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A proteomic landscape of pharmacologic perturbations for functional relevance

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Journal of Pharmaceutical Analysis 2024年第1期14卷 128-139页

作者： Zhiwei Liu Shangwen Jiang Bingbing Hao Shuyu Xie Yingluo Liu Yuqi Huang Heng Xu Cheng Luo Min Huang minjia tan Jun-Yu Xu State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing210023China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdong528400China State Key Laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing210023China

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.

关键词： Proteomics Drug Perturbation Drug target Drug combination

In-depth urinary and exosome proteome profiling analysis identifies novel biomarkers for diabetic kidney disease

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Science China(Life Sciences) 2023年第11期66卷 2587-2603页

作者： Shichun Du Linhui Zhai Shu Ye Le Wang Muyin Liu minjia tan Department of Endocrinology Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200092China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesGuangdong 528400China Department of Cardiology Shanghai Institute of Cardiovascular DiseasesZhongshan HospitalFudan UniversityShanghai 200032China

Diabetic kidney disease(DKD)is a major microvascular complication of type 2 diabetes mellitus(T2DM).Monitoring the early diagnostic period and disease progression plays a crucial role in treating *** this study,to comprehensively elucidate the molecular characteristics of urinary proteins and urinary exosome proteins in type 2 DKD,we performed large-scale urinary proteomics(n=144)and urinary exosome proteomics(n=44)analyses on T2DM patients with albuminuria in varying *** dynamics analysis of the urinary and exosome proteomes in our study provides a valuable resource for discovering potential urinary biomarkers in patients with DKD.A series of potential biomarkers,such as SERPINA1 and transferrin(TF),were detected and validated to be used for DKD diagnosis or disease *** results of our study comprehensively elucidated the changes in the urinary proteome and revealed several potential biomarkers reflecting the progression of DKD,which provide a reference for DKD biomarker screening.

关键词： diabetic kidney disease type 2 diabetes mellitus urinary proteome urinary exosome proteome biomarkers

Phosphoproteomics Reveals the AMPK Substrate Network in Response to DNA Damage and Histone Acetylation

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Genomics, Proteomics & Bioinformatics 2022年第4期20卷 597-613页

作者： Yuejing Jiang Xiaoji Cong Shangwen Jiang Ying Dong Lei Zhao Yi Zang minjia tan Jia Li National Center for Drug Screening State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Chemical Proteomics Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Open Studio for Druggability Research of Marine Natural Products Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266237China

AMP-activated protein kinase(AMPK)is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various *** studies have demonstrated the regulatory roles of AMPK in DNA repair,but the underlying mechanisms remain to be fully ***,using mass spectrometry-based proteomic technologies,we systematically investigate the regulatory network of AMPK in DNA damage response(DDR).Our system-wide phosphoproteome study uncovers a variety of newly-identified potential substrates involved in diverse biological processes,whereas our system-wide histone modification analysis reveals a link between AMPK and histone *** with these findings,we discover that AMPK promotes apoptosis by phosphorylating apoptosis-stimulating of p53 protein 2(ASPP2)in an irradiation(IR)-dependent manner and regulates histone acetylation by phosphorylating histone deacetylase 9(HDAC9)in an IR-independent ***,we reveal that disrupting the histone acetylation by the bromodomain BRD4 inhibitor JQ-1 enhances the sensitivity of AMPKdeficient cells to ***,our study has provided a resource to investigate the interplay between phosphorylation and histone acetylation underlying the regulatory network of AMPK,which could be beneficial to understand the exact role of AMPK in DDR.

