BIM, a key proapoptotic member of the BCL-2 family of proteins, is essential for apoptosis triggered by tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). However, the precise molecular ...BIM, a key proapoptotic member of the BCL-2 family of proteins, is essential for apoptosis triggered by tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). However, the precise molecular mechanism by which EGFR-TKIs induce BIM expression has remained unclear. A previous study of ours showed that the activetion of c-Jun NH2-terminal kinase (JNK) is critical for the TKI-induced apoptosis in PC-9 cells, a gefitinib-sensitive human NSCLC cell line. In this study, we therefore examined the effect of JNK activation on BIM expression and further investigated the mechanism responsible for TKI-induced apoptosis in PC-9 cells. Northern blotting analysis revealed that the TKI AG1478 induced a substantial increase in the level of BIM mRNA. However, this TKI-induced increase was not observed in dominant-negative JNK overexpressing cell line J12A5 or in the TKI-resistant cell line HP-5R, in which JNK is not activated in response to AG1478. Therefore, JNK activation was correlated with the up-regulation of BIM expression. BIM is known to be a downstream target of forkhead box protein O (FOXO) transcription factors. Immunoblot analysis indicated that the levels of FOXO1, FOXO3a, and FOXO4 transcription factors increased after AG1478 treatment of PC-9 cells but that they were not increased in either J12A5 or HP-5R cells, indicating that FOXO was increased in PC-9 cells through JNK activation. FOXO1 knockdown in PC-9 cells decreased EGFR-TKI-induced BIM expression and apoptosis. These findings provide evidence that JNK activation and subsequent increased FOXO expression play a critical role in EGFR-TKI-induced BIM expression and apoptosis.展开更多
Aqueous Zn metal batteries(AZMBs)show significant potential for flexible energy storage devices.However,the Zn anodes face persistent challenges in practical applications(including dendrite growth,corrosion,and hydrog...Aqueous Zn metal batteries(AZMBs)show significant potential for flexible energy storage devices.However,the Zn anodes face persistent challenges in practical applications(including dendrite growth,corrosion,and hydrogen evolution),which compromise cycling stabilities and Coulombic efficiencies,thereby hindering commercialization of AZMBs.Herein,a self-supporting framework is synthesized by electrostatic spinning and controllable pyrolysis using gelatin and ammonium metavanadate as precursors.The framework consists of N-doped carbon fibers integrated with amorphous VOx(denoted as VOx@GC),which serves to modify the Zn anode.It is revealed that the VOx@GC host contains abundant metal and non-metal zincophilic sites,which not only facilitates Zn^(2+)desolvation and decreases diffusion resistance,but also provides plentiful nucleation sites.Consequently,the nucleation barrier of Zn^(2+)is substantially reduced,promoting dendrite-free Zn^(2+)deposition.In symmetric cells,the VOx@GC modified Zn anode(VOx@GC@Zn)realizes a long cycling life of 4000 and 1600 h with low polarization potentials under low and high capacities conditions,respectively.The VOx@GC@Zn//NH_(4)V_(4)O_(10)full cell provides a high capacity of 219.6 mAh·g^(-1)over 2000 cycles at 2 A·g^(-1)(N/P=4.2).Furthermore,the pouch cell maintains good performance over 300 cycles at 0.2 A·g^(-1),with a capacity retention of 88.3%,highlighting strong potential for practical applications.展开更多
Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
文摘BIM, a key proapoptotic member of the BCL-2 family of proteins, is essential for apoptosis triggered by tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). However, the precise molecular mechanism by which EGFR-TKIs induce BIM expression has remained unclear. A previous study of ours showed that the activetion of c-Jun NH2-terminal kinase (JNK) is critical for the TKI-induced apoptosis in PC-9 cells, a gefitinib-sensitive human NSCLC cell line. In this study, we therefore examined the effect of JNK activation on BIM expression and further investigated the mechanism responsible for TKI-induced apoptosis in PC-9 cells. Northern blotting analysis revealed that the TKI AG1478 induced a substantial increase in the level of BIM mRNA. However, this TKI-induced increase was not observed in dominant-negative JNK overexpressing cell line J12A5 or in the TKI-resistant cell line HP-5R, in which JNK is not activated in response to AG1478. Therefore, JNK activation was correlated with the up-regulation of BIM expression. BIM is known to be a downstream target of forkhead box protein O (FOXO) transcription factors. Immunoblot analysis indicated that the levels of FOXO1, FOXO3a, and FOXO4 transcription factors increased after AG1478 treatment of PC-9 cells but that they were not increased in either J12A5 or HP-5R cells, indicating that FOXO was increased in PC-9 cells through JNK activation. FOXO1 knockdown in PC-9 cells decreased EGFR-TKI-induced BIM expression and apoptosis. These findings provide evidence that JNK activation and subsequent increased FOXO expression play a critical role in EGFR-TKI-induced BIM expression and apoptosis.
