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Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

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Nano Research 2024年第4期17卷 2899-2907页

作者： Zesen Ma Haiyang Tong Sijin Lin Li Zhou Demeng Sun Baoqing Li changlin tian Jiaru Chu Department of Precision Machinery and Precision Instrumentation University of Science and Technology of ChinaHefei 230027China Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes University of Science and Technology of ChinaHefei 230027China Science Island Branch Graduate SchoolUniversity of Science and Technology of ChinaHefei 230026China Anhui Provincial Key Laboratory of High Field Magnetic Resonance Imaging High Magnetic Field LaboratoryHefei Institute of Physical ScienceChinese Academy of SciencesHefei 230031China Anhui Provincial Engineering Laboratory of Peptide Drugs University of Science and Technology of ChinaHefei 230027China School of Biomedical Engineering Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaSuzhou 215127China

Lipid nanoparticles(LNPs)have emerged as highly effective delivery systems for nucleic acid-based ***,the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical *** this work,we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three ***,a theoretical predictive method,which controls the mixing time to be equal across different chips,is developed to ensure consistent particle size and size distribution of the synthesized *** loaded with small interfering RNA(siRNA)were synthesized at different flow rates,exhibiting consistent physical properties,including particle size,size distribution and encapsulation *** work provides a practical approach for scalable synthesis of LNPs consistently,offering the potential to accelerate the transition of nucleic acid drug development into clinical application.

关键词： lipid nanoparticles nucleic acid delivery microfluidics scalable synthesis consistent particle size

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Analysis of the electron transfer pathway in small laccase by EPR and UV-vis spectroscopy coupled with redox titration

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Magnetic Resonance Letters 2024年第3期4卷 52-59页

作者： Lu Yu Aokun Liu Jian Kuang Ruotong Wei Zhiwen Wang changlin tian High Magnetic Field Laboratory Hefei Institutes of Physical ScienceChinese Academy of SciencesHefei230031China Department of Endocrinology Institute of Endocrine and Metabolic DiseaseThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineHefei National Research Center for Physical Sciences at the MicroscaleJoint Center for Biological Analytical ChemistryAnhui Engineering Laboratory of Peptide DrugAnhui Laboratory of Advanced Photonic Science and TechnologyUniversity of Science and Technology of ChinaHefei230026China

Bacterial small laccases(SLAC) are promising industrial biocatalysts due to their ability to oxidize a broad range of substrates with exceptional thermostability and tolerance for alkaline p H. Electron transfer between substrate, copper centers, and O2is one of the key steps in the catalytic turnover of SLAC. However, limited research has been conducted on the electron transfer pathway of SLAC and SLAC-catalyzed reactions, hindering further engineering of SLAC to produce tunable biocatalysts for novel applications. Herein, the combinational use of electron paramagnetic resonance(EPR) and ultraviolet-visible(UV-vis) spectroscopic methods coupled with redox titration were employed to monitor the electron transfer processes and obtain further insights into the electron transfer pathway in SLAC. The reduction potentials for type 1 copper(T1Cu), type 2 copper(T2Cu) and type 3copper(T3Cu) were determined to be 367 ± 2 mV, 378 ± 5 m V and 403 ± 2 mV,respectively. Moreover, the reduction potential of a selected substrate of SLAC, hydroquinone(HQ), was determined to be 288 mV using cyclic voltammetry(CV). In this way, an electron transfer pathway was identified based on the reduction potentials. Specifically,electrons are transferred from HQ to T1Cu, then to T2Cu and T3Cu, and finally to ***, superhyperfine splitting observed via EPR during redox titration indicated a modification in the covalency of T2Cu upon electron uptake, suggesting a conformational alteration in the protein environment surrounding the copper sites, which could potentially influence the reduction potential of the copper sites during catalytic processes. The results presented here not only provide a comprehensive method for analyzing the electron transfer pathway in metalloenzymes through reduction potential measurements, but also offer valuable insights for further engineering and directed evolution studies of SLAC in the aim for biotechnological and industrial applications.

