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Inner nuclear membrane protein TMEM201 maintains endothelial cell migration and angiogenesis by interacting with the LINC complex

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Journal of Molecular Cell Biology 2022年第3期14卷 48-60页

作者： Yutian Zhang Ya Kong Haoran Guo Yun Liu Yi Zang Jia Li University of Chinese Academy of Sciences Beĳing 100049China state key laboratory of drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China state key laboratory of Natural Medicines Jiangsu Key Laboratory of Drug ScreeningChina Pharmaceutical UniversityNanjing 210009China School of pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Open Studio for druggability Research of Marine Natural Products Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266237China

The nuclear envelope comprises the outer nuclear membrane,inner nuclear membrane(INM),and ***∼60 INM proteins have been identified,only a few of them have been well characterized,revealing their crucial *** group focused on the INM protein transmembrane protein 201(TMEM201),whose role in cellular function remains to be *** this study,we investigated the role of TMEM201 in endothelial cell migration and *** of TMEM201 expression by short hairpin RNA-mediated interference impeded human umbilical vein endothelial cell(HUVEC)angiogenic behavior in tube formation and fibrin gel bead sprouting ***,TMEM201-deficient HUVECs exhibited impaired migration *** next explored the underlying mechanism and found that the N-terminal of TMEM201 interacted with the linker of nucleoskeleton and cytoskeleton complex and was required for regulating endothelial cell migration and *** in vitro findings were further confirmed by using in vivo *** Tmem201-knockout mice,retinal vessel development was arrested and aortic ring sprouting was *** addition,loss of tmem201 impaired zebrafish intersegmental vessel *** summary,TMEM201 was shown to regulate endothelial cell migration and control the process of *** study is the first to reveal the role of INM proteins in the vascular system and angiogenesis.

关键词： transmembrane protein 201 inner nuclear membrane LINC complex endothelial cell migration angiogenesis

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Machine learning-based solubility prediction and methodology evaluation of active pharmaceutical ingredients in industrial crystallization

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Frontiers of Chemical Science and Engineering 2022年第4期16卷 523-535页

作者： Yiming Ma Zhenguo Gao Peng Shi Mingyang Chen Songgu Wu Chao Yang Jing-Kang Wang Jingcai Cheng Junbo Gong School of Chemical Engineering and Technology State Key Laboratory of Chemical EngineeringTianjin UniversityTianjin 300072China The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin Tianjin 300072China key laboratory of Green process and Engineering Institute of Process EngineeringChinese Academy of SciencesBeijing 100190China

Solubility has been widely regarded as a fundamental property of small molecule drugs and drug candidates,as it has a profound impact on the crystallization *** prediction,as an alternative to experiments which can reduce waste and improve crystallization process efficiency,has attracted increasing ***,there are still many urgent challenges thus *** we used seven descriptors based on understanding dissolution behavior to establish two solubility prediction models by machine learning *** solubility data of 120 active pharmaceutical ingredients(APIs)in ethanol were considered in the prediction models,which were constructed by random decision forests and artificial neural network with optimized data structure and model ***,a comparison with traditional prediction methods including the modified solubility equation and the quantitative structure-property relationships model was carried *** highest accuracy shown by the testing set proves that the ML models have the best solubility prediction *** linear regression and stepwise regression were used to further investigate the critical factor in determining solubility *** results revealed that the API properties and the solute-solvent interaction both provide a nonnegligible contribution to the solubility value.

关键词： solubility prediction machine learning artificial neural network random decision forests

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

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Science China Life Sciences 2024年第12期67卷 2664-2677页

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 Shanghai Tech 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 c GAMP, 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 Transformer CPI 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(Lico D) is identified as a potent and selective STING inhibitor. Lico D 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. Lico D 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 Lico D in treating STING-driven inflammatory diseases. It also demonstrates the utility of the Transformer CPI model in discovering allosteric compounds beyond the conventional binding pockets.

关键词： cGAS-STING signaling STING inhibitor TransformerCPI model Licochalcone D inflammatory diseases

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Design, synthesis and biological evaluation of a novel platinum(Ⅱ)complex possessing bioreductive groups for cancer therapy

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Chinese Chemical Letters 2019年第1期30卷 243-246页

作者： Chengken Chen Chunmei Gao Zigao Yuan Yuyang Jiang Department of Chemistry Tsinghua University The Ministry-Province Jointly Constructed Base for state key lab-Shenzhen key laboratory of Chemical Biology The Graduate School at Shenzhen Tsinghua University College of Chemistry and Chemical Engineering Shenzhen University Shenzhen Kivita Innovative drug Discovery Institute Department of Pharmacology and pharmaceutical Sciences School of Medicine Tsinghua University