关键词： AMPK Phosphoproteomics Histone modification DNA damage Apoptosis

Drug repurposing for cancer treatment through global propagation with a greedy algorithm in a multilayer network

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Cancer Biology & Medicine 2022年第1期19卷 74-89页

作者： Xi Cheng Wensi Zhao Mengdi Zhu Bo Wang Xuege Wang Xiaoyun Yang Yuqi Huang minjia tan Jing Li Department of Bioinformatics and Biostatistics School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China The Chemical Proteomics Center and State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Tissue Microenvironment and Tumor Shanghai Institute of Nutrition and HealthShanghai Institutes for Biological SciencesUniversity of Chinese Academy of SciencesChinese Academy of Sciences(CAS)Shanghai 200031China

Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug *** aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly ***:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug *** performed additional experimental validation for the dominant repurposed drugs in ***:The overall performance of the model was well supported by cross-validation and literature *** on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity *** of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative *** analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA ***,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft ***:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

关键词： Database drug repurposing machine learning network random walk proteomics analysis

Nucleolus localization of SpyCas9 affects its stability and interferes with host protein translation in mammalian cells

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Genes & Diseases 2022年第3期9卷 731-740页

作者： Renke tan Wenhao Du Yiyang Liu Xiaoji Cong Meirong Bai Chenxiao Jiang Zengxia Li minjia tan Dengke K.Ma Qiang Huang Wei Jiang Yongjun Dang Key Laboratory of Metabolism and Molecular Medicine the Ministry of EducationDepartment of Biochemistry and Molecular BiologySchool of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghai 200032PR China State Key Laboratory of Genetic Engineering School of Life SciencesFudan UniversityShanghai 200043PR China Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203PR China Cardiovascular Research Institute University of CaliforniaSan FranciscoCA 94158USA

The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing *** enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA,and the Cas9 protein,which has endonuclease activity,will cut a double strand break at specific ***,Cas9 is a foreign protein in mammalian cells,and the potential risks associated with its introduction into mammalian cells are not fully *** this study,we performed pull-down and mass spectrometry(MS)analysis of Streptococcus pyogenes Cas9(SpyCas9)interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the ***,we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal(NoDS).Compared with wild-type(WT)Cas9,NoDS-mutated variants of Cas9(mCas9)are less stable,although their gene editing activity is minimally *** of WT Cas9,but not mCas9,causes general effects on transcription and protein translation in the host ***,identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo,and the removal of NoDS in Cas9 may enhance its safety for future clinical use.

关键词： CRISPR/Cas9 Gene editing Global transcription Nucleolus detention signal Translation

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一种新的证据冲突识别与调整方法

上海交通大学学报 2022年第8期56卷 1043-1050页

作者：张鑫谈敏佳南京理工大学自动化学院南京210094

针对现有方法在识别证据冲突方面存在的不足,结合传统证据冲突,提出一种证据冲突识别与调整的方法.该方法首先将传统证据冲突的加权平均值作为识别指标,其次引入可信度和不确定度,以是否为互异证据间冲突分两种情形确定权重系数.然后,... 详细信息

针对现有方法在识别证据冲突方面存在的不足,结合传统证据冲突,提出一种证据冲突识别与调整的方法.该方法首先将传统证据冲突的加权平均值作为识别指标,其次引入可信度和不确定度,以是否为互异证据间冲突分两种情形确定权重系数.然后,结合传统证据冲突和Jousselme信息距离对识别出的证据冲突加以调整.该方法以传统证据冲突为基础,确保了识别指标的代表性和识别结果的真实性,此外,权重系数综合考虑证据内和证据间的可信度,也更具代表性.最后,选取降低程度和平均偏差分析验证了所提方法.研究结果表明,所提方法的识别精度较高,能够有效地调整证据冲突.

