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Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2^(-/-)Mice and Human Intrahepatic Cholangiocyte Organoid Models

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Research 2024年第2期2023卷 355-372页

作者： Qigu Yao Wenyi Chen Yingduo Yu Feiqiong Gao Jiahang Zhou Jian Wu Qiaoling Pan Jinfeng Yang Lingling Zhou Jiong Yu hongcui cao Lanjuan Li State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases Cllaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affliated HospitalZhejang University School of Medicine79 Qingchun Rd.Hangzhou 310003China National Clinical Research Center for Infectious Diseases HangzhouChina Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province 79 Qingchun Rd.Hangzhou 310003China Jjinan Microecological Biomedicine Shandong Laboratory Jinan 250117China

Primary sclerosing cholangitis(PSC)is a biliary disease accompanied by chronic inflammation of the liver and biliary *** stem cells(MSCs)are used to treat liver diseases because of their immune regulation and regeneration-promoting *** study was performed to explore the therapeutic potential of human placental MSCs(hP-MSCs)in PSC through the Takeda G protein-coupled receptor 5(TGR5)receptor *** tissues were collected from patients with PSC and healthy donors(n=4)for RNA sequencing and intrahepatic cholangiocyte organoid ***-MSCs were injected via the tail vein into Mdr2^(-/-),bile duct ligation(BDL),and 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary *** in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry(LC-MS/MS).Compared with healthy controls,liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis,and marked downregulation of bile acid receptor TGR5 ***-MSC treatment apparently reduced the inflammation,cholestasis,and fibrosis in Mdr2^(-/-),BDL,and DDC model *** activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway,hP-MSC treatment promoted the proliferation of cholangiocytes,and affected the transcription of downstream nuclear factorκB through regulation of the binding of TGR5 and Pellino3,thereby affecting the cholangiocyte inflammatory phenotype.

关键词： inflammation TGR5 Human

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Prognostic Nomogram for Patients with Hepatitis E Virus-related Acute Liver Failure:A Multicenter Study in China

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Journal of Clinical and Translational Hepatology 2021年第6期9卷 828-837页

作者： Jian Wu Cuifen Shi Xinyu Sheng Yanping Xu Jinrong Zhang Xinguo Zhao Jiong Yu Xinhui Shi Gongqi Li hongcui cao Lanjuan Li State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infec-tious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Depart-ment of Laboratory Medicine Shanghai Tongji HospitalTongji University School of MedicineShanghaiChina Department of Infectious Disease The Second People’s Hospital of Yancheng CityYanchengJiangsuChina Department of Laboratory Medicine The People’s Hospital of Dafeng CityYanchengJiangsuChina Department of Respiration The Fifth People’s Hospital of WuxiWuxiJiangsuChina Department of Laboratory Medicine The First People’s Hospital of Yancheng CityYanchengJiangsuChina Department of Clinical Laboratory Linyi Traditional HospitalLinyiShandongChina Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases HangzhouZhejiangChina

Background and Aims:Timely and effective assessment scoring systems for predicting the mortality of patients with hepatitis E virus-related acute liver failure(HEV-ALF)are urgently *** present study aimed to establish an effective nomogram for predicting the mortality of HEV-ALF ***:The nomogram was based on a cross-sectional set of 404 HEV-ALF patients who were identified and enrolled from a cohort of 650 patients with liver *** compare the performance with that of the model for end-stage liver disease(MELD)scoring and CLIF-Consortiumacute-on-chronic liver failure score(CLIF-C-ACLFs)models,we assessed the predictive accuracy of the nomogram using the concordance index(C-index),and its discriminative ability using time-dependent receiver operating characteristics(td-ROC)analysis,***:Multivariate logistic regression analysis of the development set carried out to predict mortality revealed that γ-glutamyl transpeptidase,albumin,total bilirubin,urea nitrogen,creatinine,international normalized ratio,and neutrophil-to-lymphocyte ratio were independent factors,all of which were incorporated into the new nomogram to predict the mortality of HEV-ALF *** area under the curve of this nomogram for mortality prediction was 0.671(95%confidence interval:0.602-0.740),which was higher than that of the MELD and CLIF-C-ACLFs ***,the td-ROC and decision curves analysis showed that both discriminative ability and threshold probabilities of the nomogram were superior to those of the MELD and CLIF-C-ACLFs models.A similar trend was observed in the validation ***:The novel nomogram is an accurate and efficient mortality prediction method for HEV-ALF patients.

关键词： Hepatitis E Acute liver failure Nomogram Mortality prediction Scoring model

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MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan Lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu hongcui cao Lanjuan Li State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117China Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage *** placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver ***,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC *** results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in ***,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular ***,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

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Dynamic changes of key metabolites during liver fibrosis in rats by UPLC-MS

Dynamic changes of key metabolites during liver fibrosis in ...

