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Hippo(YAP)-autophagy axis protects against hepatic ischemia-reperfusion injury through JNK signaling

Chinese Medical Journal 2024年第6期137卷 657-668页

作者： Shuguang Zhu Xiaowen Wang Haoqi Chen Wenfeng Zhu Xuejiao Li Ruiwen Cui Xiaomeng Yi Xiaolong Chen Hua Li Genshu Wang Department of Hepatic Surgery Liver TransplantationThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Hepatology lab The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of General Surgery The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Organ Transplantation The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Renal Transplantation Guangdong Provincial Hospital of Chinese MedicineGuangzhouGuangdong 510630China Department of Surgical Intensive Care unit The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Hepatic Surgery Liver TransplantationGuangdong Provincial Hospital of Chinese MedicineGuangzhouGuangdong 510630China

Background:Hepatic ischemia-reperfusion injury(HIRI)remains a common complication during liver transplantation(LT)in patients.As a key downstream effector of the Hippo pathway,Yes-associated protein(YAP)has been reported to be involved in various physiological and pathological processes.However,it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.Methods:Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation.Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation.Results:Autophagy was activated in the post-perfusion liver grafts during LT in patients,and the expression of YAP positively correlated with the autophagic level of hepatocytes.liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI(P<0.05).YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models(P<0.05).Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine.In addition,inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species(P<0.05).Moreover,the regulation of autophagy by YAP during HIRI was mediated by AP1(c-Jun)N-terminal kinase(JNK)signaling through binding to the transcriptional enhanced associate domain(TEAD).Conclusions:YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes.Targeting Hippo(YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

关键词： YAP-signaling proteins Autophagy c-Jun N-terminal kinase Ischemia-reperfusion injury liver transplantation

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Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 241-248页

作者： Chao Sun George Boon-Bee Goh Wan-Cheng Chow Wah-Kheong Chan Grace Lai-Hung Wong Wai-Kay Seto Yi-Hsiang Huang Han-Chieh Lin I-Cheng Lee Hye Won Lee Seung Up Kim Vincent Wai-Sun Wong Jian-Gao Fan Center for Fatty liver Disease Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Lab of Pediatric Gastroenterology and NutritionShanghai 200092China Department of Gastroenterology&Hepatology Singapore General HospitalSingaporeSingapore Gastroenterology and Hepatology unit Department of MedicineFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia Department of Medicine and Therapeutics and State Key laboratory of Digestive Disease The Chinese University of Hong KongHong KongChina Department of Medicine The University of Hong KongHong KongChina Institute of Clinical Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina Division of Gastroenterology and Hepatology Taipei Veterans General HospitalTaipeiTaiwanChina Faculty of Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina Department of Internal Medicine Yonsei University College of MedicineSeoulKorea

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value oflaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

关键词： Nonalcoholic fatty liver disease Impaired renal function Agile 3+ Agile 4 Metabolic syndrome

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FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1605-1623页

作者： Zhifeng Huang Tongtong Pan Liang Xu Lu Shi Xiong Ma Liya Zhou Luyao Wang Jiaojiao Wang Guoqing Zhu Dazhi Chen Lingtao Song Xiaomin Pan Xiaodong Wang Xiaokun Li Yongde Luo Yongping Chen Hepatology Diagnosis and Treatment Center Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseasesthe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325035China Oujiang laboratory(Zhejiang lab for Regenerative Medicine Vision and Brain Health)&School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhou 325035China School of laboratory Medicine and Life Sciences Wenzhou Medical University&Key Laboratory of Laboratory MedicineMinistry of EducationWenzhou Medical UniversityWenzhou 325035China Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200001China Hangzhou Medical College Hangzhou 311300China

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine;however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

关键词： Fibroblast growthfactor 4 Fibroblast growth factor receptor 4 Immune liver injury Ca^(2+)/Calmodulin dependent protein

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Systematic comparison of experimental and human obstructive cholestasis reveals conservation of canonical pathway activation and biomarkers relevant for cholestatic liver disease

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Genes & Diseases 2023年第1期10卷 18-21页

