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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6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

Stage at diagnosis of colorectal cancer through diagnostic route:Who should be screened?

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World Journal of Gastroenterology 2024年第10期30卷 1368-1376页

作者： Nobukazu Agatsuma Takahiro Utsumi Yoshitaka Nishikawa Takahiro Horimatsu Takeshi Seta Yukitaka Yamashita Yukari Tanaka Takahiro Inoue Yuki Nakanishi Takahiro Shimizu Mikako Ohno Akane Fukushima Takeo Nakayama Hiroshi Seno Department of Gastroenterology and hepatology Kyoto University Graduate School of MedicineKyoto 606-8507Japan Department of Gastroenterology and hepatology Japanese Red Cross Wakayama Medical CenterWakayama 640-8558Japan Department of Health Informatics Kyoto University School of Public HealthKyoto 606-8501Japan Institute for Advancement of Clinical and Translational Science(iACT) Kyoto University HospitalKyoto 606-8507Japan Medical Support Section Medical Affairs DivisionKyoto University HospitalKyoto 606-8507Japan

BACKGROUND Colorectal cancer(CRC)is a global health concern,with advanced-stage diagnoses contributing to poor *** efficacy of CRC screening has been well-established;nevertheless,a significant proportion of patients remain unscreened,with>70%of cases diagnosed outside *** identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources,the association between the diagnostic routes and identification of these subgroups has been less *** the Japanese cancer registry,the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related *** To clarify the stage at CRC diagnosis based on diagnostic *** We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two *** diagnostic routes were primarily classified into three groups:Cancer screening,follow-up,and *** early-stage was defined as Stages 0 or *** and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups,referencing the follow-up *** adjusted covariates were age,sex,and tumor *** Of the 2083 patients,715(34.4%),1064(51.1%),and 304(14.6%)belonged to the follow-up,symptomatic,and cancer screening groups,*** the 2083 patients,CRCs diagnosed at an early stage were 57.3%(410 of 715),23.9%(254 of 1064),and 59.5%(181 of 304)in the follow-up,symptomatic,and cancer screening groups,*** symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group[P<0.001,adjusted odds ratio(aOR),0.23;95%confidence interval(95%CI):0.19-0.29].The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening gro

关键词： Colorectal neoplasms Cancer registry Diagnostic route Cancer screening Stage at diagnosis

Genetic risk stratification of inflammatory bowel disease-associated venous thromboembolism:An Asian perspective

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World Journal of Gastroenterology 2024年第9期30卷 1250-1252页

作者： James Guoxian Huang division of Gastroenterology Hepatology and NutritionDepartment of PaediatricsKhoo Teck Puat-National University Children’s Medical InstituteNational University Health SystemSingapore 119228Singapore Department of Paediatrics Yong Loo Lin School of MedicineNational University of SingaporeSingapore 119228Singapore

The utilisation of polygenic scoring models may enhance the clinician’s ability to risk stratify an inflammatory bowel disease patient’s individual risk for venous thromboembolism(VTE)and guide the appropriate usage... 详细信息

关键词： Thromboembolism Inflammatory bowel disease Genetic screening Venous thromboembolism Thromboprophylaxis

Screening for metabolic dysfunction-associated fatty liver disease:Time to discard the emperor’s clothes of normal liver enzymes?

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World Journal of Gastroenterology 2024年第22期30卷 2839-2842页

作者： Chen-Xiao Huang Xiao-Dong Zhou Calvin Q Pan Ming-Hua Zheng Metabolic Dysfunction-Associated Fatty Liver Disease Research Center Department of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina Department of Cardiovascular Medicine The Key Laboratory of Cardiovascular Diseases of WenzhouThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhou 325000Zhejiang ProvinceChina division of Gastroenterology and hepatology Department of MedicineNew York University Langone HealthNew York University Grossman School of MedicineNew YorkNY 11355United States Institute of hepatology Wenzhou Medical UniversityKey Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang ProvinceWenzhou 325000Zhejiang ProvinceChina

Metabolic dysfunction-associated fatty liver disease(MAFLD)is the most prevalent chronic liver condition *** liver enzyme-based screening methods have limitations that may missed diagnoses and treatment *** Chen et al,the risk of developing MAFLD remains elevated even when alanine aminotransferase levels fall within the normal ***,there is an urgent need for advanced diagnostic techniques and updated algorithms to enhance the accuracy of MAFLD diagnosis and enable early *** paper proposes two potential screening methods for identifying individuals who may be at risk of developing MAFLD:Lowering these thresholds and promoting the use of noninvasive liver fibrosis scores.