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2018年浙江省检验医学学术年会

作者： Jiong Yu Deying Chen jing Ma hongcui cao State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases First Affiliated HospitalCollege of MedicineZhejiang University Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases

Introduction:Fibrosis is the single-most important predictor of significant morbidity and mortality in patients with chronic liver *** non-invasive tests for monitoring fibrosis are lacking,and new biomarkers of liver fibrosis and function are ***:Dynamic changes in metabolic profiles and biomarker concentrations in rat serum during liver fibrosis progression were investigated using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass ***:To investigate the dynamic changes of metabolites during the process of liver fibrosis,sera from control and fibrosis model rats were analyzed at five different time *** investigated the association of liver fibrosis with 21 metabolites including hydroxyethyl glycine,l-threonine,

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The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4＋CD25＋ regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment

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Cellular & Molecular Immunology 2016年第5期13卷 678-687页

作者： Jiezuan Yang Guoping Sheng Dangsheng Xiao Haiyan Shi Wei Wu Haifeng Lu Ping Yi hongcui cao Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases The First Affiliated Hospital College of Medicine Zhejiang University Hangzhou 310003 Zhejiang Province PR China

The frequency and T-cell receptor beta-chain variable （TCRBV） patterns of peripheral CD4＋CD25＋ regulatory T-cells （Tregs） are ambiguously altered in chronic hepatitis B （CHB） patients following tenofovir disoproxil fumarate （TDF） treatment. Moreover, the clinical significance of these parameters in relation to hepatitis B e antigen （HBeAg） seroconversion （SC） is largely unknown. In this study, the circulation of Tregs in HBeAg-positive CHB patients was determined by flow cytometry, and the molecular profiles of frequent TCRBV patterns of Tregs were analyzed using a gene melting spectral pattern. The parameters, such as Treg frequency, the number of skewed TCRBV patterns, hepatitis B virus （HBV） DNA levels, and alanine aminotransferase （ALT） levels, were analyzed by comparing their associations in seroconverting and non-seroconverting patients following TDF treatment. The Treg frequency was significantly correlated with the ALT level in seroconverting but not in non-seroconverting patients. Similarly, skewed TCRBV patterns were remarkably associated with HBV DNA levels in the SC group. Six TCRBV families （BV3, BV11, BV12, BV14, BV20, and BV24） were more prevalent than other TCRBV members in seroconverting patients pretreated with TDF, while BV12, BV15, and BV22 were predominant in non-seroconverting patients during TDF treatment. Taken together, the preferential TCRBV patterns may be associated with immune responses related to SC. The dynamic frequency and skewed TCRBV patterns of peripheral Tregs could contribute to predicting SC in CHB patients. Moreover, the conserved TCRBV complementarity-determining region （CDR3） motif may be targeted to develop personalized immunotherapy for CHB patients.

关键词： chronic hepatitis B individual treatment gene melting spectral pattern regulatory T-cells T-cell receptorbeta-chain variable

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Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1αpathways

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2023年第1期24卷 50-63页

作者： Qiong ZHAO Luwen ZHANG Qiufen HE Hui CHANG Zhiqiang WANG hongcui cao Ying ZHOU Ruolang PAN Ye CHEN Department of Genetics and Department of Genetic and Metabolic DiseaseThe Children's HospitalZhejiang University School of MedicineNational Clinical Research Center for Child HealthHangzhou 310052China Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders Institute of GeneticsZhejiang UniversityHangzhou 310058China State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Xiangshan Hospital of TCM Medical and Health Group Ningbo 315700China Zhejiang Provincial Key Laboratory of Cell-Based Drug and Applied Technology Development Hangzhou 311121China

Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor *** present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)***,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor *** TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen ***,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy ***,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.

关键词： Transfer RNA(tRNA) tRNA methyltransferase 5(TRMT5) Hepatocellular carcinoma(HCC) Hypoxia-inducible factor-1α(HIF-1α)

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戊型肝炎:从幕后走到台前

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临床肝胆病杂志 2023年第11期39卷 2521-2523页

作者：吴健向泽曹红翠苏州市立医院检验医学中心江苏苏州215008 中国戊型肝炎研究协助组(CCSHE) 江苏苏州215008 浙江大学医学院杭州310000 浙江大学医学院附属第一医院传染病重症诊治全国重点实验室国家感染性疾病临床医学研究中心感染性疾病诊治协同创新中心杭州310003