作者： Eva Gijbels Kevin De Muynck Bart Vanderborght Tim Meese Filip Van Nieuwerburgh Aude Vanlander Frederik Berrevoet Bart Hendrikx Anne Hoorens Hans Van Vlierberghe Mathieu Vinken Lindsey Devisscher Department of Pharmaceutical and Pharmacological Sciences Vrije Universiteit Brussel1090 BrusselsBelgium Gut-liver Immunopharmacology unit Basic and Applied Medical SciencesLiver Research Centre GhentFaculty of Medicine and Health SciencesGhent University9000 GhentBelgium Hepatology Research unit Internal Medicine and PaediatricsLiver Research Centre GhentFaculty of Medicine and Health SciencesGhent University9000 GhentBelgiumd lab of Pharmaceutical Biotechnology Ghent University9000 GhentBelgium NXTGNT Ghent University9000 GhentBelgium Department of HPB Surgery and liver Transplantation Ghent University Hospital9000 GhentBelgium Department of Pathology Ghent University Hospital9000 GhentBelgium Hepatology Research unit Internal Medicine and PaediatricsLiver Research Centre GhentFaculty of Medicine and Health SciencesGhent University9000 GhentBelgium

Cholelithiasis-induced cholestasis is one of the most common causes of hospitalization due to gastrointestinal disease,yet considerable knowledge gaps exist in the pathogenesis of this disease.This can partially be explained by inadequate characterization of experimental cholestasis models.Here,we compared the transcriptional profile of commonly used mouse models for obstructive cholestasis and benchmarked them to human disease to identify the model(s)best suited for cholelithiasis-induced cholestasis research and to uncover conserved mechanisms involved in human and murine cholestasis.

关键词： cholestasis obstructive pathogenesis

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Role of zonula occludens in gastrointestinal and liver cancers

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World Journal of Clinical Cases 2022年第12期10卷 3647-3661页

作者： Amit Kumar Ram Balasubramaniyan Vairappan liver Diseases Research lab Department of BiochemistryJawaharlal Institute of Postgraduate Medical Education and ResearchPondicherry 605006India

A growing body of evidence suggests that tight junction(TJ)proteins play a crucial role in the pathogenesis of various diseases,including gastrointestinal(GI)cancer and hepatocellular carcinoma(HCC).TJ proteins primarily maintain the epithelial and endothelial cells intact together through integral proteins however,recent reports suggest that they also regulate gene expression necessary for cell proliferation,angiogenesis,and metastasis through adapter proteins such as zonula occludens(ZO).ZO proteins are membrane-associated cytosolic scaffolding proteins that modulate cell proliferation by interacting with several transcription factors.Reduced ZO proteins in GI cancer and HCC are correlated with tumor development and poor prognosis.Pubmed has searched for using the keyword ZO and gastric cancer,ZO and cancer,and ZO and HCC for the last ten years to date.This review summarized the role of ZO proteins in cell proliferation and their expression in GI cancer and HCC.Furthermore,therapeutic interventions targeting ZO in GI and liver cancers are reviewed.

关键词： Tight junction Zonula occludens-1 Zonula occludens-1 associated nucleic acid binding protein Hepatocellular carcinoma Colon cancer Gastric cancer

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A review of the literature on the use of CRISPR/Cas9 gene therapy to treat hepatocellular carcinoma

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Oncology Research 2024年第3期32卷 439-461页

作者： ELHAM AMJAD RAFAELE PEZZANI BABAK SOKOUTI Biotechnology Research Center Tabriz University of Medical SciencesTabriz***Iran Phytotherapy lab Endocrinology UnitDipartimento di Medicina(DIMED)University of PadovaVia Ospedale 105Padova35128Italy Associazione Italiana Per La Ricerca Oncologica Di Base Associazione Italiana Per La Ricerca Oncologica Di BasePadova35128Italy

