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Science China Chemistry 2023年第6期66卷 1701-1706页

作者： Zhaoming Ma Lantian Sun Jianrong Steve Zhou State Key Laboratory of Chemical Oncogenomics Guangdong Provincial Key Laboratory of Chemical GenomicsSchool of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China Department of Chemistry Hong Kong Baptist UniversityHong KongChina

Enantioselective domino alkenylation-alkynylation of olefins is achieved for the first time,using terminal alkynes directly as pronucleophiles.The new reaction enables facile construction of azacycles carrying quaternary stereocenters,including 5–7 membered pyrrolidines,piperidines and tetrahydroazepines.Moreover,alkynyl groups in azacyclic products provide a useful handle for derivatization that formed both fused and bridged azabicycles.

关键词： membered cycles synthesis

Co-culture of tumor spheroids and monocytes in a collagen matrix-embedded microfluidic device to study the migration of breast cancer cells

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Chinese chemical Letters 2019年第2期30卷 331-336页

作者： Tianying Yuan Dan Gao Shangfu Li Yuyang jiang State Key Laboratory of Chemical Oncogenomics The Graduate School at Shenzhen Tsinghua University key laboratory of Metabolomics at Shenzhen School of Medicine Tsinghua University

Recapitulating the tumor microenvironment is a major challenge in the development of in vitro tumor model for the study of cancer biology and therapeutic treatments. 3D multicellular tumor spheroids (MCTS) have been used as reliable models of mimicking in vivo solid tumors. Macrophages and extracellular matrix (ECM), regarded as two key factors of the tumor microenvironment, play significant roles in tumor progression and drug resistance. In order to investigate their effects on tumor cell migration, a microfluidic chip-based 3D breast cancer model was developed by co-culturing monodisperse MCTS with monocytes in 3 D collagen matrix. A reversible bonding technique was employed for the fabrication of the microfluidic chip, which made it easier for MCTS formation and tailoring the MCTS co-culture conditions. When co-culturing monocytes with low invasive T47D spheroids or high invasive MD-MBA-231 spheroids, we found that T47 D cells with the stimulation of macrophage colony-stimulating factor (M-CSF) and MD-MBA-231 cells could polarize monocytes into tumor-associated macrophages (TAMs). The increased stiffness via increasing collagen concentration decreased tumor cell migration, whereas the presence of TAMs enhanced the migration ability of cells.Moreover, M-CSF-activated TAMs promoted the migration of T47 D tumor cells via the regulation of TGFβ1. Overall, this 3D co-culture microfluidic model may be useful for studying tumor progress and may offer a reliable and low-cost method for evaluation of drug efficiency.

关键词： Tumor microenvironment Multicellular tumor spheroids Tumor-associated macrophages Extracellular matrix stiffness Microfluidics

Optimized Target-AID system efficiently induces single base changes in zebrafish

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Journal of Genetics and Genomics 2018年第4期45卷 215-217页

作者： Xiaochan Lu Yunxing Liu Guanrong Yan Song Li Wei Qin Shuo Lin State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical Genomics Peking University Shenzhen Graduate School Department of Molecular Cell and Development Biology University of CaliforniaLos Angeles

CRISPR-Cas system has been widely adapted as a platform for genome editing in various eukaryotic organisms, including zebrafish（Cong et al., 2013; Hwang et al., 2013）. One of the important applications of CRISPR-Cas... 详细信息

关键词： AID Optimized Target-AID system efficiently induces single base changes in zebrafish Target

An integrated microfluidic chip-mass spectrometry system for rapid antimicrobial resistance analysis of bacteria producingβ-lactamases

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Chinese chemical Letters 2023年第5期34卷 323-326页

作者： Zhaochen Su Wanting Hu Lizhen Ye Dan Gao Jin-Ming Lin State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical BiologyTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China Department of Chemistry Beijing Key Laboratory of Microanalytical Methods and InstrumentationKey Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology(Ministry of Education)Tsinghua UniversityBeijing 100084China

Bacteria producingβ-lactamases have become a major issue in the global public health field.To restrain the development of drug resistance and reduce the abuse of antibiotics,it is very important to rapidly identify bacteria producingβ-lactamases and put forward a reasonable treatment plan.Here,an integrated microfluidic chip-mass spectrometry system was proposed for rapid screening ofβ-lactamaseproducing bacteria and optimization ofβ-lactamase inhibitor dosing concentration.The concentration gradient generator followed by an array of bacterial culture chambers,as well as micro-solid-phase extraction columns was designed for sample pretreatment before mass analysis.By using the combination system,the process of the hydrolysis of antibiotics byβ-lactamase-producing bacteria could be analyzed.To validate the feasibility,four antibiotics and two antibiotic inhibitors were investigated using three strains including negative control,SHV-1 and TEM-1 strains.SHV-1 and TEM-1 strains were successfully distinguished as theβ-lactamase producing strains.And the acquired optimal concentrations ofβ-lactamase inhibitors were in accordance with the results by that obtained from the traditional microdilution broth method.The total analysis time only needed around 2 h,which was faster than conventional methods that require a few days.The technique presented herein provides an easy and rapid protocol forβ-lactamase resistance related studies,which is important for the inhibition of antimicrobial resistance development and the reduction of antibiotics abuse.

