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Hydrophobic tag tethering degrader as a promising paradigm of protein degradation:Past,present and future perspectives

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Chinese Chemical Letters 2024年第8期35卷 187-200页

作者： Si ha Jiacheng zhu Hua Xiang Guoshun Luo State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry China Pharmaceutical UniversityNanjing 211198China

Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic ***,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable *** recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and *** an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule ***-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning *** employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical *** this review,we provide a comprehensive overview of the development history and the reported mechanism of action of ***,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated ***,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.

关键词： Targeted protein degradation(TPD) Hydrophobic tag Degrader Hydrophobic tag tethering degrader(HyTTD) Targeted therapy

The Effect of Moisture in Different Altitude Layers on the Eastward Propagation of MJO

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Journal of Meteorological Research 2024年第3期38卷 437-452页

作者： Xiaoyu zhu Zhong ZHONG Yimin zhu Yunying LI Yijia HU Yao ha College of Meteorology and Oceanography National University of Defense TechnologyChangsha410000China Key Laboratory for Virtual Geographic Environment School of Geography ScienceNanjing Normal UniversityNanjing210023China Jiangsu Collaborative Innovation Center for Climate Change School of Atmospheric SciencesNanjing UniversityNanjing210000China

In this study,driven by ERA5 reanalysis data,the Weather Research and Forecasting(WRF)version 4.0 was used to investigate the eastward propagation of the Madden-Julian oscillation(MJO)in the tropical atmosphere during December-February(DJF)of 2007/*** experiment with 11 cumulus parameterization schemes respectively shows that the Grell 3D scheme is one of several worse ones in describing MJO *** addition,still by use of the Grell 3D scheme,four nudging assimilation experiments for water vapor in all model vertical layers(Ndg_all),lower layers(Ndg_low),middle layers(Ndg_mid),and upper layers(Ndg_upp)were *** is found that when the water vapor in the model approaches to the observed value,the model performance for MJO activities is improved *** the four nudging simulations,Ndg_all certainly performs *** Ndg_mid is important for the MJO-filtered profiles related to moisture,Ndg_low and Ndg_upp exhibit superiority to Ndg_mid in simulating MJO eastward ***_low has advantages when MJO features are represented by zonal wind at 850 hPa and precipitation because the lower-level MJO-filtered moisture is conducive to the existence of lower-level condensational heating to the east of the MJO convective ***_upp performs better when describing the MJO eastward propagation features by outgoing longwave radiation(OLR)since it can capture the moisture and cloud top temperature of deep convection associated with MJO,as well as front Walker *** results suggest that the lower-level moisture is more important in regulating the MJO eastward propagation,and the observed maximum MJO-filtered moisture in the middle troposphere might be a phenomenon accompanying the MJO deep convection,but not a factor controlling its eastward propagation.

关键词： Madden-Julian oscillation(MJO) nudging technique Weather Research and Forecasting(WRF)model vertical moisture structure

RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis

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Signal Transduction and Targeted Therapy 2022年第8期7卷 3032-3044页

作者： ha zhu Kun Chen Yali Chen Juan Liu Xiaomin Zhang Yumei Zhou Qiuyan Liu Bingjing Wang Taoyong Chen Xuetao Cao National Key Laboratory of Medical Immunology Institute of ImmunologySecond Military Medical University200433 ShanghaiChina Department of Immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina Frontier Research Center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai University310071 TianjinChina

RNA-binding proteins(RBPs)play important roles in cancer development and ***,the tumor-promoting RBPs and their partners,which may potentially serve as the cancer therapeutic targets,need to be further ***,we report that zinc finger CCHC domain-containing protein 4(ZCCHC4)is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma(HCC),pancreatic cancer and colon ***4 promotes chemoresistance of HCC cells to DNA-damage agent(DDA)both in vitro and in *** cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDAinduced antitumor ***,ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA(lncRNA)AL133467.2 to hamper its pro-apoptotic ***,ZCCHC4 blocks the interaction between AL133467.2 andγH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to *** of ZCCHC4 promotes AL133467.2 andγH2AX interaction for enhancing chemosensitivity in HCC ***,our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects,providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.

