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Sample records for acetaminophen-induced liver injury

  1. Acetaminophen-induced acute liver injury in HCV transgenic mice

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    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  2. Translational biomarkers of acetaminophen-induced acute liver injury.

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    Beger, Richard D; Bhattacharyya, Sudeepa; Yang, Xi; Gill, Pritmohinder S; Schnackenberg, Laura K; Sun, Jinchun; James, Laura P

    2015-09-01

    Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

  3. Sestrin2 protects against acetaminophen-induced liver injury.

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    Kim, Seung Jung; Kim, Kyu Min; Yang, Ji Hye; Cho, Sam Seok; Kim, Ji Young; Park, Su Jung; Lee, Sang Kyu; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan

    2017-05-01

    Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

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    Zhang, Jingyao; Zhang, Simin; Bi, Jianbin; Gu, Jingxian; Deng, Yan; Liu, Chang

    2017-04-01

    Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS

  5. Free radical scavenging activity of Berberine in acetaminophen induced liver injury

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    Suhail Ahmed Almani

    2017-01-01

    Full Text Available Objective: Evaluation of free radical scavenging activity of Berberine (BBR in acetaminophen (AAP induced liver injury. Study design: Experimental study Place and Duration: Animal house, Isra University Hyderabad from October 2015 to March 2016. Methodology: A sample of 80 male Wistar rats was selected according to inclusion and exclusion criteria and was divided into a control and three experimental groups. Acetaminophen, N-acetyl cysteine (NAC and BBR were administered in standard doses. Blood samples were collected by cardiac puncture after 18 hours of post experiment period. Liver function test, anti oxidant enzymes and malondialdehyde (MDA were detected by ELISA assay kit (Fortress Diagnostics. The data was analyzed on Statistix 10.0 software (USA at 95% CI (P≤ 0.05. Results: The BBR showed anti oxidant and anti peroxidant activity against acetaminophen induced liver injury. BBR treated animals showed increased serum and tissue SOD, GPX, CAT, and GSSH with a reduction in tissue MDA (p=0.0001. Liver injury ameliorating effect of BBR was superior to N-acetyl cysteine. Conclusion: The present study suggests Berberine protects against acetaminophen-induced liver injury by its free radical scavenging activity.

  6. Acetaminophen-induced acute liver injury in mice.

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    Mossanen, J C; Tacke, F

    2015-04-01

    The induction of acute hepatic damage by acetaminophen (N-acetyl-p-aminophenol [APAP]), also termed paracetamol, is one of the most commonly used experimental models of acute liver injury in mice. The specific values of this model are the highly reproducible, dose-dependent hepatotoxicity of APAP and its outstanding translational importance, because acetaminophen overdose is one of the most frequent reasons for acute liver failure (ALF) in humans. However, preparation of concentrated APAP working solutions, application routes, fasting period and variability due to sex, genetic background or barrier environment represent important considerations to be taken into account before implementing this model. This standard operating procedure (SOP) provides a detailed protocol for APAP preparation and application in mice, aimed at facilitating comparability between research groups as well as minimizing animal numbers and distress. The mouse model of acetaminophen poisoning therefore helps to unravel the pathogenesis of APAP-induced toxicity or subsequent immune responses in order to explore new therapeutic interventions for improving the prognosis of ALF in patients.

  7. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

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    H. P. Kopylchuk

    2017-04-01

    Full Text Available Arginase activity and L-arginine content in both cytosolic and mitochondrial fractions of rat liver cells under the conditions of toxic injury on the background of protein deprivation was studied. The most significant reduction of arginase activity in liver cells and depletion of L-arginine pool was found in rats with toxic acetaminophen-induced liver injury maintained on the ration balanced by all nutrients as well as in protein deficiency rats. It was concluded that reduction of the arginase activity in the cytosolic fraction of rat liver cells, combined with simultaneous decrease of L-arginine content, may be considered as one of the mechanisms of ornithine cycle disturbance. The decline of activity of mitochondrial isoform of arginase II, for certain, is related with activation of NO-synthase system.

