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Identification of the cytochrome P450s responsible for the biosynthesis of two types of aporphine alkaloids and their de novo biosynthesis in yeast

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Journal of Integrative Plant Biology 2024年第8期66卷 1703-1717页

作者： Qishuang Li Xiang Jiao Xinyi Li Wenlong Shi Ying Ma Xiangmei Tan Jingyi Gan Jimei Liu Jian Yang Jian Wang Baolong Jin Tong Chen Ping Su Yujun Zhao Yifeng Zhang Jinfu Tang Guanghong Cui Yun Chen Juan Guo Luqi Huang School of Traditional Chinese Pharmacy China Pharmaceutical UniversityNanjing 211198China State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs National Resource Center for Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China Department of Life Sciences Chalmers University of TechnologyGothenburg SE-41296Sweden State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaThe Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Aporphine alkaloids have diverse pharmacological activities;however,our understanding of their biosynthesis is relatively *** studies have classified aporphine alkaloids into two categories based on the configuration and number of substituents of the D-ring and have proposed preliminary biosynthetic pathways for each *** this study,we identified two specific cytochrome P450 enzymes(CYP80G6 and CYP80Q5)with distinct activities toward(S)-configured and(R)-configured substrates from the herbaceous perennial vine Stephania tetrandra,shedding light on the biosynthetic mechanisms and stereochemical features of these two aporphine alkaloid ***,we characterized two CYP719C enzymes(CYP719C3 and CYP719C4)that catalyzed the formation of the methylenedioxy bridge,an essential pharmacophoric group,on the A-and D-rings,respectively,of aporphine *** the functional characterization of these crucial cytochrome P450 enzymes,we reconstructed the biosynthetic pathways for the two types of aporphine alkaloids in budding yeast(Saccharomyces cerevisiae)for the de novo production of compounds such as(R)-glaziovine,(S)-glaziovine,and *** study provides key insight into the biosynthesis of aporphine alkaloids and lays a foundation for producing these valuable compounds through synthetic biology.

关键词： aporphine alkaloids biosynthesis CYP719C CYP80 engineered yeast

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Thermal Property Enhancement of a Novel Shape-Stabilized Sodium Acetate Trihydrate-Acetamide/Expanded Graphite-Based Composite Phase Change material

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Journal of Thermal Science 2024年第4期33卷 1564-1576页

作者： AN Zhoujian HOU Wenjie DU Xiaoze HUANG Zhongzheng MOMBEKI PEA Hamir Johan ZHANG Dong LIU Xiaomin College of Energy and Power Engineering Lanzhou University of TechnologyLanzhou730050China Key Laboratory of Multi-supply System with Solar Energy and Biomass of gansu Province Lanzhou730050China gansu Natural Energy Research institute Lanzhou730046China

Phase change materials(PCMs)are a kind of highly efficient thermal storage materials which have a bright application prospect in many fields such as energy conservation in buildings,waste heat recovery,battery thermal management and so *** inorganic hydrated salt PCMs have received increasing attention from researchers due to their advantages of being inexpensive and ***,inorganic hydrated salt PCMs are still limited by the aspects of inappropriate phase change temperature,liquid phase leakage,large supercooling and severe phase separation in the application *** this work,sodium acetate trihydrate was selected as the basic inorganic PCM,and a novel shape-stabilized composite phase change material(CPCM)with good thermal properties was prepared by adding various functional *** first,the sodium acetate trihydrate-acetamide binary mixture was prepared and the melting point was adjusted using *** the binary mixture was incorporated into expanded graphite to synthesize a novel shape-stabilized *** thermophysical properties of the resultant shape-stabilized CPCM were systematically *** microscopic morphology and chemical structure of the obtained shape-stabilized CPCM were characterized and *** experiment results pointed out that acetamide could effectively lower the melting point of sodium acetate *** obtained shape-stabilized CPCM modified with additional 18%(mass fraction)acetamide and 12%(mass fraction)expanded graphite exhibited good shape stability and thermophysical characteristics:a low supercooling degree of 1.75℃and an appropriate melting temperature of 40.77℃were obtained;the latent heat of 151.64 kJ/kg and thermal conductivity of 1.411 W/(m·K)were also ***,after 50accelerated melting-freezing cycles,the obtained shape-stabilized CPCM represented good thermal reliability.

