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Transcriptome-Wide Identification and Functional Analysis of PgSQE08-01 Gene in Ginsenoside Biosynthesis in Panax ginseng C.A.Mey.

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Phyton-International Journal of Experimental Botany 2024年第2期93卷 313-327页

作者： Lei Zhu Lihe Hou Yu Zhang Yang Jiang Yi Wang Meiping Zhang mingzhu zhao Kangyu Wang College of Life Science Jilin Agricultural UniversityChangchun130118China Jilin Engineering Research Center Ginseng Genetic Resources Development and Utilization Changchun130118China Jilin Academy of Vegetable and Flower Sciences Changchun130033China

Panax ginseng C.A.Mey.is an important plant species used in traditional Chinese medicine,whose primary active ingredient is a ginsenoside.Ginsenoside biosynthesis is not only regulated by transcription factors but also controlled by a variety of structural genes.Nonetheless,the molecular mechanism underlying ginsenoside biosynthesis has always been a topic in the discussion of ginseng secondary metabolites.Squalene epoxidase(SQE)is a key enzyme in the mevalonic acid pathway,which affects the biosynthesis of secondary metabolites such as terpenoid.Using ginseng transcriptome,expression,and ginsenoside content databases,this study employed bioinformatic methods to systematically analyze the genes encoding SQE in ginseng.We first selected six PgSQE candidates that were closely involved in ginsenoside biosynthesis and then identified PgSQE08-01 to be highly associated with ginsenoside biosynthesis.Next,we constructed the overexpression vector pCAMBIA3301-PgSQE08-01 and the RNAi vector pART27-PgSQE08-01 and transformed ginseng adventitious roots using Agrobacterium rhizogenes,to obtain positive hairy-root clones.Thereafter,quantitative reverse transcriptionpolymerase chain reaction and high-performance liquid chromatography were used to determine the expression of relevant genes and ginsenoside content,respectively.Then,we focused on the function of PgSQE08-01 gene,which was noted to be involved in ginsenoside biosynthesis.Thus,these findings not only provided a molecular basis for the identification of important functional genes in ginseng but also enriched genetic resources for the biosynthesis of ginsenosides using synthetic biology.

关键词： Panax ginseng pgSQE08-01 gene squalene epoxidase ginsenoside ginseng hairy roots

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Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin Chengwei Wu Li Feng Xiuyan Yang mingzhu zhao Yingyi Chen Shaoyong Lu Zhen Zheng Xiaobing Lan Yi Wang Yan Zheng Xuefeng Lu Qiufen Zhang Jian Zhang State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and BioinformaticsCenter Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China Department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China College of Pharmacy Ningxia Medical UniversityYinchuan 750004China Department of Pancreatic Surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal Pancreatic cancer metastasis

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Promoting or inhibiting? Green fiscal policy and urban green innovation

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Chinese Journal of Population,Resources and Environment 2023年第4期21卷 257-268页

作者： Jinrui Chen Zhuoji Zheng Xianfeng Han mingzhu zhao Mengfei Yin School of Business Administration Zhejiang Gongshang UniversityHangzhou 310018China School of Management and Economics Kunming University of Science and TechnologyKunming 650500China

Can green fiscal policy(GFP)incentivize the proliferation of urban green innovation(GI)and be a novel cata‐lyst for energy conservation and emission reduction within the“dual-carbon”framework?This paper explores GFP ramifications for GI by implementing a difference-in-differences model in a natural experiment centered on the“Comprehensive Demonstration City of Energy Saving and Emission Reduction Fiscal Policies”.The em‐pirical analysis reveals several key findings:(1)GFP exhibits significant augmentation at the GI level,with an observable evolutionary trend of increasing marginal impact.Importantly,these outcomes withstand rigorous robustness tests,including propensity score matching.(2)A mechanism analysis elucidates the dual impact of GFP on GI growth.GFP directly fosters GI advancement indirectly by promoting talent aggregation,expanding scientific and technological investment,and attracting external financial resources.(3)A heterogeneity analy‐sis demonstrates that GFP enhancement of GI is closely associated with the patent category,manifesting a dis‐tinct pattern of“eastern region>other regions”and“non-resource cities>resource cities”.The study’s em‐pirical findings offer crucial real-world insights to guide the Chinese government in formulating a more effi‐cient GFP and facilitating the expansion of innovative endeavors while contributing to environmentally sus‐tainable and high-value development.

