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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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Editorial of special column on Drug targets and drug development for Alzheimer's disease

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1686-1687页

作者： wen-xing ding Russell H.Swerdlow Department of Pharmacology Toxicology and TherapeuticsDepartment of Internal Medicinethe University of Kansas Medical CenterKansas CityKS 66160USA Department of Neurology the University of Kansas Medical CenterKansas CityKS 66160USA

Alzheimer's disease(AD)is the most common form of progressive dementia in people aged 65 years and over.The major pathological features of AD are the accumulation of extracellularβ-amyloid plaques and intracellular neurofibrillary tangles composed of aggregated,hyperphosphorylated tau.In addition to an accumulation of protein aggregates,mitochondrial dysfunction,altered lipid metabolism and increased neuroinflammation also play critical roles in the pathogenesis of AD and its associated dementia.

关键词： Alzheimer metabolism inflammation

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Donut and spheroid mitochondria: eating, regenerating or trash them out?

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Life Metabolism 2023年第3期2卷 2-4页

作者： wen-xing ding Han-Ming Shen Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160United States Division of Gastroenterology Hepatology and MobilityDepartment of Internal MedicineUniversity of Kansas Medical CenterKansas CityKS 66160United States Faculty of Health Sciences Ministry of Education Frontiers Science Center for Precision OncologyUniversity of MacaoMacao 999078China

In response to stress,mitochondrion undergoes constant morphological changes,including the formation of donut and spheroid mitochondria,and both are believed to be implicated in its biological functions.Mitochondria are critical for cellular metabolic homeostasis and cell survival and death in eukaryotic cells.Mitochondria are dynamic organelles that constantly undergo fission and fusion.Mitochondrial homeostasis is tightly regulated by mitophagy for the removal of damaged or excess mitochondria and by mitochondria biogenies of new mitochondria.Mitochondria can also undergo other morphological transformation,such as formation of donut-like mitochondria or mitochondrial spheroids,and can also be secreted into the extracellular spaces.Here we discuss the mechanistic insights and physiological relevance of the donut-like mitochondria or mitochondrial spheroids and the secretion of mitochondria in cell biology.

关键词： functions insight excess

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Recent insights into the pathogeneses and therapeutic targets of liver diseases: Summary of the 4th Chinese American liver Society/Society of Chinese Bioscientists in America Hepatology Division Symposium in 2021

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Liver Research 2022年第1期6卷 50-57页

作者： wen-xing ding Hua Wang Yuxia Zhang On behalf of the Chinese American Liver Society Symposium Organizing Committee Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA Department of Oncology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina 不详

The 4th Chinese American Liver Society(CALS)/Society of Chinese Bioscientists in America(SCBA)Hepatology Division Annual Symposium was held virtually on October 29e30,2021.The goal of the CALS Symposium was to present and discuss the recent research data on the pathogenesis and therapeutic targets of liver diseases among the CALS members,trainees and invited speakers.Here we briefly introduce the history of the CALS/SCBA Hepatology Division and highlight the presentations that focus on the current progresses on basic and translational research in liver metabolism,bile acid biology,alcohol-related liver disease,drug-induced liver injury,cholestatic liver injury,non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and liver cancer.

关键词： Liver diseases Alcohol-related liver disease(ALD) Cholestasis Drug-induced liver injury(DILI) Hepatocellular carcinoma(HCC) Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH) Symposium

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A fluorescence imaging based-assay to monitor mitophagy in cultured hepatocytes and mouse liver

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Liver Research 2021年第1期5卷 16-20页

作者： Xiaowen Ma wen-xing ding Department of Pharmacology Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityKSUSA

Background and aim Mitophagy is a lysosomal degradation pathway that selectively removes damaged,aged and dysfunctional mitochondria.Recent advances in understanding mitophagy highlight its importance in various physiological and pathological conditions including liver diseases.However,reliable quantitative assays to monitor mitophagy in cultured cells and in tissues are still scarce.Methods We describe a detailed protocol for monitoring mitophagy in primary cultured hepatocytes and mouse livers using cytochrome C oxidase subunit 8(Cox8)-enhanced green fluorescent protein(EGFP)-mCherry,a dual color fluorescence based-imaging method.Results Mitochondria are visualized in yellow fluorescence due to the merged EGFP and mCherry signal.In contrast,autolysosome enclosed mitochondria are shown as red puncta due to quenching of EGFP green fluorescence in acidic compartments.Quantifying the number of red-only puncta in each cell can obtain a quantitative measure for mitophagy.Conclusions Cox8-EGFP-mCherry assay can specifically target to mitochondria and be used to monitor mitophagy in vitro and in vivo.

关键词： Autophagy Cox8-EGFP-mCherry Fluorescence microscopy Mitochondria Lysosome

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Adipose tissue autophagy and homeostasis in alcohol-induced liver injury

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Liver Research 2017年第1期1卷 54-62页

作者： Yuan Li wen-xing ding Department of Pharmacology Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityKSUSA

Alcohol consumption leads to injury in multiple organs and systems,including the liver,brain,heart,skeletal muscle,pancreas,bone,immune system,and endocrine system.Emerging evidence indicates that alcohol also promotes adipose tissue dysfunction,which may contribute to injury progression in other organs and systems.Autophagy is a lysosomal degradation pathway that has been shown to regulate adipose tissue homeostasis and adipogenesis.Increasing evidence also demonstrates that alcohol consumption affects autophagy in multiple tissues.This review summarizes current knowledge regarding the effect of autophagy on adipose tissue and its potential roles in alcohol-induced adipose tissue atrophy as well as its contribution to alcohol-induced liver injury.

