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Mitochondrial dysfunction: A promising therapeutic target for liver diseases

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Genes & diseases 2024年第3期11卷 324-337页

作者： Ping Chen Lichao Yao Mengqin Yuan Zheng Wang Qiuling Zhang Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430060China State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310003China

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy,which is mainly produced by the mitochondria.Liver tissues of pa-tients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mito-chondrial lesions,mitochondrial DNA damage,disturbed mitochondrial dynamics,and compromised ATP production.Overproduction of mitochondrial reactive oxygen species in-duces oxidative damage to mitochondrial proteins and mitochondrial DNA,decreases mito-chondrial membrane potential,triggers hepatocyte inflammation,and promotes programmed cell death,all of which impair liver function.Mitochondrial DNA may be a poten-tial novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus.We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases,such as hepatocellular carcinoma,viral hepatitis,drug-induced liver injury,alcoholic liver disease,and non-alcoholic fatty liver disease.This review also discusses mito-chondrion-centric therapies for treating liver diseases.

关键词： Chronic diseases Liverdamage Mesenchymalstem cell Mitochondrial dysfunction Oxidativestress

Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

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Chinese Medical Journal 2024年第4期137卷 457-464页

作者： Mengqin Yuan Jian He Xue Hu Lichao Yao Ping Chen Zheng Wang Pingji Liu Zhiyu Xiong Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430000China Department of Gastroenterology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong 510010China State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Centre for Infectious DiseasesCollaborative Innovation Centre for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310000China

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains unclear.Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)analyses.Methods:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018.Subsequently,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and NAFLD.The primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD.Sensitivity analyses were adopted to confirm the robustness of the results.Results:A total of 3144 participants were enrolled for our observational study in NHANES.Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with NAFLD.Moreover,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and NAFLD.Similar results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and NAFLD.The sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

关键词： Hypertension Non-alcoholic fatty liver disease National Health and Nutrition Examination Survey Mendelian randomization analysis Causality

Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

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Science China(Life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang Lanjuan Li State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Liver disease,a major health concern worldwide,is a serious and progressive disorder.Herein,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome.As liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse models.The metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC group.The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC.Based on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were depleted.The increased abundance of C.albicans and depletion of S.cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC.Moreover,the administration of C.albicans and S.cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC.Therefore,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

Dynamic changes and clinical value of lipocalin 2 in liver diseases caused by microbial infections

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World Journal of Hepatology 2024年第2期16卷 177-185页

作者： Feng Chen Shan-Shan Wu Chao Chen Cheng Zhou State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003Zhejiang ProvinceChina

Lipocalin 2(LCN2)plays a pivotal role in iron metabolism,particularly in the context of microbial infection resistance(e.g.,viruses,bacteria,parasites,etc.).LCN2 combats microbial infection by directly assisting the body in competing with microorganisms for iron,inducing immune cells to secrete various cytokines to enhance systemic immune responses,or recruiting neutrophils to infectious sites.The liver serves as the primary organ for LCN2 secretion during microbial infections.This review encapsulates recent advances in dynamic changes,clinical values,and the effects of LCN2 in infectious liver diseases caused by various microbial microorganisms.

关键词： Lipocalin 2 Microbial infection Immunity Liver diseases

Knowledge,Attitude,and Practice Towards Mpox and Associated Factors Among HIV-Infected Individuals—Beijing Municipality,China,2023

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China CDC weekly 2024年第7期6卷 109-117,I0001,I0002页

作者： Yue Gu Ruiqi Ren Jing Han Wenqing Bai Yuanyuan Zhang Haoliang Liu Zhaohe Li Chao Li Rui Song Lei Zhou Chinese Center for Disease Control and Prevention BeijingChina National Center for infectious diseases Beijing Ditan HospitalCapital Medical UniversityBeijingChina Beijing Key Laboratory of Emerging infectious diseases Institute of Infectious DiseasesBeijing Ditan HospitalCapital Medical UniversityBeijingChina Nanjing Medical University Nanjing CityJiangsu ProvinceChina

Summary What is already known about this topic?Approximately 50%of patients with mpox are human immunodeficiency virus(HIV)-infected globally.Studies have shown that individuals with advanced HIV infection tend to hav... 详细信息

关键词： mortality Infect clinical

A prognostic four-gene signature and a therapeutic strategy for hepatocellular carcinoma:Construction and analysis of a circRNA-mediated competing endogenous RNA network

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Hepatobiliary & Pancreatic diseases International 2024年第3期23卷 272-287页

作者： Hai-Yan Zhang Jia-Jie Zhu Zong-Ming Liu Yu-Xuan Zhang Jia-Jia Chen Ke-Da Chen Zhejiang Chinese Medical University Hangzhou 310053China Shulan International Medical College Zhejiang Shuren UniversityHangzhou 310015China State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

