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Chinese Medical Journal 2022年第14期135卷 1673-1681页

作者： Yizhi Zhang Yu Chen Fourth Department of liver Disease(Difficult and Complicated liver Diseases and Artificial liver Center) Beijing You’an Hospital Affiliated to Capital Medical UniversityBeijing 100069China Beijing Municipal Key laboratory of liver Failure and Artificial liver Treatment research Beijing 100069China

Non-alcoholic fatty liver disease(NAFLD)is a disorder of lipid metabolism.The lipotoxic intermediates of lipid metabolism cause mitochondrial dysfunction and endoplasmic reticulum stress.Organelle-specific autophagy is responsible for the removal of dysfunctional organelles to maintain intracellular homeostasis.Lipophagy contributes to lipid turnover by degrading lipid droplets.The level of autophagy changes during the course of NAFLD,and the activation of hepatocyte autophagy might represent a method of treating NAFLD.

关键词： Autophagy Lipophagy Mitophagy Reticulophagy Non-alcoholic fatty liver disease

New insights in the pathogenesis of alcohol-related liver disease:The metabolic,immunologic,and neurologic pathways

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liver research 2023年第1期7卷 1-8页

作者： Tom Ryu Kyurae Kim Sung Eun Choi Katherine Po Sin Chung Won-Il Jeong laboratory of liver research Graduate School of Medical Science and EngineeringKAISTDaejeonRepublic of Korea

Alcohol-related liver disease(ALD)became an important health issue worldwide.Following chronic alcohol consumption,the development of ALD might be caused by metabolic and immunologic factors,such as reactive oxygen species(ROS)and pro-inflammatory cytokines.For example,hepatic cytochrome P4502E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure.In addition,damage-and pathogen-associated molecular patterns stimulate their specific receptors in nonparenchymal cells,including Kupffer cells,hepatic stellate cells(HSCs),and lymphocytes,which result in hepatocyte death and infiltration of pro-inflammatory cells(e.g.,neutrophils and macrophages)in the liver.Moreover,our studies have suggested the novel involvement of neurologic signaling pathways(e.g.,endocannabinoid and glutamate)through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis.Additionally,agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis.Furthermore,organ-crosstalk has emerged as a critical issue in ALD.Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut,leading to endotoxin leakage into the portal circulation,or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver.In summary,this review addresses multiple pathogeneses of ALD,provides novel neurologic signaling pathways,and emphasizes the importance of organ-crosstalk in the development of ALD.

关键词： Alcohol-related liver disease(ALD) Cannabinoid receptor Steatohepatitis Lipopolysaccharide(LPS) Metabotropic glutamate receptor(mGluR) Toll-like receptor 4(TLR4)

Concomitant extrahepatic autoimmune diseases do not compromise the long-term outcomes of primary biliary cholangitis

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Hepatobiliary & Pancreatic Diseases International 2022年第6期21卷 577-582页

作者： Sha Chen Meng-Qi Li Wei-Jia Duan Bu-Er Li Shu-Xiang Li Ting-Ting Lv Lin Ma Ji-Dong Jia liver research Center Beijing Friendship HospitalCapital Medical UniversityBeijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center for Digestive Diseases95 Yong’an RoadBeijing 100050China

Background:Primary biliary cholangitis(PBC)patients often have concomitant extrahepatic autoimmune(EHA)diseases including Sjögren’s syndrome(SS),systemic sclerosis(SSc),rheumatoid arthritis(RA),and autoimmune thyroid disease.The present study aimed to describe the prevalence of EHA diseases in PBC and explore the impact of EHA diseases on the long-term outcomes of PBC in Chinese patients.Methods:Medical records of PBC patients diagnosed in our institute were retrospectively reviewed.Pa-tients were followed up by a standardized telephone interview.The endpoints were defined as liver-related death and/or liver transplantation.Results:Totally 247 of the 985(25.1%)PBC patients enrolled in the study had at least one concomi-tant EHA disease.Sjögren’s syndrome(n=140,14.2%)was the most frequent one,followed by rheuma-toid arthritis(RA)(n=56,5.7%)and Hashimoto’s thyroiditis(n=45,4.6%).Patients with EHA dis-eases were more common in females(P<0.001)and in those with a family history of autoimmune disease(P=0.017).Overall,no differences were found between PBC patients with and without EHA dis-eases in terms of biochemical response rates to ursodeoxycholic acid,the incidence of hepatic events,or transplant-free survival.RA and EHA≥2 were protective factors for hepatic events in univariate Cox analysis,but the results became insignificant in multivariate analysis.Conclusions:Concomitant EHA diseases were common in PBC patients but did not compromise the long-term outcomes of PBC.