戊型肝炎是由HEV感染引起的病毒性肝炎。HEV主要有4种基因型,分别为基因1~4型。相较乙型肝炎和丙型肝炎,既往戊型肝炎相关研究进展较为缓慢。然而,近年来我国对于戊型肝炎关注度逐步升高,实现了从幕后走向台前。首先,我国人口基数较大,... 详细信息

戊型肝炎是由HEV感染引起的病毒性肝炎。HEV主要有4种基因型,分别为基因1~4型。相较乙型肝炎和丙型肝炎,既往戊型肝炎相关研究进展较为缓慢。然而,近年来我国对于戊型肝炎关注度逐步升高,实现了从幕后走向台前。首先,我国人口基数较大,HEV感染人数多,疾病负担较重,因而需高度重视戊型肝炎预防、诊断和治疗。其次,世界卫生组织提出“于2030年全球消除病毒性肝炎”的宏伟目标,我国在乙型肝炎和丙型肝炎防治现已取得卓越成效。目前,我国戊型肝炎发病率和病死率已超过甲型肝炎,对戊型肝炎的积极有效防治意义重大。最后,国内戊型肝炎领域研究者自发组成中国戊型肝炎研究协助组,制定相关专家共识,建立国内外合作平台,进一步推动我国戊型肝炎相关研究热潮。

关键词：戊型肝炎公共卫生诊断治疗学

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Metabonomics study on Chinese miniature pigs with acute liver failure after treated by transplanting placental mesenchymal stem cells

Metabonomics study on Chinese miniature pigs with acute live...

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中华医学会第十三次全国感染病学术会议

作者： hongcui cao Jing Ma Jiong Yu Xiaoru Su Jinfeng Yang Qiaoling Pan Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases the First Affiliated HospitalMedical CollegeZhejiang University

Metabonomics has become a highly sensitive and powerful tool for the screening of biomarkers and elucidation of biochemical *** has found broad application in the research of hepatic failure which always results in apparent disturbance of endogenous ***,we have confirmed the therapeutic effect of human placenta mesenchymal stem cells(hPMSCs)on D-galactosamine(GalN)-induced liver injury

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Effectiveness of non-bioartificial liver on acute fatty liver of pregnancy

Effectiveness of non-bioartificial liver on acute fatty live...

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第三届全国病毒性肝炎慢性化重症化基础与临床研究进展学术会议

作者：喻成波 Jiajia Chen Weibo Du Ping Chen Jianrong Huang Yuemei Chen hongcui cao Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases The First Affiliated HospitalSchool of MedicineZhejiang University.Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases

Background Acute fatty liver of pregnancy(AFLP) can lead to fatal liver damage that occur in the third trimester or early postpartum *** effect of traditional therapy is not very ideal for facilitating hepatic *** safety and effect of non-bioartificial liver(NBAL) in application for treating AFLP are lacking systematic introduction. Aim Analysis of the timing and efficacy of non-bioartificial liver(NBAL) in the treatment of acute fatty liver of pregnancy(AFLP). Methods We observed the clinical data of 5 cases of AFLP treated with NBAL from 2007 to 2012 including symptoms,physical signs,adverse effects,and compared all relevant laboratory test results before and after NBAL. Results (1) Side effects during NBAL were slight and well-tolerated,and no patients interrupted treatment because of negligible side effects;Clinical symptoms,signs,and liver and renal functions can be ameliorated significantly after NBAL;(2) In the 5 cases treated,4 were cured,1 succeeded in bridging to transplantation;(3) In the 4 cases cured,the sooner a AFLP patient received NBAL the better the curative effect. Conclusion Treatment of AFLP by NBAL is safe and effective,and early application of NBAL in AFLP patients can effectively treat and reverse progress of the disease.

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Molecular characteristics of the T cell receptor beta variable repertoire within peripheral lymphocytes and T cell subsets in chronic asymptomatic HBV carrier

Molecular characteristics of the T cell receptor beta variab...

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第四届全国病毒性肝炎慢性化、重症化基础与临床研究进展学术会议

作者： Jiezuan Yang Ping Yi Haifeng Lu Ping Ye Linfeng Jin Hua Zhang hongcui cao Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases the First Affiliated HospitalCollege of MedicineZhejiang University Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Zhejiang University

Background HBV-infected individuals are immune tolerant or have deleted HBV antigenspecific T cell clones,which are thought to underlie the pathogenesis in chronic asymptomaticHBV carriers（AsC）.The importance of CD4and CD8T cells in protection against HBV is well known,and T cell receptor beta variable（TCRBV）reflects the composition and function of T ***,the molecular profiles of TCRBV in CD4,CD8T cell subsets and peripheral

关键词： HBV Molecular characteristics of the T cell receptor beta variable repertoire within peripheral lymphocytes and T cell subsets in chronic asymptomatic HBV carrier PBMCs

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