关键词： sodium acetate trihydrate melting point modification agent expanded graphite shape stability thermal conductivity enhancement

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AAV-mediated gene therapies by miniature gene editing tools

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Science China Life Sciences 2024年

作者： Xiangfeng Kong Tong Li Hui Yang Shanghai institute of materia medica Chinese Academy of Sciences institute of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences HuidaGene Therapeutics Co. Ltd. Shanghai Center for Brain Science and Brain-Inspired Technology

The advent of CRISPR-Cas has revolutionized precise gene editing. While pioneering CRISPR nucleases like Cas9 and Cas12 generate targeted DNA double-strand breaks(DSB) for knockout or homology-directed repair, next generation CRISPR technologies enable gene editing without DNA DSB. Base editors directly convert bases, prime editors make diverse alterations, and dead Cas-regulator fusions allow nuanced control of gene expression, avoiding potentially risks like translocations. Meanwhile, the discovery of diminutive Cas12 orthologs and Obligate Mobile Element-Guided Activity(OMEGA) nucleases has overcome cargo limitations of adeno-associated viral vectors, expanding prospects for in vivo therapeutic delivery. Here, we review the ever-evolving landscape of cutting-edge gene editing tools, focusing on miniature Cas12 orthologs and OMEGA effectors amenable to single AAV packaging. We also summarize CRISPR therapies delivered using AAV vectors, discuss challenges such as efficiency and specificity, and look to the future of this transformative field of in vivo gene editing enabled by AAV vectors delivery.

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Substrate and Functional Diversity of Protein Lysine Post-translational Modifica

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Genomics, Proteomics & Bioinformatics 2024年第1期22卷 29-49页

作者： Bingbing Hao Kaifeng Chen Linhui Zhai Muyin Liu Bin Liu Minjia Tan State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Tianjian Laboratory of Advanced Biomedical Sciences Institute of Advanced Biomedical SciencesZhengzhou UniversityZhengzhou 450001China Zhongshan institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshan 528400China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China Department of Cardiology Shanghai Institute of Cardiovascular DiseasesZhongshan HospitalFudan UniversityShanghai 200032China Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening College of PharmacyJiangsu Ocean UniversityLianyungang 222005China

Lysine post-translational modifications(PTMs)are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone *** of lysine PTMs is implicated in many diseases,and targeting lysine PTM regulatory factors,including writers,erasers,and readers,has become an effective strategy for disease *** continuing development of mass spectrometry(MS)technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of *** global characterization of lysine PTMs is crucial for deciphering the regulatory networks,molecular functions,and mechanisms of action of lysine *** this review,we focus on lysine PTMs,and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS *** also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.

关键词： Protein lysine PTM Regulatory enzyme PTM crosstalk Drug target Acylation

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Identification, pathogenicity, and fungicide sensitivity of Eutiarosporella dactylidis associated with leaf blight on maize in China

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Journal of Integrative Agriculture 2024年第3期23卷 888-900页

作者： Cheng Guo Xiaojie Zhang Baobao Wang Zhihuan Yang Jiping Li Shengjun Xu Chunming Wang Zhijie Guo Tianwang Zhou Liu Hong Xiaoming Wang Canxing Duan institute of Plant Protection Gansu Academy of Agricultural SciencesLanzhou 730070China Pratacultural College Gansu Agricultural UniversityLanzhou 730070China Shijiazhuang Academy of Agriculture and Forestry Sciences Shijiazhuang 050050China institute of Crop Sciences Chinese Academy of Agricultural SciencesBejing 100081China

