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Signal Transduction and Targeted Therapy 2022年第5期7卷 1746-1755页

作者： Wei Deng Qi Lv Fengdi Li Jiangning Liu Zhiqi Song Feifei Qi Qiang Wei Pin Yu Mingya Liu Shasha Zhou Yaqing Zhang Hong Gao Nan Wang Zijing Jia Kai Gao Jiayi Liu Chong Xiao Haiquan Shang Xiangxi Wang Linlin Bao Chuan Qin beijing key laboratory for animal models of emerging and Remerging infectious diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing 100021China National Center of Technology Innovation for animal Model BeijingChina CAS key laboratory of Infection and Immunity National Laboratory of MacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of Radiology Beijing Anzhen HospitalCapital Medical UniversityBeijingChina

Variants of concern(VOCs)like Delta and Omicron,harbor a high number of mutations,which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies(NAbs).In this study,Rhesus macaques immunized with 2-dose inactivated vaccines(Coronavac)were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine,or a bivalent inactivated vaccine(Beta and Delta)to determine the effectiveness of sequential immunization.The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type.

关键词： neutral harbor Omi

Integrated histopathological,lipidomic,and metabolomic profiles reveal mink is a useful animal model to mimic the pathogenicity of severe COVID-19 patients

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Signal Transduction and Targeted Therapy 2022年第2期7卷 560-572页

作者： Zhiqi Song Linlin Bao Wei Deng Jiangning Liu Erjun Ren Qi Lv Mingya Liu Feifei Qi Ting Chen Ran Deng Fengdi Li Yunpeng Liu Qiang Wei Hong Gao Pin Yu Yunlin Han Wenjie Zhao Junjun Zheng Xujian Liang Fuhe Yang Chuan Qin NHC key laboratory of Human Disease Comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina Shi Jia Zhuang Academy Of Agricultural And Forestry Sciences ShijiazhuangChina Institute of Special animal and Plant Sciences of CAAS ChangchunChina Chinese Academy of Agricultural Sciences(CAAS) BeijingChina

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is transmitted on mink farms between minks and humans in many countries.However,the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown.Here,we demonstrated that minks were largely permissive to SARS-CoV-2,characterized by severe and diffuse alveolar damage,and lasted at least 14 days post inoculation(dpi).We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular,hepatobiliary,urinary,endocrine,digestive,and immune systems.The viral protein partially co-localized with activated Mac-2+macrophages throughout the body.Moreover,we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks,especially at 6 dpi,and were similar to that of patients with severe and fatal COVID-19.Particularly,altered metabolic pathways,abnormal digestion,and absorption of vitamins,lipids,cholesterol,steroids,amino acids,and proteins,consistent with hepatic dysfunction,highlight metabolic and immune dysregulation.Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation.Melatonin,which has significant anti-inflammatory and immunomodulating effects,was significantly downregulated at 6 dpi and displayed potential as a targeted medicine.Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients,delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies,vaccine research,and potential biomarkers.

关键词： patients alterations vitamin

Era of the 4D animal model

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animal models and Experimental Medicine 2023年第2期6卷 178-182页

作者： Lihong Zhang Jindan Guo Jiangning Liu NHC key laboratory of Human Disease Comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina

Revealing the entire dynamics of pathogenesis is critical for understanding,preventing and treating human disease but is limited by systematic clinical sampling.This drawback can be overcome with animal model studies.Recent advances in phenotyping,omics and bioinformatics technologies promote the development of the 4D animal model to simulate and digitally display the spatiotemporal landscapes of phenotypes and molecular dynamics in human diseases and reveal novel targets for diagnosis and therapy.In this commentary,the origin,supporting technologies,content,function and application,and advantages of 4D animal models over clinical studies and traditional animal models,as well as their limitations,are presented.

关键词： animal model database digitally display human diseases spatiotemporal landscapes

A broadly neutralizing human monoclonal antibody against the hemagglutinin of avian influenza virus H7N9

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Chinese Medical Journal 2022年第7期135卷 799-805页

作者： Jingxin Li Li Zhang Linlin Bao Yuxiao Wang Lin Qiu Jialei Hu Rong Tang Huiyan Yu Jun Shan Yan Li Chuan Qin Fengcai Zhu Department for Vaccine Clinical Evaluation NHC Key Laboratory of Enteric Pathogenic MicrobiologyJlangsu Provincial Center for Diseases Control and PreventionNanjingJiangsu 210009China Institute of laboratory animal Science Chinese Academy of Medical Sciences(CAMS)&Comparative Medicine CenterPeking Union Medical Collage(PUMC)Key Laboratory of Human Disease Comparative MedicineMinistry of HealthBeijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesBeijing 100101China Department of Public Health Southeast UniversityNanjingJiangsu 210009China Shanghai Institute for Biological Sciences Chinese Academy of SciencesShanghai 200031China