关键词： damage resistance colon

菘蓝4-香豆酸:辅酶A连接酶全基因家族的鉴定及表达分析

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中国中药杂志 2024年第2期49卷 361-369页

作者：张苛苛谭宇萍徐欢欢孙术富肖建才徐朝阳王晨晨朱哈修杨健李大勇唐金富中国中医科学院中药资源中心道地药材品质保障与资源持续利用全国重点实验室北京100700 北京市农林科学院蔬菜研究所蔬菜种质改良北京市重点实验室北京100097 山东师范大学生命科学学院山东济南250014

4-香豆酸:辅酶A连接酶(4-coumarate:CoA ligase,4CL)是植物中类黄酮、可溶性酚酯、木脂素和木质素等苯丙烷类化合物上游途径的关键酶。该研究基于菘蓝基因组数据库,以拟南芥Arabidopsis thaliana的13个4CL家族成员为参考序列,获取菘蓝4C... 详细信息

4-香豆酸:辅酶A连接酶(4-coumarate:CoA ligase,4CL)是植物中类黄酮、可溶性酚酯、木脂素和木质素等苯丙烷类化合物上游途径的关键酶。该研究基于菘蓝基因组数据库,以拟南芥Arabidopsis thaliana的13个4CL家族成员为参考序列,获取菘蓝4CL基因家族的候选成员,并进行生物信息学分析、4CL基因表达模式及类黄酮代谢成分积累模式等研究。结果共获得13条菘蓝4CL基因家族成员,分别命名为Ii4CL1~Ii4CL13,分别定位到1、2、3、4、6号染色体上。基因结构与保守结构域分析发现菘蓝4CL基因家族成员的内含子数目为1~12,蛋白结构域具有高度保守性。顺式作用元件分析表明在菘蓝4CL基因家族成员启动子序列中存在多个响应元件,其中茉莉酸反应元件数量最多。共线性分析表明菘蓝4CL基因家族成员与同科植物拟南芥之间存在更近的亲缘关系。qPCR结果显示,菘蓝4CL基因家族表达分析发现10个4CL基因在菘蓝的地上部分相对表达量更高。对菘蓝不同部位类黄酮化合物的含量进行检测,发现菘蓝的类黄酮主要积累在地上部分。该研究为深入探索菘蓝4CL基因家族成员参与菘蓝类黄酮生物合成的分子机制奠定了基础。

关键词： 4-香豆酸:辅酶A连接酶菘蓝生物信息学分析类黄酮

The relationship between the expression of Survivin in human non-small cell lung cancer and microvessel density

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The Chinese-German Journal of Clinical Oncology 2008年第7期7卷 387-389页

作者： Zhenghua Wang Minwen ha Zhitu zhu Department of Oncology The First Affiliated Hospital of Liaoning Medical University Jinzhou 121001 China

Objective: To investigate microvessel density (MVD) and expression of Survivin in non-small cell lung cancer (NSCLC), and to explore their correlations to clinicopathologic features of NSCLC. Methods: 66 specimens of tumor adjacent tissues, and 20 specimens of benign lesions were detected by SP immunohistochemistry; their interrelations and correlations to clinicopathologic features of NSCLC were analyzed. Results: Positive rate of Survivin in NSCLC was significantly higher than that in adjacent tissues and benign lesions (54.5% vs. 30 %, P had statistical significance. Its expression was 74.1% in lymphatic metastasis group, which was obviously higher than that in no lymphatic metastasis group, which was 48.7%. The rate of MVD in Survivin positive group was obviously higher than that of Survivin negative group. Conclusion: The expression of Survivin is connected with the degree of differentiation on lung cancer and lymphatic metastasis, which indicates Survivin can be as an index for the judgment of condition and the evaluation of prognosis, the expression of Survivin is direct correlation with that of MVD. It is evident that Survivin functions the promotion of tumor angiogenesis.

关键词： Survivin microvessel density (MVD) non-small cells lung cancer (NSCLC)

Downregulated expression of GFRa1 promotes HCC progression though Epithelial-to-Mesenchymal Transition

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Downregulated expression of GFRa1 promotes HCC progression t...

