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Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway:An experimental study 被引量:10
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作者 Hong Zhang Yang Liu +1 位作者 Li-Kun Wang Na Wei 《Asian Pacific Journal of Tropical Medicine》 SCIE CAS 2017年第5期493-496,共4页
Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and r... Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury. 展开更多
关键词 drug-induced liver injury anti-tuberculosis drug Pyrrolidine dithiocarbamate JAK2 STAT3
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Effects of Yigan Capsule on the expression of HMGB1,RAGE and NF-κB protein in rats with drug-induced liver injury
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作者 TANG Ya LI Jun +4 位作者 QI Yazhi CAO Rui ZHAI Yan-ling HAN Yu-sheng XU Qiang 《Journal of Hainan Medical University》 CAS 2024年第4期8-14,共7页
Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced... Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI. 展开更多
关键词 Yigan capsule anti-tuberculosis drug-induced liver injury HMGB1 RAGE NF-κB
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Drug-induced liver injury: Do we know everything? 被引量:14
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作者 Tamara Alempijevic Simon Zec Tomica Milosavljevic 《World Journal of Hepatology》 CAS 2017年第10期491-502,共12页
Interest in drug-induced liver injury(DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating th... Interest in drug-induced liver injury(DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of Liver Tox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain. 展开更多
关键词 acute liver failure drug-induced liver injury Hepatoxicity Acetaminophen toxicity Cholestatic injury liver biopsy PHARMACOEPIDEMIOLOGY Herbal-induced liver injury Hy’s law
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Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients 被引量:11
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作者 Matthias Buechter Paul Manka +6 位作者 Falko Markus Heinemann Monika Lindemann Hideo Andreas Baba Martin Schlattjan Ali Canbay Guido Gerken Alisan Kahraman 《World Journal of Gastroenterology》 SCIE CAS 2018年第13期1410-1418,共9页
AIM To investigate potential triggering factors leading to acute liver failure(ALF) as the initial presentation of autoimmune hepatitis(AIH).METHODS A total of 565 patients treated at our Department between 2005 and 2... AIM To investigate potential triggering factors leading to acute liver failure(ALF) as the initial presentation of autoimmune hepatitis(AIH).METHODS A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients(9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver(AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data(liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients.RESULTS The majority of patients with ALF were female(84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for antiliver kidney microsomal antibody(LKM). We could identify potential triggering factors in 26/52(50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF(57.7%), virus-induced ALF(30.8%), and preceding surgery in general anesthesia(11.5%), respectively. Unfortunately, 6 out of 52 patients(11.5%) did not survive ALF and 3 patients(5.7%) underwent liver transplantation(LT). Comparing data of survivors and patients with non-recovery following treatment, MELDscore(P < 0.001), age(P < 0.05), creatinine(P < 0.01), and finally, ALT-values(P < 0.05) reached statistical significance. CONCLUSION Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome. 展开更多
关键词 acute liver failure AUTOIMMUNE hepatitis drug-induced liver injury TRIGGERING factors MELD-score
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Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure 被引量:4
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作者 Jia-Hang Zhou Xuan Lu +2 位作者 Cui-Lin Yan Xin-Yu Sheng Hong-Cui Cao 《World Journal of Stem Cells》 SCIE 2021年第3期208-220,共13页
Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mim... Drug-induced liver injury(DILI),which refers to liver damage caused by a drug or its metabolites,has emerged as an important cause of acute liver failure(ALF)in recent years.Chemically-induced ALF in animal models mimics the pathology of DILI in humans;thus,these models are used to study the mechanism of potentially effective treatment strategies.Mesenchymal stromal cells(MSCs)possess immunomodulatory properties,and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF.Here,we summarize some of the existing research on the interaction between MSCs and immune cells,and discuss the possible mechanisms underlying the immunomodulatory activity of MSCs in chemically-induced ALF.We conclude that MSCs can impact the phenotype and function of macrophages,as well as the differentiation and maturation of dendritic cells,and inhibit the proliferation and activation of T lymphocytes or B lymphocytes.MSCs also have immunomodulatory effects on the production of cytokines,such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6,in animal models.Thus,MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future. 展开更多
