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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian Chen Huimin Liu Xiulian Miao Yan Guo Zhiwen Fan Jie Li Yong Xu Zilong Li State key laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of infectious diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and infectious diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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Cinobufotalin prevents bone loss induced by ovariectomy in mice through the BMPs/SMAD and Wnt/β-catenin signaling pathways

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animal models and Experimental Medicine 2024年第3期7卷 208-221页

作者： Da-zhuang Lu Li-jun Zeng Yang Li Ran-li Gu Meng-long Hu Ping Zhang Peng Yu Xiao Zhang Zheng-wei Xie Hao Liu Yong-sheng Zhou Department of Prosthodontics Peking University School and Hospital of StomatologyBeijingChina National Center of Stomatology BeijingChina National Clinical Research Center for Oral diseases BeijingChina beijing key laboratory of Digital Stomatology BeijingChina Department of Cariology and Endodontology Peking University School and Hospital of StomatologyBeijingChina Peking University International Cancer Institute Peking University Health Science CenterPeking UniversityBeijingChina Central laboratory Peking University School and Hospital of StomatologyBeijingChina National Engineering Research Center of Oral Biomaterials and Digital Medical Devices BeijingChina

Background:Osteoporosis is a chronic bone disease characterized by bone loss and decreased bone strength.However,current anti-resorptive drugs carry a risk of various complications.The deep learning-based efficacy prediction system(DLEPS)is a forecasting tool that can effectively compete in drug screening and prediction based on gene expression changes.This study aimed to explore the protective effect and potential mechanisms of cinobufotalin(CB),a traditional Chinese medicine(TCM),on bone loss.Methods:DLEPS was employed for screening anti-osteoporotic agents according to gene profile changes in primary osteoporosis.Micro-CT,histological and morphological analysis were applied for the bone protective detection of CB,and the osteogenic differentiation/function in human bone marrow mesenchymal stem cells(hBMMSCs)were also investigated.The underlying mechanism was verified using qRT-PCR,Western blot(WB),immunofluorescence(IF),etc.Results:A safe concentration(0.25mg/kg in vivo,0.05μM in vitro)of CB could effectively preserve bone mass in estrogen deficiency-induced bone loss and promote osteogenic differentiation/function of hBMMSCs.Both BMPs/SMAD and Wnt/β-catenin signaling pathways participated in CB-induced osteogenic differentiation,further regulating the expression of osteogenesis-associated factors,and ultimately promoting osteogenesis.Conclusion:Our study demonstrated that CB could significantly reverse estrogen deficiency-induced bone loss,further promoting osteogenic differentiation/function of hBMMSCs,with BMPs/SMAD and Wnt/β-catenin signaling pathways involved.

关键词： BMPs/SMAD bone loss cinobufotalin hBMMSCs osteogenesis osteoporosis Wnt/β-catenin signaling pathways

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Integrating host biological and ecological variables to predict probability of haemosporidian infection in raptors

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Avian Research 2024年第2期15卷 255-264页

作者： Kai Gao Xuemei Yang Xi Huang Wenhong Deng Ministry of Education key laboratory for Biodiversity Science and Ecological Engineering College of Life SciencesBeijing Normal UniversityBeijing100875China

Variations in host traits that influence their exposure and susceptibility may impact probability of vector-transmitted diseases.Therefore,identifying the predictors of infection probability is necessary to understand the risk of disease outbreaks during expanding environmental perturbation.Here,we conducted a large survey based on microscopic examination and molecular analysis of haemosporidian parasite infection in raptors rescued at the beijing Raptor Rescue Centre.Combining these data with biological and ecological variables of the raptors,we determined predictors that affect the probability of haemosporidian infection using generalized linear mixed models and multimodel inference.Our results showed that infection probability exhibited considerable variation across host species in raptors,and body mass,sex,and evolutionary history played relatively weaker roles in driving infection probability.Instead,activity pattern,age,geographic range size,migration distance,and nest type were important predictors of the probability of haemosporidian infection,and the role of each predictor differed in the three main haemosporidian genera(Plasmodium,Haemoproteus,and Leucocytozoon).This macro-ecological analysis will add to our understanding of host traits that influence the probability of avian haemosporidian infection and will help inform risk of emerging diseases.

