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Unraveling the complex roles of macrophages in obese adipose tissue:an overview

Frontiers of Medicine 2024年第2期18卷 205-236页

作者： Chang Peng Jun Chen Rui Wu Haowen Jiang Jia Li Hangzhou Institute for Advanced Study University of Chinese Academy of SciencesHangzhou310000China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China University of Chinese Academy of Sciences Beijing100049China Department of Prosthodontics Shanghai Engineering Research Center of Advanced Dental Technology and MaterialsShanghai Key Laboratory of Stomatology&Shanghai Research Institute of StomatologyNational Clinical Research Center for Oral DiseasesShanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai200011China

Macrophages,a heterogeneous population of innate immune cells,exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases.The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects,inducing insulin resistance through increased inflammation,impaired thermogenesis,and adipose tissue fibrosis.Meanwhile,adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis,facilitating the clearance of dead adipocytes,and promoting mitochondrial transfer.Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions.Recently,the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology.In this review,we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity,as well as explore the potential of drug delivery systems targeting macrophages,aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.

关键词： obesity inflammation adipose tissue macrophages adipose tissue homeostasis

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Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders

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Science China(Life Sciences) 2024年第6期67卷 1170-1182页

作者： Jiaming Liu Liangkui Li Dijin Xu Yuqi Li Tao Chen Yeyang Liu Yuqian Bao Yan Wang Longyan Yang Peng Li Li Xu State Key laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences Beijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijing 100084China Shanghai Qi Zhi Institute Shanghai 200232China Shanghai Key laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Tianjian laboratory of Advanced Biomedical Sciences Zhengzhou UniversityZhengzhou 450001China Department of Physiology School of Basic Medical SciencesGannan Medical UniversityGanzhou 341000China Department of Endocrinology and Metabolism Shanghai Jiao Tong University School of Medicine Affiliated Sixth People’s HospitalShanghai 200025China Center for Endocrine Metabolism and Immune Diseases Beijing Luhe HospitalCapital Medical UniversityBeijing 101149China Beijing Key laboratory of Diabetes Research and Care Beijing 101149China

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders.These people store fat in subcutaneous adipose tissue(SAT)rather than in visceral adipose tissue(VAT).However,the molecules participating in this specific scenario remain elusive.Rab18,a lipid droplet(LD)-associated protein,mediates the contact between the endoplasmic reticulum(ER)and LDs to facilitate LD growth and maturation.In the present study,we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice.Rab18 adipocyte-specific knockout(Rab18 AKO)mice had a decreased volume ratio of SAT to VAT compared with wildtype mice.When subjected to high-fat diet(HFD),Rab18 AKO mice had increased ER stress and inflammation,reduced adiponectin,and decreased triacylglycerol(TAG)accumulation in SAT.In contrast,TAG accumulation in VAT,brown adipose tissue(BAT)or liver of Rab18AKO mice had a moderate increase without ER stress stimulation.Rab18 AKO mice developed insulin resistance and systematic inflammation.Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT,similar to the counterpart mice.Furthermore,Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress,indicating the involvement of Rab18 in alleviating lipid toxicity.Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT.In conclusion,our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

关键词： Rab18 subcutaneous adipose tissue(SAT) metabolically healthy obesity(MHO) lipotoxicity ER stress ectopic lipid storage LD-ER contact

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Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 623-634页

作者： Jiacheng Xiong Rongrong Cui Zhaojun Li Wei Zhang Runze Zhang Zunyun Fu Xiaohong Liu Zhenghao Li Kaixian Chen Mingyue Zheng Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215000China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and TechnologyShanghaiTech UniversityShanghai 200031China State Key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics.AOX-mediated metabolism can result in unexpected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely available at https://***.

关键词： Drugmetabolism Aldehyde oxidase Transferlearning Graph neural network Kinase inhibitor

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αExtractor: a system for automatic extraction of chemical information from biomedical literature

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Science China(Life Sciences) 2024年第3期67卷 618-621页

作者： Jiacheng Xiong Xiaohong Liu Zhaojun Li Hongzhong Xiao Guangchao Wang Zhenjiang Niu Chaoyuan Fei Feisheng Zhong Gang Wang Wei Zhang Zunyun Fu Zhiguo Liu Kaixian Chen Hualiang Jiang Mingyue Zheng Drug Discovery and Design Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China AI Department Suzhou Alphama Biotechnology Co.Ltd.Suzhou 215125China College of Computer and Information Engineering Dezhou UniversityDezhou 253023China

Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.

