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中国科学:生命科学英文版 2023年第9期66卷 2138-2151页

作者： Yingxiu Luo Mengjia He Jie Yang Feifei Zhang Jie Chen Xuyang Wen Jiayan Fan Xianqun Fan Peiwei Chai Renbing Jia Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China shanghai key laboratory of Orbital Diseases and Ocular oncology Shanghai 200023China

Retinoblastoma, the most prevalent primary intraocular tumor in children, leads to vision impairment, disability and even death.In addition to RB1 inactivation, MYCN activation has been documented as another common oncogenic alteration in retinoblastoma and represents one of the high-risk molecular subtypes of retinoblastoma. However, how MYCN contributes to the progression of retinoblastoma is still incompletely understood. Here, we report that MYCN upregulates YTHDF1, which encodes one of the reader proteins for N6-methyladenosine(m^(6)A) RNA modification, in retinoblastoma. We further found that this MYCN-upregulated m^(6)A reader functions to promote retinoblastoma cell proliferation and tumor growth in an m^(6)A bindingdependent manner. Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their m RNAs and enhancing m RNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.

关键词： MYCN YTHDF1 m^(6)A CDK5R1 retinoblastoma

Verteporfin-mediated on/off photoswitching functions synergistically to treat choroidal vascular diseases

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Bioactive Materials 2022年第8期7卷 402-415页

作者： Yahan Ju Xiaochan Dai Zhimin Tang Zunzhen Ming Ni Ni Dongqing Zhu Jing Zhang Bo Ma Jiajing Wang Rui Huang Siyu Zhao Yan Pang Ping Gu Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai200011PR China shanghai key laboratory of Orbital Diseases and Ocular oncology Shanghai200011PR China Central laboratory Shanghai Tenth People’s HospitalTongji UniversityShanghai200072PR China

Choroidal vascular diseases,such as age-related macular degeneration,are the leading cause of vision impairment and are characterized by pathological angiogenesis.Verteporfin-mediated photodynamic therapy is a current strategy that selectively occludes choroidal neovasculature.However,the clinically used large-dose systemic administration increases the risk of systemic adverse events,such as phototoxicity to superficial tissues.In this study,we developed an in situ verteporfin delivery system with a photoswitching synergistic function that disassembles in response to intraocular inflammatory enzymes.Under light-on conditions,verteporfin-mediated photodynamic therapy effectively occurs and this leads to vascular occlusion.Under light-off conditions,non-photoactive verteporfin negatively regulates vascular endothelial growth factor-induced angiogenesis as a yes-associated protein inhibitor.Taken together,our system serves as an intraocular verteporfin reservoir to improve the bioavailability of verteporfin by innovatively exploiting its photochemical and biological functions.This work provides a promising strategy with synergistic antiangiogenic effects for the treatment of choroidal vascular diseases.

关键词： Pathological neovascularization Photodynamic therapy Bio-responsive release In situ drug delivery

PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS1/2 hexamer stability

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Blood Science 2023年第1期5卷 39-50页

作者： Lili Song Peifeng Li Huiying Sun Lixia Ding Jing Wang Benshang Li Bin-Bing S.Zhou Haizhong Feng Yanxin Li Pediatric Translational Medicine Institute Key Laboratory of Pediatric Hematology and Oncology Ministry of HealthState Key Laboratory of Oncogenes and Related GenesDepartment of Hematology&OncologyShanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghaiChina State key laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular SynthesisShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiChina State key laboratory of Oncogenes and Related Genes Renji-Med X Clinical Stem Cell Research CenterRen Ji HospitalShanghai Cancer InstituteShanghai Jiao Tong University School of MedicineShanghaiChina

Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(PRPS2)mutations drive ALL relapse through influencing PRPS1/2 hexamer stability.Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples.The effects of PRPS2 mutations on cell survival,cell apoptosis,and drug resistance were evaluated.In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed.Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry(UPLC–MS/MS).Integrating sequencing data with clinical information,we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy.Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability,leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance.The 3-amino acid V103-G104-E105,the key difference between PRPS1 and PRPS2,insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer,leading to its low enzyme activity.In addition,we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models.Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.