关键词： Green fiscal policy Green innovation Difference-in-differences modeling Dual-carbon goal Mechanism analysis

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Emerging insights into heterotrimeric G protein signaling in plants

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Journal of Genetics and Genomics 2016年第8期43卷 495-502页

作者： Quan Xu mingzhu zhao Kun Wu Xiangdong Fu Qian Liu Rice Research Institute of Shenyang Agricultural University Key Laboratory of Northern Japonica Rice Genetics and BreedingMinistry of Education and Liaoning ProvinceKey Laboratory of Northeast Rice Biology and Genetics and BreedingMinistry of Agriculture The State Key Laboratory of Plant Cell and Chromosome Engineering Institute of Genetics and Developmental BiologyChinese Academy of Sciences

Heterotrimeric guanine nucleotide-binding protein （G protein） signaling is an evolutionarily conserved mechanism in diverse eukaryotic organisms. In plants, the repertoire of the heterotrimeric G protein complex, which is composed of the Ga, Gβ, and Gy subunits, is much simpler than that in metazoans, and the identity of typical G protein-coupled receptors （GPCRs） together with their ligands still remains unclear. Comparative phenotypic analysis in Arabidopsis and rice plants using gain- and loss-of-function mutants of G protein components revealed that heterotrimeric G protein signaling plays important roles in a wide variety of plant growth and developmental processes. Grain yield is a complex trait determined by quantitative trait loci （QTL） and is influenced by soil nitrogen availability and environmental changes. Recent studies have shown that the manipulation of two non-canonical Gy subunits, GS3 （GRAIN SIZE 3） and DEP1 （DENSE AND ERECT PANICLE 1）, represents new strategies to simultaneously increase grain yield and nitrogen use efficiency in rice. This review discusses the latest advances in our understanding of the heterotrimeric G protein signal transduction pathway and its application in improving yield and stress tolerance in crops.

关键词： G protein signalingNon-canonical G subunitsDEP1GS3Yield potential

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Mechanism of allosteric activation of SIRT6 revealed by the action of rationally designed activators

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Acta Pharmaceutica Sinica B 2021年第5期11卷 1355-1361页

作者： Shaoyong Lu Yingyi Chen Jiacheng Wei mingzhu zhao Duan Ni Xinheng He Jian Zhang Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China State Key Laboratory of Oncogenes and Related Genes Renji HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200127China The Charles Perkins Centre University of SydneySydney NSW 2006Australia

The recent discovery of activator compounds binding to an allosteric site on the NAD+-dependent protein lysine deacetylase,sirtuin 6(SIRT6)has attracted interest and presents a pharmaceutical target for aging-related and cancer diseases.However,the mechanism underlying allosteric activation of SIRT6 by the activator MDL-801 remains largely elusive because no major conformational changes are observed upon activator binding.By combining molecular dynamics simulations with biochemical and kinetic analyses of wild-type SIRT6 and its variant M136 A,we show that conformational rotation of 2-methyl-4-fluoro-5-bromo substituent on the right phenyl ring(R-ring)of MDL-801,which uncovers previously unseen hydrophobic interactions,contributes to increased activating deacetylation activity of SIRT6.This hypothesis is further supported by the two newly synthesized MDL-801 derivatives through the removal of the 5-Br atom on the R-ring(MDL-801-D1)or the restraint of the rotation of the R-ring(MDL-801-D2).We further propose that the 5-Br atom serves as an allosteric driver that controls the ligand allosteric efficacy.Our study highlights the effect of allosteric enzyme catalytic activity by activator binding and provides a rational approach for enhancing deacetylation activity.