基金supported by the National Key R&D Program of China(No.2022YFE0110400)the National Natural Science Foundation of China(Nos.52130206,22178016,U24A20526,and 52221006)+2 种基金the Fundamental Research Funds for the Central Universities(Nos.JD2513 and JD2520)the Beijing-Tianjin-Hebei Cooperative Research Special Project(No.B2024202081)the High-performance computing platform of BUCT.
文摘Aqueous Zn metal batteries(AZMBs)show significant potential for flexible energy storage devices.However,the Zn anodes face persistent challenges in practical applications(including dendrite growth,corrosion,and hydrogen evolution),which compromise cycling stabilities and Coulombic efficiencies,thereby hindering commercialization of AZMBs.Herein,a self-supporting framework is synthesized by electrostatic spinning and controllable pyrolysis using gelatin and ammonium metavanadate as precursors.The framework consists of N-doped carbon fibers integrated with amorphous VOx(denoted as VOx@GC),which serves to modify the Zn anode.It is revealed that the VOx@GC host contains abundant metal and non-metal zincophilic sites,which not only facilitates Zn^(2+)desolvation and decreases diffusion resistance,but also provides plentiful nucleation sites.Consequently,the nucleation barrier of Zn^(2+)is substantially reduced,promoting dendrite-free Zn^(2+)deposition.In symmetric cells,the VOx@GC modified Zn anode(VOx@GC@Zn)realizes a long cycling life of 4000 and 1600 h with low polarization potentials under low and high capacities conditions,respectively.The VOx@GC@Zn//NH_(4)V_(4)O_(10)full cell provides a high capacity of 219.6 mAh·g^(-1)over 2000 cycles at 2 A·g^(-1)(N/P=4.2).Furthermore,the pouch cell maintains good performance over 300 cycles at 0.2 A·g^(-1),with a capacity retention of 88.3%,highlighting strong potential for practical applications.
基金This research was supported in part by the Japan Agency for Medical Research and Development(AMED)(JP15ck0106096 to TK)Japan Science and Tech-nology Agency(JST)Core Research for Evolutionary Science and Technology(JPMJCR1689 to RH)+5 种基金Artifi-cial Intelligence,Big Data,IoT,Cyber Security Integration Project of the Public/Private R&D Investment Strategic Expansion Program(JPMJCR18Y4 to RH)the Japan Soci-ety for the Promotion of Science(JSPS)Grant-in-Aid for Scientific Research(S)(17H06162 to HN),Grant-in-Aid for Scientific Research(B)(20H03695 to KS),Grants-in-Aid for the Tailor-Made Medical Treatment Program(BioBank Japan Project)from the Japanese Ministry of Education,Culture,Sports,ScienceandTechnology(MEXT),Princess Takamatsu Cancer Research Fund,and National Cancer Center Research and Development Fund(NCC Biobank and NCC Core Facility).The J-MICC study was supported by Grants-in-Aid for Scientific Research for Priority Areas of Cancer(No.17015018 to KW)Innovative Areas(No.221S0001 to KW)from MEXTby JSPS Grant-in-Aid for Scientific Research Grant(No.16H06277[CoBiA])The JPHC Study was supported by National Cancer Center Research and Development Fund since 2011(latest grant number:2020-J4)and a Grant-in-Aid for Cancer Research from the Ministry of Health,Labor and Welfare of Japan(1989-2010).ToMMoissupportedinpartbyMEXT-JSTand AMED(most recent grant numbers:JP20km0105001 and JP20km0105002)Iwate Tohoku Medical Megabank Orga-nization(Iwate Medical University)is supported in part by MEXT-JST and AMED(most recent grant numbers:JP20km0105003 and JP20km0105004).
文摘Dear editor,Lung carcinoma is responsible for the highest fatal-ity rate among cancer-related deaths globally,with lung adenocarcinoma(LADC)emerging as the prevailing sub-type.