关键词： Autophagy Alcohol Adipose tissue Liver Alcoholic liver disease

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Lipid droplet dynamics in alcoholic fatty liver disease

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Liver Research 2019年第3期3卷 185-190页

作者： Ryan J.Schulze wen-xing ding Department of Biochemistry and Molecular Biology and the Division of Gastroenterology and Hepatology Mayo ClinicRochesterMNUSA Department of Pharmacology Toxicologyand TherapeuticsThe University of Kansas Medical CenterKansas CityKSUSA

The rising incidence of alcohol-related liver disease(ALD)demands making urgent progress in understanding the fundamental molecular basis of alcohol-related hepatocellular damage.One of the key early events accompanying chronic alcohol usage is the accumulation of lipid droplets(LDs)in the hepatocellular cytoplasm.LDs are far from inert sites of neutral lipid storage;rather,they represent key organelles that play vital roles in the metabolic state of the cell.In this review,we will examine the biology of these structures and outline recent efforts being made to understand the effects of alcohol exposure on the biogenesis,catabolism,and motility of LDs and how their dynamic nature is perturbed in the context of ALD.

关键词： Lipid droplet(LD) Alcohol Autophagy Lipolysis Hepatocyte Steatosis

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Regulation of the homeostasis of hepatic endoplasmic reticulum and cytochrome P450 enzymes by autophagy

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Liver Research 2018年第3期2卷 138-145页

作者： Xiaowen Ma Clayre Parson wen-xing ding Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA

The endoplasmic reticulum(ER)is an intracellular organelle consisting of a continuous network of membranes.In the liver,the ER is highly active in protein modification,lipid metabolism,and xenobiotic detoxification.Maintaining these complicated processes requires elaborate control of the ER lumen environment as well as the ER volume.Increasing evidence suggests that autophagy plays a critical role in regulating the homeostasis of hepatic ER contents and levels of cytochrome P450(CYP)enzymes via selective ER-phagy.This review will provide an overview of ER-phagy,summarizing the possible roles of recently identified ER-phagy receptor proteins in regulating the homeostasis of hepatic ER and CYP enzymes as well as outlining the various implications of ER-phagy in ER-related liver diseases.

关键词： Alcoholic liver disease Endoplasmic reticulum(ER)-phagy Endoplasmic reticulum(ER)stress Cytochrome P450(CYP)enzymes Liver diseases Non-alcoholic fatty liver disease(NAFLD) Non-alcoholic steatohepatitis(NASH)

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Chlorpromazine protects against acetaminophen-induced liver injury in mice by modulating autophagy and c-Jun N-terminal kinase activation

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Liver Research 2019年第1期3卷 65-74页

作者： Yuan Li Hong-Min Ni Hartmut Jaeschke wen-xing ding Department of Pharmacology Toxicology and TherapeuticsThe University of Kansas Medical CenterKansas CityKSUSA

Background and aim:Overdose of acetaminophen(APAP)leads to liver injury,which is one of the most common causes of liver failure in the United States.We previously demonstrated that pharmacological activation of autophagy protects against APAP-induced liver injury in mice via removal of damaged mitochondria and APAP-adducts(APAP-ADs).Using an image-based high-throughput screening for autophagy modulators,we recently identified that chlorpromazine(CPZ),a dopamine inhibitor used for anti-schizophrenia,is a potent autophagy inducer in vitro.Therefore,the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing autophagy.Methods:Wild type C57BL/6J mice were injected with APAP to induce liver injury.CPZ was administrated either at the same time with APAP(co-treatment)or 2 h later after APAP administration(post-treat-ment).Hemotoxyline and eosin(H&E)staining of liver histology,terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling(TUNEL)staining of necrotic cell death as well as serum levels of alanine aminotransferase(ALT)were used to monitor liver injury.Results:We found that CPZ markedly protected against APAP-induced liver injury as demonstrated by decreased serum levels of ALT,liver necrotic areas as well as TUNEL-positive cells in mice that were either co-treated or post-treated with CPZ.Mechanistically,we observed that CPZ increased the number of autolysosomes and decreased APAP-induced c-Jun N-terminal kinase activation without affecting the metabolic activation of APAP.Pharmacological inhibition of autophagy by chloroquine partially weak-ened the protective effects of CPZ against APAP-induced liver injury.Conclusions:Our results indicate that CPZ ameliorates APAP-induced liver injury partially via activating hepatic autophagy and inhibiting JNK activation.

关键词： Chlorpromazine(CPZ) Acetaminophen(APAP) Drug-induced liver injury Necrosis Autolysosome Hepatotoxicity Glutathione(GSH) Oxidant stress

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Alcohol and drug-induced liver injury:Metabolism,mechanisms,pathogenesis and potential therapies

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Liver Research 2019年第3期3卷 129-131页

作者： wen-xing ding Li Yang Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA Institute of Chinese Materia Medica Shanghai University of Traditional Chinese MedicineShanghaiChina

The liver is one of the major metabolic organs in the body,playing a critical role in the metabolism of carbohydrates,proteins,amino acids,lipids,drugs and xenobiotics.As a result,the liver often becomes the target of drug and xenobiotics-induced damage.Currently,the most common cause for acute liver failure in the United States and multiple European countries is drug-induced liver injury(DILI).This is one of the leading causes for halting drug development and removing drugs from the consumer market.

关键词： drugs metabolism organs

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