关键词： Allosteric driver Allosteric sites Allosteric mechanisms Drug design Enzyme catalysis Protein dynamics

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Targeting a cryptic allosteric site of SIRT6 with small-molecule inhibitors that inhibit the migration of pancreatic cancer cells

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Acta Pharmaceutica Sinica B 2022年第2期12卷 876-889页

作者： Qiufen Zhang Yingyi Chen Duan Ni Zhimin Huang Jiacheng Wei Li Feng Jun-Cheng Su Yingqing Wei Shaobo Ning Xiuyan Yang mingzhu zhao Yuran Qiu Kun Song Zhengtian Yu Jianrong Xu Xinyi Li Houwen Lin Shaoyong Lu Jian Zhang State Key Laboratory of Oncogenes and Related Genes Department of PharmacyRenji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong University School of MedicineShanghai 200025China Nutshell Therapeutics Shanghai 201203China Academy of Integrative Medicine Shanghai University of Traditional Chinese MedicineShanghai 201203China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

SIRT6 belongs to the conserved NAD^(+)-dependent deacetylase superfamily and mediates multiple biological and pathological processes.Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics,which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases.Here,developing a reversed allosteric strategy Allo Reverse,we identified a cryptic allosteric site,Pocket Z,which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD^(+).Based on Pocket Z,we discovered an SIRT6 allosteric inhibitor named JYQ-42.JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation,with an IC50 of 2.33μmol/L.JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production.JYQ-42,to our knowledge,is the most potent and selective allosteric SIRT6 inhibitor.This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

关键词： SIRT6 Molecular dynamics simulations Reversed allostery Allosteric inhibitor Pancreatic cancer Cell migration Cytokine production

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Chinese expert consensus on diagnosis and treatment of anal intraepithelial neoplasia

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Gynecology and Obstetrics Clinical Medicine 2024年第1期4卷 3-10页

作者： Yanyun Li Hongwei Zhang Qing Cong mingzhu Li Hui Bi Yun zhao Zhixue You Qi Zhou Li Geng Mingrong Qie Fanghui zhao Linhong Wang Beihua Kong Ding Ma Long Sui Lihui Wei Hospital and Institute of Obstetrics and Gynecology Fudan UniversityShanghaiChina Department of Obstetrics and Gynecology Peking University People's HospitalBeijingChina Department of Obstetrics and Gynecology Peking University First HospitalBejingChina Department of Obstetrics and Gynecology Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated HospitalNanjingJiangsuChina Chongqing University Cancer Hospital ChongqingChina Department of Obstetrics and Gynecology Peking University Third HospitalBejingChina Sichuan University West China Second University Hospital ChengduSichuanChina National Center for Chronic and Non-communicable Disease Control and Prevention Chinese Center for Disease Control and PreventionBeijingChina Department of Obstetrics and Gynecology Qilu Hospital of Shandong UniversityJinanShandongChina Department of Obstetrics and Gynecology Tongji HospitalTongji Medical Cllege of HUSTWuhanChina

Anal high-grade squamous intraepithelial lesion(HSIL)refers to the precancerous lesions of anal squamous cell carcinoma(ASCC).Anal cancer is often asymptomatic in its early stage.

关键词： diagnosis squamous intraepithelial

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原发性噬血细胞综合征患者临床和基因突变特征及对预后的影响

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中华医学杂志 2024年第23期104卷 2160-2166页

作者：窦留瑞喻明珠石林张嘉吴林王晶石王昭首都医科大学附属北京友谊医院血液科北京

目的探讨原发性噬血细胞综合征(HLH)患者的临床和基因突变特征及对预后的影响。方法回顾性选取2013年1月至2022年12月首都医科大学附属北京友谊医院收治并确诊的63例病历资料完整的原发性HLH患者为研究对象, 分析患者的临床及实验室特... 详细信息