关键词 Mesenchymal stromal cell Immune response drug-induced liver injury acute liver failure Dendritic cell
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Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury
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作者 Yu-Ting Xiong Jian-Fei Wang +11 位作者 Le Li Zhi-Fang Bai Yan Liu Ang Huang Ke-Xin Wang Yiming Fu Wucai Yang Chang Guo Mengwen He Wen-Chang Wang Chun-Yan Wang Dong Ji 《iLIVER》 2024年第2期35-42,共8页
Background and aims:Currently,research on biopsy-proven acute drug-induced liver injury(DILI)remains limited.This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation ... Background and aims:Currently,research on biopsy-proven acute drug-induced liver injury(DILI)remains limited.This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation in patients with acute DILI.Methods:An ambispective cohort study was conducted on biopsy-proven acute DILI patients admitted to our hospital from 2012 to 2018.Using the Scheuer scoring system,patients were categorized into G0-2 or G3-4 groups and followed up for 12 months after first admission.Clinical characteristics and outcomes were retrieved from medical records.Results:The median age of the 157 enrolled patients(65.6%female)was 40.4(interquartile range(IQR),31.9-49.1)years.The median latency and length of hospitalization were 30.0(IQR,5.0-60.0)and 18.0(IQR,12.0-26.0)days.The proportions of patients in the G0-2 and G3-4 groups were 54.8%and 45.2%,respectively.Logistic regression analysis revealed that females(odds ratio(OR):2.623,95%confidence interval(CI):1.169-5.887,p=0.019),higher body mass index(OR:1.168,95%CI:1.029-1.325,p=0.016),higher total bilirubin(OR:1.004,95%CI:1.000-1.007,p=0.047),and lower prothrombin activity(OR:0.976,95%CI:0,957-0.995,p=0.013)were associated with significant hepatic inflammation.The predominance of the hepatocellular injury pattern(60.5%)at admission transformed into a predominance of the cholestatic pattern(60.5%)at discharge.During follow-up,23 patients(14.6%)developed chronic DILI,with nine patients(5.7%)progressing to cirrhosis.Moreover,15 female patients(9.6%)developed autoimmunity(3cases in the G0-2 group vs 12 cases in the G3-4 group,p<0.05).Conclusion:Acute DILI patients with high-risk factors were more likely to develop significant hepatic inflammation,and females with significant inflammation were at a higher risk of developing autoimmunity during follow-up. 展开更多
关键词 acute drug-induced liver injury liver biopsy Hepatic inflammation FEMALE AUTOIMMUNITY CHRONICITY
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Liver injury induced by paracetamol and challenges associated with intentional and unintentional use 被引量:5
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作者 Laura Rotundo Nikolaos Pyrsopoulos 《World Journal of Hepatology》 CAS 2020年第4期125-136,共12页
Drug induced liver injury(DILI)is a common cause of acute liver injury.Paracetamol,also known as acetaminophen,is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeuti... Drug induced liver injury(DILI)is a common cause of acute liver injury.Paracetamol,also known as acetaminophen,is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels.Hepatotoxicity from paracetamol overdose,whether intentional or nonintentional,is the most common cause of DILI in the United States and remains a global issue.Given the increased prevalence of combination medications in the form of pain relievers and antihistamines,paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity,as evidenced by its contribution to over half of all acute liver failure cases in the United States.This is especially concerning given that,when co-ingested with other medications,the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy.This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options. 展开更多
关键词 PARACETAMOL drug-induced liver injury HEPATOTOXICITY acute liver failure
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Liver involvement in the drug reaction,eosinophilia,and systemic symptoms syndrome 被引量:3
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作者 Sylvia A Martinez-Cabriales Neil H Shear Emmanuel I Gonzalez-Moreno 《World Journal of Clinical Cases》 SCIE 2019年第6期705-716,共12页