关键词： Metabolic dysfunction-associated fatty liver disease Non-alcoholic fatty liver disease Alanine aminotransferase Liver enzymes Screening Noninvasive liver fibrosis scores

Clinical application of COVID-19 vaccine in liver transplant recipients

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 339-343页

作者： Feng-Chao Liu Man Xie Wei Rao division of hepatology Liver Disease CenterThe Affiliated Hospital of Qingdao UniversityQingdao 266000China Organ Transplantation Center The Affiliated Hospital of Qingdao UniversityQingdao 266000China Institute of Organ Donation and Transplantation of Qingdao University Qingdao 266000China Department of Gastroenterology The Affiliated Hospital of Qingdao UniversityQingdao 266000China

Background:Solid organ transplant(SOT)activities,such as liver transplant,have been greatly influenced by the pandemic of coronavirus disease 2019(COVID-19),a disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Immunosuppressed individuals of liver transplant recipients(LTRs)tend to have a high risk of COVID-19 infection and related ***,COVID-19 vaccination has been recommended to be administered as early as possible in *** sources:The keywords“liver transplant”,“SARS-CoV-2”,and“vaccine”were used to retrieve articles published in ***:The antibody response following the 1st and 2nd doses of vaccination was disappointingly low,and the immune responses among LTRs remarkably improved after the 3rd or 4th dose of *** the 3rd or 4th dose of COVID-19 vaccine increased the antibody titer,a proportion of patients remained ***,recent studies showed that SARS-CoV-2 vaccine could trigger adverse events in LTRs,including allograft rejection and liver ***:This review provides the recently reported data on the antibody response of LTRs following various doses of vaccine,risk factors for poor serological response and adverse events after vaccination.

关键词： Liver transplant COVID-19 SARS-CoV-2 Vaccine Antibody response

Impact of ursodeoxycholic acid therapy in autoimmune liver disease patients with COVID-19 and its clinical prognosis

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Biosafety and Health 2024年第3期6卷 165-170页

作者： Minghui Li Weihua Cao Tingting Jiang Wen Deng Shiyu Wang Shuling Wu Lu Zhang Yao Lu Min Chang Ruyu Liu Xiaoyan Ding Ge Shen Yuanjiao Gao Hongxiao Hao Xiaoxue Chen Leiping Hu Mengjiao Xu Yuyong Jiang Wei Yi Yao Xie Rui Song Department of hepatology division 2 Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of hepatology division 2 Peking University Ditan Teaching HospitalBeijing 100015China Department of Medical Oncology Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Center of Integrative Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of Gynecology and Obstetrics Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of Infectious Disease Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

To explore the impact of ursodeoxycholic acid(UDCA)on severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and clinical outcomes in patients with autoimmune liver disease(AILD).Patients diagnosed with AILD were enrolled and divided into a UDCA group and a non-UDCA group based on whether they received UDCA *** data were collected regarding AILD diagnosis,treatment,biochemical indicators,and imaging *** incidence of SARS-CoV-2 infection and the prognosis of AILD patients were observed.A total of 1,138 patients completed *** usage rate of hormone(P=0.003)and immunosuppressant(P=0.001)used for treating AILD in the non-UDCA group was markedly lower than in the UDCA *** UDCA usage rate was markedly lower in SARS-CoV-2 infected patients than in uninfected patients(P=0.003).The rate of SARS-CoV-2 infection in the non-UDCA group was significantly higher than in the UDCA group(P=0.018).Logistic regression analysis showed that UDCA use(P=0.003)was correlated to a lower incidence of SARS-CoV-2,while immunosuppressant use(P=0.017)increased the *** time from SARS-CoV-2 infection was markedly longer for those receiving UDCA treatment than those in the non-UDCA group(P=0.018).UDCA is associated with low SARS-CoV-2 incidence in AILD patients,while immunosuppressant increases its incidence *** receiving UDCA treatment have a longer recovery time after being infected.

关键词： Ursodeoxycholic acid(UDCA) Autoimmune liver disease(AILD) Coronavirus disease 2019(COVID-19) Primary biliary cholangitis(PBC) Autoimmune hepatitis(AIH)

Can rifaximin for hepatic encephalopathy be discontinued during broad-spectrum antibiotic treatment?

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World Journal of hepatology 2024年第2期16卷 115-119页

作者： Chien-Hao Huang Piero Amodio division of hepatology Department of Gastroenterology and HepatologyChang-Gung Memorial HospitalLinkou Medical CenterTaoyuan 333Taiwan Department of Clinical and Experimental Medicine University of PaduaPadova 35122Italy