Background:The new emerging avian influenza A H7N9 virus,causing severe human infection with a mortality rate of around 41%.This study aims to provide a novel treatment option for the prevention and control of H7N9.Methods:H7 hemagglutinin(HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province,China.The human monoclonal antibodies(mAbs)were generated by amplification and cloning of these HA-specific B cells.First,all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay.Then,those mAbs,exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting(HAI)and microneutralizationin vitro assays.Finally,the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models.Results:The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes,including H1N1 and H3N2.The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50(TCID_(50))of H7N9 virus(influenza A/Nanjing/1/2013)invitro,with neutralizing activity as low as 78 ng/mL.In addition,the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically.Conclusion:The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.

关键词： Avian influenza H7N9 Monoclonal antibody Neutralizing activity

Differences of core genes in liver fibrosis and hepatocellular carcinoma:Evidence from integrated bioinformatics and immunohistochemical analysis

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World Journal of Gastrointestinal Oncology 2022年第7期14卷 1265-1280页

作者： Yue Li Shou-Li Yuan Jing-Ya Yin Kun Yang Xin-Gang Zhou Wen Xie Qi Wang Department of Pathology Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China beijing key laboratory of emerging infectious diseases Beijing 100015China key laboratory of animal Ecology and Conservation Biology Institute of ZoologyBeijing 100101China Center of Liver diseases Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

BACKGROUND Liver fibrosis and hepatocellular carcinoma(HCC)are common adverse consequences of chronic liver injury.The interaction of various risk factors may cause them to happen.Identification of specific biomarkers is of great significance for understanding the occurrence,development mechanisms,and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.AIM To identify liver fibrosis-related core genes,we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.METHODS Gene expression profiles of three datasets,GSE14323,GSE36411,and GSE89377,obtained from the Gene Expression Omnibus(GEO)database,were analyzed,and differentially expressed genes(DEGs)between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams.The WebGestalt online tool was used to identify DEGs enriched in biological processes,molecular functions,cellular components,and Kyoto Encyclopedia of Genes and Genomes pathways.The protein–protein interactions of DEGs were visualized using Cytoscape with STRING.Next,the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride(CCl_(4))-induced liver cirrhosis mouse model and in patient liver samples.Finally,Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.RESULTS Forty-five DEGs(43 upregulated and 2 downregulated genes)associated with liver cirrhosis were identified from three GEO datasets.Ten hub genes were identified,which were upregulated in liver cirrhosis.Western blot and immunohistochemical analyses of the three core genes,decorin(DCN),dermatopontin(DPT),and SRY-box transcription factor 9(SOX9),revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model.The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis,and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients.However

关键词： Liver cirrhosis Hepatocellular carcinoma Bioinformatical analysis Decorin Dermatopontin SRY-box transcription factor 9

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

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Acta Pharmaceutica Sinica B 2024年第1期14卷 319-334页

作者： Ying Qin Dekang Li Chunting Qi Huaijiang Xiang Huyan Meng Jingli Liu Shaoqing Zhou Xinyu Gong Ying Li Guifang Xu Rui Zu Hang Xie Yechun Xu Gang Xu Zheng Zhang Shi Chen Lifeng Pan Ying Li Li Tan Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 201210China University of Chinese Academy of Sciences Beijing 100049China State key laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China State key laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Institute of Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People’s Hospitalthe Second Affiliated HospitalSchool of MedicineSouthern University of Science and TechnologyShenzhen 518112China Department of Burn and Plastic Surgery Shenzhen Institute of Translational MedicineShenzhen University Medical SchoolShenzhen Second People’s Hospitalthe First Affiliated Hospital of Shenzhen UniversityShenzhen 518035China

Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

关键词： RIPK1 Necroptosis Type-II kinase inhibitors Rational design Lead optimization Structure‒activity relationship Anti-inflammation Preclinical drug discovery

sRAGE alleviates SARS-CoV-2-induced pneumonia in hamster

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Signal Transduction and Targeted Therapy 2022年第3期7卷 610-612页

