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High-throughput screening of novel TFEB agonists in protecting against acetaminopheninduced liver injury in mice

Acta Pharmaceutica Sinica B 2024年第1期14卷 190-206页

作者： Xiaojuan Chao Mengwei Niu Shaogui Wang Xiaowen Ma Xiao Yang Hua Sun Xujia Hu Hua Wang Li Zhang Ruili Huang Menghang Xia Andrea Ballabio Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Oncology the First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China National Center for Advancing Translational Sciences National Institutes of HealthBethesdaMD 20892USA Telethon Institute of Genetics and Medicine TIGEMPozzuoliNaples 80131Italy Medical Genetics Department of Translational MedicineFederico II UniversityNaples 80131Italy Department of Molecular and Human Genetics Baylor College of MedicineHoustonTX 77030USA Department of Internal Medicine Division of GastroenterologyHepatology&MotilityUniversity of Kansas Medical CenterKansas CityKS 66160USA

Macroautophagy(referred to as autophagy hereafter)is a major intracellular lysosomal degradation pathway that is responsible for the degradation of misfolded/damaged proteins and organelles.Previous studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein adducts.The lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with autophagosomes.In the present study,we showed that transcription factor EB(TFEB),a master transcription factor for lysosomal biogenesis,was impaired by APAP resulting in decreased lysosomal biogenesis in mouse livers.Genetic loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,respectively.Mechanistically,overexpression of TFEB increased clearance of APAP protein adducts and mitochondria biogenesis as well as SQSTM1/p62-dependent non-canonical nuclear factor erythroid 2-related factor 2(NRF2)activation to protect against AILI.We also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB agonists.Among these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI in mice.In conclusion,genetic and pharmacological activating TFEB may be a promising approach for protecting against AILI.

关键词： Autophagy DILI Drug screening Hepatotoxicity Lysosome Mitochondria Mitophagy NRF2

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抗结核药物性肝损伤的新型生物标志物研究进展

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中华结核和呼吸杂志 2024年第5期47卷 469-474页

作者：王乐乐刘松涛唐神结李佩波重庆市公共卫生医疗救治中心结核病研究室重庆400036 重庆市公共卫生医疗救治中心重庆400036 首都医科大学附属北京胸科医院、北京市结核病胸部肿瘤研究所北京101149

抗结核药物性肝损伤(ATB-DILI)是结核病患者在抗结核治疗过程中最常见的不良反应。目前ATB-DILI的诊断主要依赖于转氨酶等传统生物标志物,但这些指标对肝毒性特异性低,不能解释肝损伤机制,无法预测ATB-DILI的早期发病。本文通过ATB-DIL... 详细信息

抗结核药物性肝损伤(ATB-DILI)是结核病患者在抗结核治疗过程中最常见的不良反应。目前ATB-DILI的诊断主要依赖于转氨酶等传统生物标志物,但这些指标对肝毒性特异性低,不能解释肝损伤机制,无法预测ATB-DILI的早期发病。本文通过ATB-DILI早期预测、严重程度预测以及治疗和预防三个方面,对目前有潜在前景的ATB-DILI生物标志物作一阐述。

关键词：生物标志物结核病患者抗结核药物性肝损伤抗结核治疗早期预测肝毒性不良反应 DILI

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Liver Fibrosis Helps to Distinguish Autoimmune Hepatitis from DILI with Autoimmune Features: A Review of Twenty Cases

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Journal of Clinical and Translational Hepatology 2019年第1期7卷 21-26页

作者： Christopher A.Febres-Aldana Sarah Alghamdi Kritika Krishnamurthy Robert J.Poppiti Department of Pathology and Laboratory Medicine Mount Sinai Medical CenterMiami BeachFLUSA Herbert Wertheim College of Medicine Florida International UniversityMiamiFLUSA

Background and Aims:Drug-induced liver injury with autoimmune features(AI-DILI)mimics the clinical presentation,and laboratory and pathologic features of idiopathic autoimmune hepatitis(AIH).We aimed to identify histopathologic hallmarks to differentiate these entities.Methods:All liver biopsies archived for the past 10 years were reviewed retrospectively to identify cases of recently detected liver injury associated with predominantly lymphoplasmacytic interphase hepatitis,positive markers for liver autoimmunity,and negative tests for viral hepatitis.Twenty cases were divided into AIH(n=12)or AI-DILI(n=8)groups.Blind qualitative evaluation of necroinflammatory changes and liver fibrosis were performed according to the Scheuer scoring system.Cellular densities were determined using ImageJ(V1.51t,National Institutes of Health,Bethesda,MD,USA).Fibrosis was assessed on Masson trichrome-stained slides,and collagen deposition was estimated following a protocol of color deconvolution.Results:Necroinflammatory changes as well as densities(portal and lobular)of neutrophils and eosinophils,intracellular cholestasis,and regenerative changes did not differ between the two groups(P≥0.05).Neutrophil densities but not eosinophils showed a positive correlation with the severity of hepatocellular damage(r=0.6and 0.58,vs.alanine aminotransferase,PDILI(PDILI(PDILI or AIH,advanced stages of liver fibrosis can be used to support the diagnosis of AIH in some cases.Definitive diagnosis of AI-DILI requires follow-up and demonstration of complete remission after drug withdrawal with no need for immunosuppression.