关键词： has such knowledge

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Probing the dynamic thermodynamic resolution and biological activity of Cu(Ⅱ) and Pd(Ⅱ) complexes with Schiff base ligand derived from proline

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Chinese Chemical Letters 2024年第4期35卷 99-105页

作者： Tao Yu Vadim A.Soloshonok Zhekai Xiao Hong Liu Jiang Wang State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmacy University of Chinese Academy of SciencesBeijing 100049China Department of Organic Chemistry Ⅰ Faculty of ChemistryUniversity of the Basque Country UPV/EHUSan Sebastian 20018Spain IKERBASQUE Basque Foundation for ScienceBilbao 48013Spain School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China lingang laboratory Shanghai 200031China

Schiff base metal complexes are of great importance in pharmaceutical science owing to their unique chemical properties, which enable them to exhibit diverse biological activities such as anti-bacterial,anti-oxidant, anti-inflammatory, and anti-tumor properties. Furthermore, Schiff base metal complexes can serve as reagents and catalysts in chemical reactions. This review aims to provide an overview of our recently published studies on Cu(Ⅱ) and Pd(Ⅱ) complexes derived from proline Schiff base ligands. We also discuss the potential applications of these metal complexes in the fields of antibacterial and chiral resolution.

关键词： Schiff bases Biological activity Tailor-made amino acids Asymmetric synthesis Chiral tridentate ligands Square-planar Cu(Ⅱ)-complexes Square-planar Pd(Ⅱ)-complexes

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Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A2A adenosine receptors and histone deacetylases

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Chinese Chemical Letters 2024年第1期35卷 295-299页

作者： Ruiquan Liu Wenwen Duan Wenzhong Yan Jinfeng Zhang Jianjun Cheng iHuman Institute ShanghaiTech UniversityShanghai 201210China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

The A_(2A)adenosine receptor(A_(2A)AR)has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical trials.However,A_(2A)AR antagonists show limited efficacy as monotherapies.Herein,we communicate our design and synthesis of a novel series of A_(2A)AR/histone deacetylase(HDAC)bifunctional inhibitors,based on the core structure of the A_(2A)AR antagonist The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine core.The binding affinity for A_(2A)AR and inhibitory activity against HDACs of all the new compounds were tested.A number of compounds exhibited nanomolar or subnanomolar activity against both targets and some showed equally potent antiproliferative activity against MC38,CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in vitro.The binding poses of compound 5a in both A_(2A)AR and HDAC1 were predicted by molecular docking studies.Collectively,these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A_(2A)AR/HDAC dual-acting compounds as novel antitumor agents.

关键词： Bifunctional A_(2A)AR antagonism HDAC inhibition Cancer Immunotherapy

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A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

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Cancer Communications 2024年第3期44卷 438-442页

作者： Yingqiang Liu Linjiang Tong Mengge Zhang Qi Zhang Qiupei Liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie Division of Antitumor Pharmacology&State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China University of Chinese Academy of Sciences BeijingP.R.China Department of Chemical and Environmental Engineering University of Nottingham Ningbo ChinaNingboZhejiangP.R.China Zhongshan Institute for Drug Discovery Shanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP.R.China Shandong laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantaiShandongP.R.China Small-Molecule Drug Research Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiP.R.China

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

关键词： alterations KRAS sarcoma

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Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu Drug Discovery and Design Center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key laboratory of Medical Molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research Center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

关键词： calpain overcome entrance

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Genetic Approaches for Neural Circuits Dissection in Non-human Primates

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Neuroscience Bulletin 2023年第10期39卷 1561-1576页

作者： Ling Li Zhen Liu Institute of Neuroscience CAS Center for Excellence in Brain Science and Intelligence TechnologyCAS Key Laboratory of Primate NeurobiologyState Key Laboratory of NeuroscienceChinese Academy of SciencesShanghai 200031China Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology Shanghai 200031China University of Chinese Academy of Sciences Beijing 100049China

Genetic tools,which can be used for the morphology study of specific neurons,pathway-selective connectome mapping,neuronal activity monitoring,and manipulation with a spatiotemporal resolution,have been widely applied to the understanding of complex neural circuit formation,interactions,and functions in rodents.Recently,similar genetic approaches have been tried in non-human primates(NHPs)in neuroscience studies for dissecting the neural circuits involved in sophisticated behaviors and clinical brain disorders,although they are still very preliminary.In this review,we introduce the progress made in the development and application of genetic tools for brain studies on NHPs.We also discuss the advantages and limitations of each approach and provide a perspective for using genetic tools to study the neural circuits of NHPs.

关键词： Genetic tool Neural circuit Non-human primate

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Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4918-4933页

作者： Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou lingang laboratory Shanghai 200031China State Key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Drug Discovery&Development Center Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Shandong laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug DiscoveryYantai 264117China School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China

a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

关键词： Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide

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