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

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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 *** studies showed that autophagy protects against acetaminophen(APAP)-induced injury(AILI)via selective removal of damaged mitochondria and APAP protein *** lysosome is a critical organelle sitting at the end stage of autophagy for autophagic degradation via fusion with *** 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 *** loss-of and gain-of function of hepatic TFEB exacerbated or protected against AILI,***,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 *** also performed an unbiased cell-based imaging high-throughput chemical screening on TFEB and identified a group of TFEB *** these agonists,salinomycin,an anticoccidial and antibacterial agent,activated TFEB and protected against AILI 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

Mechanisms of sterile inflammation in acetaminophen hepatotoxicity

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Cellular & Molecular Immunology 2018年第1期15卷 74-75页

作者： Hartmut jaeschke Department of Pharmacology Toxicology&TherapeuticsUniversity of Kansas Medical CenterKansas City66160KSUSA.

Acetaminophen(APAP)hepatotoxicity is the most frequent cause of acute liver failure in many Western *** intracellular signaling mechanisms of APAP-induced cell death have been extensively studied,and the critical roles of key features such as reactive metabolite generation,glutathione depletion,mitochondrial oxidant stress and peroxynitrite formation,mitochondrial dysfunction,and nuclear DNA fragmentation are all well-established.1 Not surprisingly,a substantial number of intracellular molecules,termed damage-associated molecular patterns(DAMPs),are passively released into the circulation during the resulting *** include high mobility group box 1 protein,nuclear DNA fragments and mitochondrial DNA,with most being recognized by pattern recognition receptors such as various Toll-like receptors(TLRs)on macrophages.

关键词： fragmentation nitrite sterile

Novel insight into mechanisms of cholestatic liver injury

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World Journal of Gastroenterology 2012年第36期18卷 4985-4993页

作者： Benjamin L Woolbright Hartmut jaeschke Department of Pharmacology Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityKS 66160United States

Cholestasis results in a buildup of bile acids in serum and in *** studies into the mechanisms of cholestatic liver injury strongly implicated bile acidinduced apoptosis as the major cause of hepatocellular *** work has focused both on the role of bile acids in cell signaling as well as the role of sterile inflammation in the *** in modern analytical methodology have allowed for more accurate measuring of bile acid concentrations in serum,liver,and bile to very low levels of ***,toxic bile acid levels are seemingly far lower than previously *** initial hypothesis has been based largely upon the exposure of μmol/L concentrations of toxic bile acids and bile salts to primary hepatocytes in cell culture,the possibility that in vivo bile acid concentrations may be far lower than the observed in vitro toxicity has far reaching implications in the mechanism of *** review will focus on both how different bile acids and different bile acid concentrations can affect hepatocytes during cholestasis,and additionally provide insight into how these data support recent hypotheses that cholestatic liver injury may not occur through direct bile acid-induced apoptosis,but may involve largely inflammatory cell-mediated liver cell necrosis.

关键词： Bile acids Cholestasis Apoptosis Necro-sis Neutrophils Innate immunity Bile duct ligation

Alcoholic Hepatitis:Lost in Translation

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Journal of Clinical and Translational Hepatology 2018年第1期6卷 89-96页

作者： Benjamin L. Woolbright Hartmut jaeschke Department of Pharmacology Toxicology&TherapeuticsUniversity of Kansas Medical CenterKansas CityKansasUSA

Alcoholic hepatitis is the most severe and acute form of alcoholic liver *** mortality rate associated with alcoholic hepatitis is high,largely due to the lack of suitable pharmacological *** there has been substantial research in the area,generating pharmacological interventions has been plagued by the lack of a robust mouse model both for testing and for understanding the underlying pathology.A number of major notable advances have been made in this area recently,with the goal of generating a mouse model of alcoholic *** purpose of this article is to review recent advances in modeling alcoholic liver disease both in vitro and in vivo in the mouse,and place them in the context of the greater spectrum of alcoholic liver disease,with a focus on how we can translate current advances into a high-fidelity model of alcoholic *** addition,we will review the basic mechanisms of alcoholic hepatitis as it is currently understood,focusing on recent advancements in diagnosis,prognosis and current pathophysiology,especially as it relates to the profound immune dysfunction present during alcoholic hepatitis.

关键词： Alcoholic hepatitis Alcohol Liver disease Cirrhosis Prognosis Keratin-18

Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

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World Journal of Gastroenterology 2010年第19期16卷 2448-2450页

作者： Hartmut jaeschke C David Williams Mitchell R McGill Anwar Farhood Department of Pharmacology Toxicology and Therapeutics University of Kansas Medical Center Kansas City KS 66160 United States Department of Pathology Brackenridge Hospital Austin TX 78701 United States

Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.