关键词： Electron paramagnetic resonance Redox titration Electron transfer Reduction Potential Small laccase

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A cytochrome c551 mediates the cyclic electron transport chain of the anoxygenic phototrophic bacterium Roseiflexus castenholzii

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Plant Communications 2024年第2期5卷 79-93页

作者： Lu Yu Zhenzhen Min Menghua Liu Yueyong Xin Aokun Liu Jian Kuang Wenping Wu Jingyi Wu Huimin He Jiyu Xin Robert EBlankenship changlin tian Xiaoling Xu Department of Biochemistry and Molecular Biology School of Basic Medical Sciences and Affiliated HospitalKey Laboratory of Aging and Cancer Biology of Zhejiang ProvinceHangzhou Normal UniversityHangzhou 311121China High Magnetic Field Laboratory Chinese Academy of SciencesHefei 230031China Photosynthesis Research Center College of Life and Environmental SciencesHangzhou Normal UniversityHangzhou 311121China The First Affiliated Hospital of USTC Division of Life Sciences and MedicineCenter for Bioanalytical ChemistryHefei National Laboratory of Physical Science at MicroscaleUniversity of Science and Technology of ChinaHefei 230026China Departments of Biology and Chemistry Washington University in St.LouisSt.LouisMO 63130USA

Roseiflexus castenholzii is a gram-negativefilamentous phototrophic bacterium that carries out anoxygenic photosynthesis through a cyclic electron transport chain(ETC).The ETC is composed of a reaction center(RC)–light-harvesting(LH)complex(rcRC–LH);an alternative complex III(rcACIII),which functionally re-places the cytochrome bc1/b6f complex;and the periplasmic electron acceptor auracyanin(rcAc).Although compositionally and structurally different from the bc1/b6f complex,rcACIII plays similar essential roles in oxidizing menaquinol and transferring electrons to the ***,rcACIII-mediated electron transfer(which includes both an intraprotein route and a downstream route)has not been clearly elucidated,nor have the details of cyclic ***,we identify a previously unknown monoheme cytochrome c(cyt c551)as a novel periplasmic electron acceptor of *** reduces the light-excited rcRC–LH to complete a cyclic *** also reveal the molecular mechanisms involved in the ETC using electron paramagnetic resonance(EPR),spectroelectrochemistry,and enzymatic and structural *** that electrons released from rcACIII-oxidized menaquinol are transferred to two alternative periplasmic electron acceptors(rcAc and cyt c551),which eventually reduce the rcRC to form the complete cyclic *** work serves as a foundation for further studies of ACIII-mediated electron transfer in anoxygenic photosynthesis and broadens our under-standing of the diversity and molecular evolution of prokaryotic ETCs.

关键词： cytochrome c menaquinol oxidoreductase electron transport chain electron paramagnetic reso-nance light-harvesting complex

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Recent advances in chemical protein synthesis:method developments and biological applications

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Science China Chemistry 2024年第4期67卷 1060-1096页

作者： Suwei Dong Ji-Shen Zheng Yiming Li Huan Wang Gong Chen Yongxiang Chen Gemin Fang Jun Guo Chunmao He Honggang Hu Xuechen Li Yanmei Li Zigang Li Man Pan Shan Tang changlin tian Ping Wang Bian Wu Chuanliu Wu Junfeng Zhao Lei Liu State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Division of Life Sciences and Medicine University of Science and Technology of ChinaHefei 230027China School of Food and Biological Engineering Engineering Research Center of Bio-processMinistry of EducationHefei University of TechnologyHefei 230009China School of Chemistry and Chemical Engineering Nanjing UniversityNanjing 210023China State Key Laboratory of Elemento-Organic Chemistry Nankai UniversityTianjin 300071China Department of Chemistry Tsinghua UniversityBeijing 100084China Institute of Health Sciences Anhui UniversityHefei 230601China College of Chemistry Central China Normal UniversityWuhan 430079China School of Chemistry and Chemical Engineering South China University of TechnologyGuangzhou 510640China School of Medicine or Institute of Translational Medicine Shanghai UniversityShanghai 200444China Department of Chemistry The University of Hong KongHong Kong 999077China Shenzhen Graduate School Peking UniversityShenzhen 518055China School of Chemistry and Chemical Engineering Shanghai Jiao Tong UniversityShanghai 200240China School of Life Sciences University of Science and Technology of ChinaHefei 230026China Department of Chemical Biology Shanghai Jiao Tong UniversityShanghai 200240China Institute of Microbiology Chinese Academy of SciencesBeijing 100101China Department of Chemistry Xiamen UniversityXiamen 361005China School of Pharmaceutical Science Guangzhou Medical UniversityGuangzhou 511436China