Noncoding RNAs instruct the Cas9 nuclease to site speifillyl cleave DNA in the CRISPR/Cas9 system.Despite the high incidence of hepatocellular carcinoma(HCC),the patient's outcome is poor.As a result of the emergence of therapeutic resistance in HCC patients,dlinicians have faced difficulties in treating such tumor.In addition,CRISPR/Cas9 screens were used to identify genes that improve the dlinical response of HCC patients.It is the objective of this article to summarize the current understanding of the use of the CRISPR/Cas9 system for the treatment of cancer,with a particular emphasis on HCC as part of the current state of knowledge.Thus,in order to locate recent developments in oncology research,we examined both the Scopus database and the PubMed database.The ability to selectively interfere with gene expression in combinatorial CRISPR/Cas9 screening can lead to the discovery of new effective HCC treatment regimens by combining clinically approved drugs.Drug resistance can be overcome with the help of the CRISPR/Cas9 system.HCC signature genes and resistance to treatment have been uncovered by genome-scale CRISPR activation screening although this method is not without limitations.It has been extensively examined whether CRISPR can be used as a tool for disease research and gene therapy.CRISPR and its applications to tumor research,particularly in HCC,are examined in this study through a review of the literature.

关键词： CRISPR/Cas9 system Gene therapy Tumor Hepatocellular carcinoma liver cancer Gene editing

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Modulating the Intestinal Microbiota:Therapeutic Opportunities in liver Disease

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Journal of Clinical and Translational Hepatology 2020年第1期8卷 87-99页

作者： Cyriac Abby Philips Philip Augustine Praveen Kumar Yerol Ganesh Narayan Ramesh Rizwan Ahamed Sasidharan Rajesh Tom George Sandeep Kumbar The liver unit Monarch Liver Lab and Division of GastroenterologyCochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Department of Gastroenterology State Government Medical CollegeThrissurKeralaIndia Department of Gastroenterology Aster MedcityKochiKeralaIndia

Gut microbiota has been demonstrated to have a significant impact on the initiation,progression and development of complications associated with multiple liver diseases.Notably,nonalcoholic fatty liver diseases,including nonalcoholic steato-hepatitis and cirrhosis,severe alcoholic hepatitis,primary scle-rosing cholangitis and hepatic encephalopathy,have strong links to dysbiosis–or a pathobiological change in the microbiota.In this review,we provide clear and concise discussions on the human gut microbiota,methods of identifying gut microbiota and its functionality,liver diseases that are affected by the gut microbiota,including novel associations under research,and provide current evidence on the modulation of gut microbiota and its effects on specific liver disease conditions.

关键词： Microbiome Metagenomics NGS Cirrhosis Illumina

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Still'dwelling in the possibility'-critical update on stem cell therapy for acute on chronic liver failure

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World Journal of Stem Cells 2020年第10期12卷 1124-1132页

作者： Cyriac Abby Philips Philip Augustine the liver unit and monarch liver lab Cochin Gastroenterology GroupErnakulam Medical CenterKochi 682025KeralaIndia Department of Gastroenterology and Advanced GI Endoscopy Cochin Gastroenterology GroupErnakulam Medical CenterKochi 682025KeralaIndia

Stem cells therapy could improve survival in patients with liver failure.Studies on stem cell therapy and related growth factors in decompensated cirrhosis has been on the forefront but has shown heterogenous results.Recent high-quality studies have shown a lack of efficacy and safety.Patients with acute-on-chronic liver failure(ACLF)are a unique group with high mortality in the short-term associated with rapid onset extrahepatic organ failures.In these patients,there is an urgent need to identify treatments that can improve liver cell function and mass,prevent sepsis/organ failure,ameliorate systemic inflammation,and increase transplant-free survival.Stem cells are a novel treatment in ACLF but with unclear efficacy and safety.In this narrative review,we discuss the basics of liver regeneration in patients with ACLF and update current clinical status of stem cell use in patients with ACLF for improving our understanding of future directions.

