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| 1 | Efects of a bioartificial liver support system on a cetaminophen-induced acute liver failure canines显示文摘Seeinvitedcommentaryonpage286Subjectheadingsliversupportsystem;acuteliverfailure;canines;porcinehepatocytes;bioartificiallive... | XUE Yi Long 1, ZHAO Shi Feng 2, ZHANG Zuo Yun 1, WANG Yue Feng 1, LI Xin Jian 1, HUANG Xiao Qiang 3, LUO Yun 1, HUANG Ying Cai 4 and LIU Cheng Gui 1 | 1999 | World Journal of Gastroenterology1999，5，4： | 19 |
| 2 | Dissecting the molecular pathophysiology of drug-induced liver injury显示文摘Drug-induced liver injury(DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways. | Hui Ye Leonard J Nelson Manuel Gómez del Moral Eduardo Martínez-Naves Francisco Javier Cubero | 2018 | World Journal of Gastroenterology2018，24，13： | 19 |
| 3 | A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition显示文摘We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription. | WANG Yu-Xin DU Yi LIU Xia-Fei YANG Fang-Xiu WU Xiao TAN Li LU Yi-Hong ZHANG Jing-Wei ZHOU Fang WANG Guang-Ji | 2019 | Chinese Journal of Natural Medicines2019，17，7： | 18 |
| 4 | Liuweiwuling tablets attenuate acetaminophen-induced acute liver injury and promote liver regeneration in mice显示文摘AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration. | Yan-Chang Lei Wen Li Pan Luo | 2015 | World Journal of Gastroenterology2015，21，26： | 12 |
| 5 | Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity:current understanding and future perspectives显示文摘Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling.Their central role in energy metabolism,as well as their high abundance in hepatocytes,make them important targets for drug-induced hepatotoxicity.This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen,diclofenac,anti-tuberculosis drugs such as rifampin and isoniazid,anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids.The utilization of circulating mitochondrialspecific biomarkers in understanding mechanisms of toxicity in humans will also be examined.In summary,it is well-established that mitochondria are central to acetaminophen-induced cell death.However,the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis,In contrast,the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans.Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.Relevance for patients:This review focuses on the role of mitochondrial dysfunction in liver injury mechanisms of clinically important drugs like acetaminophen,diclofenac,rifampicin,isoniazid,amiodarone and others.A better understanding of the mechanisms in animal models and their translation to patients will be critical for the identification of new therapeutic targets. | Anup Ramachandran Luqi Duan Jephte Y.Akakpo Hartmut Jaeschke | 2018 | Journal of Clinical & Translational Research2018，4，1： | 8 |
| 6 | Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options显示文摘Acetaminophen,also known as N-acetyl-p-aminophenol(APAP),is commonly used as an antipyretic and analgesic agent.APAP overdose can induce hepatic toxicity,known as acetaminophen-induced liver injury(AILI).However,therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting.Hence,there is a need to understand the potential pathological mechanisms underlying AILI.In this review,we summarize three main mechanisms involved in the pathogenesis of AILI:hepatocyte necrosis,sterile inflammation,and hepatocyte regeneration.The relevant factors are elucidated and discussed.For instance,N-acetyl-p-benzoquinone imine(NAPQI)protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis,danger-associated molecular patterns(DAMPs)are released to elicit sterile inflammation,and certain growth factors contribute to liver regeneration.Finally,we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists.This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future. | Xiaopeng CAI Huiqiang CAI Jing WANG Qin YANG Jun GUAN Jingwen DENG Zhi CHEN | 2022 | Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)2022，23，4： | 7 |