关键词：证据冲突加权平均值综合可信度权重系数

SPA: A Quantitation Strategy for MS Data in Patient-derived Xenograft Models

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Genomics, Proteomics & Bioinformatics 2021年第4期19卷 522-533页

作者： Xi Cheng Lili Qian Bo Wang minjia tan Jing Li Department of Bioinformatics and Biostatistics School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China The Chemical Proteomics Center and State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China

With the development of mass spectrometry(MS)-based proteomics technologies,patient-derived xenograft(PDX),which is generated from the primary tumor of a patient,is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a ***,the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse *** this study,by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark,we developed and evaluated a new method,SPA(shared peptide allocation),for protein quantitation by considering the unique and shared peptides of both *** results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed *** validation on a pair of gastric PDX samples(one bearing FGFR2 amplification while the other one not)showed that our new method not only significantly improved the overall protein identification,but also detected the differential phosphorylation of FGFR2 and its downstream mediators(such as RAS and ERK)*** tool pdx SPA is freely available at https://***/LiLab-Proteomics/pdx SPA.

关键词： Patient-derived xenograft model Label-free Shared peptide FGFR2 amplification Biomarker

Diffractive neural networks with improved expressive power for gray-scale image classification

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Photonics Research 2024年第6期12卷 1159-1166页

作者： minjia ZHENG WENZHE LIU LEI SHI JIAN ZI State Key Laboratory of Surface Physics Key Laboratory of Micro-and Nano-Photonic Structures(Ministry of Education)and Department of PhysicsFudan UniversityShanghai 200433China Institute for Nanoelectronic Devices and Quantum Computing Fudan UniversityShanghai 200433China Collaborative Innovation Center of Advanced Microstructures Nanjing UniversityNanjing 210093China Shanghai Research Center for Quantum Sciences Shanghai 210315China

In order to harness diffractive neural networks(DNNs)for tasks that better align with real-world computer vision requirements,the incorporation of gray scale is ***,DNNs are not powerful enough to accomplish gray-scale image processing tasks due to limitations in their expressive *** our work,we elucidate the relationship between the improvement in the expressive power of DNNs and the increase in the number of phase modulation layers,as well as the optimization of the Fresnel number,which can describe the diffraction *** demonstrate this point,we numerically trained a double-layer DNN,addressing the prerequisites for intensitybased gray-scale image ***,we experimentally constructed this double-layer DNN based on digital micromirror devices and spatial light modulators,achieving eight-level intensity-based gray-scale image classification for the MNIST and Fashion-MNIST data *** optical system achieved the maximum accuracies of 95.10%and 80.61%,respectively.

关键词： process. mirror limitations

Corrosion behavior and protection mechanism of carbon steel coated with ethylene chlorotrifluoroethylene(ECTFE)

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Journal of Zhejiang University-Science A(Applied Physics & Engineering) 2024年第6期25卷 502-515页

作者： Peihu SHEN Jun WEN Biqin DONG Hedong LI minjia WANG School of Civil Engineering and Architecture Zhejiang Sci-Tech UniversityHangzhou310018China College of Civil and Transportation Engineering Shenzhen UniversityShenzhen518061China Zhejiang Research Institute of Chemical Industry Co. Ltd.Hangzhou310023China

Ethylene chlorotrifluoroethylene(ECTFE)coating was applied to the surface of carbon steel through electrostatic spraying and low-temperature heat *** morphology and structure of the coating were analyzed using various characterization *** electrochemical data of the coated steel soaked in 3.5%(mass fraction)NaCl solution for 90 d at different periods were also *** findings indicate that the outer surface of the coating remains structurally stable before and after soaking.F can diffuse into the steel substrate,facilitating the bonding between the coating and the steel substrate,but the free F also induces a weakening effect on the crystalline *** to the thickness of the coating edge and the susceptibility to infiltration of the corrosive medium,under-film micro-zone corrosion occurs at a slow *** soaking for 90 d,the impedance modulus measures approximately 10^(4)Ω·cm^(2),and the open circuit potential(OCP)is−0.61 *** self-corrosion current density is 1.13×10^(−6)A/cm^(2),resulting in a calculated coating protection rate of 99.29%.In summary,despite edge corrosion occurring,the ECTFE coating provides excellent corrosion protection.

关键词： Coating Fluorine resin Edge corrosion Corrosive behavior Electrochemical performance