First described in 1996,the drug reaction,eosinophilia,and systemic symptoms syndrome(DReSS) is considered,along with Stevens-Johnson syndrome and toxic epidermal necrolysis,a severe cutaneous drug reaction. It is cha... First described in 1996,the drug reaction,eosinophilia,and systemic symptoms syndrome(DReSS) is considered,along with Stevens-Johnson syndrome and toxic epidermal necrolysis,a severe cutaneous drug reaction. It is characterized by the presence of a maculopapular erythematous skin eruption,fever,lymphadenopathy,influenza-like symptoms,eosinophilia,and visceral involvement such as hepatitis,pneumonitis,myocarditis,pericarditis,nephritis,and colitis. The prognosis of patients with DReSS is related to the severity of visceral involvement. The mortality ranges from approximately 5% to 10%,and death is mainly due to liver failure,which is also the organ most commonly involved in this syndrome. Although it was previously hypothesized in 1994,DReSS syndrome can lead to reactivation of one or more human herpesvirus family members. Now being included as diagnostic criteria in a proposed diagnostic score system,this reactivation can be detected up to 2-3 wk after DReSS syndrome onset. Other causes of mortality in DReSS syndrome include myocardial or pulmonary lesions and hemophagocytosis. We reviewed the literature of previously reported case-series of DReSS and liver involvement,highlighting the pattern of liver damage,the treatment used,and the outcome. 展开更多
关键词 Drug reaction eosinophilia and systemic symptoms syndrome Severe cutaneous drug reactions drug-induced hypersensitivity syndrome drug-induced liver injury acute liver failure
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Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury 被引量:1
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作者 Georgia Zeng Guy D.Eslick Martin Weltman 《iLIVER》 2023年第2期122-129,共8页
Background and aims:Drug-induced liver injury(DILI)is a leading cause of death from acute liver failure(ALF).Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosp... Background and aims:Drug-induced liver injury(DILI)is a leading cause of death from acute liver failure(ALF).Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase(ALP)levels is associated with a 10%or greater chance of progression to transplant or liver-related death.This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury.Methods:We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022.Our primary outcome was to compare acute outcomes including ALF,liver-related death,and liver transplant between patients experiencing hepatocellular,cholestatic,and mixed patterns of DILI.Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury.Pooled odds ratios(ORs)and 95%confidence intervals(CIs)were calculated using a random-effects model.Results:Overall,12 studies comprising 4290 patients were included.Patients with cholestatic DILI demonstrated similar rates of ALF(OR:0.80,95%CI:0.46–1.40,p=0.429)and liver-related death(OR:0.92,95%CI:0.50–1.69,p=0.792)compared to patients with hepatocellular DILI.Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI(OR:2.53,95%CI:1.34–4.79,p=0.004). 展开更多
关键词 drug-induced liver injury Idiosyncratic hepatotoxicity acute liver failure liver-related death META-ANALYSIS
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Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk 被引量:6
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作者 Melissa M.Clemens Stefanie Kennon-McGill +9 位作者 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 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2021年第12期3836-3846,共11页
We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also beneficial.To test that,we treated mic... We previously demonstrated that endogenous phosphatidic acid(PA)promotes liver regeneration after acetaminophen(APAP)hepatotoxicity.Here,we hypothesized that exogenous PA is also beneficial.To test that,we treated mice with a toxic APAP dose at 0 h,followed by PA or vehicle(Veh)posttreatment.We then collected blood and liver at 6,24,and 52 h.Post-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 alone.Interestingly,PA did not affect canonical mechanisms of APAP toxicity.Instead,transcriptomics revealed that PA activated interleukin-6(IL-6)signaling in the liver.Consistent with that,serum IL-6 and hepatic signal transducer and activator of transcription 3(Stat3)phosphorylation increased in PA-treated mice.Furthermore,PA failed to protect against APAP in IL-6-deficient animals.Interestingly,IL-6 expression increased 18-fold in adipose tissue after PA,indicating that adipose is a source of PA-induced circulating IL-6.Surprisingly,however,exogenous PA did not alter regeneration,despite the importance of endogenous PA in liver repair,possibly due to its short half-life.These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model. 展开更多
关键词 acute liver injury acute liver failure ADIPOKINE Cytokine Dietary supplement drug-induced liver injury HEPATOTOXICITY Lipid
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Mitochondrial Damage and Drp1 Overexpression in Rifampicin-and Isoniazid-induced Liver Injury Cell Model 被引量:4
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作者 Fangfang Li Juan Zhou +2 位作者 Yi Li Kewei Sun Jun Chen 《Journal of Clinical and Translational Hepatology》 SCIE 2019年第1期40-45,共6页