Hepatic encephalopathy(HE)is a formidable complication in patients with decompensated cirrhosis,often necessitating the administration of rifaximin(RFX)for effective ***,is a gut-restricted,poorly-absorbable oral rifamycin derived antibiotic that can be used in addition to lactulose for the secondary prophylaxis of *** has shown notable reductions in infection,hospital readmission,duration of hospital stay,and ***,limited data exist about the concurrent use of RFX with broad-spectrum antibiotics,because the patients are typically excluded from studies assessing RFX efficacy in HE.A pharmacist-driven quasi-experimental pilot study was done to address this *** argue against the necessity of RFX in HE during broad-spectrum antibiotic treatment,particularly in critically ill patients in intensive care unit(ICU).The potential for safe RFX discontinuation without adverse effects is clearly illuminated and valuable insight into the optimization of therapeutic strategies is *** findings also indicate that RFX discontinuation during broadspectrum antibiotic therapy was not associated with higher rates of delirium or coma,and this result remained robust after adjustment in multivariate ***,rates of other secondary clinical and safety outcomes,including ICU mortality and 48-hour changes in vasopressor requirements,were ***,since the activity of RFX is mainly confined to the modulation of gut microbiota,its potential utility in patients undergoing extensive systemic antibiotic therapy is debatable,given the overlapping antibiotic ***,this suggests that the action of RFX on HE is class-specific(related to its activity on gut microbiota),rather than drug-specific.A recent double-blind randomized controlled(ARiE)trial provided further evidence-based support for RFX withdrawal in critically ill cirrhotic ICU patients receiving broad-spectrum *** studies prompt further discussion about

关键词： Rifaximin discontinuation Hepatic encephalopathy Broad-spectrum antibiotics Crit-ically ill Medical intensive care unit Pharmacist-driven protocol

The gut microbiome modulate response to immunotherapy in cancer

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Science China Life Sciences 2024年

作者： Shan-Shan Jiang Zi-Ran Kang Ying-Xuan Chen Jing-Yuan Fang division of Gastroenterology and hepatology Shanghai Institute of Digestive Disease NHC Key Laboratory of Digestive Diseases State Key Laboratory for Oncogenes and Related Genes Renji Hospital School of Medicine Shanghai Jiao Tong University

Gut microbiota have been reported to play an important role in the occurrence and development of malignant tumors. Currently, clinical studies have identified specific gut microbiota and its metabolites associated with efficacy of immunotherapy in multiple types of *** investigations have elucidated that gut microbiota modulate the antitumor immunity and affect the efficacy of cancer immunotherapy. Certain microbiota and its metabolites may favorably remodel the tumor microenvironment by engaging innate and/or adaptive immune cells. Understanding how the gut microbiome interacts with cancer immunotherapy opens new avenues for improving treatment strategies. Fecal microbial transplants, probiotics, dietary interventions, and other strategies targeting the microbiota have shown promise in preclinical studies to enhance the immunotherapy. Ongoing clinical trials are evaluating these approaches. This review presents the recent advancements in understanding the dynamic interplay among the host immunity, the microbiome, and cancer immunotherapy, as well as strategies for modulating the microbiome, with a view to translating into clinical applications.

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Serum markers for detecting histological features of autoimmune hepatitis and predicting prognosis in patients with antinuclear antibody-positive drug-induced liver injury

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Portal Hypertension & Cirrhosis 2024年第2期3卷 96-104页

作者： Feiyu Zhang Meishan Jin Hongqin Xu Peng Xiao Yanhang Gao division of hepatology The First Hospital of Jilin UniversityJilin UniversityChangchunJilinChina division of Pathology The First Hospital of Jilin UniversityJilin UniversityChangchunJilinChina

Aims:Although useful for distinguishing drug-induced liver injury(DILI)from autoimmune hepatitis(AIH),liver biopsy is an invasive examination,and the presence of antinuclear antibody(ANA)positivity in patients with DILI could lead to excessive use of ***,we aimed to identify screening markers for histological features of AIH in patients with ANA-positive DILI and verify their clinical outcomes after 1 ***:This retrospective study included patients with ANA-positive DILI,who underwent liver biopsy between January 2017 and April *** pathologists identified histological features of *** detected the independent indicators associated with histological features of AIH using logistic *** evaluated their diagnostic ability for histological features of AIH using the receiver operating characteristic *** followup period to determine clinical outcomes was 1 year after DILI ***χ2 test or Fisher's exact test was used to compare categorical data and the Wilcoxon rank-sum test was used to compare continuous *** p<0.05 was considered to indicate ***:The final analysis included 125 patients with ANA-positive DILI,of whom 18 had AIH-like *** independently associated with AIH-like histology included globulin levels(odds ratio[OR]=1.154,95%confidence interval[CI]=1.046-1.288;p=0.006)and ANA titer≥1:1000(OR=3.531,95%CI=1.136-11.303;p=0.029).The optimal globulin cutoff indicating AIH-like histology was 31.8 g/*** globulin level in combination with ANA titer≥1:1000(area under the curve=0.785,95%CI=0.738-0.832)provided a sensitivity of 100%and a specificity of 57%for indicating histological features of AIH in patients with ANA-positive *** follow-up,more patients developed AIH in the group with AIH-like histology than in the group without AIH-like histology(35.3%vs.0,p<0.001).Conclusions:For patients with ANA-positive DILI and ANA titer≥1:1000 or globulin≥31.8 g/L,liver biopsy is recomm

关键词： antibodies autoimmune hepatitis chemical-and drug-induced liver injury histology immunoglobulins