Cisplatin is one of the most successful antitumor agents, yet also restricted by its poor cellular uptake and low selectivity. Since 3-(2-nitrophenyl) propionic acid(NPPA) has been reported as a bioreductive prodrug moiety, herein we combined NPPA with cisplatin(compound 1) to improve its lipophilicity and targetability and then to improve the antitumor outcomes. In addition, compound 2 possessing 3-phenyl propionic acid(PPA) was also synthesized as a comparison to test the influence of the NPPA to the cytotoxicity, since PPA was not a bioreductive moiety. Bioevaluations showed that 1 displayed more potent antitumor potency than cisplatin and 2, suggesting Pt(II) complexes possessing NPPA groups may be a good strategy for future platinum drug discovery.

关键词： Platinum compounds Bioreductive Nitrophenylalkanoic group Cellular uptake Antitumor

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eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

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Journal of Molecular Cell Biology 2020年第6期12卷 403-409页

作者： Dieter AWolf Yingying Lin Haoran Duan Yabin Cheng School of pharmaceutical Sciences Fujian Provincial Key Laboratory of Innovative Drug Target Research&Innovation Center for Cell Stress SignalingXiamen UniversityXiamen 361102China

Studies over the past three years have substantially expanded the involvements of eukaryotic initiation factor 3 (eIF3) in messenger RNA (mRNA) translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination, and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and post-translational modifications.

关键词： mRNA translation translation initiation factor eIF3 protein homeostasis cancer

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Progress in pathogenesis and treatment of type A hepatic encephalopathy in acute liver failure:a comprehensive review

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Pharmacology Discovery 2024年第1期4卷 1-11页

作者： Ye-Xin Xu He Wang Kang-Rui Hu Bo-Yu Shen Lin Xie Guang-Ji Wang Yan Liang key lab of drug Metabolism&Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Hepatic encephalopathy is a serious neuropsychiatric complication caused by liver failure,which is characterized by the development of cognitive and motor disorders into ***,hepatic encephalopathy can be divided into three types(A,B,and C)according to the *** A hepatic encephalopathy(AHE)caused by acute liver failure seriously affects the prognosis of patients,ranging from mild neuropsychological changes to coma,brain edema,and even *** far,the research on the pathogenesis of AHE has focused on the toxic effects of ammonia on the central nervous system,metabolic disorders(glutamine and lactate accumulation),neurotransmission alteration,systemic inflammation,especially *** these mechanisms are not independent,but mutually have synergistic *** clinic,treatment of AHE based on only one mechanism is often *** clarify the pathogenesis and the interaction among the mechanisms will be beneficial to the effective treatment of AHE and reduce the *** aim of this review is to provide comprehensive scientific evidence for the clinical treatment of AHE via collecting and analyzing the latest mechanism of AHE,and clarifying the relationship among these mechanisms combing the investigation of the latest research progress of drug treatment of acute liver ***,we find that the pathogenesis of AHE is a complex neurocognitive disorder shaped by interactions among hyperammonemia,inflammation,and changes in neurotransmission,the signaling pathways thereby integrating the inflammatory and neurological inputs to impact pathophysiological or neurobehavioral outcomes.

关键词： type A hepatic encephalopathy ammonia glutamine lactate,inflammation,blood-brain barrier,neurotransmission

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Therapeutic applications of genetic code expansion

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Synthetic and Systems Biotechnology 2018年第3期3卷 150-158页

作者： Yujia Huang Tao Liu state key laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing100191China

In nature,a limited,conservative set of amino acids are utilized to synthesize *** code expansion technique reassigns codons and incorporates noncanonical amino acids(ncAAs)through orthogonal aminoacyltRNA synthetase(aaRS)/tRNA *** past decade has witnessed the rapid growth in diversity and scope for therapeutic applications of this ***,we provided an update on the recent progress using genetic code expansion in the following areas:antibody-drug conjugates(ADCs),bispecific antibodies(BsAb),immunotherapies,long-lasting protein therapeutics,biosynthesized peptides,engineered viruses and cells,as well as other therapeutic related applications,where the technique was used to elucidate the mechanisms of biotherapeutics and drug targets.

