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Discovery of the first potent proteolysis targeting chimera(PROTAC) degrader of indoleamine 2,3-dioxygenase 1

Acta Pharmaceutica Sinica B 2020年第10期10卷 1943-1953页

作者： Mingxing Hu Weilin Zhou Yijie Wang Dongping Yao Tinghong Ye Yuqin Yao Bin Chen Gongping Liu Xifei Yang Wei Wang Yongmei Xie State Key Laboratory of Biotherapy and Cancer Center Department of Laboratory MedicineWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengdu 610041China Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Innovation Center of Neuroregeneration Nantong UniversityNantong 226019China Key Laboratory of Modern Toxicology of Shenzhen Shenzhen Centre for Disease Control and PreventionShenzhen 518055China

Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.

关键词： IDO1 PROTAC Protein degradation Ubiquitin proteasome system Tumor immune escape

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Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-βpathway

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1732-1743页

作者： Xiaoxue Yang Liping Ma Rong Wei Tinghong Ye JianKang Zhou Maoyao Wen Ruoting Men Rami I.Aqeilan Yong Peng Li Yang Department of Gastroenterology&Hepatology West China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Centre West China HospitalSichuan Universityand Collaborative Innovation Centre for BiotherapyChengdu 610041China School of Bioscience and Technology Chengdu medical collegeChengdu 610500China Department of Immunology&Cancer Research Hebrew University-Hadassah Medical SchoolJerusalemIsrael

The activation of hepatic stellate cells(HSCs)participates in liver fibrosis,and emerging evidences indicate that microRNAs(miRNAs)are abnormally expressed during HSC activation.However,the potential roles of miRNAs in liver fibrosis still remain elusive.Therefore,this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism.We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro,and during liver fibrogenesis in CCl4-treated rats,and its liver expression was increased in the patients with cirrhosis.By the luciferase assay and RT-qPCR,we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-βtreatment.Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers,such as fibronectin and connective tissue growth factor(CTGF),whereas the forced expression of miR-199a-3p exhibited opposite effects,demonstrating the role of miR-199a-3p in promoting HSC activation.Mechanistically,miR-199a-3p plays an important role in TGF-βsignalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I(TGFβRI).Importantly,administration of antagomiR-199a-3p in the CCl4-treated mice significantly ameliorated hepatic fibrosis.In conclusion,Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-βpathway.Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.

关键词： Twist1 miR hepatic

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A nonenzymatic electrochemical sensor for the detection of hydrogen peroxide in vitro and in vivo fibrosis models

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Chinese Chemical Letters 2024年第3期35卷 394-398页

作者： Hongyao Liu Yan Yu Taixiong Xue Cailing Gan Yuting Xie Doudou Wang Peilin Li Zhiyong Qian Tinghong Ye Department of Gastroenterology and Hepatology Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer and Frontiers Science Center for Disease-Related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Fibrosis occurs due to the excessive deposition of extracellular matrix caused by cell injury.After various types of tissue injury,the dysregulation of the internal response can eventually lead to the destruction of organ structure and dysfunction.There is increasing evidence that oxidative stress,which is characterized by excessive production of hydrogen peroxide(H_(2)O_(2)),is an important cause of fibrosis.Therefore,we synthesized a biosensitive and efficient electrochemical H_(2)O_(2)sensor based on PtNi nanoparticle-doped N-reduced graphene oxide(PtNi-N-rGO)to detect H_(2)O_(2)released from transforming growth factorβ1(TGFβ1)-induced myofibroblast.In addition,the sensor could easily detect changes in H_(2)O_(2)in the lung and bronchoalveolar lavage fluid(BALF)of mice with pulmonary fibrosis.Furthermore,the sensor could also detect H_(2)O_(2)in activated hepatic stellate cells and the liver of carbon tetrachloride(CCl_(4))-induced liver fibrosis.Moreover,the alterations in H_(2)O_(2)detected by the sensor were consistent with nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)protein expression and the staining results of pathological sections.Taken together,these results highlight the use of H_(2)O_(2)sensors for the rapid detection of fibrosis and facilitate the rapid evaluation of antifibrotic drug candidates.

关键词： Fibrosis H_(2)O_(2) Electrochemical sensor NOX4 Nintedanib

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Tuna dark muscle peptides modulate host iron metabolism in the intestine through the gut microbiota and ameliorate iron deficiency anemia

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Food Science and Human Wellness 2024年

作者： Jiaojiao Han Jiayi Xiong Zhixiang Bai Yang Qin Chenyang Lu Jun Zhou ye Li tinghong Ming Zhen Zhang Xiurong Su State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo University School of Marine Science Ningbo University

Iron deficiency anemia (IDA) is a nutritional deficiency disease with a high incidence rate worldwide. Bioactive peptides are safe and effective， have multiple functions and can serve as potential candidates for alleviating IDA. In this study， the anti-anemia effects of tuna dark muscle peptides were explored in a diet-induced IDA mouse model. The results showed that tuna dark muscle peptides alleviated the IDA phenotype， oxidative stress and iron metabolism. In addition， tuna dark muscle peptides reversed gut microbiota dysbiosis in IDA mice. Furthermore， the transplanted fecal microbiota from tuna dark muscle peptide-treated mice also alleviated IDA symptoms and regulated iron metabolism and the gut microbiota， indicating that the anti-anemic effects were at least partially mediated by the gut microbiota. Thus， we identified a new and safe prebiotic material to alleviate IDA and provided ideas for the development of peptides. At the same time， these data also provided a theoretical basis for fecal microbiota transplantation (FMT) to alleviate IDA.