| 7 | Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity显示文摘The metabolic intermediate of acetaminophen(APAP)can cause severe hepatocyte necrosis,which triggers aberrant immune activation of liver non-parenchymal cells(NPC).Overzealous hepatic inflammation determines the morbidity and mortality of APAP-induced liver injury(AILI).Interleukin-1 receptor(IL-1R)signaling has been shown to play a critical role in various inflammatory conditions,but its precise role and underlying mechanism in AILI remain debatable.Herein,we show that NLRP3 inflammasome activation of IL-1βis dispensable to AILI,whereas IL-1α,the other ligand of IL-1R1,accounts for hepatic injury by a lethal dose of APAP.Furthermore,Kupffer cells function as a major source of activated IL-1αin the liver,which is activated by damaged hepatocytes through TLR4/MyD88 signaling.Finally,IL-1αis able to chemoattract and activate CD11b^(+)Gr-1^(+) myeloid cells,mostly neutrophils and inflammatory monocytes,to amplify deteriorated inflammation in the lesion.Therefore,this work identifies that MyD88-dependent activation of IL-1αin Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1αis a promising therapeutic target for AILI treatment. | Chao Zhang Jin Feng Jun Du Zhiyong Zhuo Shuo Yang Weihong Zhang Weihong Wang Shengyuan Zhang Yoichiro Iwakura Guangxun Meng Yang-Xin Fu Baidong Hou Hong Tang | 2018 | Cellular & Molecular Immunology2018，15，11： | 7 |
| 8 | Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology显示文摘Acetaminophen(APAP)overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation.Studies in the mouse model,which closely reproduces the human condition,have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine(NAPQI),which depletes cellular glutathione and forms protein adducts on mitochondrial proteins.This leads to mitochondrial oxidative and nitrosative stress,accompanied by activation of c-jun N-terminal kinase(JNK)and its translocation to the mitochondria.This then amplifies the mitochondrial oxidant stress,resulting in translocation of Bax and dynamin related protein 1(Drp1)to the mitochondria,which induces mitochondrial fission,and ultimately induction of the mitochondrial membrane permeability transition(MPT).The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor(AIF)and endonuclease G into the cytosol and their translocation to the nucleus,causing nuclear DNA fragmentation and activation of regulated necrosis.Though these cascades of events were primarily identified in the mouse model,studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose,indicate that a number of mechanistic events are identical in mice and humans.Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for significant clinical use in the near future.Relevance for patients:This review focuses on the mechanisms behind APAP-induced hepatotoxicity and the relevance of these to the human pathophysiology.Current investigations on various biomarkers which may be useful in clinical management of APAP overdose patients are also discussed. | Anup Ramachandran Hartmut Jaeschke | 2017 | Journal of Clinical & Translational Research2017，3，1： | 6 |
| 9 | Protective effects of Phyllanthus acidus(L.) Skeels leaf extracts on acetaminophen and thioacetamide induced hepatic injuries in Wistar rats显示文摘Objective:To investigate and compare the hepatoprotective effects of crude ethanolic and aqueous extracts of Phyllanthus acidus(L.) Skeels(P.acidus) leaves on acetaminophen(APAP) and thioacetamide(TAA) induced liver toxicity in wistar rats.Silymarin was the reference hepatoprotective agent.Methods:In two different sets of experiments,the P.acidus extracts (200 and 400 mg/kg,body weight) and silymarin(100 mg/kg,body weight) were given orally for 7 days and a single dose of APAP(2 g/kg,per oral) or TAA(100 mg/kg,subcutaneous) were given to rats.The level of serum aspartate transaminase(AST),alanine transaminase(ALT),alkaline phosphatase(ALP),total bilirubin and total protein were monitored to assess hepatotoxicity and hepatoprotection.Results:APAP or TAA administration caused severe hepatic damage in rats as evident from significant rise in serum AST,ALT,ALP,total bilirubin and concurrent depletion in total serum protein.The P.acidus extracts and silymarin prevented the toxic effects of APAP or TAA on the above serum parameters indicating the hepatoprotective action.The aqueous extract was found to be more potent than the corresponding ethanolic extract against both toxicants.The phenolic and flavonoid content(175.02±4.35 and 74.68±1.28,respectively) and 2,2-diphenyl-1- picrylhydrazil(DPPH)[IC50=(33.2±0.31)μg/mL]scavenging potential was found maximum with aqueous extract as compared to ethanolic extract.Conclusions:The results of present study suggests that the aqueous extract of P.acidus leaves has significant hepatoprotective activity on APAP and TAA induced hepatotoxicity,which might be associate with its high phenolic and flavonoid content and antioxidant properties. | Nilesh Kumar Jain Abhay K Singhai | 2011 | Asian Pacific Journal of Tropical Medicine2011，4，6： | 6 |