作者： Xiuqin Zhang Dan Li Rui Sun Xinli Hu Zhiqi Song Xiaotian Ni Hua Zhu Tiannan Guo Chuan Qin Rui-Ping Xiao Institute of Molecular Medicine College of Future TechnologyPeking UniversityBeijingChino key laboratory of Human Disease Comparative Medicine of National Health Commission of the People’s Republic of China Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina Westlake laboratory of Life Sciences and Biomedicine Key Laboratory of Structural Biology of Zhejiang ProvinceSchool of Life SciencesWestlake UniversityHangzhouChina

Dear Editor Since last year,the most demanding task of the global pharmaceutical community has been focused on the development of strategies to treat coronavirus disease 2019(COVID-19).To date,several vaccines have been developed and already demonstrated their efficacy in reducing the incidence of COVID-19.1 However,the development of drugs treating COVID-19 is lagging far behind,and all the current treatment regimens have their limitations.

关键词： drugs regimen pneumonia

Neurotrophins and neural stem cells in posttraumatic brain injury repair

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animal models and Experimental Medicine 2024年第1期7卷 12-23页

作者： Wenwen Guo Ke Liu Yinghua Wang Xu Ge Yifan Ma Jing Qin Caiqin Zhang Ya Zhao Changhong Shi laboratory animal Center Fourth Military Medical UniversityXi'anP.R.China Gansu University of Traditional Chinese Medicine LanzhouP.R.China Medical College of Yan'an University Yan'anP.R.China

Traumatic brain injury(TBI)is the main cause of disability,mental health disorder,and even death,with its incidence and social costs rising steadily.Although different treatment strategies have been developed and tested to mitigate neurological decline,a definitive cure for these conditions remains elusive.Studies have revealed that vari-ous neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation,apoptosis,blood-brain barrier permeability,neurite regeneration,and memory function.These factors are instrumental in alleviating neu-roinflammation and promoting neuroregeneration.In addition,neural stem cells(NSC)contribute to nerve repair through inherent neuroprotective and immunomodulatory properties,the release of neurotrophins,the activation of endogenous NSCs,and in-tercellular signaling.Notably,innovative research proposals are emerging to combine BDNF and NSCs,enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI.In this review,we summarize the mechanism of neurotrophins in promoting neurogen-esis and restoring neural function after TBI,comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI,and investigate their interaction with NSCs.This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI,thereby promoting the progress of TBI therapeutics.

关键词： mutual effect neural stem cells neurological function neurotrophins traumatic brain injury

Effectiveness and mechanisms of adiposederived stem cell therapy in animal models of Parkinson’s disease:a systematic review and meta-analysis

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Translational Neurodegeneration 2021年第2期10卷 166-177页

作者： keya Li Xinyue Li Guiying Shi Xuepei Lei Yiying Huang Lin Bai Chuan Qin NHC key laboratory of Human Disease Comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing 100021China

animal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells(ADSCs).Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease(PD).Here,eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention.Quality assessment was conducted using a 10-item risk of bias tool.For the subsequent meta-analysis,study characteristics were extracted and effect sizes were computed.Ten out of 2324 published articles(n=169 animals)were selected for further meta-analysis.After ADSC therapy,the rotation behavior(10 experiments,n=156 animals)and rotarod performance(3 experiments,n=54 animals)were improved(Panimal models of PD.The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects.The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.

关键词： Parkinson’s disease Adipose-derived stem cells animal model Stem cell therapy Meta-analysis Neurogenesis Neuroprotection

SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterolincreased endosomal pH of alveolar macrophages

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Cellular & Molecular Immunology 2022年第2期19卷 210-221页

作者： Zhenfeng Wang Jiadi Lv Pin Yu Yajin Qu Yabo Zhou Li Zhou Qiangqiang Zhu Shunshun Li Jiangping Song Wei Deng Ran Gao Yuying Liu Jiangning Liu Wei-Min Tong Chuan Qin Bo Huang Department of Immunology&National key laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences(CAMS)&Peking Union Medical CollegeBeijing 100005China NHC key laboratory of Human Disease Comparative Medicine Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious DiseasesInstitute of Laboratory Animal ScienceCAMS and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina State key laboratory of Cardiovascular Disease Fuwai HospitalNational Center for Cardiovascular DiseasesCAMS and Peking Union Medical CollegeBeijingChina Department of Pathology Institute of Basic Medical SciencesCAMS and Peking Union Medical CollegeBeijingChina Department of Biochemistry&Molecular Biology Tongji Medical CollegeHuazhong University of Science&TechnologyWuhan 430030China

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against SARS-CoV-2 infection.Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation.This pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal acidification.In addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects.These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

关键词： SARS-CoV-2 microparticles Alveolar macrophages Endosomes Lysosomes