| 1 | A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer显示文摘Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation. | Tiantian Xu Qisheng Ma Yanan Li Qing Yu Peichen Pan Yawen Zheng Zhijian Li Xiufang Xiong Tingjun Hou Bin Yu Hongmin Liu Yi Sun | 2022 | Signal Transduction and Targeted Therapy2022，7，11： | 2 |
| 4 | Strontium doped electrospinning fiber membrane with antibacterial and osteogenic properties prepared by pulse electrochemical method显示文摘The osteogenic differentiation and new bone formation are commonly delayed by bacterial infection of orthopedic implants,which is urgent to be resolved quickly in the clinic.The current paper prepared a strontium-doped elec-trospinning fiber membrane with antibacterial and osteogenic properties by pulse electrochemical method.Poly-lactic acid/hydroxyapatite(PLLA/HA)composite fiber substrate was fabricated by electrospinning technology,and strontium doped SrHA/Cu/Polypyrrole(PPy)composite coating was constructed with pulse electrodeposi-tion method on its surface.The strontium doping technique,degradation of Sr^(2+)and Cu^(2+),cellular compatibility,and the antibacterial activity of the fiber membrane were examined.The results revealed that the deposition of phosphorus and calcium on composite fiber was the highest,indicating good biological activity.The release of Sr^(2+)and Cu^(2+)was stable and gradual due to the modulation of PPy.The composite fiber presented excellent antibacterial performance and the antibacterial rate was close to 100%against Staphylococcus aureus and Es-cherichia coli.Furthermore,it is conducive to the adhesion,spread,and proliferation of vascular endothelial cells and osteoblasts,namely outstanding osteogenesis and angiogenesis abilities.In conclusion,the multifunctional PLLA/HA@SrHA/Cu/PPy composite fiber membrane with good antibacterial and osteogenic activity by electro-spinning technology and pulsed electrochemical deposition method provides an effective strategy for the poor bone healing of infected bone defects. | Yonggang Liu Bolin Zhang Feifei Liu Yani Qiu Wenbo Mu Liang Chen Chuang Ma Tingjun Ye Yingbo Wang | 2022 | Engineered Regeneration2022，3，4： | 0 |
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