关键词： Drug resistance Childhood acute lymphoblastic leukemia PRPS2 Purine metabolism Tumor relapse

Crosstalk between metabolic reprogramming and epigenetics in cancer:updates on mechanisms and therapeutic opportunities

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Cancer Communications 2022年第11期42卷 1049-1082页

作者： Tongxin Ge Xiang Gu Renbing Jia Shengfang Ge Peiwei Chai Ai Zhuang Xianqun Fan Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011P.R.China shanghai key laboratory of Orbital Diseases and Ocular oncology Shanghai 200011P.R.China

Reversible,spatial,and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis.Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation.Epigenetic dysregulation is a common fea-ture of human cancers,which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression.The epigenome is sensitive to metabolic changes.Metabolism produces various metabolites that are substrates,cofactors,or inhibitors of epigenetic enzymes.Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epige-netic landscape,inducing transcriptional responses to heterogeneous metabolic requirements.Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels.Epigenetic modifiers,chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism,facilitating malignant transformation.However,the significance of the close connection between metabolism and epi-genetics in the context of cancer has not been fully deciphered.Thus,it will be constructive to summarize and update the emerging new evidence support-ing this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options.In this review,we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aber-rations and metabolic rewiring to cancer initiation and development.Finally,we highlight the potential therapeutic opportunities for hematological malig-nancies and

关键词： cancer epigenetics metabolic reprogramming RNA epigenetics therapy

Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

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Frontiers of Medicine 2022年第5期16卷 784-798页

作者： Yan Zhang Baoyuan Zhang Yongyun Li Yuting Dai Jiaoyang Li Donghe Li Zhizhou Xia Jianming Zhang Ping Liu Ming Chen Bo Jiao Ruibao Ren shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiCollaborative Innovation Center of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Ophthalmology Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Orbital Diseases and Ocular OncologyShanghai 200001China Department of Biology Brandeis UniversityWalthamMA 02454USA

More than 85%of patients with uveal melanoma(UM)carry a GNAQ or GNA11 mutation at a hotspot codon(Q209)that encodes G proteinαsubunit q/11 polypeptides(Gα_(q/11)).GNAQ/11 relies on palmitoylation for membrane association and signal transduction.Despite the palmitoylation of GNAQ/11 was discovered long before,its implication in UM remains unclear.Here,results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells.Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^(Q209L)-induced malignant transformation in NIH3T3 cells.Importantly,the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells,which are much more dependent on Gα_(q/11) signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations.Furthermore,the palmitoylation inhibitor,2-bromopalmitate,also specifically disrupted Gα_(q/11) downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor,ABT-199,in vitro.The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.

关键词： uveal melanoma mutant GNAQ/11 palmitoylation BCL2 combination target therapy

Three transcription factors and the way immune cells affected by different plasma change in opposite ways in the development of the syndrome of pre-eclampsia

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Chinese Medical Journal 2014年第12期127卷 2252-2258页

作者： Liang Zhou Zhu Jing Wang Yunfei Wang You Zhang Yu Lin Jianhua Di Wen Department of Obstetrics and Gynecology Ren Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China shanghai key laboratory of gynecologic oncology Shanghai 200127China

Background How the transcriptional factors regulated the innate and adaptive immune system in pregnancy and preeclampsia are less understood.Nevertheless,what the plasma work in the development of this disease was not sure.The present study was design to evaluate what the transcriptional factors change in innate and adaptive immune system and what the plasma do in this filed.Methods Peripheral blood mononuclear cells （PBMC） from non-pregnant women （n=18）,women with clinically normal pregnancies （n=23） and women with pre-eclampsia （n=20） were separated from peripheral blood to isolate monocytes and T cells.The purity of monocytes and T cells were analysed by flow cytometry.Monocytes and T cells were stimulated in either lipopolysaccharides （LPS） or phorbol-myristate-acetate （PMA）,respectively.Transcription Factor Arrays were used to screen the transcription factors of interest in comparing of different groups.PBMC were isolated from another 8 nonpregnant samples were co-incubated with different groups of plasma.Polymerase chain reaction （PCR） was performed using whole cell extractions of the samples.Results Nuclear factor of activated T-cells-1 （NFAT-1）,signal transducers and activators of transcription-1 （STAT-1） and activator protein-1 （AP-1） are up-regulated in monocytes in pregnancy and more so in pre-eclampsia.On the the contrary,NFAT-1,STAT-1 and AP-1 are down-regulated in T cells in pregnancy and more so in pre-eclampsia.A reduction was observed in interferon （IFN）-y,interleukin （IL）-12 and IL-4 expression in T cells incubated with pre-eclamptic plasma.An elevation was observed in tumor necrosis factor （TNF）-α,IL-1 and IL-12 expression in monocytes incubated with preeclamptic plasma.Conclusions Innate immunity is over activated and adaptive immunity is over suppressed in the development of preeclampsia.NFAT-1,STAT-1 and AP-1 might be the central transcription factors in the pathogenesis of pre-eclampsia.They induced some changes in plasma and ＂educate＂ the monocytes and T cells for relevant cytokine product