关键词： DILI Autoimmune hepatitis Liver fibrosis Digital pathology

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Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3791-3805页

作者： Hui Qian Qingyun Bai Xiao Yang Jephte Y.Akakpo Lili Ji Li Yang Thomas Rulicke Kurt Zatloukal Hartmut Jaeschke Hong-Min Ni Wen-Xing Ding Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160USA The MOE Key Laboratory for Standardization of Chinese Medicines Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese MedicinesInstitute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai 201203China School of Chemistry and Bioengineering Yichun UniversityYichun 336000China Department of Biomedical Sciences University of Veterinary Medicine Vienna Veterina¨rplatzVienna 1210Austria The Institute of Pathology Medical University of GrazGraz A-8036Austria

Acetaminophen(APAP)overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States.We investigated the role of p62/SQSTM1(referred to as p62)in APAP-induced liver injury(AILI)in mice.We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment,which was inversely correlated with the hepatic levels of APAPadducts.APAP also activated mTOR at 24 h,which is associated with increased cell proliferation.In contrast,p62 knockout(KO)mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment.Surprisingly,p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h.We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor(VWF)and platelet aggregation,which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment.Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.

关键词： Autophagy Coagulation DILI Liver regeneration Macrophage Hepatotoxicity Platelet

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Mechanisms of immune checkpoint inhibitormediated liver injury

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3727-3739页

作者： Layla Shojaie Myra Ali Andrea Iorga Lily Dara Division of Gastrointestinal and Liver Diseases Department of MedicineKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Research Center for Liver Disease Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Keck School of Medicine University of Southern CaliforniaLos AngelesCA 90033USA U.S.Food and Drug Administration Center for Devices and Radiological HealthSilver SpringMD 20993USA UMBC Center for Accelerated Real Time Analytics University of MarylandBaltimore CountyBaltimoreMD 21250USA

The immune checkpoints,cytotoxic T-lymphocyte-associated antigen 4(CTLA-4) and programmed cell death protein-1/ligand-1(PD-1/PD-L1) are vital contributors to immune resulation and tolerance.Recently immune checkpoint inhibitors(ICIs) have revolutionized cancer therapy;however,they come with the cost of immune related adverse events involving multiple organs such as the liver.Due to its constant expo sure to foreign antigens,the liver has evolved a high capacity for immune tolerance,therefore,blockade of the immune checkpoints can result in aberrant immune activation affecting the liver in up to 20% of patients depending on the agent(s) used and underlying factors.This type of hepatotoxicity is termed immune mediated liver injury from checkpoint inhibitors(ILICI) and is more common when CTLA4 and PD-1/PDL1 are used in combination.The underlying mechanisms of this unique type of hepatotoxicity are not fully understood;however,the contribution of CD8^(+) cytotoxic T lymphocytes,various CD4^(+) T cells populations,cytokines,and the secondary activation of the innate immune system leading to liver injury have all been suggested.This review summarizes our current understanding of the underlying mechanisms of liver injury in immunotherapy using animal models of ILICI and available patient data from clinical studies.

关键词： Hepatotoxicity DILI Immunotherapy Cell death Hepatocyte CTLA-4 PD-1 PD-L1 Necrosis Apoptosis

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Outcomes and Toxicology of Herbal Drugs in Alcoholic Hepatitis-A Single Center Experience from India

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Journal of Clinical and Translational Hepatology 2019年第4期7卷 329-340页

作者： Cyriac Abby Philips Sasidharan Rajesh Tom George Rizwan Ahamed Sandeep Kumbar Philip Augustine The Liver Unit and Monarch Liver Lab Cochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia Interventional Radiology Department of Gastroenterology and HepatologyCochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia Gastroenterology and Advanced G.I.Endoscopy Cochin Gastroenterology GroupErnakulam Medical CenterKochiKeralaIndia