目的探讨原发性噬血细胞综合征(HLH)患者的临床和基因突变特征及对预后的影响。方法回顾性选取2013年1月至2022年12月首都医科大学附属北京友谊医院收治并确诊的63例病历资料完整的原发性HLH患者为研究对象, 分析患者的临床及实验室特征、基因突变特征、功能学特征、治疗转归及预后。随访截至2023年6月30日, 中位随访时间[M(Q1, Q3)]为47(21, 76)个月。采用Kaplan-Meier生存曲线分析总生存率, 采用Cox比例风险回归模型分析预后影响因素。结果 63例原发性HLH患者包括男35例, 女28例, 中位发病年龄[M(Q1, Q3)]为 17(7, 27)岁。初诊时临床表现主要为发热(93.7%, 59/63)、脾大(87.3%, 55/63)、噬血现象(65.1%, 41/63)、肝大(52.4%, 33/63)及中枢神经系统受累(38.1%, 24/63), 39例患者(61.9%)初诊时合并EB病毒感染。PRF1和UNC13D基因突变最常见(74.6%, 47/63), PRF1基因最常见的变异位点是c.1349C>T, UNC13D基因最常见的变异位点是c.2588G>A。76.2%(48/63)患者自然杀伤细胞活性减低, 52.7%(29/55)患者细胞毒细胞脱颗粒功能减低或缺如。脱颗粒相关基因缺陷的原发性HLH患者中, 79.2%(19/24)存在脱颗粒功能受损。1年、3年总生存率分别为74.8%、66.7%。多因素Cox比例风险回归模型分析显示, 外周血EB病毒拷贝数≥10 000拷贝/ml(HR=3.523, 95%CI:1.418～8.757, P=0.007)是影响预后的危险因素。结论原发性HLH患者初诊时临床表现主要为发热、脾大、噬血现象、肝大及中枢神经系统受累;PRF1和UNC13D基因是最常见的突变基因;外周血高拷贝数EB病毒感染是影响预后的危险因素。

关键词：噬血细胞综合征基因特征临床特征预后

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中国共产党坚持胸怀天下的内涵、理论和实践探赜

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中共云南省委党校学报 2024年第3期25卷 55-63页

作者：赵成江李明珠兰州理工大学马克思主义学院兰州730050

坚持胸怀天下是中国共产党百年奋斗的十条历史经验之一,也是贯穿习近平新时代中国特色社会主义思想的重要世界观和方法论。对坚持胸怀天下这一理论的学理阐释要从三个方面进行探赜:在本质内涵层面,要考察“胸怀天下”的词义内涵与外延,... 详细信息

坚持胸怀天下是中国共产党百年奋斗的十条历史经验之一,也是贯穿习近平新时代中国特色社会主义思想的重要世界观和方法论。对坚持胸怀天下这一理论的学理阐释要从三个方面进行探赜:在本质内涵层面,要考察“胸怀天下”的词义内涵与外延,认识到它是贯穿中国共产党兴衰始终的真理性认识和彰显中国共产党初心使命的国际胸怀。在理论来源层面,可以追溯到马克思主义科学理论渊源、中华优秀传统文化根源和党百余年峥嵘历史岁月。在实践要求层面,首要的就是心系祖国大地、中华儿女;其次,要弘扬全人类共同价值;最后,要胸怀世界,构建人类命运共同体。

关键词：坚持胸怀天下百年奋斗实践要求构建人类命运共同体

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承压水作用下岩质地层基坑抗突涌安全厚度研究

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建筑结构学报 2024年第6期45卷 213-223页

作者：王洪涛李建华殷允腾张红军宣兆腾赵明珠山东建筑大学土木工程学院山东济南250101 山东建筑大学建筑结构加固改造与地下空间工程教育部重点实验室山东济南250101 济南城建集团有限公司山东济南250031 山东省地质科学研究院山东济南250013

受下部承压水作用,基坑开挖后坑底发生突涌破坏是普遍存在的工程灾害。为保障基坑安全,设置足够的坑底厚度是阻止此类破坏的关键。基于塑性上限定理,将坑底突涌破坏范围分为上部被动区与下部剪切区两部分,分析了岩质地层中基坑突涌破坏... 详细信息

受下部承压水作用,基坑开挖后坑底发生突涌破坏是普遍存在的工程灾害。为保障基坑安全,设置足够的坑底厚度是阻止此类破坏的关键。基于塑性上限定理,将坑底突涌破坏范围分为上部被动区与下部剪切区两部分,分析了岩质地层中基坑突涌破坏机制。进一步,基于Hoek-Brown强度准则,推导了突涌破坏面曲线方程解析表达式,并给出了基坑临界安全厚度与承压水压力的理论预测公式。在此基础上,分析得到了被动区厚度、承压水压力、岩体强度参数等对基坑安全厚度及破坏范围的影响规律,并与现有研究方法、数值模拟得到的结果进行对比,验证了所提出方法的有效性。结果显示,基坑临界安全厚度与承压水压力、岩体经验参数等正相关,与被动区厚度、经验参数、岩体抗压强度、抗拉强度和重度等负相关。

关键词：基坑突涌承压水 Hoek-Brown强度准则上限定理安全厚度

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