关键词： Activity pattern emerging infectious diseases Infection probability Interspecific variation Migratory exposure

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Coxsackievirus B3 HFMD animal models in Syrian hamster and rhesus monkey

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Virologica Sinica 2024年第2期39卷 290-300页

作者： Suqin Duan Wei Zhang Yongjie Li Yanyan Li Yuan Zhao Weihua Jin Quan Liu Mingxue Li Wenting Sun Lixiong Chen Hongjie Xu Jie Tang Jinghan Hou Zijun Deng Fengmei Yang Shaohui Ma Zhanlong He Institute of Medical Biology Chinese Academy of Medical Sciences Medical Primate Research Center Peking Union Medical CollegeYunnan Key Laboratory of Vaccine Research Development on Severe Infectious DiseaseKunming650118China

Coxsackievirus B3(CVB3)is the pathogen causing hand,foot and mouth disease(HFMD),which manifests across a spectrum of clinical severity from mild to severe.However,CVB3-infected mouse models mainly demonstrate viral myocarditis and pancreatitis,failing to replicate human HFMD symptoms.Although several enteroviruses have been evaluated in Syrian hamsters and rhesus monkeys,there is no comprehensive data on CVB3.In this study,we have first tested the susceptibility of Syrian hamsters to CVB3 infection via different routes.The results showed that Syrian hamsters were successfully infected with CVB3 by intraperitoneal injection or nasal drip,leading to nasopharyngeal colonization,acute severe pathological injury,and typical HFMD symptoms.Notably,the nasal drip group exhibited a longer viral excretion cycle and more severe pathological damage.In the subsequent study,rhesus monkeys infected with CVB3 through nasal drips also presented signs of HFMD symptoms,viral excretion,serum antibody conversion,viral nucleic acids and antigens,and the specific organ damages,particularly in the heart.Surprisingly,there were no significant differences in myocardial enzyme levels,and the clinical symptoms resembled those often associated with common,mild infections.In summary,the study successfully developed severe Syrian hamsters and mild rhesus monkey models for CVB3-induced HFMD.These models could serve as a basis for understanding the disease pathogenesis,conducting pre-trial prevention and evaluation,and implementing post-exposure intervention.

关键词： Coxsackievirus B3(CVB3) Hand foot and mouth disease(HFMD) animal models Syrian hamster Rhesus monkey

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Comparison of the replication and neutralization of different SARS-CoV-2 Omicron subvariants in vitro

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animal models and Experimental Medicine 2023年第1期6卷 51-56页

作者： Yaqing Zhang Qi Lv Feifei Qi Fengdi Li Ran Deng Xujian Liang Mingya Liu Yiwei Yan Linlin Bao beijing key laboratory for animal models of emerging and reemerging infectious diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina National Center of Technology Innovation for animal Model BeijingChina

Background:New Omicron subvariants are emerging rapidly from BA.1 to BA.4 and BA.5.Their pathogenicity has changed from that of wild-type(WH-09)and Omicron variants have over time become globally dominant.The spike proteins of BA.4 and BA.5 that serve as the target for vaccine-induced neutralizing antibodies have also changed compared to the previous subvariants,which is likely to cause immune es-cape and the reduction of the protective effect of the vaccine.Our study addresses the above issues and provides a basis for formulating relevant prevention and control strategies.Methods:We collected cellular supernatant and cell lysates and measured the viral titers,viral RNA loads,and E subgenomic RNA(E sgRNA)loads in different Omicron subvariants grown in Vero E6 cells,using WH-09 and Delta variants as a reference.Additionally,we evaluated the in vitro neutralizing activity of different Omicron sub-variants and compared it to the WH-09 and Delta variants using macaque sera with different types of immunity.Results:As the SARS-CoV-2 evolved into Omicron BA.1,the replication ability in vitro began to decrease.Then with the emergence of new subvariants,the replication ability gradually recovered and became stable in the BA.4 and BA.5 subvariants.In WH-09-inactivated vaccine sera,geometric mean titers of neutralization antibodies against different Omicron subvariants declined by 3.7~15.4-fold compared to those against WH-09.In Delta-inactivated vaccine sera,geometric mean titers of neutrali-zation antibodies against Omicron subvariants declined by 3.1~7.4-fold compared to those against Delta.Conclusion:According to the findings of this research,the replication efficiency of all Omicron subvariants declined compared with WH-09 and Delta variants,and was lower in BA.1 than in other Omicron subvariants.After two doses of inactivated(WH-09 or Delta)vaccine,cross-neutralizing activities against various Omicron subvariants were seen despite a decline in neutralizing titers.