Background and Aims:We aimed to study clinical out-comes and liver biopsy features of alcoholic hepatitis(AH)patients on complementary and alternative medicines(CAMs)and to analyze the retrieved drugs for chemical and toxic components linked to drug-induced liver injury.Methods:We retrospectively assessed clinical,biochemical and liver bi-opsy features of AH patients on CAM with drug-induced liver injury(AH-CAM,n=27)and compared them to a control group(classical AH,n=29)on standard of care.Patients without liver biopsy evaluation and other causes for liver dis-ease were excluded.Samples of the CAMs(n=42)from pa-tients were retrieved and assessed for chemical and toxins.Results:All were males,and significantly worse clinical pre-sentation,biochemical severity,and liver disease scores were notable in patients with AH-CAM.Traditional Ayurve-dic-polyherbal formulations were the most commonly used CAM.On liver histology,varying grades of severe-necrosis,severe hepatocellular,canalicular,cholangiolar cholestasis with predominant lymphocytic-portal-inflammation and varying grades of interface-hepatitis were noted in AH-CAM.Analysis of CAMs revealed presence of heavy metals up to 100,000 times above detectable range and adulter-ants,such as antibiotics,chemotherapy agents,nonsteroi-dal anti-inflammatory drugs,alcohols,antidepressants,anxiolytics,and recreational drugs.On follow up,a signifi-cantly higher number of patients with AH on CAM died at end of 1,3-and-6-months compared to controls(37%vs.83%,29%vs.62%,18%vs.52%respectively;p<0.001).Conclusions:Patients with AH and CAM-related drug-induced liver injury have extremely poor short-term survival in the absence of liver transplantation compared to those patients with AH on evidence-based management.Early transplant referral and educating on and curbing of CAM use in severe liver disease through strict monitoring of unregulated traditional health practices can help ease the burden of liver-related death.

关键词： Hepatitis Alcohol CAM DILI Ayurveda

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Idiosyncratic Drug-Induced Liver Injury Linked to Polygonum multiflorum:A Case Study by Pharmacognosy

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Chinese Journal of Integrative Medicine 2017年第8期23卷 625-630页

作者： LI Chun-yu HE Qin GAO Dan LI Rui-yu ZHU Yun LI Hui-fang FENG Wu-wen YANG Mei-hua XIAO Xiao-he WANG Jia-bo Institute of Medicinal Plant Development Chinese Academy of Medical Sciences & Peking Union Medical College China Military Institute of Chinese Medicine 302 Military Hospital School of Pharmacy Hunan University of Traditional Chinese Medicine School of Pharmacy Shanxi University of Traditional Chinese Medicine

The use of Chinese medicinal herbs（CMH）continues to expand rapidly across the world with a deep belief that herbs are safe because they are＂natural＂.（1）However,a survey of the literature indicates that CMH related hepatotoxicity is increasing and has been a worldwide problem.（2,3）Polygonum multiflorum Thunb.（P.multiflorum）,officially listed in the Pharmacopoeia of the People＇s Republic of China.

关键词： Idiosyncratic Drug-Induced Liver Injury Linked to Polygonum multiflorum:A Case Study by Pharmacognosy UHPLC DILI

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普瑞巴林致肝脏转氨酶急性升高1例

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中国医院药学杂志 2023年第21期43卷 2467-2470页

作者：陈娅彭俊李超马雪蒋倩四川省肿瘤临床医学研究中心四川省肿瘤医院·研究所四川省癌症防治中心电子科技大学附属肿瘤医院药学部四川成都610041 四川省肿瘤临床医学研究中心四川省肿瘤医院·研究所四川省癌症防治中心电子科技大学附属肿瘤医院胸外科四川成都610041 重庆大学附属肿瘤医院药学部重庆400030

药物性肝损伤(drug-inducedliverinjury,DILI)是最常见的药物不良反应之一,大型回顾性研究[1]发现,我国DILI年发生率约为每10万人23.80例,远高于西方国家报道数据。普瑞巴林是作用于γ-氨基丁酸的结构类似物,通过调节钙通道发挥镇痛作用... 详细信息

药物性肝损伤(drug-inducedliverinjury,DILI)是最常见的药物不良反应之一,大型回顾性研究[1]发现,我国DILI年发生率约为每10万人23.80例,远高于西方国家报道数据。普瑞巴林是作用于γ-氨基丁酸的结构类似物,通过调节钙通道发挥镇痛作用,临床主要用于神经病理性疼痛或肌纤维痛等的治疗[2],常见不良反应有头晕、嗜睡和乏力等,鲜见DILI相关不良反应报道。本文为1例普瑞巴林致DILI的病例报道,并结合文献资料进一步分析该药致DILI的特点和转归情况,以为临床实践中普瑞巴林DILI的发现、识别与处理提供更多参考信息。