后现代主义——一种现代性危机的社会和文化观照

第十届全国免疫学学术大会

作者： Qiuyan Liu ha zhu Chen Chen Qinchun Tan Xuetao Cao National Key Laboratory of Medical Immunology & Institute of Immunology Second Military Medical University Institute of Immunology Zhejiang University School of Medicine National Key Laboratory of Medical Molecular Biology & Department of Immunology Chinese Academy of Medical Sciences

Background and Purposes:Accumulating evidences implies that the neurotrophic factor and their receptors contribute to tumor ***α1 is a GPI-anchored receptor for glial cell line-derived neurotrophic factor(GDNF),a neuronal growth factor with widespread functions in the developing and adult nervous *** GFRα1 was found to be predominantly expressed in mouse and human adult ***,GFRα1 level in HCC cell lines and tumor tissue significantly *** carcinoma(HCC)is one of the most common cancers worldwide and is among the leading causes of cancer-related death,especially in ***,the role for GFRα1 in hepatocellular carcinoma(HCC)progression remains ***:We found that compared to the matched non-neoplastic tissue or normal liver,GFRα1 was down-regulated abundantly at both m RNA and protein level in HCC and HCC cell *** GFRα1 expression level in HCC is stronglyinversely correlates with the survival of HCC ***,silence GFRα1 expression in HCC cell lines markedly increases tumor cells proliferation,adhesion,migration and invasion in vitro and enhances tumor growth and reduce tumor-bearing mice survival in ***,elevated expression of GFRα1 in HCC cell lines significantly reverses these ***,silence GFRα1 expression in HCC cell lines could promote epithelial-to-mesenchymal transition(EMT),down-regulated epithelial markers expression including ZO-1,Claudin-1 and E-Cadherin,and upregulated mesenchymal markers expression includingβ-Catenin,N-Cadherin,Vimentin and ***:GFRα1 was significantly down-regulated in HCC tumor tissue,and downregulated expression of GFRa1in HCC could promote HCC progression in vitro and in vivo,and epithelial-to-mesenchymal transition(EMT)was involved in GFRa1-mediated HCC progression.

关键词： HCC GFRα1 GDNF EMT

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湖南师范大学社会科学学报 2007年第2期36卷 92-94,144页

作者：朱海龙湖南师范大学期刊社湖南长沙410081

从后现代主义这样一种文化和社会现实出发,认为无论人们对后现代主义的理解是多么的泛滥、矛盾与冲突,其形式又是怎样的丰富而让人难以把握,但它无法形成一个统一独立体系,其实质只是现代性危机社会和文化的观照。

关键词：后现代主义现代性现实

Downregulated expression of GFRα1 promotes HCC progression though Epithelial-to-Mesenchymal Transition

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Downregulated expression of GFRα1 promotes HCC progression ...

锌指蛋白调控肿瘤免疫原性的作用及其机制的研究进展

第十四届全国肿瘤生物治疗大会

作者： Qiuyan Liu ha zhu Kun Chen Qinchun Tan Jin Hou Yuanyuan Zheng Xuetao Cao National Key Laboratory of Medical Immunology & Institute of Immunology Second Military Medical University Institute of Immunology Zhejiang University School of Medicine National Key Laboratory of Medical Molecular Biology & Department of Immunology Chinese Academy of Medical Sciences

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中国肿瘤生物治疗杂志 2023年第10期30卷 925-930页

作者：闵楠(综述) 朱哈(审阅) 海军军医大学基础医学院免疫学教研室暨免疫与炎症全国重点实验室上海200433

寻找对肿瘤免疫原性具有关键调控作用的生物治疗靶点是抑制肿瘤免疫逃逸、提高肿瘤免疫治疗效果的关键。锌指蛋白(ZFP)通过与DNA、RNA、蛋白质的相互作用,调控肿瘤抗原的形成、肿瘤表面MHC分子及其共刺激分子的表达、损伤相关分子模式... 详细信息

寻找对肿瘤免疫原性具有关键调控作用的生物治疗靶点是抑制肿瘤免疫逃逸、提高肿瘤免疫治疗效果的关键。锌指蛋白(ZFP)通过与DNA、RNA、蛋白质的相互作用,调控肿瘤抗原的形成、肿瘤表面MHC分子及其共刺激分子的表达、损伤相关分子模式的释放等,影响肿瘤细胞的免疫原性及肿瘤微环境(TME)中免疫细胞的分布和功能,进而在调节抗肿瘤免疫应答和肿瘤免疫逃逸中发挥重要作用。近年来,临床前及临床研究探索将ZFP相关的生物治疗方法应用于肿瘤免疫治疗,主要聚焦在免疫检查点阻断治疗、免疫细胞治疗,以及免疫治疗联合治疗策略展现出了可喜的应用前景。

关键词：锌指蛋白肿瘤肿瘤免疫免疫原性免疫治疗