| 10 | Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles显示文摘Liver fibrosis is the common consequence of almost all liver diseases and has become an urgent clinical problem without efficient therapies.Recent evidence has shown that hepatocytes-derived extracellular vesicles(EVs)play important roles in liver pathophysiology,but little is known about the role of damaged hepatocytes-derived EVs in hepatic stellate cell(HSC)activation and following fibrosis.Tetramethylpyrazine(TMP)from Ligusticum wallichii Franchat exhibits a broad spectrum of biological activities including liver protection.In this study,we investigated whether TMP exerted liver-protective action through regulating EV-dependent intercellular communication between hepatocytes and HSCs.Chronic liver injury was induced in mice by CCl_(4)(1.6 mg/kg,i.g.)twice a week for 8 weeks.In the last 4 weeks of CCl_(4) administration,mice were given TMP(40,80,160 mg·kg^(-1)·d^(-1),i.g.).Acute liver injury was induced in mice by injection of a single dose of CCl_(4)(0.8 mg/kg,i.p.).After injection,mice were treated with TMP(80 mg/kg)every 24 h.We showed that TMP treatment dramatically ameliorated CCl_(4)-induced oxidative stress and hepatic inflammation as well as acute or chronic liver fibrosis.In cultured mouse primary hepatocytes(MPHs),treatment with CCl_(4) or acetaminophen resulted in mitochondrial dysfunction,release of mitochondrial DNA(mtDNA)from injured hepatocytes to adjacent hepatocytes and HSCs through EVs,mediating hepatocyte damage and fibrogenic responses in activated HSCs;pretreatment of MPHs with TMP(25μM)prevented all these pathological effects.Transplanted serum EVs from TMP-treated mice prevented both initiation and progression of liver fibrosis caused by CCl_(4).Taken together,this study unravels the complex mechanisms underlying the protective effects of TMP against mtDNA-containing EV-mediated hepatocyte injury and HSC activation during liver injury,and provides critical evidence inspiring the development of TMP-based innovative therapeutic agents for the treatment of liver fibrosis. | Ya-jing Li Run-ping Liu Ming-ning Ding Qi Zheng Jian-zhi Wu Xiao-yong Xue Yi-qing Gu Bo-ning Ma Ya-jie Cai Shuo Li Sheng Lin Lu-yong Zhang Xiaojiaoyang Li | 2022 | Acta Pharmacologica Sinica2022，43，8： | 5 |
| 11 | Artificial liver support in pigs with acetaminophen-induced acute liver failure显示文摘AIM To establish a reversible porcine model of acute liver failure(ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen(APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group(n = 11), in which a treatment procedure was performed, or a control group(n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased(P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h(at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group(P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution.Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment(P < 0.05). CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system(ZHj-3) is safe and effective for the APAP-induced porcine ALF model. | Guo-Lin He Lei Feng Lei Cai Chen-jie Zhou Yuan Cheng Ze-Sheng jiang Ming-xin Pan Yi Gao | 2017 | World Journal of Gastroenterology2017，23，18： | 5 |
| 12 | Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity显示文摘Background:Obesity is often associated with nonalcoholic fatty liver disease(NAFLD),which refers to a large spectrum of hepatic lesions including fatty liver,nonalcoholic steatohepatitis(NASH)and cirrhosis.Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs.Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD.Aim:The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity.For this purpose,we performed a data-mining analysis using different queries including drug-induced liver injury(or DILI),drug-induced hepatotoxicity,fatty liver,nonalcoholic fatty liver disease(or NAFLD),steatosis and obesity.The main data from the collected articles are reported in this review and when available,some pathophysiological hypotheses are put forward.Relevance for patients:Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen,halothane,methotrexate,rosiglitazone,stavudine and tamoxifen.For some of these drugs,experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD.Other drugs such as pentoxifylline,phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not.Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes,hyperlipidemia and coronary heart disease,it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening. | Julie Massart Karima Begriche Caroline Moreau Bernard Fromenty | 2017 | Journal of Clinical & Translational Research2017，3，1： | 4 |
| 13 | N-acetylcysteine and glycyrrhizin combination:Benefit outcome in a murine model of acetaminophen-induced liver failure显示文摘BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries.Substantial progress has been made in understanding the mechanism of hepatocellular injury,but N-acetylcysteine remains the only effective treatment despite its short therapeutic window.Thus,other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity.Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1)protein,a member of the family of damage-associated molecular pattern,known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments.Mice fasted for 15 h were treated with acetaminophen(500 mg/kg)or vehicle(phosphate-buffered saline)by intraperitoneal injection and separated into the following groups:Glycyrrhizin(200 mg/kg);N-acetylcysteine(150 mg/kg);and N-acetylcysteine/glycyrrhizin.In all groups,mice were sacrificed 12 h following acetaminophen administration.The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase.Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections.Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature,we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg)in mice induced severe liver injury as evidenced by increases in alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score.Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury.Thus,the co-administration of glycyrrhizin and N-acetylcysteine was investigated.Administered concomitantly with acetaminophen,the combination significantly reduced the severity of liver injury.Delayed administration of the combination of drugs,2 h or 6 h after acetaminophen,also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone.In addition,administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that,compared to N-acetylcysteine alone,co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury.Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity. | Charlotte Minsart Sandrine Rorive Arnaud Lemmers Eric Quertinmont Thierry Gustot | 2020 | World Journal of Hepatology2020，12，9： | 4 |
| 14 | Curcumin protects against acetaminophen-induced apoptosis in hepatic injury显示文摘AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phosphate-buffered saline(PBS)intraperitoneally(ip);GroupⅡ[APAP+carboxymethylcellulose(CMC)]mice received 1%CMC(vehicle)2h before APAP injection;GroupⅢ(APAP+CMN)mice received curcumin(10 or 20 mg/kg,ip)2 h before before or after APAP challenge.In GroupsⅡandⅢ,APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg.CMN was dissolved in 1%CMC.Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase(ALT)levels in serum and malondialdehyde(MDA)accumulation,superoxide dismutase(SOD)activity and hepatocyte apoptosis in liver tissues.RESULTS:Both pre-and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group(10 mg/kg:801.46±661.34 U/L;20 mg/kg:99.68±86.48 U/L vs 5406.80±1785.75 U/L,P<0.001,respectively).The incidence of liver necrosis was significantly lowered in CMN treated animals.MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group,but increased in APAP treated group(10.96±0.87 nmol/mg protein vs 16.03±2.58 nmol/mg protein,P<0.05).The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected(24.54±4.95 U/mg protein vs 50.21±1.93 U/mg protein,P<0.05).Furthermore,CMN treatment efficiently protected against APAPinduced apoptosis via increasing Bcl-2/Bax ratio.CONCLUSION:CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases. | Gang Li Jun-Bao Chen Chao Wang Zhi Xu Hao Nie Xiao-Yan Qin Xiao-Mei Chen Quan Gong | 2013 | World Journal of Gastroenterology2013，19，42： | 4 |