关键词： Microfluidics Mass spectrometry β-Lactamases Antimicrobial resistance Inhibitor

Single-cell metabolite analysis on a microfluidic chip

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Chinese chemical Letters 2022年第6期33卷 2883-2892页

作者： Chenlong Wang Wanting Hu Liandi Guan Xiaoping Yang Qionglin Liang Center for Synthetic and Systems Biology Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical BiologyMinistry of EducationDepartment of ChemistryTsinghua UniversityBeijing 100084China State Key Laboratory of Chemical Oncogenomics The Graduate SchoolTsinghua UniversityShenzhen 518055China

Metabolites can directly reflect and modulate cell responses and phenotypical changes by influencing energy balances,intercellular signals,and many other cellular functions throughout the lifespan of cells.Taking into account the heterogeneity of cells,single-cell metabolite analysis offers an insight into the functional process within one cell.Microfluidics as a powerful tool has attracted significant interest in the single-cell metabolite analysis field.The microfluidic platform is possible to observe,classify,and stimulate individual cells.It can also transport single-cell to subsequent analysis steps in a fast and controllable way to determine and analyze the composition and content of metabolites.The reviews of topics in microfluidics for single-cell metabolite analysis have been published in the past few years.However,most of them focused on metabolite analysis with mass spectrometry.Here,we covered the advances of microfluidic devices for single-cell metabolite analysis,with a focus on single-cell isolation and manipulation.What is more,we summarized the detection methods and applications of single-cell metabolites.

关键词： Single-cell Metabolomics Microfluidic Cell trapping Cell manipulation Detection

Development of a cell-permeable adenine-derived probe for capture of nucleotide-binding proteins in living cells

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Chinese chemical Letters 2024年第3期35卷 243-246页

作者： Lihong Liu Rui Chen Gang Xue Chenzhou Hao Weizhi Weng Zhengying Pan State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Adenine is an essential building block of genetic material and a range of coenzymes.chemical probes containing an adenine moiety have been used in kinase profiling studies in cell lysates.Here we report that adenine-derived small-molecule probes with an activated ester reactive group can covalently modify a conserved lysine residue of protein kinases and capture a number of nucleotide-binding proteins within living cells.

关键词： Adenine-derived probe Cell-permeable Lysine residue Protein kinases Nucleotide-binding proteins

A cellular chip-MS system for investigation of Lactobacillus rhamnosus GG and irinotecan synergistic effects on colorectal cancer

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Chinese chemical Letters 2022年第4期33卷 2096-2100页

作者： Wanting Hu Dan Gao Zhaochen Su Rui Qian Yu Wang Qionglin Liang State Key Laboratory of Chemical Oncogenomics the Graduate School at ShenzhenTsinghua UniversityShenzhen 518055China Department of Chemistry Center for Synthetic and Systems BiologyKey Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology(Ministry of Education)Tsinghua UniversityBeijing 100084China

Colorectal cancer(CRC) is still the leading cause of cancer death worldwide, but the clinical effect of drug therapy such as irinotecan is not an ideal way at present. In recent years, probiotics have attracted much attention, and the combination of probiotics may play an important role in the prevention and treatment of CRC. This work proposed a cellular chip-MS system, to study the synergistic effects of probiotic Lactobacillus rhamnosus GG(L.GG) and irinotecan on HCT116 cells by cell viability and on-line mass spectrometry(MS) analysis. The double-layer chip sandwiched with a polycarbonate membrane can coculture HCT116 cells and L.GG. And the solid phase microextraction chip can be used for desalination and concentration. Finally, the extracted chemicals were entered the electrospray ionization quadrupole time-of-flight MS to detect irinotecan metabolites. The results showed that with the increasing concentration of co-cultured L.GG, the percentage of living HCT116 cells decreased, but the relative amount of metabolized SN-38 by HCT116 cells increased. Therefore, the microfluidic system can be used to detect and monitor the synergistic effect of irinotecan-L.GG combination on HCT116 cells. In summary, our study provided experimental evidence for the first time with potential applications of irinotecan-L.GG combination in CRC treatment, and the cellular chip-MS system as a powerful tool can be used in the experiments of probiotics as new drugs.