Background and Aims:Rifampicin(RFP)and isoniazid(INH)are widely used as anti-tuberculosis agents.However,the mechanisms underlying the involvement of reactive oxygen species and mitochondria in RFP-and INH-related hep... Background and Aims:Rifampicin(RFP)and isoniazid(INH)are widely used as anti-tuberculosis agents.However,the mechanisms underlying the involvement of reactive oxygen species and mitochondria in RFP-and INH-related hepatotoxicity have not been established yet.This study aimed to observe the intracellular mechanisms leading to mitochondrial dysfunction and morphological changes in RFP-and INH-induced hepatocyte injury.Methods:Cell injury,changes in mitochondrial function,and expression and activation of dynamin related protein 1(Drp1),known as the main protein for mitochondrial fission,were analyzed in cultured QSG7701 cells exposed to RFP and INH.Results:INH and RFP treatment induced pronounced hepatocyte injury and increased cell death.In the similar context of aspartate aminotransferase elevation and adenosine triphosphate synthesis decrease,changes in mitochondrial membrane permeability and reactive oxygen species in hepatocytes induced by RFP were significantly different from those induced by INH(p<0.05).Particularly,we observed the overactivation and mitochondrial translocation of Drp1 in RFP-induced cell injury,which was not occurred with exposure to INH.Conclusions:RFP-induced hepatotoxicity may be closely related to mitochondrial dysfunction and Drp1-mediated mitochondrial fission. 展开更多
关键词 anti-tuberculosis drug-induced liver injury Drp1 Mitochondrial dysfunction Mitochondrial fission
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Endogenous peroxynitrite activated fluorescent probe for revealing anti-tuberculosis drug induced hepatotoxicity 被引量:1
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作者 Nannan Wang Han Wang +5 位作者 Jian Zhang Xin Ji Huihui Su Jinying Liu Jiamin Wang Weili Zhao 《Chinese Chemical Letters》 SCIE CAS CSCD 2022年第3期1584-1588,共5页
Py^(+)razinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxy... Py^(+)razinamide (PZA), isoniazid (INH) and rifampicin (RFP) are all commonly used anti-tuberculosis drugs in clinical practice, and long-term medication may cause severe liver damage and toxicity. The level of peroxynitrite (ONOO^(-)) generated in liver has long been regarded as a biomarker for the prediction and measurement of drug-induced liver injury (DILI). In this article, we constructed a BODIPY-based fluorescent probe (BDP-Py^(+)) that enabled quickly and sensitively detect and image ONOO^(-) in vivo. Utilizing this probe, we demonstrated the change of ONOO^(-) content in cells and mice model of DILI induced by acetaminophen (APAP), and for the first time revealed the mechanism of liver injury induced by antituberculosis drug PZA. Moreover, BDP-Py^(+) could be applied to screen out and evaluate the hepatotoxicity of different anti-tuberculosis drugs. Comparing with the existing serum enzymes detection and H&E staining, the probe could achieve early diagnosis of DILI before solid lesions in liver via monitoring the up-regulation of ONOO^(-) levels. Collectively, this work will promote the understanding of the pathogenesis of anti-tuberculosis drug induced liver injury (ATB-DILI), and provide a powerful tool for the early diagnosis and treatment of DILI. 展开更多
关键词 anti-tuberculosis drug induced liver injury PEROXYNITRITE Fluorescent probe drug-induced liver injury BIOIMAGING
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Pre-treatment twice with liposomal clodronate protects against acetaminophen hepatotoxicity through a pre-conditioning effect 被引量:2
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作者 Melissa M.Clemens Joel H.Vazquez +3 位作者 Stefanie Kennon-McGill Sandra S.McCullough Laura P.James Mitchell R.McGill 《Liver Research》 2020年第3期145-152,共8页
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 controversial.Early research revealed that macrophage inhib... 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 controversial.Early research revealed that macrophage inhibitors protect against APAP injury.However,later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate(LC)exacerbates the toxicity.To our surprise,during other studies,we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity,in contrast to acute pre-treatment.The aim of this study was to confirm that observation and to explore the mechanisms.Methods: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 post-APAP.We 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)immunofluorescence.We also confirmed the ablation of macrophages by F4/80 immunohistochemistry.Results: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 bioactivation.Importantly,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 ligase.Oxidative stress was lower in the LC groups at both time points.Finally,total Nrf2 immunofluorescence was higher in the LC group.Conclusions:We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase.Investigators using twice or possibly more LC pre-treatments to deplete macrophages,including peritoneal macrophages,should be aware of this possible confounder. 展开更多
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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