关键词： pre-eclampsia monocytes T cells transcription factors

Sustained delivery of vascular endothelial growth factor mediated by bioactive methacrylic anhydride hydrogel accelerates peripheral nerve regeneration after crush injury

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Neural Regeneration Research 2022年第9期17卷 2064-2071页

作者： Wanlin Xu Yifan Wu Hao Lu Yun Zhu Jinhai Ye Wenjun Yang Department of Oral and Maxillofacial-Head and Neck oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina Jiangsu key laboratory of Oral Diseases Department of Oral and Maxillofacial SurgeryThe Affiliated Stomatological Hospital of Nanjing Medical UniversityNanjingJiangsu ProvinceChina

Neurotrophic factors,currently administered orally or by intravenous drip or intramuscular injection,are the main method for the treatment of peripheral nerve crush injury.However,the low effective drug concentration arriving at the injury site results in unsatisfactory outcomes.Therefore,there is an urgent need for a treatment method that can increase the effective drug concentration in the injured area.In this study,we first fabricated a gelatin modified by methacrylic anhydride hydrogel and loaded it with vascular endothelial growth factor that allowed the controlled release of the neurotrophic factor.This modified gelatin exhibited good physical and chemical properties,biocompatibility and supported the adhesion and proliferation of RSC96 cells and human umbilical vein endothelial cells.When injected into the epineurium of crushed nerves,the composite hydrogel in the rat sciatic nerve crush injury model promoted nerve regeneration,functional recovery and vascularization.The results showed that the modified gelatin gave sustained delivery of vascular endothelial growth factors and accelerated the repair of crushed peripheral nerves.

关键词： bioactive material controlled release crush injury hydrogel muscle function nerve regeneration peripheral nerve sciatic function index vascular endothelial growth factor vascularization

In-situ magnetic field enhanced performances in ferromagnetic FeCo_(2)O_(4) nanofibers-based rechargeable Zinc-air batteries

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Journal of Energy Chemistry 2023年第3期78卷 447-453,I0013页

作者： Zhengmei Zhang Lei Jia Tong Li Jinmei Qian Xiaolei Liang Desheng Xue Daqiang Gao key laboratory for Magnetism and Magnetic Materials of Ministry of Education Lanzhou UniversityLanzhou 730000GansuChina key laboratory of Atomic and Molecular Physics&Function Material of Gansu Province Northwest Normal UniversityLanzhou 730070GansuChina Department of Obstetrics and Gynecology Key Laboratory for Gynecologic Oncology Gansu Provincethe First Hospital of Lanzhou UniversityLanzhou 730000GansuChina

Field-assisted electrocatalytic reactions are demonstrated to be sufficient strategies in enhancing the electrocatalyst activities for oxygen evolution reaction(OER).Here,we report the in-situ magnetic field enhanced electrocatalytic activity in ferromagnetic FeCo_(2)O_(4)nanofibers.Our results demonstrate that the overpotential of FeCo_(2)O_(4)nanofibers at 10 mA cm^(-2)shows a left-shift of 40 mV for the OER by applying an external magnetic field,and no obvious change has been observed in the non-ferromagnetic-order Co3O4nanofibers.Calculation results indicate that there are more overlaps between the density of states for Co3d and O 2p by applying an external magnetic field.Accordingly,the spin hybridization of 3d-2p and the kinetics of spin charge transfer are optimized in ferromagnetic FeCo_(2)O_(4),which can promote the adsorption of oxygen-intermediates and electron transfer,significantly improving its electrocatalytic efficiency.What’s more,the maximum power density of the FeCo_(2)O_(4)nanofibers based Zn-air battery(ZAB)increases from 97.3 mW cm^(-2)to 108.2 mW cm^(-2)by applying an external magnetic field,providing a new idea for the application of magnetic cathode electrocatalysts in ZABs.