  8. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

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    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...... performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 microg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase...... in AFP above 4 microg/L occurred in 158 (79%) of 201 survivors compared with 11 of 33 nonsurvivors (33%; P AFP occurred a mean of 1.0 days (range, -2 to +6 days) after peak ALT in survivors compared with 4.1 days (range, +2 to +7 days) in nonsurvivors (P

  9. Acetaminophen-induced liver injury: Implications for temporal homeostasis of lipid metabolism and eicosanoid signaling pathway.

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    Suciu, Maria; Gruia, Alexandra T; Nica, Dragos V; Azghadi, Seyed M R; Mic, Ani A; Mic, Felix A

    2015-12-05

    Acetaminophen is a commonly used drug that induces serious hepatotoxicity when overdosed, leading to increased levels of serum aminotransferases. However, little knowledge exists linking acetaminophen to liver free fatty acids and the eicosanoid-mediated signaling pathway. To this end, adult NMRI mice injected with a dose of 400 mg/kg acetaminophen were monitored for one week post-treatment. Consistent changes were observed in serum transaminases, profile of hepatic free fatty acids, expression of cyclooxygenase, elongase, lipogenesis, and lipolysis genes; as well as in expression patterns of cyclooxygenase-1 and -2 in the liver. Both linoleic acid and arachidonic acid--substrates in eicosanoid biosynthesis--were significantly influenced by overdose, and the latter peaked first among the free fatty acids examined here. There was a close similarity between the temporal dynamics of linoleic acid and aspartate aminotransferases. Moreover, serum transaminases were reduced by cyclooxygenase-2 inhibitors, but not by cyclooxygenase-1 inhibitors. Our results hence attest to the hazard of acetaminophen overdose on the temporal homeostasis of hepatic concentrations of free fatty acids and expression of key genes underlying liver lipid metabolism. There is also evidence for activation of a cyclooxygenase-mediated signaling pathway, especially the cyclooxygenase 2-prostanoid pathway, during acetaminophen-induced liver injury. Therefore, the results of the present study should provide valuable information to a wide audience, working to understand the health hazard of this drug and the implications of the eicosanoid signaling pathway in liver pathophysiology.

  10. Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice.

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    Maes, Michaël; Crespo Yanguas, Sara; Willebrords, Joost; Weemhoff, James L; da Silva, Tereza Cristina; Decrock, Elke; Lebofsky, Margitta; Pereira, Isabel Veloso Alves; Leybaert, Luc; Farhood, Anwar; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2017-08-15

    Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5h. Sampling was performed 3, 6, 24 and 48h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury

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    Xie, Yuchao; Ramachandran, Anup [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Breckenridge, David G.; Liles, John T. [Department of Biology, Gilead Sciences, Inc., Foster City, CA (United States); Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-07-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24 h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5 h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. - Highlights: • Two ASK1 inhibitors protected against acetaminophen-induced liver injury. • The ASK1 inhibitors protect when used as pre- or post-treatment. • Protection by ASK1 inhibitor is

  12. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

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    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP

  13. Protective Properties of Flavonoid Extract of Coagulated Tofu (Curdled Soy Milk Against Acetaminophen-Induced Liver Injury in Rats