| 15 | CXCL16 deficiency attenuates acetaminopheninduced hepatotoxicity through decreasing hepatic oxidative stress and inflammation in mice显示文摘Chemokine C-X-C ligand 16 (CXCL16 ) ,一种单个通行证的类型我属于 CXC chemokine 家庭的膜蛋白质,与在肝损害的煽动性的反应有关。在现在的学习,我们调查了 CXCL16 的 pathophysiological 角色,唯一的膜界限 chemokine,在导致的 acetaminophen (APAP ) 在老鼠的 hepatotoxicity。老鼠与 APAP 被注射,并且血和织物样品在不同时间点被收获。浆液高活动性的组盒子 1 并且 CXCL16 层次被三明治免疫分析确定。肝织物节与 hematoxylin 曙红或与染色的 dihydroethidium 被染色。CXCL16 和另外的 cytokines 的表情被即时聚合酶链反应检验。Ly6-B, p-jun N 终端 kinase (p-JNK ) ,和 JNK 表情被西方的污点分析测量。细胞内部的谷胱甘肽,反应的氧种类,和 malondialdehyde 层次也被测量。APAP 服药过量增加了肝的 CXCL16 mRNA 和浆液 CXCL16 蛋白质层次。CXCL16 缺乏的老鼠显著地展出了更少的肝损害和肝的坏死,以及更低的死亡比野类型(WT ) 响应 APAP 服药过量处理的老鼠。提高的 APAP 在 WT 老鼠的呼吸的链激活,它是强烈在 CXCL16 大美人老鼠颠倒了的氧化应力和减少的 mitochondrial 的生产。另外, CXCL16 缺乏禁止了嗜中性的渗入和 APAP 服药过量处理触发的 proinflammatory cytokines 的生产。我们的学习表明 CXCL16 是对导致 APAP 的 hepatotoxicity 的肝免疫者反应的一个批评管理者,因此由指向 CXCL16 为导致药的尖锐的肝失败的处理提供潜在的策略。 | Hong Wang Yihui Shao Saisai Zhang Anqi Xie Yanna Ye Lihua Shi Leigang Jin Xuebo Pan Zhuofeng Lin Xiaokun Li Shulin Yang | 2017 | Acta Biochimica et Biophysica Sinica2017，49，6： | 4 |
| 16 | A sensitive acetaminophen sensor based on Co metal–organic framework(ZIF-67)and macroporous carbon composite显示文摘The composite of zeolitic imidazolate frameworks(ZIF-67)and ordered macroporous carbon(OMC)was successfully synthesized via in situ growth from the OMC matrix.The ZIF67–OMC composite was verified by scanning electron microscopy(SEM)and transmission electron microscopy(TEM),powder X-ray diffraction(XRD)and electrochemical impedance spectroscopy(EIS)and then evaluated as a modified material for electrochemical sensor.Benefitting from the large surface area and enhanced conductivity of the ZIF67–OMC composite,ZIF67–OMC nanocomposite showed superior electrocatalytic performance toward acetaminophen(AP)oxidation.The redox reaction of AP underwent a quasi-reversible redox reaction with higher anodic current at ZIF67–OMC modified electrode compared with the bare glassy carbon electrode(GCE).In optimal condition,the ZIF67–OMC/GCE was stable,reproducible and had a linear range of 0.05–100 μmol·L^(-1) AP concentration,with the detection limit of 20 nmol·L^(-1)(signal-to-noise of S/N=3).In addition,the prepared sensing platform for the detection of AP was evaluated for the compound paracetamol tablets and urine samples. | Jing Tang Zhen-Zhen Hui Tao Hu Xin Cheng Jia-Hao Guo Zi-Rong Li Hao Yu | 2022 | Rare Metals2022，41，1： | 3 |
| 17 | Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity显示文摘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. | Hartmut Jaeschke C David Williams Mitchell R McGill Anwar Farhood | 2010 | World Journal of Gastroenterology2010，16，19： | 3 |
| 18 | Regulation of macrophage activation in the liver after acute injury: Role of the fibrinolytic system显示文摘The liver functions,in part,to prevent exposure of the body to potentially harmful substances ingested in the diet.While it is highly efficient at accomplishing this,it is frequently prone to liver injury due to the biotransformation of xenobiotics into toxic metabolites.To counter this injury,the liver has evolved a unique capacity to rapidly and efficiently repair itself.Successful resolution of acute liver injury relies on hepatic macrophage populations that orchestrate the reparative response.After injury,Kupffer cells,the resident macrophages of the liver,become activated and secrete proinflammatory cytokines.These cytokines recruit other immune cells,including monocyte-derived macrophages,to the liver where they contribute to the repair process.Monocyte-derived macrophages traffic into the necrotic foci where they rapidly phagocytose dead cell debris.Simultaneous with this process,these cells change phenotype from a proinflammatory macrophage to a prorestorative macrophage that produce pro-mitogenic growth factors and antiinflammatory cytokines.Ultimately this process triggers resolution of inflammation,and along with proliferation of other hepatic cells,restores the liver architecture and function.While the mechanisms regulating specific macrophage functions during repair remain to be elucidated,recent studies indicate a key role for the fibrinolytic system in coordinating macrophage function during repair.In this review,we will highlight the function and role of hepatic macrophages in repair after acute liver injury,and will discuss the role of the fibrinolytic enzyme,plasmin,in regulation of these various processes. | Katherine Roth Jenna Strickland Bryan L Copple | 2020 | World Journal of Gastroenterology2020，26，16： | 3 |