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Protective effects and microarray-based mechanism of sea cucumber hydrolysates against high-glucose induced nephrotoxicity in mouse glomerulus mesangial cells

未来食品学报(英文)

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未来食品学报(英文) 2024年第3期4卷 233-240页

作者： Lingxin Geng Jiaojiao Han Jun Zhou ye Li tinghong Ming Zhen Zhang Chenyang Lu Xiurong Su State Key Laboratory for Quality and Safety of Argo-products School of Marine ScienceNingbo UniversityNingbo 315211China

Diabetic nephropathy(DN)is a common type of end-stage renal disease and glomerular mesangial cells(GMCs)are widely used as a cell model for DN.This study firstly investigated the inhibitory effects of the Apostichopus japonicus and Acaudina leucoprocta hydrolysates on cellular growth under high-glucose treatment,better inhibitory effect of A.japonicus hydrolysate was observed compared to that of A.leucoprocta hydrolysate.Subsequently,the global transcription profiles obtained via microarray analysis showed that 6070 and 7015 genes were identified in the A.japonicus and A.leucoprocta groups compared with the model group,respectively.Among them,transcriptions of the slc30a4,slc35dl,tppp3,tp53inpl,bcl-2,apafl,alox12b and adrala genes were restored from the levels of the model group to those of the control group,contributed to cell mitosis and proliferation in both treatment groups.In addition,other apoptosis-related genes,such as bcl-6,clu,foxo3 and akt,showed opposite trends between two groups,which might cause the difference in inhibitory effect.We preliminarily proposed that the regulation effects of A.japonicus and A.leucoprocta on the genes involved in cellular mitosis,proliferation and apoptosis,might contribute to their inhibitory activity on GMCs under high-glucose environment.

关键词： Diabetic nephropathy Apostichopus japonicus Acaudina leucoprocta Hydrolysate Rat mesangial cell Microarray

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Rosa roxburghii tratt juice ameliorated lung fibrosis by inhibiting inflammatory infiltration and epithelial-mesenchymal transition

Rosa roxburghii tratt juice ameliorated lung fibrosis by inh...

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健康中国·烹饪营养·产业创新——2019健康中国与食品营养产业发展论坛暨四川省营养学会、四川省食品科学技术学会学术年会

作者： Liqun Wang Sha Li Yali Li Qianyu Zhang Li Tian Yuanle Deng Wenya Yin Tinghong Ye West China School of Public Health and Healthy Food Evaluation Research Center and West China Fourth Hospital Sichuan University State Key Laboratory of Biotherapy Sichuan University

Background:Pulmonary fibrosis (PF) is a clinical manifestation of chronic lung injury to the end stage.Due to the deterioration of the environment and the accelerated of aging population,pulmonary

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抗A型流感病毒聚合酶碱性蛋白1多克隆抗体的制备和鉴定

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生物工程学报 2016年第1期32卷 105-113页

作者：秦玉洁张廷虹叶昕中国科学院微生物研究所北京100101

流感病毒属于正黏病毒科,为有包膜包裹的单股负链RNA病毒。它的8个基因片段编码至少16种病毒蛋白,其中3个蛋白组成流感病毒的聚合酶复合体。流感病毒聚合酶碱性蛋白1(PB1)是该复合体的组分之一,在病毒的转录、复制及重配中发挥重要的作... 详细信息

流感病毒属于正黏病毒科,为有包膜包裹的单股负链RNA病毒。它的8个基因片段编码至少16种病毒蛋白,其中3个蛋白组成流感病毒的聚合酶复合体。流感病毒聚合酶碱性蛋白1(PB1)是该复合体的组分之一,在病毒的转录、复制及重配中发挥重要的作用。为研究其功能,构建His-PB1(aa 550–755)融合蛋白原核表达质粒,IPTG诱导融合蛋白表达,通过镍柱亲和将其纯化,然后作为抗原免疫家兔。对抗血清进行间接ELISA检测,表明抗体效价可达1∶100 000。兔源PB1蛋白抗血清经亲和纯化后,用于免疫印迹检测流感病毒WSN毒株PB1蛋白以及外源转染的FLAG-PB1蛋白,结果表明该PB1抗体具有良好的特异性,同时也能特异性识别其他亚型的A型流感病毒的PB1蛋白,为进一步研究流感病毒PB1蛋白的功能奠定了基础。