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    Ndatsu Yakubu

    2016-01-01

    Full Text Available The total flavonoid contents of the various coagulated tofu and the hepatoprotective potential of all tofu flavonoid extracts were investigated. Tofu was prepared from locally sourced coagulants (steep water, alum, lemon, and lemon peel ash extract. Total flavonoid contents of all coagulated tofu were investigated as established in vitro flavonoid assay. The hepatoprotective activities of tofu flavonoid extracts against acetaminophen-induced hepatic cell toxicity in rats was also investigated in this study. The activity was analyzed by assessing the levels of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP and lactate dehydrogenase (LDH. The concentrations of the serum sugar, total protein, albumin, and cholesterol as well as prothrombin time (PT of experimental rats with histopathological analysis were also conducted. The range of the total flavonoid contents of tofu was 4.3-6.4 mg/g. Tofu flavonoid extracts significantly reduced the activities of serum AST, ALT, ALP, and LDH; total cholesterol, and sugar levels, but total protein and albumin concentrations increased compared to acetaminophen-intoxicated rats. Also, the prothrombin time prolongation of serum in acetaminophen intoxicated rats was reduced. Histology of the liver tissue demonstrated that tofu flavonoid extracts inhibited the acetaminophen-induced hepatic cell necrosis, decreased inflammatory cell infiltration and accelerated hepatocellular regeneration. Therefore, all tofus exhibited high total flavonoid contents, and the tofu supplement in human diets is highly recommended as it can be used as a functional food to prevent liver injuries.

  14. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

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    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect from APAP

  15. Protective effects of red wine polyphenols and grape-seed proanthocyanidin extract on acetaminophen-induced liver injury

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    El-Sayed M. El-Sayed

    2014-11-01

    Full Text Available The present study was designed to examine the potential protective effects of red wine polyphenols (RWPs and grape seed proanthocyanidin extract (GSPE against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard reference hepatoprotective agent. A single dose of acetaminophen (800 mg/kg, injected intraperitoneally to male rats, caused a significant increase in serum ALT, AST, alkaline phosphatase (ALP, bilirubin, total cholesterol (TC, triglycerides(TG, tumor necrosis factor alpha (TNF-α, and liver contents of thiobarbituric acid reactive substances (TBARS measured as malondialdehyde (MDA and nitric oxide (NO with significant decrease in serum albumin, HDL cholesterol, reduced glutathione (GSH and hepatic activities of catalase (CAT, superoxide dismutase (SOD and caspase-3 in liver tissue as compared with the control group. On the other hand, administration of each of GSPE (100 mg/kg/day, p.o., RWPs (40 mg/kg/day, p.o. and silymarin (100 mg/kg/day, p.o. for 15 consecutive days significantly ameliorated the liver injury which confirmed by the histopathological examination. It was concluded that RWPs and GSPE showed protective effects against acute acetaminophen hepatotoxicity where RWPs were more effective than GSPE; most probably through their antioxidant, anti-inflammatory and anti-apoptotic effects.

  16. Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury

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    Graubardt, Nadine; Vugman, Milena; Mouhadeb, Odelia; Caliari, Gabriele; Pasmanik-Chor, Metsada; Reuveni, Debby; Zigmond, Ehud; Brazowski, Eli; David, Eyal; Chappell-Maor, Lousie; Jung, Steffen; Varol, Chen

    2017-01-01

    Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA-seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p ≤ 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance. PMID:28620383

  17. Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury

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    Lu, Yan; Zhang, Cheng; Chen, Yuan-Hua; Wang, Hua; Zhang, Zhi-Hui; Chen, Xi; Xu, De-Xiang

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury. PMID:28205631

  18. Visualization of acetaminophen-induced liver injury by time-of-flight secondary ion mass spectrometry.

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    Murayama, Yohei; Satoh, Shuya; Hashiguchi, Akinori; Yamazaki, Ken; Hashimoto, Hiroyuki; Sakamoto, Michiie

    2015-11-01

    Time-of-flight secondary ion mass spectrometry (MS) provides secondary ion images that reflect distributions of substances with sub-micrometer spatial resolution. To evaluate the use of time-of-flight secondary ion MS to capture subcellular chemical changes in a tissue specimen, we visualized cellular damage showing a three-zone distribution in mouse liver tissue injured by acetaminophen overdose. First, we selected two types of ion peaks related to the hepatocyte nucleus and cytoplasm using control mouse liver. Acetaminophen-overdosed mouse liver was then classified into three areas using the time-of-flight secondary ion MS image of the two types of peaks, which roughly corresponded to established histopathological features. The ion peaks related to the cytoplasm decreased as the injury became more severe, and their origin was assumed to be mostly glycogen based on comparison with periodic acid-Schiff staining images and reference compound spectra. This indicated that the time-of-flight secondary ion MS image of the acetaminophen-overdosed mouse liver represented the chemical changes mainly corresponding to glycogen depletion on a subcellular scale. In addition, this technique also provided information on lipid species related to the injury. These results suggest that time-of-flight secondary ion MS has potential utility in histopathological applications.