The central dogma of modern biology underscores the pivotal roles proteins play in diverse biological processes,the study of which necessitates advanced methods to produce proteins with precision and *** protein synthesis,a powerful approach utilizing chemical reactions for the de novo construction of structurally accurate proteins,has emerged as a transformative tool for studying proteins and generating protein derivatives/mimics inaccessible by natural biological machinery,including post-translationally modified proteins,proteins comprised of unnatural amino acids,as well as mirror-image *** review summarizes recent strides in synthetic method developments for chemical protein synthesis,including innovative techniques in solid-phase peptide synthesis,the challenges presented by difficult sequences in either synthesis or folding and the exploration of novel ligation reactions using both chemical and enzymatic ***,the review also delves into newly developed protocols for site-selective protein modifications and the generation of stapled or macrocyclized peptides/miniproteins,highlighting the power of chemical methods to make structurally diverse *** applications of synthetic proteins in investigating post-translational modifications(phosphorylation,lipidation,glycosylation,ubiquitination,etc.),mirror-image biological processes and drug development are further ***,these topics provide a comprehensive overview of the current landscape of chemical protein synthesis.

关键词： chemical protein synthesis solid-phase peptide synthesis ligation reactions post-translational modifications mirror-image proteins peptide drugs

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非酒精性脂肪性肝病新药的临床研究进展

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中国现代应用药学 2024年第6期41卷 858-863页

作者：田长林李玉琴刘洪涛河北医科大学研究生学院石家庄050000 河北省人民医院临床医学研究中心石家庄050000

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是临床上最常见的慢性肝病,全球发病率约为25%,NAFLD可进展为肝纤维化、肝硬化和肝细胞癌,严重威胁人类健康。目前中国尚未批准任何治疗药物上市,新药研发迫在眉睫。NAFLD... 详细信息

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是临床上最常见的慢性肝病,全球发病率约为25%,NAFLD可进展为肝纤维化、肝硬化和肝细胞癌,严重威胁人类健康。目前中国尚未批准任何治疗药物上市,新药研发迫在眉睫。NAFLD发病机制复杂,单一用药很难取得好的疗效。几种不同作用机制的药物联合使用是治疗NAFLD的必然趋势。通过联合用药可能降低药物的不良反应,发挥协同作用产生更好的疗效。本文综述了NAFLD新药联合用药的最新临床研究进展,以期为后续NAFLD新药开发和临床合理用药提供参考。

关键词：非酒精性脂肪性肝病代谢相关脂肪性肝病联合用药

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Chemical protein synthesis-assisted high-throughput screening strategies for D-peptides in drug discovery

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Chinese Chemical Letters 2020年第9期31卷 2365-2374页

作者： Ying Li Xiuxiu Cao changlin tian Ji-Shen Zheng Department of Chemistry School of Life SciencesHefei National Laboratory for Physical Sciences at the MicroscaleUniversity of Science and Technology of ChinaHefei 230027China High Magnetic Field Laboratory Chinese Academy of SciencesHefei 230031China

D-peptides are recognized as a new class of synthetic chemical drugs and they possess many interesting advantages such as high enzymatic stability,improved oral bioavailability,as well as high binding affinity and ***,D-peptide drugs have been attracting increasing attention in both academic and industrial researches over recent *** D-peptide etelcalcetide has even entered the market that targets the calcium(Ca2+)-sensing receptor(CaSR) to fight secondary *** discovery and optimization of D-peptide ligands that can bind to various disease-related targets with high specificity and potency is of great importance for the development of D-peptide *** review surveys the recent method development in this area especially the chemical protein synthesis-assisted high-throughput screening strategies for D-peptide ligands and their application in drug discovery.

