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The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells

research 2024年第2期2023卷 373-387页

作者： Di Wu Yi Sun cancer institute(Key Laboratory of cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China cancer Center of zhejiang University Hangzhou 310029China Zhejang Provincial Clinical research Center for cancer Zhejang ProvinceChina Key Laboratory of Molecular Biology in Medical Sciences Zhejang ProvinceChina research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

Neddylation is necessary for activation of Cullin-RING ligases(CRLs),which degrade various immune regulatory *** recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T(T_(reg))cells had no obvious phenotype,the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different *** these E2s or E3s compensate each other in functional regulations of T_(reg)cells is,however,previously *** this report,we generated Foxp3^(Cre);Ube2m^(fl/fl);Ube2f^(fl/fl)or Foxp3^(Cre);Rbx1^(fl/fl);Sag^(fl/fl)double-null mice by simultaneous deletion of both neddylation E2s or E3s in T_(reg)cells,***,Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m-null mice,indicating that Ube2m markedly compensates Ube2f in T_(reg)*** minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-null mice is likely due to already severe phenotypes of the later,indicating a minor compensation of Rbx1 for *** RNA profiling-based analyses revealed that up-and down-regulations of few signaling pathways in T_(reg)cells are associated with the severity of autoimmune ***,severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T_(reg)cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of T_(reg)cell fitness.

关键词： Foxp3 inflammation markedly

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Current status of early gastric cancer screening research

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cancer Biology & Medicine 2024年第3期21卷 218-222页

作者： Can Hu Li Yuan Xiangdong Cheng Department of Gastric surgery Zhejiang Cancer HospitalHangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhouZhejiang 310022China Key Laboratory of Prevention Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang ProvinceHangzhou 310022China zhejiang Provincial research Center for Upper Gastrointestinal Tract cancer Zhejiang Cancer HospitalHangzhou 310022China

Gastric cancer is a predominant threat to the health and well-being of China's residents. Data from the World Health Organization(WHO) in 2020 revealed that gastric cancer in China notably accounted for 44.0% of new c... 详细信息

关键词： cancer Gastric gastric

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Protein neddylation and its role in health and diseases

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1869-1904页

作者： Shizhen Zhang Qing Yu Zhijian Li Yongchao Zhao Yi Sun Department of Breast Surgery the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China cancer institute(Key Laboratory of cancer Prevention and Intervention China National Ministry of Education)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China institute of Translational Medicine Zhejiang University School of MedicineHangzhou 310029China Department of Thyroid Surgery Zhejiang Cancer HospitalInstitute of Basic Medicine and Cancer(IBMC)Chinese Academy of SciencesHangzhou 310022China Key Laboratory of Head&Neck cancer Translational research of zhejiang Province Hangzhou 310022China Department of Hepatobiliary and Pancreatic Surgery Zhejiang University School of MedicineHangzhou 310029China zhejiang Provincial Key Laboratory of Pancreatic Disease The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310029China zhejiang University cancer Center Hangzhou 310029China Leading Innovative and Entrepreneur Team Introduction Program of zhejiang Hangzhou 310024China research Center for Life Science and Human Health Binjiang Institute of Zhejiang UniversityHangzhou 310053China

NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin *** of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular ***,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among ***,targeting neddylation becomes an attractive strategy for the treatment of these *** this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin *** further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic ***,few perspectives were proposed for extensive future investigations.

关键词： NEDD8 attached attractive

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The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding zhejiang Province Key Laboratory of Anti-cancer Drug research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal *** binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive *** downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen *** suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal *** also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor ***,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell *** Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other *** and clinical development of inhibitors targeting Ado generation or AdoRs is ***,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

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Weight change and all-cause and cause-specific mortality:A 25-year follow-up study

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Chinese Medical Journal 2024年第10期137卷 1169-1178页

作者： Huan Yang Jianbing Wang Xiaokun Wang Wanyi Sun Chenyunhao Tong Jinhu Fan Youlin Qiao Christian *** Department of cancer Epidemiology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Public Health Zhejiang University School of MedicineNational Clinical Research Center for Children’s HealthHangzhouZhejiang 310058China Metabolic Epidemiology Branch Division of Cancer Epidemiology and GeneticsNational Cancer InstituteRockvilleMD 20850USA

Background:Whether the dynamic weight change is an independent risk factor for mortality remains *** study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial(NIT)***:Body weight of 21,028 healthy residents of Linxian,Henan province,aged 40-69 years was measured two times from 1986 to *** events were prospectively collected up to *** maintenance group(weight changecancer(HR_(cancer)=1.12,95%CI:1.03-1.21,P=0.009),and heart disease(HR_(Heart diseases)=1.21,95%CI:1.11-1.31,Pcancer)=0.89,95%CI:0.79-0.99,P=0.033)lower risk of cancer mortality and 23%higher risk of stroke mortality(HR_(Stroke)=1.23,95%CI:1.12-1.34,Pcancer death(HR_(Overweight to normal)=1.20,95%CI:1.04-1.39;HR_(Becoming underweight)=1.44,95%CI:1.24-1.67),while stable overweight could increase the risk of total death(HR_(Stable overweight)=1.11,95%CI:1.05-1.17)and death from stroke(HR_(Stable overweight)=1.44,95%CI:1.33-1.56).Interaction effects were observed between age and weight change on cancer mortality,as well as between baseline BMI and weight change on all-cause,heart disease,and stroke mortality(all P_(