关键词： Irinotecan Lactobacillus rhamnosus Microfluidics Mass spectrometry Colorectal cancer

Unveiling E2F4,TEAD1 and AP-1 as regulatory transcription factors of the replicative senescence program by multi-omics analysis

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Protein & Cell 2022年第10期13卷 742-759页

作者： Yuting Wang Liping Liu Yifan Song Xiaojie Yu Hongkui Deng School of Basic Medical Sciences State Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing 100191China The MOE key laboratory of Cell Proliferation and Differentiation College of Life SciencesPeking-Tsinghua Center for Life SciencesPeking UniversityBeijing 100871China State Key Laboratory of Chemical Oncogenomics School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China

Senescence,a stable state of growth arrest,affects many physiological and pathophysiological processes,especially aging.Previous work has indicated that transcription factors(TFs)play a role in regulating senescence.However,a systematic study of regulatory TFs during replicative senescence(RS)using multiomics analysis is still lacking.Here,we generated timeresolved RNA-seq,reduced representation bisulfite sequencing(RRBS)and ATAC-seq datasets during RS of mouse skin fibroblasts,which demonstrated that an enhanced inflammatory response and reduced proliferative capacity were the main characteristics of RS in both the transcriptome and epigenome.Through integrative analysis and genetic manipulations,we found that transcription factors E2F4,TEAD1 and AP-1 are key regulators of RS.Overexpression of E2f4 improved cellular proliferative capacity,attenuated SA-β-Gal activity and changed RS-associated differentially methylated sites(DMSs).Moreover,knockdown of Tead1 attenuated SA-β-Gal activity and partially altered the RS-associated transcriptome.In addition,knockdown of Atf3,one member of AP-1 superfamily TFs,reduced Cdkn2a(p16)expression in pre-senescent fibroblasts.Taken together,the results of this study identified transcription factors regulating the senescence program through multi-omics analysis,providing potential therapeutic targets for anti-aging.

关键词： transcription factor senescence multiomics

Simultaneous capture of ISG15 conjugating and deconjugating enzymes using a semi-synthetic ISG15-Dha probe

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Science China Chemistry 2023年第3期66卷 837-844页

作者： Chuntong Li Tian Wang Lujun Liang Guochao Chu Jiachen Zhang Wei He Lei Liu Jinghong Li Department of Chemistry Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologyCenter for Synthetic and Systems BiologyState Key Laboratory of Chemical Oncogenomics(Shenzhen)Tsinghua UniversityBeijing 100084China School of Pharmaceutical Sciences Tsinghua UniversityBeijing 100084China Center for BioAnalytical Chemistry Hefei National Laboratory of Physical Science at MicroscaleUniversity of Science and Technology of ChinaHefei 230026China

ISG15 is a ubiquitin-like(Ubl) protein attached to substrate proteins by ISG15 conjugating enzymes whose dysregulation is implicated in a multitude of disease processes, but the probing of these enzymes remains to be accomplished. Here, we describe the development of a new activity-based probe ISG15-Dha(dehydroalanine) through protein semi-synthesis. In vitro crosslinking and cell lysate proteomic profiling experiments showed that this probe can sequentially capture ISG15 conjugating enzymes including E1 enzyme UBA7, E2 enzyme UBE2L6, E3 enzyme HERC5, the previously known ISG15 deconjugating enzyme(USP18), as well as some other enzymes(USP5 and USP14) which we additionally confirmed to impart deISGylation activity. Collectively, ISG15-Dha provides a new tool that can simultaneously capture ISG15 conjugating and deconjugating enzymes for biochemical or pharmacological studies.

关键词： ISG15-Dha probe semi-synthesis activity based probe proteomics ISGylation

Theoretical insight into the activity and selectivity in palladium/Ming-Phos-catalyzed three-component asymmetric synthesis of gem-diarylmethine silanes

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Science China Chemistry 2023年第10期66卷 2817-2827页

作者： Bo Xiao Tian-Yu Sun Junliang Zhang Yun-Dong Wu State Key Laboratory of Chemical Oncogenomics Key Laboratory of Computational Chemistry and Drug DesignSchool of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China Institute of chemical Biology Shenzhen Bay LaboratoryShenzhen 518132China Department of Chemistry Fudan UniversityShanghai 200438China College of Chemistry and Molecular Engineering Peking UniversityBeijing 100871China

Recently,a three-component coupling reaction for efficient construction of gem-diarylmethine silanes was developed,utilizing a Pd-Ming-Phos catalyst.To explore the underlying mechanism governing this intriguing reaction,we have conducted comprehensive density functional theory(DFT)computations(M06-L/SDD/6-311++G(d,p)/SMD//B3LYP-D3/lanl2dz/6-31G(d,p)).DFT calculations reveal that the oxidative addition of Ar Br to Pd(0)is the rate-determining step,and the carbenation process of Ph CHN_(2)to Pd(Ⅱ)is the enantioselectivity-determining step.Moreover,the Ming-Phos ligand exhibits a self-adaptive nature,allowing it to dynamically adapt its coordination patterns with the metal center in different elementary steps,thereby enhancing the overall reactivity.The enantioselectivity is determined by both the trans effect and the side-arm effect of the ligand.This mechanism nicely explains why TY-Phos with P-tBu_(2)instead of the Ming-Phos with P-Ph2results in poor reactivity and much reduced enantioselectivity.This study not only provides deeper insights into the functioning principles of Sad Phos ligands but also offers valuable guidance for future ligand modifications and optimizations.

关键词： self-adaptive effect side-arm effect Ming-Phos ligand gem-diarylmethine silanes DFT study