关键词： Genetic code expansion Noncanonical amino acids Biotherapeutics Antibody-drug conjugates Live-attenuated vaccines

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Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3134-3149页

作者： Xiaojia Liu Mingxiao Yin Jingwen Dong Genxiang Mao Wenjian Min Zean Kuang Peng Yang Lu Liu Na Zhang Hongbin Deng Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Zhejiang Provincial key lab of Geriatrics Department of GeriatricsZhejiang HospitalHangzhou 310013China state key laboratory of Natural Medicines and Jiang Su key laboratory of drug Design and Optimization China Pharmaceutical UniversityNanjing 210009China Qingdao Women and Children’s Hospital Qingdao UniversityQingdao 266034China

Programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)cascade is an effective therapeutic target for immune checkpoint blockade(ICB)*** PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor *** flow cytometry-based assay,we identify tubeimoside-1(TBM-1)as a promising antitumor immune modulator that negatively regulates PD-L1 ***-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of ***,TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma(LLC)and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell ***,TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent,autophagy-independent ***-1 selectively binds to the mammalian target of rapamycin(m TOR)kinase and suppresses the activation of m TORC1,leading to the nuclear translocation of TFEB and lysosome ***,the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells(MDSCs)and regulatory T(Treg)*** findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

关键词： PD-L1 Immune checkpoint blockade Transcription factor EB Lysosome mTOR

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NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and drug Repositioning

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Genomics, Proteomics & Bioinformatics 2021年第4期19卷 549-564页

作者： Zihu Guo Yingxue Fu Chao Huang Chunli Zheng Ziyin Wu Xuetong Chen Shuo Gao Yaohua Ma Mohamed Shahen Yan Li Pengfei Tu Jingbo Zhu Zhenzhong Wang Wei Xiao Yonghua Wang College of Life Science Northwest UniversityXi'an 710069China College of Life Science Northwest A&F UniversityYangling 712100China Zoology Department Faculty of ScienceTanta UniversityTanta 31527Egypt key laboratory of Industrial Ecology and Environmental Engineering(Ministry of Education) Faculty of ChemicalEnvironmental and Biological Science and TechnologyDalian University of TechnologyDalian 116024China state key laboratory of Natural and Biomimetic drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China School of Food Science and Technology Dalian Polytechnic UniversityDalian 116034China state key laboratory of new-tech for Chinese Medicine pharmaceutical process Lianyungang 222001China

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes(DAGs),which are important for understanding disease initiation and developing precision ***,DAGs often contain large amounts of redundant or false positive information,leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human *** this study,a networkoriented gene entropy approach(NOGEA)is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene *** addition,we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression *** genes may also be used to extract the underlying information of different diseases,thus revealing mechanisms of disease *** importantly,approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network,which provides a new way for predicting drug-disease *** this method,11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro ***,the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence,thus providing a valuable strategy for drug efficacy screening and *** codes are publicly available at https://***/guozihuaa/NOGEA.

关键词： Systems pharmacology Gene entropy Disease gene network Disease comorbidity drug repositioning

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Identification of microRNA-like RNAs in Ophiocordyceps sinensis

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Science China(Life Sciences) 2019年第3期62卷 349-356页

作者： Wen Zhang Xiaona Li Lina Ma Uzair Urrehman Xilinqiqige Bao Yujing Zhang Chen-Yu Zhang Dongxia Hou Zhen Zhou state key laboratory of pharmaceutical Biotechnology Jiangsu Engineering Research Center for microRNA Biology and Biotechnology NJU Advanced Institute for Life Sciences (NAILS) School of Life Sciences Nanjing University The drug laboratory of Mongolian Medicine and Pharmacy Institute Inner Mongolia International Mongolian Hospital

Ophiocordyceps sinensis is well known as a traditional Chinese medicine and has widely been used for over 2,000 years to stimulate immune system, decrease blood pressure and to inhibit tumor growth. While miRNAs are increasingly recognized for their roles in post-transcriptional regulation of gene expression in animals and plants, miRNAs in fungi were less studied until the discovery of microRNA-like RNA(milRNA). High-throughput sequencing and bioinformatics approaches were used to identify conserved and novel milRNAs in O. sinensis. 40 conserved milRNAs were identified, while 23 pre-miRNA candidates encoding 31 novel milRNAs were predicted. Furthermore, the potential target genes of milRNAs in human were predicted and gene ontology analysis was applied to these genes. Enrichment analysis of GO-represented biological process showed that target genes of both conserved and novel milRNAs are involved in development, metabolic and immune processes, indicating the potential roles of milRNAs of O. sinensis in pharmacological effects as health food and traditional Chinese medicine. This study is the first report on genome-wide analysis of milRNAs in O. sinensis and it provides a useful resource to further study the potential roles of milRNAs as active components of O. sinensis in health food or traditional Chinese medicine.

关键词： Ophiocordyceps sinensis O.sinensis miRNA milRNA high-throughput sequencing

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