Background:Hepatocellular carcinoma(HCC)has a poor long-term prognosis.The competition of circular RNAs(circRNAs)with endogenous RNA is a novel tool for predicting HCC prognosis.Based on the alterations of circRNA regulatory networks,the analysis of gene modules related to HCC is feasible.Methods:Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in HCC.Gene function,pathway,and protein interaction analyses were performed for the differentially expressed genes(DEGs)in this regulatory network.In the proteinprotein interaction network,hub genes were identified and subjected to regression analysis,producing an optimized four-gene signature for prognostic risk stratification in HCC patients.Anti-HCC drugs were excavated by assessing the DEGs between the low-and high-risk groups.A circRNA-microRNA-hub gene subnetwork was constructed,in which three hallmark genes,KIF4A,CCNA2,and PBK,were subjected to functional enrichment analysis.Results:A four-gene signature(KIF4A,CCNA2,PBK,and ZWINT)that effectively estimated the overall survival and aided in prognostic risk assessment in the The Cancer Genome Atlas(TCGA)cohort and International Cancer Genome Consortium(ICGC)cohort was developed.CDK inhibitors,PI3K inhibitors,HDAC inhibitors,and EGFR inhibitors were predicted as four potential mechanisms of drug action(MOA)in high-risk HCC patients.Subsequent analysis has revealed that PBK,CCNA2,and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion,regulating microsatellite instability(MSI),and exerting an impact on HCC progression.Conclusions:The present study highlights the role of the circRNA-related regulatory network,identifies a four-gene prognostic signature and biomarkers,and further identifies novel therapy for HCC.

关键词： Hepatocellular carcinoma circRNA-related ceRNA network Biomarker Least absolute shrinkage and selection operator Bioinformatics

Silent battles:immune responses in asymptomatic SARS-CoV-2 infection

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Cellular & Molecular Immunology 2024年第2期21卷 159-170页

作者： Nina Le Bert Taraz Samandari Program in Emerging infectious diseases Duke-NUS Medical SchoolSingaporeSingapore

SARS-CoV-2 infections manifest with a broad spectrum of presentations,ranging from asymptomatic infections to severe pneumonia and fatal outcomes.This review centers on asymptomatic infections,a widely reported phenomenon that has substantially contributed to the rapid spread of the pandemic.In such asymptomatic infections,we focus on the role of innate,humoral,and cellular immunity.Notably,asymptomatic infections are characterized by an early and robust innate immune response,particularly a swift type 1 IFN reaction,alongside a rapid and broad induction of SARS-CoV-2-specific T cells.Often,antibody levels tend to be lower or undetectable after asymptomatic infections,suggesting that the rapid control of viral replication by innate and cellular responses might impede the full triggering of humoral immunity.Even if antibody levels are present in the early convalescent phase,they wane rapidly below serological detection limits,particularly following asymptomatic infection.Consequently,prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus.

关键词： COVID-19 asymptomatic cellular immunity antibody

AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway

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Hepatobiliary & Pancreatic diseases International 2024年第1期23卷 43-51页

作者： Qing-Qi Zhang Qian Chen Pan Cao Chun-Xia Shi Lu-Yi Zhang Lu-Wen Wang Zuo-Jiong Gong Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhan 430060China

Background:Acute liver failure(ALF)is an unpredictable and life-threatening critical illness.The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure.Methods:Animals were divided into 3 groups,normal,thioacetamide(TAA,ALF model)and TAA+AGK2.Cultured L02 cells were divided into 5 groups,normal,TAA,TAA+mitofusin 2(MFN2)-siRNA,TAA+AGK2,and TAA+AGK2+MFN2-siRNA groups.The liver histology was evaluated with hematoxylin and eosin staining,inositol-requiring enzyme 1(IRE1),activating transcription factor 6β(ATF6β),protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)and phosphorylated-PERK(p-PERK).C/EBP homologous protein(CHOP),reactive oxygen species(ROS),MFN2 and glutathione peroxidase 4(GPX4)were measured with Western blotting,and cell viability and liver chemistry were also measured.Mitochondriaassociated endoplasmic reticulum membranes(MAMs)were measured by immunofluorescence.Results:The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis,which were reduced by AGK2 pre-treatment.In comparison to the normal group,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+in the TAA-induced ALF model group were significantly increased,which were decreased by AGK2 pre-treatment.The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group,which were enhanced by AGK2 pretreatment.Compared with the TAA-induced L02 cell,apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group.AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1,ATF6β,p-PERK,CHOP,ROS and Fe2+and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell.Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells.Conclusions:The d

关键词： SIRT2 inhibitor AGK2 Acute liver failure MFN2 Ferroptosis

Co-immunoprecipitation for identifying protein–protein interaction on lipid droplets

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Biophysics Reports 2024年第2期10卷 102-110页

作者： Xiaochuan Fu Shuyan Zhang Pingsheng Liu Institute of Biophysics Chinese Academy of Sciences University of Chinese Academy of Sciences Institute of infectious diseases Beijing Key Laboratory of Emerging Infectious Diseases Beijing Ditan HospitalCapital Medical University Beijing Institute of infectious diseases

The lipid droplet(LD) is a conserved organelle that exists in almost all organisms, ranging from bacteria to mammals. Dysfunctions in LDs are linked to a range of human metabolic syndromes. The formation of protein complexes on LDs is crucial for maintaining their function. Investigating how proteins interact on LDs is essential for understanding the role of LDs. We have developed an effective method to uncover protein–protein interactions and protein complexes specifically on LDs. In this method, we conduct co-immunoprecipitation(co-IP) experiments using LD proteins extracted directly from isolated LDs, rather than utilizing proteins from cell lysates. To elaborate, we begin by purifying LDs with high-quality and extracting LD-associated proteins. Subsequently, the co-IP experiment is performed on these LD-associated proteins directly, which would enhance the co-IP experiment specificity of LDassociated proteins. This method enables researchers to directly unveil protein complexes on LDs and gain deeper insights into the functional roles of proteins associated with LDs.

关键词： Lipid droplet Co-immunoprecipitation Protein interaction