关键词： cross-neutralize Omicron replication SARS-CoV-2

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Characteristics of animal models for COVID-19

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animal models and Experimental Medicine 2022年第5期5卷 401-409页

作者： Feifei Qi Chuan Qin beijing key laboratory for animal models of emerging and reemerging infectious diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina National Center of Technology Innovation for animal Model BeijingChina

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is the causative agent of coronavirus disease 2019(COVID-19),the most consequential pandemic of this century,threatening human health and public safety.SARS-CoV-2 has been continuously evolving through mutation of its genome and variants of concern have emerged.The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID-19,a core requirement for the prevention and control of SARS-CoV-2 pandemic.The animal model construction techniques developed during the SARS-CoV and MERS-CoV pandemics were rapidly deployed and applied in the establishment of COVID-19 animal models.To date,a large number of animal models for COVID-19,including mice,hamsters,minks and nonhuman primates,have been established.infectious diseases produce unique mani-festations according to the characteristics of the pathogen and modes of infection.Here we classified animal model resources around the infection route of SARS-CoV-2,and summarized the characteristics of the animal models constructed via transnasal,localized,and simulated transmission routes of infection.

关键词： animal model characteristics establishment SARS-CoV-2

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Sequentially immune-induced antibodies could cross-neutralize SARS-CoV-2 variants

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animal models and Experimental Medicine 2022年第1期5卷 89-93页

作者： Qi Lv Shasha Zhou Feifei Qi Yaqing Zhang Fengdi Li Mingya Liu Linlin Bao beijing key laboratory for animal models of emerging and reemerging infectious diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina National Center of Technology Innovation for animal Model BeijingChina

Background:The Omicron(B.1.1.529)SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein.Since the vaccine-induced neutralizing antibody targets are the spike protein,this may lead to the possibility of vaccine-induced hu-moral immunity escape.Methods:We measured the neutralizing activity in vitro for Omicron and compared this with wild type(WH-09)and Delta variants in human and monkey sera from different types of immunity.The monkey sera samples were collected at 1 and 3 months post three-dose inactivated(PiCoVacc)and recombinant protein(ZF2001)vaccination.Human sera were collected from 1 month post three-dose inactivated vaccination.Results:In inactivated vaccine sera,at 1/3 months post three-dose,geometric mean titers(GMTs)of neutralization antibody(NAb)against the Omicron variant were 4.9/5.2-fold lower than those of the wild type.In recombinant protein vaccine sera,GMTs of NAb against Omicron were 15.7/8.9-fold lower than those of the wild type.In human sera,at 1 month post three-dose inactivated vaccination,GMTs of NAb against Omicron were 3.1-fold lower than those of the wild type.Conclusion:This study demonstrated that despite a reduction in neutralization titers,cross-neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.

关键词： cross-neutralize Omicron SARS-CoV-2 sequentially immune

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Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK-STAT pathway

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2554-2566页

作者： Jingyi Tan Jiayu Zhang Cheng Hu Gongwei Wang Qianyao Ren Chaoqun Wang Jia Dan Zexin Zeng Jun Hu Wenbo Zhu Jiankai Liang Jing Cai Ying Liu Guangmei Yan Yuan Lin Department of Pharmacology Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China The Sixth Affiliated Hospital Sun Yat-sen UniversityGuangzhou 510655China Department of Urology the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China Advanced Medical Technology Center the First Affiliated Hospital-Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China key laboratory of Human Microbiome and Elderly Chronic diseases Ministry of EducationGuangzhou 510655China Department of infectious diseases the Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510630China

Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacokinetics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

