates repair pathways through Cu^(2+)-mediated glutathione(GSH)depletion and TH588-mediated MTH1 inhibition.Meanwhile,both generated Cu^(+)ions and existing ones within the nanoassembly initiate a Fentonlike reaction,leading to the accumulation of•OH.This strategy enhances CDT efficiency with minimal side effects,improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.展开更多
MTH1(mut T homolog1)是Mut T的同源酶,是一种核苷酸焦磷酸酶,主要参与DNA损伤修复过程,尤其在肿瘤细胞的DNA复制过程中发挥着重要角色。最新的研究表明,MTH1可以清除肿瘤细胞中受损DNA功能结构的氧化构件,使得肿瘤细胞继续分裂与增殖,...MTH1(mut T homolog1)是Mut T的同源酶,是一种核苷酸焦磷酸酶,主要参与DNA损伤修复过程,尤其在肿瘤细胞的DNA复制过程中发挥着重要角色。最新的研究表明,MTH1可以清除肿瘤细胞中受损DNA功能结构的氧化构件,使得肿瘤细胞继续分裂与增殖,从而维持肿瘤细胞的生存,而更为重要的是正常细胞不需要MTH1,因此,MTH1有可能只与异常的细胞生长密切相关,这使得MTH1作为治疗靶点成为人们关注的焦点。该文着重对MTH1与肿瘤关系最新的研究成果进行综述,探讨MTH1维持肿瘤生长的相关机制及其与肿瘤治疗的关系,为靶向MTH1治疗肿瘤提供新的思路,为肿瘤研究工作者提供重要参考。展开更多
目的建立敲减MTH1基因的HeLa细胞稳定细胞株,研究MTH1基因的低表达对HeLa细胞内RNA氧化程度的影响。方法设计并合成针对MTH1基因的3条siRNA,分别转染HeLa细胞,选择干扰效果最为理想的靶序列连接入反转录病毒载体Retro-Q,在293T细胞内包...目的建立敲减MTH1基因的HeLa细胞稳定细胞株,研究MTH1基因的低表达对HeLa细胞内RNA氧化程度的影响。方法设计并合成针对MTH1基因的3条siRNA,分别转染HeLa细胞,选择干扰效果最为理想的靶序列连接入反转录病毒载体Retro-Q,在293T细胞内包装病毒颗粒,将病毒转染HeLa细胞后使用嘌呤霉素筛选抗性克隆株,用western b lot技术检测克隆株的MTH1的表达量以确定干扰效果最理想的稳定细胞株,用API5000型质谱仪检测稳定细胞株RNA中的8-oxoG与G的含量以评价RNA的氧化程度。结果本研究设计的3条siRNA中有2条干扰效率可达90%以上,所建立的敲减MTH1基因HeLa细胞稳定细胞株的干扰效果达80%以上,质谱检测结果表明MTH1基因低表达的稳定细胞株每106个G中含有14.9个8-oxoG,而对照细胞中则仅含9.7个8-oxoG。结论 MTH1基因的低表达可引起HeLa细胞中RNA氧化程度明显升高。展开更多
To improve the naphtha composition prediction model based on molecular type homologous series matrix （MTHS）, this paper puts forward a novel molecular matrix to characterize the naphtha composition and the norreal d...To improve the naphtha composition prediction model based on molecular type homologous series matrix （MTHS）, this paper puts forward a novel molecular matrix to characterize the naphtha composition and the norreal distribution hypothesis to better describe the molecular composition distribution within each homologous series of the molecular matrix. Through prediction calculation of eight groups of naphtha samples and eight groups of gasoline samples, it is verified that the normal distribution hypothesis is more applicable than gamma distribution hypothesis for the prediction model. According to the prediction results of the samples, the restrain range of normal distribution parameters during model computing process is summarized. With the bulk properties of naphtha samples and the value range of distribution parameters as input conditions, this study utilizes the improved novel molecular matrix to predict the composition of naphtha samples. As the results show, the novel molecular matrix can predict more detailed composition information of naphtha and improve prediction accuracy with less unknown parameters.展开更多
基金funded by Tongzhou District Health Development Research Reserve Project Foundation(No.KJ2024CX024)Natural Science Foundation of Tianjin City(No.23JCQNJC01640)+1 种基金National Natural Science Foundation of China(Nos.82304393,22404122)Beijing Nova Program(No.Z211100002121127).
