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Pre-treatment twice with liposomal clodronate protects against acetaminophen hepatotoxicity through a pre-conditioning effect

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Liver research 2020年第3期4卷 145-152页

作者： Melissa M.Clemens Joel H.Vazquez Stefanie Kennon-mcgill Sandra S.McCullough Laura P.James mitchell r.mcgill Department of Pharmacology and Toxicology College of MedicineUniversity of Arkansas for Medical SciencesLittle RockARUSA Interdisciplinary Graduate Program in Biomedical Sciences Graduate SchoolUniversity of Arkansas for Medical SciencesLittle RockARUSA Department of Environmental and Occupational Health Fay W.Boozman College of Public HealthUniversity of Arkansas for Medical SciencesLittle RockARUSA Department of Pediatrics College of MedicineUniversity of Arkansas for Medical SciencesLittle RockARUSA Center for Dietary Supplement research University of Arkansas for Medical SciencesLittle RockARUSA

Background and aim:Acetaminophen(APAP)overdose is a major cause of acute liver injury,but the role of macrophages in the propagation of the hepatotoxicity is *** research revealed that macrophage inhibitors protect against APAP ***,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the *** our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute *** aim of this study was to confirm that observation and to explore the ***:We treated mice with empty liposomes(LE)or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0,2,and 6 h *** then measured liver injury(serum alanine aminotransferase activity,histology),APAP bioactivation(total glutathione,APAP-protein adducts),oxidative stress(oxidized glutathione(GSSG)),glutamate-cysteine ligase subunit c(Gclc)mrNA,and nuclear factor erythroid 2-related factor(Nrf2)*** also confirmed the ablation of macrophages by F4/80 ***:Pre-treatment twice with LC dramatically reduced F4/80 staining,protected against liver injury,and reduced oxidative stress at 6 h post-APAP,without affecting APAP ***,Gclc mrNA was higher in the LC group at 0 h and total glutathione was higher at 2 h,indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine *** stress was lower in the LC groups at both time ***,total Nrf2 immunofluorescence was higher in the LC ***:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine *** using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this poss

关键词： Acetaminophen(APAP) Acute liver failure(ALF) Damage-associated molecular patterns(DAMPs) Drug-induced liver injury Liposomal clodronate(LC) Kupffer cells Nuclear factor erythroid 2-related factor(Nrf2) Sterile inflammation Stress response

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Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3836-3846页

作者： Melissa M.Clemens Stefanie Kennon-mcgill Joel H.Vazquez Owen W.Stephens Erich A.Peterson Donald J.Johann Felicia D.Allard Eric U.Yee Sandra SMcCullough Laura P.James Brian N.Finck mitchell r.mcgill Department of Pharmacology and Toxicology College of MedicineUniversity of Arkansas for Medical SciencesLittle RockAR 72205USA Interdisciplinary Graduate Program in Biomedical Sciences Graduate SchoolUniversity of Arkansas for Medical SciencesLittle RockAR 72205USA Department of Environmental and Occupational Health Fay W.Boozman College of Public HealthUniversity of Arkansas for Medical SciencesLittle RockAR 72205USA Winthrop P.rockefeller Cancer Institute University of Arkansas for Medical SciencesLittle RockAR 72205USA Department of Pathology Renaissance School of MedicineStony Brook UniversityStony BrookNY 11794USA Department of Pediatrics College of MedicineUniversity of Arkansas for Medical SciencesLittle RockAR2205USA Division of Geriatrics and Nutritional Sciences Department of Internal MedicineWashington University School of MedicineSt.LouisMO 63110USA Center for Dietary Supplement research University of Arkansas for Medical SciencesLittle RockAR 72205USA

We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)***,we hypothesized that exogenous PA is also *** test that,we treated mice with a toxic APAP dose at 0 h,followed by PA or vehicle(Veh)*** then collected blood and liver at 6,24,and 52 ***-treatment with PA 2 h after APAP protected against liver injury at 6 h,and the combination of PA and N-acetyl-L-cysteine(NAC)reduced injury more than NAC ***,PA did not affect canonical mechanisms of APAP ***,transcriptomics revealed that PA activated interleukin-6(IL-6)signaling in the *** with that,serum IL-6 and hepatic signal transducer and activator of transcription 3(Stat3)phosphorylation increased in PA-treated ***,PA failed to protect against APAP in IL-6-deficient ***,IL-6 expression increased 18-fold in adipose tissue after PA,indicating that adipose is a source of PA-induced circulating ***,however,exogenous PA did not alter regeneration,despite the importance of endogenous PA in liver repair,possibly due to its short *** data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.