Maize(Zea mays L.) is an economically vital grain crop that is cultivated worldwide. In 2011, a maize foliar disease was detected in Lingtai and Lintao counties in gansu Province, China. The characteristic signs and symptoms of this disease include irregular chlorotic lesions on the tips and edges of infected leaves and black punctate fruiting bodies in dead leaf tissues. Given favourable environmental conditions, this disease spread to areas surrounding gansu. In this study, infected leaves were collected from gansu and Ningxia Hui Autonomous Region between 2018and 2020 to identify the disease-causing pathogen. Based on morphological features, pathogenicity tests, and multilocus phylogenetic analysis involving internal transcribed spacer(ITS), 18S small subunit rDNA(SSU), 28S large subunit rDNA(LSU), translation elongation factor 1-alpha(TEF), and β-tubulin(TUB) sequences, Eutiarosporella dactylidis was identified as the causative pathogen of this newly discovered leaf blight. Furthermore, an in vitro bioassay was conducted on representative strains using six fungicides, and both fludioxonil and carbendazim were found to significantly inhibit the mycelial growth of E. dactylidis. The results of this study provide a reference for the detection and management of Eutiarosporella leaf blight.

关键词： maize leaf blight morphology molecular phylogeny Eutiarosporella dactylidis fungicide sensitivity

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Changes in human settlement environments and their drivers in valley cities located in arid and semi-arid regions:A case study of Lanzhou in Western China

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Research in Cold and Arid Regions 2024年第3期16卷 149-158页

作者： Rong Zhu YouYan Jiang Bo Wang YaHui Zhang gansu institute of Architectural Design and Research LanzhouGansu 730000China College of Earth and Environmental Sciences Lanzhou UniversityLanzhouGansu 730000China Lanzhou Regional Climate Center LanzhouGansu 730020China School of Human Settlements and Civil Engineering Xi’An Jiaotong UniversityXi’AnShanxi 712000China

Development of urban human settlement environments(HSEs)is an integral part of promoting high-quality and sustainable regional development and constructing a beautiful *** city of Lanzhou,located at the geometric center of China,is the only provincial capital traversed by the Yellow *** the constraints posed by the valley topography and the need for economic development,the development of this HSE,which is located within an arid region,poses considerable ***,an understanding of the evolution of HSEs and drivers of changes in them contributes to high-quality,sustainable urban development in arid and semi-arid *** analytical model was developed using the parameters of relief degree of land surface,human comfort days,the land cover index,nighttime light index,and *** model was used in combination with population density and the gross domestic product to analyze the spatial distribution of Lanzhou's HSE and its *** results showed that landscapes in Lanzhou underwent significant changes between 2000 and 2022,with an increase in building-up land(+0.946%),cultivated land(+0.134%),and forest land(+0.018%)and a decrease in grassland(-1.10%).There was significant outward expansion of the main urban zone of Lanzhou and of various county towns,with the increase in building-up land being most *** this period,there were significant changes in the periphery of the core urban area and county towns in Lanzhou,with decreases moving from the urban center(the highest value)to the surrounding areas(Yongdeng County had the lowest value).The correlation between the HSE and population density grew stronger in Anning and Chengguan Districts but became weaker in Xigu and Qilihe *** variations in the HSE were primarily caused by climate change,followed by human activities,and were also influenced by the valley ***,the spatial distribution of population density and the HSE in Lanzhou d

关键词： Human settlement environment Vegetation index Nighttime light index Human comfort days

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Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

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Acta Pharmaceutica Sinica B 2024年第1期14卷 319-334页

作者： Ying Qin Dekang Li Chunting Qi Huaijiang Xiang Huyan Meng Jingli Liu Shaoqing Zhou Xinyu Gong Ying Li Guifang Xu Rui Zu Hang Xie Yechun Xu Gang Xu Zheng Zhang Shi Chen Lifeng Pan Ying Li Li Tan Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China School of Chinese materia medica Nanjing University of Chinese MedicineNanjing 210023China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China institute of Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People’s Hospitalthe Second Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen 518112China Department of Burn and Plastic Surgery Shenzhen Institute of Translational MedicineShenzhen University Medical SchoolShenzhen Second People’s Hospitalthe First Affiliated Hospital of Shenzhen UniversityShenzhen 518035China

Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical ***,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to ***,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical *** also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory ***,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

关键词： RIPK1 Necroptosis Type-II kinase inhibitors Rational design Lead optimization Structure‒activity relationship Anti-inflammation Preclinical drug discovery

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Identification of a dual functional betulinic acid analog for the treatment of osteoarthritis by phenotypic screening

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Science China Life Sciences 2024年

作者： Ze-Min Lin Mai Xiang Wen-Hui Wei Shu-Hui Fan Li Chen Jie Wang Xiao-Qian Yang Chun-Hao Yang Shi-Jun He Jian-Ping Zuo Laboratory of Immunopharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences School of Pharmacy University of Chinese Academy of Sciences School of Pharmacy Nanjing University of Chinese Medicine State Key Laboratory of Drug Research Department of Medicinal Chemistry Shanghai Institute of Materia Medica Chinese Academy of Sciences Innovation Research institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine Experiment Center for Science and Technology Shanghai University of Traditional Chinese Medicine

Dear Editor,Phenotypic drug discovery, which observes compound effects on physiology,has given way to targeting specific molecules, but has revived by using modern methods to find drugs based on therapeutic outcomes i...

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Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

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Science China Life Sciences 2024年

作者： Yinghui Zhang Yadan Liu Bing Jiang Lifan Chen Jie Hu Buying Niu Jie Chang Zisheng Fan Jingyi Zhou Yajie Wang Dan Teng Ning Ma Xiaofeng Wang Ruirui Yang Mingyue Zheng Sulin Zhang Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences School of Chinese materia medica Nanjing University of Chinese Medicine Shanghai institute for Advanced Immunochemical Studies and School of Life Science and Technology Shanghai Tech University School of Physical Science and Technology ShanghaiTech University School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences State Key Laboratory of Pharmaceutical Biotechnology Nanjing University

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D（LicoD） is identified as a potent and selective STING inhibitor. LicoD does not bind to the classical ligandbinding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1-/-mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer（CAC）.In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.

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Artesunate Induces Ferroptosis in Hepatic Stellate Cells and Alleviates Liver Fibrosis via the ROCK1/ATF3 Axis

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Journal of Clinical and Translational Hepatology 2024年第1期12卷 36-51页

作者： Yingqian Wang Yujia Li Yangling Qiu Min Shen Ling Wang Jiangjuan Shao Feng Zhang Xuefen Xu Zili Zhang Mei Guo Shizhong Zheng Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese materia medica Nanjing University of Chinese MedicineNanjingJiangsuChina institute of Translational Medicine Medical CollegeYangzhou UniversityYangzhouJiangsuChina Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine Nanjing University of Chinese MedicineNanjingJiangsu China

Background and Aims:Development of fibrosis in chronic liver disease requires activation of hepatic stellate cells(HSCs)and leads to a poor ***(Art)is an ester derivative of artemisinin that can induce ferroptosis in HSCs,and activated transcriptional factor 3(ATF3)is an ATF/CREB transcription factor that is induced in response to *** this study,we examined the role of the Rho-associated protein kinase 1(ROCK1)/ATF3 axis in Art-induced ferroptosis in ***:HSC activation and ferroptosis were studied in vitro by western blotting,polymerase chain reaction,immunofluorescence,and other ***3 electrophoretic mobility and ROCK1 protein stability were assayed by western *** was used to detect the interaction of ROCK1 and ATF3,as well as ATF3 phosphorylation.A ubiquitination assay was used to verify ROCK1 ***3-interfering and Rock1-overexpressing mice were constructed to validate the anti-hepatic fibrosis activity of Art in ***:Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in *** also decreased carbon tetrachloride-induced liver fibrosis in mice,which was reversed by interfering with Atf3 or overexpressing ***:The ROCK1/ATF3 axis was involved in liver fibrosis and regulation of ferroptosis,which provides an experimental basis for further study of Art for the treatment of liver fibrosis.

关键词： Ferroptosis Liver fibrosis Antioxidant system ATF3 ROCK1

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