关键词： In-situ magneticﬁeld Oxygen evolution reaction Spin hybridization Zn-air battery

A non-invasive smart scaffold for bone repair and monitoring

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Bioactive Materials 2023年第1期19卷 499-510页

作者： Yazhuo Huang Lingyu Zhang Yongrong Ji Hongpei Deng Mingce Long Shengfang Ge Yanjie Su Siew Yin Chan Xian Jun Loh Ai Zhuang Jing Ruan Department of Ophthalmology Shanghai Ninth People’s HospitalShanghai Jiaotong University School of MedicineShanghai200011China shanghai key laboratory of Orbital Diseases and Ocular oncology Shanghai200011China key laboratory of Thin Film and Microfabrication(Ministry of Education) Department of Micro/Nano ElectronicsSchool of ElectronicsInformation and Electrical EngineeringShanghai Jiaotong UniversityShanghai200240China key laboratory of Thin Film and Microfabrication Technology(Ministry of Education) School of Environmental Science and EngineeringShanghai Jiaotong UniversityShanghai200240China Institute of Materials Research and Engineering(IMRE) Agency for ScienceTechnology and Research(A*STAR)2 Fusionopolis WayInnovis#08-03Singapore138634Singapore

Existing strategies for bone defect repair are difficult to monitor.Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring.Carbon nanotubes(CNT)have promising bioactivity and electrical conductivity.In this study,a noninvasive and intelligent monitoring scaffold was prepared for bone regeneration and monitoring by integrating carboxylated CNT into chemically cross-linked carboxymethyl chitosan hydrogel.CNT scaffold(0.5%w/v)demonstrated improved mechanical properties with good biocompatibility and electrochemical responsiveness.Cyclic voltammetry and electrochemical impedance spectroscopy of CNT scaffold responded sensitively to seed cell differentiation degree in both cellular and animal levels.Interestingly,the CNT scaffold could make up the easy deactivation shortfall of bone morphogenetic protein 2 by sustainably enhancing stem cell osteogenic differentiation and new bone tissue formation through CNT roles.This research provides new ideas for the development of noninvasive and electrochemically responsive bioactive scaffolds,marking an important step in the development of intelligent tissue engineering.

关键词： Carbon nanotube Osteogenesis Electrochemical response Noninvasive monitoring Tissue engineering

Structural basis of INTAC-regulated transcription

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Protein & Cell 2023年第9期14卷 698-702页

作者： Hai Zheng Qianwei Jin Xinxin Wang Yilun Qi Weida Liu Yulei Ren Dan Zhao Fei Xavier Chen Jingdong Cheng Xizi Chen Yanhui Xu Fudan University shanghai Cancer Center Institutes of Biomedical SciencesState Key Laboratory of Genetic EngineeringShanghai Key Laboratory of Radiation Oncologyand Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical College of Fudan UniversityShanghai 200032China The International Co-laboratory of Medical Epigenetics and Metabolism Ministry of Science and TechnologyChinaDepartment of Systems Biology for MedicineSchool of Basic Medical SciencesShanghai Medical College of Fudan UniversityShanghai 200032China Human Phenome Institute Collaborative Innovation Center of Genetics and DevelopmentSchool of Life SciencesFudan UniversityShanghai 200433China

DearEditor,Eukaryotic transcription by RNA polymerase I(Pol I)is a strictly regulated process that involves the interplay of numerous factors.Promoter-proximal pausing is a regulatory mechanism that connects transcription initiation and productive elongation in metazoans(Core and Adelman,2019).Pol II forms a paused elongation complex(PEC)through binding of two transcriptional regulation factors DSIF and NELF(Vos et al.,2018).Following the duration of pausing,Pol II either proceeds into productive elongation or undergoes promoter-proximal premature transcription termination(PTT)(Kamieniarz-Gdula and Proudfoot,2019),which plays a decisive role in determining transcriptional outputs.

关键词： termination productive elongation