| 19 | Protective effect of apoptosis signal-regulating kinase1 inhibitor against mice liver injury显示文摘Objective:To explore the protective effect and its molecular mechanism of apoptosis signalregulating kinase 1(ASK1) inhibitor(GS-459679) on acetaminophen-induced liver injury in mice.Methods:The model of liver injury was established by administration of acetaminophen(APAP)(300 mg/kg,i.p.) on C57BL/6 mice.Forty-eight male C57BL/6 mice were randomly divided into four groups,consisting of control group,GS group(GS-459679,30 mg/kg,i.p.),APAPinduced group,and GS combined with APAP-induced group.For GS combined with APAPinduced group,mice were treated with GS 30 min prior to administration of APAP.After mice were euthanized at 6 h or 12 h.respectively,serum levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were analyzed,and mRNA levels of TNF- α,IL-6 and IL-1βwere tested.The activity of glutathione(GSH),oxidized GSH(GSSG) and malondialdehyde were quantified.In addition,ASK1,P-ASK1,JNK and P-JNK protein levels were tested in all groups.Results:The ASK1 and P-ASK1 levels were up-regulated in APAP-induced group.Compared to the control group,serum levels of ALT and AST.and mRNA levels of TNF- a,IL-6 and IL-1(3were increased in APAP-induced group.Meanwhile,the levels of MAD and GSSG.and the ratio of GSSG/GSH were higher and the JNK was activatedin APAP-induced group compared with that in control group.However,compared to APAP-induced group,GS combined with APAP-induced group displayed a decrease of protein expression levels of ASK 1,P-ASKI and P-JNK,a reduction of serum levels of ALT and AST,a decrease in TNF- a.IL-6 and IL-1(3 mRNA levels,and a low ration of GSSG/GSH.Conclusions:GS-459679 treatment effectively down-regulates ASK1 and P-ASK 1 expression.Addition of GS-459679 decreases the generation of liver metabolites and inflammatory factors,reduces oxidative stress reaction,inhibits JNK activation,and then protects the responsiveness to APAP-induced liver injury. | Ping He Bo Zeng Xiao-Li Zhang Dian-Liang Fang Xia-Qia Zhou Ke-Qiang Wan Wen-Guang Tian | 2016 | Asian Pacific Journal of Tropical Medicine2016，9，3： | 3 |
| 20 | Hepatoprotective effects of Nigella sativa seed extract against acetaminophen-induced oxidative stress显示文摘Objective:To investigate the protective effects of Nigella sativa seed extract(NSSE) against acetaminophen(APAP)-induced hepaloloxicity in TIB-73 cells and rats.Methods:Toxicity in TIB-73 cells was induced with 10 μmol/L APAP and the protective effects of NSSE were evaluated at 25.50.75,100 μg/mL.For in rim examination,a total of 30 rals were equally divided into five experimental groups:normal control(vehicle),APAP(800 mg/kg body weight single IP injection) as a hepatotoxic control,and three APAP and NS pretreated(2 weeks) groups(APAP+NSSE 100 mg:APAP+NSSE 300 mg and APAP+NSSK 900 mg/kg).Results:TIB-73 cell viability was drastically decreased by(49.0±l.9)%after the 10 μmol/L APAP treatment,which also increased reactive oxygen species production.Co-treatment with NSSE at 25.50.75,and 100 μg/mL significantly improved cell viability and suppressed reactive oxygen species generation.In viro the APAP induced alterations in blood lactate levels,pH,anionic gap,and ion levels(HCO_3^-,Mg^(2+) and K^+),which tended to normalize with the NSSE pretreatment.The NSSE also significantly decreased elevated serum levels of alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,and alkaline phosphatase induced by APAP,which correlated with decreased levels of hepatic lipid peroxidation(nialondialdehyde),increased superoxide dismutase levels,and reduced glutathione concentrations.Improved hepatic histology was also found in the treatment groups other than APAP group.Conclusions:The in vitro and in vim findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepalotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation. | Gareeballa Osman Adam Md.Mahbubur Rahman Sei-Jin Lee Gi-Beum Kim Hyung-Sub Kang Jin-Shang Kim Shang-Jin Kim | 2016 | Asian Pacific Journal of Tropical Medicine2016，9，3： | 2 |
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