关键词： Chemical protein synthesis Mirror-image proteins Mirror-image phage display Mirror-image one-bead one-compound(OBOC) D-Peptide drug

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降糖甲治疗2型糖尿病的机制研究

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贵州科学 2024年第1期42卷 25-32页

作者：程方玲田昌林张楠楠贵州中医药大学药学院贵州贵阳550025 贵州中医药大学基础医学院贵州贵阳550025

基于生物信息学、网络药理学和分子对接技术探讨降糖甲颗粒(JTJ)治疗2型糖尿病(T2DM)的作用机制。通过TCMSP、Uniprot数据库、swisstarget和SEA数据库筛选降糖甲颗粒的活性化合物和作用靶点,从GEO数据库获取T2DM患者组胰岛样本和非T2DM... 详细信息

基于生物信息学、网络药理学和分子对接技术探讨降糖甲颗粒(JTJ)治疗2型糖尿病(T2DM)的作用机制。通过TCMSP、Uniprot数据库、swisstarget和SEA数据库筛选降糖甲颗粒的活性化合物和作用靶点,从GEO数据库获取T2DM患者组胰岛样本和非T2DM患者组胰岛样本数据,利用R语言limma包筛选差异表达基因,二者取交集得到JTJ-T2DM共有靶点。通过Cytoscape3.9.1绘制JTJ-T2DM-靶点网络图,利用STRING数据库、Cytoscape3.9.1的cytoHubb插件制作JTJ-T2DM共有靶点的PPI网络图并获取关键靶点(Hubs)。利用DAVID平台对JTJ-T2DM共有靶点进行GO功能富集分析及KEGG通路富集分析,对共有靶点有差异表达并进行ROC分析,最后通过DS BIOVIA软件进行分子对接验证。结果显示,最终获得41个JTJ活性化合物,909个药物作用靶点,2952个T2DM靶点,JTJ-T2DM交集靶点160个,Hubs 12个;GO及KEGG富集分析结果显示,JTJ主要参与细胞凋亡等过程,调控MAPK及AGE-RAGE等信号通路而治疗T2DM;差异表达结果显示,MAPK14、PRKCZ、PTPN11具有显著差异表达且诊断价值高;分子对接结果显示(+)-丁香树脂醇-O-β-D-葡萄糖苷与LCK和PTPN11亲和力最强,蒙花苷与PRKCZ亲和力最强。本研究初步揭示了降糖甲颗粒治疗2型糖尿病的作用机制,为其治疗2型糖尿病提供充分、可靠的理论依据。

关键词：降糖甲颗粒 2型糖尿病作用机制

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基于生物信息学探讨治疗糖尿病和糖尿病肾病的共同靶点及活性化合物

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巴楚医学 2024年第1期7卷 78-85页

作者：田昌林李军田思思邓颖张楠楠贵州中医药大学基础医学院贵州贵阳550025

目的:基于生物信息学探讨治疗糖尿病(DM)和糖尿病肾病(DKD)的共同靶点,并筛选活性化合物。方法:通过GEO数据库获得DM数据集和DKD数据集,并筛选差异表达基因(DEGs)。通过R语言获得DM和DKD的交集基因,并进行基因本体论(GO)分析、京都基因... 详细信息