关键词： Pharmacokinetics Oncolytic virus JAK-STAT Anticancer

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Characteristics of gut microbiota in representative mice strains:Implications for biological research

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animal models and Experimental Medicine 2022年第4期5卷 337-349,I0002页

作者： Jianguo Guo Chenchen Song Yunbo Liu Xuying Wu Wei Dong Hua Zhu Zhiguang Xiang Chuan Qin key laboratory of Human Disease Comparative Medicine Chinese Ministry of HealthBeijing 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

Background:Experimental animals are used to study physiological phenomena,pathological mechanisms,and disease prevention.The gut microbiome is known as a potential confounding factor for inconsistent data from preclinical studies.Although many gut microbiome studies have been conducted in recent decades,few have focused on gut microbiota fluctuation among representative mouse strains.Methods:A range of frequently used mouse strains were selected from 34 isolation packages representing disease-related animal(DRA),immunity defect animal(IDA),or gene-editing animal(GEA)from the BALB/c and C57BL/6J backgrounds together with normal mice,and their microbial genomic DNA were isolated from mouse feces to sequence for the exploration of gut microbiota.Results:Mouse background strain,classification,introduced source,introduced year,and reproduction type significantly affected the gut microbiota structure(p<0.001 for all parameters),with background strain contributing the greatest influence(R^(2)=0.237).In normal groups,distinct gut microbiota types existed in different mouse strains.Sixty-four core operational taxonomic units were obtained from normal mice,and 12 belonged to Lactobacillus.Interestingly,the gut microbiota in C57BL/6J was more stable than that in BALB/c mice.Furthermore,the gut microbiota in the IDA,GEA,and DRA groups significantly differed from that in normal groups(p<0.001 for all).Compared with the normal group,there was a significantly higher Chao 1 and Shannon index(p<0.001 for all)in the IDA,GEA,and DRA groups.Markedly changed classes occurred with Firmicutes and Bacteroidetes.The abundances of Helicobacter,Blautia,Enterobacter,Bacillus,Clostridioides,Paenibacillus,and Clostridiales all significantly decreased in the IDA,GEA,and DRA groups,whereas those of Saccharimonas,Rikenella,and Odoribacter all significantly increased.

关键词： Bacteroidetes BALB/c mice C57BL/6J disease-related animal Firmicutes gene-editing animal gut microbiota i mmunity defect animal strains

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Strategies for generating mouse model resources of human disease

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Protein & Cell 2023年第12期14卷 866-870页

作者： Jirong Pan Ling Zhang Zhibing Huang Dalu Zhao He Li Yanan Fu Meng Wang Borui Chen Fuad A.Iraqi Grant Morahan Chuan Qin National Human diseases animal Model Resource Center NHC Key Laboratory of Human Disease Comparative MedicineBeijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesBeijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal SciencesCAMS&PUMCNational Center of Technology Innovation for Animal ModelChangping National Laboratory(CPNL)Beijing 102206China Department of Clinical Microbiology and Immunology Sackler Faculty of MedicineTel-Aviv UniversityRamat AvivTel Aviv 69978Israel Harry Perkins Institute of Medical Research QEII Medical Centre and Centre for Medical ResearchUniversity of Western AustraliaNedlandsPerthWA 6009Australia

The number of genetically modified mouse models that mimic human disease is growing rapidly,but only a tiny fraction has been commonly used.According to The Knockout Mouse Program(Lloyd,2011),a public resource of mouse embryonic stem cells containing a null mutation in every gene in the mouse genome,8,916 mutant mice lines were phenotyped up to 19 July 2022.Due to the poor correlation between the genomic responses in the mouse models and those responses in human disease,and since humans differ significantly in their genetic vulnerability to common diseases,we still need better mouse models,especially for common and chronic human diseases,including cancer,pulmonary and cardiovascular diseases,obesity and diabetes,behavioral disorders,and neurodegenerative diseases.These new models will be placed into a public repository,The China National Human Disease animal Model Resource Center(NAMR).This project is funded by Ministry of Science and Technology of China and specializes in the creation,introduction,collection,preservation,and supply of animal model resources forhuman diseases.

关键词： diseases cardiovascular generating

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