关键词： Portal hypertension Regenerative therapy Mesenchymal stem cells liver failure Sepsis

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Safety,immunogenicity,and preliminary efficacy of a randomized clinical trial ofomicron XBB.1.5-containing bivalent mRNA vaccine

hLife

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hLife 2024年第3期2卷 113-125页

作者： Xuanjing Yu Wei Yang Wei Li Na Wan Guanghong Yan Zumi Zhou Xiao Zhu Wei Su Yani Li Chenyu Xing Sifan Duan Houze Yu Xinshuai Zhao Chunmei Li Taicheng Zhou Dingyun You Jia Wei Zijie Zhang State Key laboratory for Conservation and Utilization of Bio-Resource and School of Life Sciences Yunnan UniversityYunnanChina Southwest united Graduate School YunnanChina State Key laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghaiChina Yunnan Vaccine laboratory YunnanChina School of Public Health Kunming Medical UniversityYunnanChina Yunnan Genvoo Biotech Ltd. YunnanChina Central lab and liver Disease Research Center The Affiliated Hospital of Yunnan UniversityYunnan UniversityYunnanChina

Periodically updating coronavirus disease 19(COVID-19)vaccines that offer broad-spectrum protection is needed giventhe strong immune evasion by the circulating omicron sublineages.The effectiveness of prototype and BA.4/5-containing bivalent mRNA vaccines is reduced when XBB subvariants predominate.We initiated an observer-blinded,threearms study in 376 patients in Chinese individuals aged from 18 to 55 years old who had previously received three dosesCOVID-19 vaccine.Immunogenicity in terms of neutralizing antibodies elicited by a 30-mg dose of XBB.1.5-containingbivalent vaccine(RQ3027),a 30-mg dose of BA.2/BA.5-Alpha/Beta bivalent vaccine(RQ3025)and their precedent 30-mg Alpha/Beta(combined mutations)monovalent mRNA vaccine(RQ3013)and safety are primary and secondary endpoints,respectively.We recorded prescribed COVID-19 cases to explore the preliminary efficacy of three vaccines.RQ3027 and RQ3025 boosters elicited superior neutralizing antibodies(NAbs)against XBB.1.5,XBB.1.16,XBB.1.9.1,and JN.1 compared to RQ3013 at day 14 in participants without SARS-CoV-2 infection.All study vaccines were welltolerated without serious adverse reactions identified.The incidence rates per 1000 person-years of COVID-19 casesduring the 2nd-19th week after randomization were lowest in RQ3027.Overall,our data show that XBB.1.5-containingbivalent booster generated superior immunogenicity and better protection against newer severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants compared to BA.2/BA.5-containing bivalent and Alpha/Beta monovalentwith no new safety concerns.

关键词： severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) JN.1 XBB lineages coronavirus disease19(COVID-19)vaccine mRNA bivalent vaccine randomized clinical trial

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Repurposing Pirfenidone for Nonalcoholic Steatohepatitis-related Cirrhosis:A Case Series

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Journal of Clinical and Translational Hepatology 2020年第1期8卷 100-105页

作者： Cyriac Abby Philips Guruprasad Padsalgi Rizwan Ahamed Rajaguru Paramaguru Sasidharan Rajesh Tom George Pushpa Mahadevan Philip Augustine the liver unit and monarch liver lab Cochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Department of Gastroenterology Cochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Department of Pathology Al Salam International HospitalBneid Al QarKuwaitIndia Department of Diagnostic and Interventional Radiology Department of Gastroenterology and The Liver UnitCochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Department of Clinical Pathology VPS Lakeshore HospitalKochiKeralaIndia

We repurposed the antifibrotic drug pirfenidone—which is approved for treatment of idiopathic lung fibrosis—in a series of patients with nonalcoholic steatohepatitis-related cirrhosis.Our report demonstrates the observed improvements in necroinflammation and regression of cirrhosis with pirfeni-done use for 12-weeks,associated with classical hepatic repair complex features on follow-up liver biopsies.This novel work could help stimulate further randomized trials of pirfe-nidone in patients with nonalcoholic steatohepatitis-related liver fibrosis or cirrhosis,for whom no recommended drug treatments exists currently.

关键词： NASH Fibrosis Antifibrotic Hepatitis Pirfenidone

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