关键词：普瑞巴林药物性肝损害 DILI 肝脏转氨酶

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Complementary and Alternative Medicine-related Drug-induced Liver Injury in Asia

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Journal of Clinical and Translational Hepatology 2019年第3期7卷 263-274页

作者： Cyriac Abby Philips Philip Augustine Sasidharan Rajesh Praveen Kumar Y Deepak Madhu The Liver Unit and Monarch Liver Lab Cochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Gastroenterology Cochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Interventional Radiology Cochin Gastroenterology GroupErnakulam Medical CentreKochiKeralaIndia Gastroenterology Government Medical CollegeThrissurKeralaIndia Gastroenterology Aster MIMSCalicutKeralaIndia

The use of complementary and alternative medicines(CAMs)for treatment of acute and chronic diseases is on the rise world over,especially in Asian countries,and mostly in China and India.Drug-induced liver injury(DILI)due to CAM is increasingly reported in the literature from multiple centers all around the world and with large-number patient series published from the West,mostly based on nation-wide DILI networks and multicenter collaboration.Comprehensive DILI networks are lacking among major Asian countries with high incidence of CAM practices.Chinese medical societies dealing with drug toxicity,CAM practice and hepatobiliary disease have adopted an integrated approach to establishing identification,diagnosis and treatment of CAM-related DILI,representing a systematic approach that could be iterated by other countries for improving patient outcomes.In this exhaustive review,we provide published data on CAM-related DILI in Asia,with detail on incidences along with analysis of patient population and their clinical outcomes.Concise and clear discussion on commonly implicated CAM agents in major Asian countries and associated chemical and toxicology analyses as well as descriptions of liver biopsy findings are discussed with future directions.

关键词： CAM Herbals Ayurveda Chinese DILI Hepatitis Cirrhosis ACLF Liver biopsy

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单核细胞趋化蛋白-1、高迁移率族蛋白-1联合外周血铁蛋白在诊断和评估药物性肝损伤中的价值

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世界华人消化杂志 2022年第24期30卷 1086-1094页

作者：鲁欢乐倪红妙张宇东刘媛杭州市第九人民医院重症医学检验科浙江省杭州市330112

背景早期准确诊断、评估药物性肝损伤(drug-induced liver injury,DILI)病情对临床治疗具有重要指导意义.DILI机制复杂,涉及多种物质,铁蛋白(serum ferritin,SF)、单核细胞趋化蛋白-1(monocyte chemotactic protein-1,MCP-1)、高迁移率族蛋白-1(highmobilitygroup protein-1,HMGB1)在肝损伤时明显升高,可能与DILI有关.目的探讨外周血SF、MCP-1、HMGB1诊断DILI的价值.方法选取2018-01/2021-02我院收治的184例DILI患者,其中94例轻度患者(轻度组)、52例中度患者(中度组)、38例重度患者(重度组),并选取同期酒精性肝病、非酒精性脂肪肝病患者70例作为非DILI肝病组以及体检中心70例健康人群作为对照组,比较各组SF、MCP-1、HMGB1水平,应用皮尔森(Pearson)分析SF、MCP-1、HMGB1与谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)、总胆红素(totalbilirubin,TBIL)、碱性磷酸酶(alkalinephosphatase,ALP)关系,斯皮尔曼(Spearman)分析SF、MCP-1、HMGB1与DILI严重程度关系,采用多分类Logistic回归方程分析DILI严重程度的相关影响因素,应用受试者工作特征曲线(receiver operating characteristic,ROC)及ROC下面积(area under the curve,AUC)分析各指标及联合诊断DILI的价值.结果ALT、AST、TBIL、ALP:重度组>中度组>轻度组>对照组(P中度组>轻度组>对照组,两两比较差异均有统计学意义(PDILI严重程度分布比较,差异有统计学意义(PDILI严重程度正相关;多分类Logistic回归方程分析显示,将ALT、AST、TBIL、ALP控制后,SF、MCP-1、HMGB1仍是DILI病情程度的相关影响因素(PDILI的AUC分别为0.870、0.803、0.859,SF、MCP-1联合HMGB1诊断DILI的AUC为0.926;SF、MCP-1、HMGB1及联合鉴别重度DILI的AUC分别为0.888、0.774、0.807、0.948.结论外周血SF、MCP-1、HMGB1与DILI及其严重程度有关,在DILI诊断及病情评估呈现出较高应用价值,可作为诊断和评估DILI病情程度的生物标志物,为临床提供参考信息.

关键词： SF MCP-1 HMGB1 DILI 严重程度

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