关键词： Primary biliary cholangitis Extrahepatic autoimmune diseases Sjögren’s syndrome Rheumatoid arthritis Prognosis

Adenovirus and severe acute hepatitis of unknown etiology in children:Offender or bystander?

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Hepatobiliary & Pancreatic Diseases International 2022年第4期21卷 354-355页

作者： Shan Shan Ji-Dong Jia liver research Center Beijing Friendship HospitalCapital Medical University/Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis/National Clinical Research Center for Digestive DiseasesBeijing 100050China

On April 6,2022,the United Kingdom Health Security Agency(UKHSA)released an alert on cases of hepatitis of unknown etiology in children[1].On April 15,2022,World Health Organization(WHO)published the first notice of this condition[2].Later on,similar cases were reported from the UK,other European countries,and other parts of the world.

关键词： etiology hepatitis cases

Control of Chronic Hepatitis B in China:Perspective of Diagnosis and Treatment

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China CDC weekly 2020年第31期2卷 596-600页

作者： Yu Wang Min Wang Guanhua Zhang Xiaojuan Ou Hong Ma Hong You Jidong Jia liver research Center Beijing Friendship HospitalCapital Medical University/Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis/National Clinical Research Center for Digestive DiseasesBeijingChina

In the last three decades,China has made extraordinary effort and achieved great progress in the control of hepatitis B.Thanks to the adoption of universal administering of HBV vaccinations for newborns since 1992,the prevalence of hepatitis B surface antigen(HBsAg)in the population born after 1992 decreased significantly resulting in a decline in the general population from 9.75%to about 6%(1).

关键词： Chronic vaccination prevalence

Outcomes of right-lobe and left-lobe living-donor liver transplantations using small-for-size grafts

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World Journal of Gastroenterology 2017年第23期23卷 4270-4277页

作者： Wong Hoi She Kenneth SH Chok James YY Fung Albert CY Chan Chung Mau Lo Department of Surgery the University of Hong Kong Department of Surgery and State Key laboratory for liver research The University of Hong Kong Department of Medicine and State Key laboratory for liver research The University of Hong Kong

AIM To analyze the outcomes of living-donor liver transplantation(LDLT) using left-lobe(LL) or right-lobe(RL) small-for-size(SFS) grafts.METHODS Prospectively collected data of adult patients who underwent LDLT at our hospital in the period from January 2003 to December 2013 were reviewed. The patients were divided into the RL-LDLT group and the LL-LDLT group. The two groups were compared in terms of short-and long-term outcomes, including incidence of postoperative complication, graft function, graft survival, and patient survival. A SFS graft was defined as a graft with a ratio of graft weight(GW) to recipient standard liver volume(RSLV)(GW/RSLV) of research into different patient conditions is needed in order to validate the use of LL graft.

关键词：为尺寸肝接枝小正确脑叶接枝左脑叶接枝生活施主肝移植

Regression of liver fibrosis: evidence and challenges

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Chinese Medical Journal 2020年第14期133卷 1696-1702页

作者： Ya-Meng Sun Shu-Yan Chen Hong You liver research Center Beijing Friendship HospitalCapital Medical UniversityBeijing Key Laboratory of Translational Medicine on Liver CirrhosisNational Clinical Research Center of Digestive DiseasesBeijing 100050China

It has been reported that liver fibrosis could be reversed after eliminating liver injuries.This article systematically summarizes the evidence of fibrosis regression based on histology,liver stiffness,and serum biomarkers,and discusses several clinically relevant challenges.Evidence from liver biopsy has been regarded as the gold standard in the assessment of fibrosis regression.Semiquantitative staging and grading systems are traditionally and routinely used to define regression.Recently,the predominantly regressive,indeterminate,and predominantly progressive score was proposed,based on the regressive features from“hepatic repair complex”,to provide additional information regarding the quality of fibrosis.For non-invasive assessment,although liver stiffness and serum biomarkers could be applied to reflect the dynamic changes of liver fibrosis,other confounding factors such as liver inflammation have to be considered.In conclusion,both histology and non-invasive methods can provide evidence regarding fibrosis regression.The predictive value of fibrosis regression in long-term prognosis warrants further investigation.