目的:基于生物信息学探讨治疗糖尿病(DM)和糖尿病肾病(DKD)的共同靶点,并筛选活性化合物。方法:通过GEO数据库获得DM数据集和DKD数据集,并筛选差异表达基因(DEGs)。通过R语言获得DM和DKD的交集基因,并进行基因本体论(GO)分析、京都基因与基因组百科全书(KEGG)富集分析、免疫浸润分析、加权基因共表达分析(WGCNA)、外部数据集差异表达分析及受试者工作特征(ROC)曲线分析以获得调控DM和DKD的关键靶点,最后进行靶点化合物筛选,并进行分子对接验证。结果:共获得DM和DKD的交集基因108个,他们主要和免疫相关,WGCNA聚焦到其中14个免疫基因,进一步通过差异表达及ROC分析获得3个调节DM和DKD的关键基因,即GALNT1、MARCKS和SLC38A1。通过CTD数据库预测得到关键靶点的化合物为叶酸、槲皮素、香豆素和酚类抗氧化剂等,分子对接证实他们之间具有较好的亲和力。结论:GALNT1、MARCKS和SLC38A1可能是DM和DKD的共同治疗靶点,叶酸、槲皮素、香豆素和酚类抗氧化剂可能是治疗DM和DKD的活性化合物。

关键词：生物信息学糖尿病糖尿病肾病

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In cell measurement of fluorescence lifetime imaging microscopy revealed C-terminal conformation changes of Ferroportin upon addition of Mn^2＋

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Chinese Chemical Letters 2018年第10期29卷 1509-1512页

作者： Mengge Zhang Ming Wen Ying Xiong Longhua Zhang changlin tian National Laboratory of Physical Sciences at Microscale and School of Life Sciences University of Science and Technology of China Hefei 230027 China High Magnetic Field Laboratory Chinese Academy of Sciences Hefei 230031 China

Fluorescence microscopy, as a sensitive method to detect microenvironment of molecules, is widely used in protein conformation and dynamic studies in live cells. Fluorescence lifetime imaging microscopy（FLIM）, which is independent of fluorophore concentrations, scattering and bleaching, is a suitable tool to analyze membrane proteins in a single cell. Ferroportin（FPN）, a multi-ion exporter in vertebrates, was modulated by metal ions with unknown mechanism. Herein, we fused green fluorescence protein on Cterminal of FPN（FPN-eGFP） and applied fluorescence lifetime to monitor conformation changes of FPN in a live cell. The fluorescence lifetime distribution showed a shift to shorter lifetime upon Mn^（2＋） treatment,suggesting a preference conformation of FPN in Mn^（2＋） exposure. It is also observed that the lifetime（rather than intensity） measurement was not strongly influenced by laser power. The observed fluorescence lifetime changes of FPN-eGFP upon Mn^（2＋） treatments indicated that extracellular metal ions can modulate FPN through conformation exchanges between several different states.

关键词： Fluorescence lifetime imaging microscopy In cell analysis of conformation change Ferroprotin

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Total chemical synthesis of bivalently modified H3 by improved three-segment native chemical ligation

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Chinese Chemical Letters 2020年第5期31卷 1267-1270页

作者： Yong Zheng Fangming Wu Shenglong Ling Jia-Bin Li changlin tian High Magnetic Field Laboratory Chinese Academy of SciencesHefei 230031China School of Life Sciences University of Science and Technology of ChinaHefei 230027China Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China

The H3 bivalent modifications of trimethylationat Lys9 and acetylation at Lys18(H3-K9 Me3-K18 Ac) were identified to collectively recruit TRIM33 in the nodal signaling *** understand the underlying mechanism of TRIM33 recruitment,the nucleosome core particles(NCPs) containing full-length H3-K9 Me3-K18 Ac were indispensable *** we developed a pseudo dipeptide strategy to efficiently prepare peptide segments,facilitating the chemical synthesis of H3-K9 Me3-K18 Ac at a tens of milligram *** synthetic H3-K9 Me3-K18 Ac was then examined by CD spectroscopy,which demonstrated a prominent shift compared to recombinant ***,bivalently modified NCPs were assembled and verified by gel mobility shift assay with good homogeneity.

关键词： Chemical protein synthesis Native chemical ligation Histone H3 Methylation Acetylation Nucleosome core particles

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