关键词： Weight change All-cause mortality cancer Stroke Heart diseases Body mass index

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Macrophage senescence in health and diseases

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1508-1524页

作者： Longling Wang Wenxiang Hong Hong Zhu Qiaojun He Bo Yang Jiajia Wang Qinjie Weng Center for Drug Safety Evaluation and research Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Nanhu Brain-Computer Interface institute Hangzhou 311100China Taizhou institute of zhejiang University Taizhou 318000China The Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310009China

Macrophage senescence,manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype,has long been consid-ered *** senescence of macrophages may lead to maladaptation,immune dysfunction,and finally the development of age-related diseases,infections,autoimmune diseases,and ***,it is a ubiquitous,multi-factorial,and dynamic complex phenomenon that also plays roles in remodeled processes,including wound repair and *** this review,we summarize some general molecular changes and several specific biomarkers during macrophage senescence,which may bring new sight to recognize senescent macrophages in different ***,we take an in-depth look at the functional changes in senescent macrophages,including metabolism,autophagy,polarization,phagocytosis,antigen presentation,and infiltration or ***,some degenerations and diseases associated with senescent macrophages as well as the mechanisms or relevant genetic regulations of senescent macrophages are integrated,not only emphasizing the possibility of regulating macrophage senescence to benefit age-associated diseases but also has an implication on the finding of potential tar-gets ordrugs clinically.

关键词： Macrophages Senescence Molecular changes Functional alterations Aging tissues Age-associated diseases Drug treatment Genetic regulation

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Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway

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Science China(Life Sciences) 2024年第7期67卷 1427-1440页

作者： Hongfeng Guo Qihang Sun Xiaoli Huang Xiaohao Wang Feng Zhang Wenzheng Qu Jinling Liu Xuejun Cheng Qiang Zhu Wen Yi Qiang Shu Xuekun Li The Children’s Hospital National Clinical Research Center for Child HealthSchool of MedicineZhejiang UniversityHangzhou 310052China The institute of Translational Medicine School of MedicineZhejiang UniversityHangzhou 310029China College of Life Sciences Zhejiang UniversityHangzhou 310058China Binjiang institute of zhejiang University Hangzhou 310053China zhejiang University cancer Center Zhejiang UniversityHangzhou 310029China

Fucosyltransferase 8(Fut8)and core fucosylation play critical roles in regulating various biological processes,including immune response,signal transduction,proteasomal degradation,and energy ***,the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains *** have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells(aNSPCs)and postnatal brain ***8 depletion reduces the proliferation of a NSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo,***,Fut8 deficiency impairs learning and memory in ***,Fut8 directly interacts with integrinα6(Itga6),an upstream regulator of the PI3kAkt signaling pathway,and catalyzes core fucosylation of *** of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to *** levels of Itga6 inhibit the activity of the PI3K/Akt signaling ***,the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 *** summary,our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

关键词： Fut8 adult neural stem/progenitor cells neurogenesis Itga6 PI3K/Akt

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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

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Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of Chinese medicine rheumatology of zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China cancer institute(Key Laboratory of cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China cancer Center of zhejiang University Hangzhou 310029China Department of Pathology and Shenzhen institute of research and Innovation The University of Hong KongHong KongChina Chongqing International institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to *** dysregulation of double-negative(DN)T cells is considered as a crucial commander during ***,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune ***,the function of neddylation in SLE is still ***,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus *** investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus *** double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus *** findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus ***,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was ***,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation ***,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE ***,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

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Effect of rice cultivar on greenhouse-gas emissions from rice-fish co-culture

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The Crop Journal 2024年第3期12卷 888-896页

作者： Kexin Xie Mengjie Wang Xiaodan Wang Fengbo Li Chunchun Xu Jinfei Feng Fuping Fang China National Rice research institute Hangzhou 310006ZhejiangChina

In aquaculture,co-culturing rice with fish may mitigate greenhouse-gas *** this study,co-culture of four rice cultivars in a laboratory-scale rice–fish system reduced CH_(4)and N_(2)O emissions relative to fish *** in CH_(4)and N_(2)O emissions among rice cultivars primarily stem from the differential effects of rice plants on plant-mediated CH_(4)transport,CH_(4)oxidation and nitrogen absorption.

关键词： Greenhouse gas emissions Aquaculture Rice-fish system Rice cultivar

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High-resolution spatiotemporal mapping:a comprehensive view of eukaryotic cell cycle proteome dynamics

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2354-2356页

作者： Jing Zou Ziran Qin Long Zhang Life Sciences institute Second Affiliated Hospital of the Zhejiang University School of MedicineThe MOE Key Laboratory of Biosystems Homeostasis&Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell BiologyZhejiang UniversityHangzhouZhejiangChina The MOE Basic research and Innovation Center for the Targeted Therapeutics of Solid Tumors The First Affiliated HospitalJiangxi Medical CollegeNanchang UniversityNanchangChina cancer Center Zhejiang UniversityHangzhouZhejiangChina

In a recent study published in Cell,Litsios et *** a highresolution spatiotemporal map of the eukaryotic cell cycle proteome.1 They identified proteome-level changes in both abundance and spatial distribution throughout the cell cycle and provided a valuable resource for future exploration into the global proteome dynamics that drive cell cycle progression(https://***/cellcycle).

关键词： al. cycle dynamics

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