文摘Metal ions trigger Fenton/Fenton-like reactions,generating highly toxic hydroxyl radicals(•OH)for chemodynamic therapy(CDT),which is crucial in inducing lethal oxidative DNA damage and subsequent cell apoptosis.However,tumor cells can counteract this damage through repair pathways,particularly MutT homolog 1(MTH1)protein attenuation of oxidative DNA damage.Suppression of MTH1 can enhance CDT efficacy,therefore,orderly integrating Fenton/Fenton-like agents with an MTH1 inhibitor is expected to significantly augment CDT effectiveness.Carrier-free CuTH@CD,self-assembled through the supramolecular orchestration ofγ-cyclodextrin(γ-CD)with Cu^(2+)and the MTH1 inhibitor TH588,effectively overcoming tumor resistance by greatly amplifying oxidative damage capability.Without additional carriers and mediated by multiple supramolecular regulatory effects,CuTH@CD enables high drug loading content,stability,and uniform size distribution.Upon internalization by tumor cells,CuTH@CD invalidates repair pathways through Cu^(2+)-mediated glutathione(GSH)depletion and TH588-mediated MTH1 inhibition.Meanwhile,both generated Cu^(+)ions and existing ones within the nanoassembly initiate a Fentonlike reaction,leading to the accumulation of•OH.This strategy enhances CDT efficiency with minimal side effects,improving oxidative damage potency and advancing self-delivery nanoplatforms for developing effective chemodynamic tumor therapies.
文摘MTH1(mut T homolog1)是Mut T的同源酶,是一种核苷酸焦磷酸酶,主要参与DNA损伤修复过程,尤其在肿瘤细胞的DNA复制过程中发挥着重要角色。最新的研究表明,MTH1可以清除肿瘤细胞中受损DNA功能结构的氧化构件,使得肿瘤细胞继续分裂与增殖,从而维持肿瘤细胞的生存,而更为重要的是正常细胞不需要MTH1,因此,MTH1有可能只与异常的细胞生长密切相关,这使得MTH1作为治疗靶点成为人们关注的焦点。该文着重对MTH1与肿瘤关系最新的研究成果进行综述,探讨MTH1维持肿瘤生长的相关机制及其与肿瘤治疗的关系,为靶向MTH1治疗肿瘤提供新的思路,为肿瘤研究工作者提供重要参考。
文摘目的建立敲减MTH1基因的HeLa细胞稳定细胞株,研究MTH1基因的低表达对HeLa细胞内RNA氧化程度的影响。方法设计并合成针对MTH1基因的3条siRNA,分别转染HeLa细胞,选择干扰效果最为理想的靶序列连接入反转录病毒载体Retro-Q,在293T细胞内包装病毒颗粒,将病毒转染HeLa细胞后使用嘌呤霉素筛选抗性克隆株,用western b lot技术检测克隆株的MTH1的表达量以确定干扰效果最理想的稳定细胞株,用API5000型质谱仪检测稳定细胞株RNA中的8-oxoG与G的含量以评价RNA的氧化程度。结果本研究设计的3条siRNA中有2条干扰效率可达90%以上,所建立的敲减MTH1基因HeLa细胞稳定细胞株的干扰效果达80%以上,质谱检测结果表明MTH1基因低表达的稳定细胞株每106个G中含有14.9个8-oxoG,而对照细胞中则仅含9.7个8-oxoG。结论 MTH1基因的低表达可引起HeLa细胞中RNA氧化程度明显升高。
基金Supported by the National Natural Science Foundation of China(U1462206)
文摘To improve the naphtha composition prediction model based on molecular type homologous series matrix （MTHS）, this paper puts forward a novel molecular matrix to characterize the naphtha composition and the norreal distribution hypothesis to better describe the molecular composition distribution within each homologous series of the molecular matrix. Through prediction calculation of eight groups of naphtha samples and eight groups of gasoline samples, it is verified that the normal distribution hypothesis is more applicable than gamma distribution hypothesis for the prediction model. According to the prediction results of the samples, the restrain range of normal distribution parameters during model computing process is summarized. With the bulk properties of naphtha samples and the value range of distribution parameters as input conditions, this study utilizes the improved novel molecular matrix to predict the composition of naphtha samples. As the results show, the novel molecular matrix can predict more detailed composition information of naphtha and improve prediction accuracy with less unknown parameters.