关键词：流感病毒 PB1 多克隆抗体亲和纯化

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Modulation of gut microbiota and serum metabolome by Apostichopus japonicus derived oligopeptide in high-fructose diet-induced hyperuricemia in mice

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Food Science and Human Wellness 2024年

作者： Jun Zhou Ziyan Wang Zhixuan Zhang Jiaojiao Han Ying Feng Jing Zhang Zhen Zhang ye Li tinghong Ming Chenyang Lu Rixin Wang Xiurong Su School of Marine Science Ningbo University Faculty of Food Science Zhejiang Pharmaceutical College Key Laboratory of Aquacultural Biotechnology Ministry of Education Ningbo University College of Life Sciences Tonghua Normal University State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo University

Fructose consumption has risen dramatically in recent decades due to the use of sucrose and high fructose corn syrup in beverages and processed foods， contributing to rising rates of hyperuricemia. The purpose of this experiment was to explore the anti-hyperuricemia effects of an active oligopeptide (GPSGRP) derived from sea cucumber in fructose induced hyperuricemia mouse model， and to clarify the underlying mechanism in sight of gut microbiota and serum metabolites. Peptide GPSGRP treatment rebalanced uric acid metabolism and alleviated inflammatory response in mice. In addition， treatment with GPSGRP decreased the abundance of Bacteroides and Proteobacteria at the phylum level， Muribaculum， Prevotella and Bacteroides at the genus level， and inhibited the related pathways of purine metabolism and glycolysis/gluconeogenesis metabolism. Moreover， serum metabolites， including linoleic acid， indole and its derivatives， arachidonic acid and uridine， as well as related metabolic pathways， such as tricarboxylic acid cycle， ketone production and sugar production， were altered in response to GPSGRP treatment. This study provides a valuable reference for the application and development of marine biological peptides in uric acid management.

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绿色建筑理念在工程设计中的融合应用

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建设科技 2022年第17期 30-32页

作者：朱伟波叶铤洪浙江省城乡规划设计研究院杭州310030

绿色、低碳、环保是当前我国建筑业发展的主要方向。在建筑工程设计中,要充分落实绿色建筑理念,并将节能、低碳融合到工程建设的各个环节当中,促进建筑行业的可持续发展。本文就当下在建筑工程设计中该如何践行绿色建筑设计理念进行分析... 详细信息

绿色、低碳、环保是当前我国建筑业发展的主要方向。在建筑工程设计中,要充分落实绿色建筑理念,并将节能、低碳融合到工程建设的各个环节当中,促进建筑行业的可持续发展。本文就当下在建筑工程设计中该如何践行绿色建筑设计理念进行分析,为提升建筑工程设计水平提供参考与借鉴。

关键词：建筑设计绿色建筑设计理念整合与应用

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Targeting fibrosis: mechanisms and clinical trials

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2469-2489页

作者： Manyu Zhao Liqun Wang Mengzhu Wang Shijie Zhou Ying Lu Huijie Cui Alexandra C.Racanelli Ling Zhang Tinghong Ye Bisen Ding Ben Zhang Jinliang Yang Yuqin Yao West China School of Public Health and West China Fourth Hospital Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Division of Pulmonary and Critical Care Medicine Joan and Sanford I.Weill Department of MedicineWeill Cornell MedicineNew YorkNY 10021USA NewYork-Presbyterian Hospital Weill Cornell MedicineNew YorkNY 10021USA College of Polymer Science and Engineering Sichuan universityChengdu 610000China Key Laboratory of Birth Defects of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu 610041China

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response.Multiple organs can develop fibrosis,including the liver,kidney,heart,and lung.Fibrosis such as liver cirrhosis,idiopathic pulmonary fibrosis,and cystic fibrosis caused substantial disease burden.Persistent abnormal activation of myofibroblasts mediated by various signals,such as transforming growth factor,platelet-derived growth factor,and fibroblast growh factor,has been recongized as a major event in the occurrence and progression of fibrosis.Although the mechanisms driving organ-specific fibrosis have not been fully elucidated,drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials.In this review,we briefly introduce the aetiology and epidemiology of several fibrosis diseases,including liver fibrosis,kidney fibrosis,cardiac fibrosis,and pulmonary fibrosis.Then,we summarise the abnormal cells(epithelial cells,endothelial cells,immune cells,and fibroblasts)and their interactions in fibrosis.In addition,we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation,extracellular matrix cross-linking,metabolism,and inflammation in fibrosis.Finally,we discuss the anti-fibrotic drugs based on their targets and clinical trials.This review provides reference for further research on fibrosis mechanism,drug development,and clinical trials.

关键词： drugs epidemiology organs

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