关键词： Acute liver injury Acute liver failure Adipokine Cytokine Dietary supplement Drug-induced liver injury Hepatotoxicity Lipid

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Acetaminophen-induced Liver Injury: from Animal Models to Humans

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Journal of Clinical and Translational Hepatology 2014年第3期2卷 153-161页

作者： Hartmut Jaeschke Yuchao Xie mitchell r.mcgill Department of Pharmacology Toxicology & Therapeutics University of Kansas Medical Center Kansas City KS USA

Drug-induced liver injury is an important clinical problem and a challenge for drug *** progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models,enormous insight has been gained in the area of predictable hepatotoxins,in particular acetaminopheninduced liver injury,from a broad range of experimental ***,mechanisms of toxicity obtained with certain experimental systems,such as in vivo mouse models,primary mouse hepatocytes,and metabolically competent cell lines,are being confirmed in translational studies in patients and in primary human *** this progress,suboptimal models are still being used and experimental data can be confusing,leading to controversial ***,this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an *** compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity,discuss controversial topics in the mechanisms,and assess how these experimental findings can be translated to the *** success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.

关键词： Drug hepatotoxicity Translational studies Necrosis,Sterile inflammation

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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

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Equity and seeking treatment for young children with fever in Nigeria: a cross-sectional study in Cross river and Bauchi States

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Infectious Diseases of Poverty 2015年第1期4卷 1-8页

作者： Bikom Patrick Odu Steven mitchell Hajara Isa Iyam Ugot robbinson Yusuf Anne Cockcroft Neil Andersson CIET Trust 71 Oxford RoadSaxonwoldJohannesburg 2196South Africa CIET/PrAM Department of Family MedicineMcGill University5858 Côte-des-NeigesSuite 300MontrealQC H3Z 1Z1Canada Community Health Department and roll Back Malaria Program CalabarCross River StateNigeria State Ministry of Health BauchiBauchi StateNigeria CIET Trust Botswana PO Box 1240GaboroneBotswana

Background:Poor children have a higher risk of contracting malaria and may be less likely to receive effective *** is an important cause of morbidity and mortality in Nigerian children and many cases of childhood fever are due to *** study examined socioeconomic factors related to taking children with fever for treatment in formal health ***:A household survey conducted in Bauchi and Cross river states of Nigeria asked parents where they sought treatment for their children aged 0–47 months with severe fever in the last month and collected information about household socio-economic *** also recorded whether there was a health facility in the *** used treatment of severe fever in a health facility to indicate likely effective treatment for *** analysis in each state examined associations with treatment of childhood fever in a health ***:43%weighted(%wt)of 10,862 children had severe fever in the last month in Cross river,and 45%wt of 11,053 children in *** these,less than half(31%wt Cross river,44%wt Bauchi)were taken to a formal health facility for *** were more likely to be taken to a health facility if there was one in the community(Or 2.31[95%CI 1.57–3.39]in Cross river,Or 1.33[95%CI 1.0–1.7]in Bauchi).Children with fever lasting less than five days were less likely to be taken for treatment than those with more prolonged fever,regardless of whether there was such a facility in their *** mothers were more likely to take children with fever to a formal health *** communities with a health facility in Cross river,children from less-poor households were more likely to go to the facility(Or 1.30;95%CI 1.07-1.58).Conclusion:There is inequity of access to effective malaria treatment for children with fever in the two states,even when there is a formal health facility in the *** the details of inequity of access in th

关键词： Severe fever Malaria Equity Access to care Nigeria

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Comparison of North American Seismic Screening Methods Applied to School Buildings

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Journal of Civil Engineering and Architecture 2012年第7期6卷 799-811页

作者： Helene Tischer Denis mitchell Ghyslaine McClure Department of Civil Engineering and Applied Mechanics McGill University Montreal QC H3A 0C3 Canada

An ongoing project at mcgill University is aimed at developing an adapted seismic screening method for schools in the province of Quebec, Canada. As part of this project the "FEMA154 rapid Visual Screening of Buildings for Potential Seismic Hazard" and the "NrC92 Manual for Screening of Buildings for Seismic Investigation" were used to assess 102 school buildings located in the city of Montreal. results for both methods are in reasonable agreement, with 65% of the buildings requiring a detailed evaluation according to FEMA154 and 50% according to NrC92. Findings highlighted the particular characteristics of educational facilities: they are low rise buildings with high incidence of structural irregularities. Accounting for them in the screening phase is essential, and is better achieved by NrC92. However, this method is largely based on expert opinion, which makes it difficult to update, while FEMA154 uses a rational methodology for calculating vulnerability scores based on the capacity spectrum approach. The FEMA154 analytical procedure allows updating and adapting the method to its use outside its intended scope.

关键词：筛选方法学校建筑抗震地震危险性应用北美能力谱方法 FEMA

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