关键词： liver fibrosis Regression Reversal liver biopsy liver stiffness Serum biomarker

The Role of Macrophage-Derived Exosomes in liver Diseases

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Infectious Diseases & Immunity 2022年第1期2卷 34-41页

作者： Wang Lu Li Bai Yu Chen Fourth Department of liver Disease(Difficult&Complicated liver Diseases and Artificial liver Center) Beijing Youan HospitalCapital Medical UniversityBeijing 100069China Beijing Municipal Key laboratory of liver Failure and Artificial liver Treatment research Beijing 100069China

Exosomes(exos)widely distributed in a variety of biological fluids,including blood,urine,saliva,sputum,breast milk,cerebrospinal fluid,and ascites,contain specific bioactive contents which are involved in physiological and pathological processes,such as signal molecular transfer,substance metabolism,gene regulation,and immune regulation.Macrophages are important innate immune cells which usually act as the first line of defense against infection,and can switch between different functional phenotypes in response to the changes around the microenvironment.Evidence suggests that macrophage-derived exos exert a crucial effect on infection,inflammation,regeneration,tumors,fibrosis,and other lesions in multiple human diseases.However,the role and mechanism of macrophage-derived exos in liver diseases remain to be explored.This review summarizes the current researches on the role and possible mechanism of macrophage-derived exos in liver diseases,with the purpose of providing new potential targets and directions for diagnostic biomarker and clinical treatment of liver diseases.

关键词： Exosomes liver disease Macrophages

MicroRNA-122-functionalized DNA tetrahedron stimulate hepatic differentiation of human mesenchymal stem cells for acute liver failure therapy

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Bioactive Materials 2023年第10期28卷 50-60页

作者： Hongyan Wei Fenfang Li Tiantian Xue Haixia Wang Enguo Ju Mingqiang Li Yu Tao laboratory of Biomaterials and Translational Medicine Center for NanomedicineThe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou510630China Guangdong Provincial Key laboratory of liver Disease research Guangzhou510630China

As the most abundant liver-specific microRNA, microRNA-122 (miR122) played a crucial role in the differentiation of stem cells into hepatocytes. However, highly efficient miR122 delivery still confronts challenges including poor cellular uptake and easy biodegradation. Herein, we for the first time demonstrated that the tetrahedral DNA (TDN) nanoplatform had great potential in inducing the differentiation of human mesenchymal stem cells (hMSCs) into functional hepatocyte-like cells (HLCs) by transferring the liver-specific miR122 to hMSCs efficiently without any extrinsic factors. As compared with miR122, miR122-functionalized TDN (TDN-miR122) could significantly up-regulate the protein expression levels of mature hepatocyte markers and hepatocyte-specific marker genes in hMSCs, indicating that TDN-miR122 could particularly activate the hepatocyte-specific properties of hMSCs for developing cell-based therapies in vitro. The transcriptomic analysis further indicated the potential mechanism that TDN-miR122 assisted hMSCs differentiated into functional HLCs. The TDN-miR122-hMSCs exhibited hepatic cell morphology phenotype, significantly up-regulated specific hepatocyte genes and hepatic biofunctions in comparison with the undifferentiated MSCs. Preclinical in vivo transplantation appeared that TDN-miR122-hMSCs in combination with or without TDN could efficiently rescue acute liver failure injury through hepatocyte function supplement, anti-apoptosis, cellular proliferation promotion, and anti-inflammatory. Collectively, our findings may provide a new and facile approach for hepatic differentiation of hMSCs for acute liver failure therapy. Further large animal model explorations are needed to study their potential in clinical translation in the future.

关键词： Hepatocyte differentiation Tetrahedral framework nucleic acids Cell therapy Transcriptomics Acute liver failure treatment

Bioengineered humanized livers as better three-dimensional drug testing model system

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World Journal of Hepatology 2018年第1期10卷 22-33页

作者： Sandeep Kumar Vishwakarma Avinash Bardia Chandrakala Lakkireddy Raju Nagarapu Md Aejaz Habeeb Aleem Ahmed Khan Central laboratory for Stem Cell research and Translational Medicine Centre for Liver Research and Diagnostics Deccan College of Medical Sciences

AIM To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. METHODS Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses.RESULTS The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs.CONCLUSION The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.

关键词： Acellularization Repopulation Drug testing Humanized liver Bioengineering