关键词： Acetaminophen Drug hepatotoxicity Herbal extracts N-acetylcysteine

Predicting the effectiveness of protected areas of Natura 2000 under climate change

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Ecological Processes 2019年第1期8卷 162-182页

作者： Mst.Umme Salma Nila Carl Beierkuhnlein Anja jaeschke Samuel Hoffmann Md Lokman Hossain Global Change Ecology International Elite Study ProgrammeUniversity of BayreuthUniversitätsstraße 3095447 BayreuthGermany Department of Biogeography University of BayreuthUniversitätsstraße 3095447 BayreuthGermany Department of Geography Hong Kong Baptist University15 Baptist University RoadKowloon TongHong Kong Department of Environmental Protection Technology German University Bangladesh1702 GazipurBangladesh.

Background:Protected areas(PAs)are aimed to hold the environmental conditions that facilitate species and ecosystems to *** can become climatically unsuitable and unable to sustain their current number of species under climate *** Natura 2000(N2K)is the largest coordinated conservation tool assigned to maintain the long-term survival of Europe’s most significant species and *** attempting to understand the effectiveness of PAs in the face of climate change scenarios,we tested two hypotheses:(1)PAs in the Alpine and the Boreal biogeographical regions will experience more newly emerged climate conditions(hotter and drier)compared to the climate representation of other biogeographical regions under future climate in Europe and(2)PAs in the Mediterranean and the Continental biogeographical regions will face more consistency in climate conditions due to less area of disappearing and novel climate in ***:Current climate data(1960–1990)and projections for 2050 and 2070 of PAs of N2K were extracted from WorldClim global climate *** components analysis(PCA)was performed to construct climate space for the PAs across the biogeographical regions based on 19 climatic variables assessed at 5-km *** 10.1 was used to map the location of the novel and disappearing ***:PAs in the Alpine region will experience more novel climate conditions in the future compared to other biogeographical *** future projections showed that 17.70%of the PAs in the Alpine region will experience novel climate by *** climate consistency was observed in the PAs in the Continental region compared to the other biogeographical *** results showed that about 176 km2 of the selected PAs in the Continental region will face new emerging climate,while about 110 km2 will disappear under RCP 8.5 *** prediction also revealed that in the Mediterranean region 08 PAs will experience novel climate and 786 km2 areas

关键词： Biodiversity conservation Biogeographical region Climate change Climate scenarios Natura 2000,Protected areas

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 *** 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 ***,the aim of the present study is to determine whether CPZ may protect against APAP-induced liver injury via inducing ***:Wild type C57BL/6J mice were injected with APAP to induce liver *** 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 ***: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 ***,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 *** inhibition of autophagy by chloroquine partially weak-ened the protective effects of CPZ against APAP-induced liver ***: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

Mitochondrial damage and biogenesis in acetaminophen-induced liver injury

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Liver Research 2019年第3期3卷 150-156页

作者： Hartmut jaeschke Luqi Duan Nga T.Nguyen Anup Ramachandran Department of Pharmacology Toxicology&TherapeuticsUniversity of Kansas Medical CenterKansas CityKSUSA

Liver injury and acute liver failure caused by acetaminophen(APAP)overdose is the clinically most important drug toxicity in Western *** investigations have revealed a central role of mitochondria in the *** formation of the reactive metabolite N-acetyl-p-benzoquinone imine(NAPQI)after an overdose leads to hepatic glutathione depletion,mitochondrial protein adducts formation and an initial oxidant stress,which triggers the activation of mitogen activated protein(MAP)kinase cascade ultimately leading to c-jun N-terminal kinase(JNK)***-JNK translocates to the mitochondria and amplifies the oxidative and nitrosative stress eventually causing the mitochondrial membrane permeability transition pore opening and cessation of adenosine triphosphate(ATP)*** addition,mitochondrial matrix swelling ruptures the outer membrane and releases endonucleases,which cause nuclear deoxyribonucleic acid(DNA)***,the nuclear DNA damage and the extensive mitochondrial dysfunction result in necrotic cell ***,the procell death signaling events are counteracted by adaptive responses such as autophagy and mitochondrial *** improved mechanistic insight into the pathophysiology leads to better understanding of the mechanisms of action of the existing antidote N-acetylcysteine and justifies the clinical testing of novel therapeutics such as 4-methylpyrazole and calmangafodipir.

关键词： Acetaminophen(APAP)hepatotoxicity Mitochondrial dysfunction Biogenesis Oxidant stress Peroxynitrite c-Jun N-terminal kinase(JNK)

Information Technology Standardiation

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北京信息科技大学学报（自然科学版） 2010年第S2期25卷 1-3页

作者： Rex jaeschke Consultant Reston VirginiaUSA

Overview of the standardization process within the Information Technology industry with emphasis on ISO/IEC JTC 1.

关键词： CEN Ecma Fast Track IEC IEEE ISO JTC 1 PAS SC SDO WG.