  19. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

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    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  20. ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury.

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    Liao, Chia-Chih; Day, Yuan-Ji; Lee, Hung-Chen; Liou, Jiin-Tarng; Chou, An-Hsun; Liu, Fu-Chao

    2017-01-01

    Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15-60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

  1. Inhibitor of Apoptosis Signal-Regulating Kinase 1 Protects Against Acetaminophen-induced Liver Injury

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    Xie, Yuchao; Ramachandran, Anup; Breckenridge, David G.; Liles, John T.; Lebofsky, Margitta; Farhood, Anwar; Jaeschke, Hartmut

    2015-01-01

    Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affected the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N-acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS-459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. PMID:25818599

  2. Moringa oleifera Lam prevents acetaminophen induced liver injury through restoration of glutathione level.

    Science.gov (United States)

    Fakurazi, S; Hairuszah, I; Nanthini, U

    2008-08-01

    Initiation of acetaminophen (APAP) toxicities is believed to be promoted by oxidative stress during the event of overdosage. The aim of the present study was to evaluate the hepatoprotective action of Moringa oleifera Lam (MO), an Asian plant of high medicinal value, against a single high dose of APAP. Groups of five male Sprague-Dawley rats were pre-administered with MO (200 and 800 mg/kg) prior to a single dose of APAP (3g/kg body weight; p.o). Silymarin was used as an established hepatoprotective drug against APAP induced liver injury. The hepatoprotective activity of MO extract was observed following significant histopathological analysis and reduction of the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in groups pretreated with MO compared to those treated with APAP alone. Meanwhile, the level of glutathione (GSH) was found to be restored in MO-treated animals compared to the groups treated with APAP alone. These observations were comparable to the group pretreated with silymarin prior to APAP administration. Group that was treated with APAP alone exhibited high level of transaminases and ALP activities besides reduction in the GSH level. The histological hepatocellular deterioration was also evidenced. The results from the present study suggested that the leaves of MO can prevent hepatic injuries from APAP induced through preventing the decline of glutathione level.

  3. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

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    Patricia Rivera

    2017-10-01

    Full Text Available Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE-peroxisome proliferators activated receptor alpha (PPARα system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP, a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM and time-course (2–6–24 h study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH, including the NAEs oleoyl ethanolamide (OEA and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg. The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver

  4. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  5. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice

    NARCIS (Netherlands)

    Swelm, R.P.L. van; Laarakkers, J.M.M.; Kuur, E.C. van der; Morava, E.; Wevers, R.A.; Augustijn, K.D.; Touw, D.J.; Sandel, M.H.; Masereeuw, R.; Russel, F.G.M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  6. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  7. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning.

    Science.gov (United States)

    Williams, C David; McGill, Mitchell R; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18h or 1h prior to an APAP overdose. Administration of allopurinol 18h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6h after APAP; however, 1h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2h) however late JNK activation (6h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18h or 1h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose.

  8. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

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    Hyunseong Kim

    Full Text Available The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2 from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg in mice. Acetaminophen (APAP is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/- mice were injected with PLA2 once a day for five days and sacrificed 24 h (h after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST and alanine aminotransferase (ALT. PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

  9. Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways

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    Fu-Chao Liu

    2016-01-01

    Full Text Available Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP- induced liver injury in a mice model. Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT and aspartate aminotransferase (AST levels, hepatic myeloperoxidase (MPO, malondialdehyde (MDA, glutathione (GSH, and superoxide dismutase (SOD activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting. Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK and extracellular signal-regulated kinase (ERK caused by APAP. Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice.

  10. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice.

    Directory of Open Access Journals (Sweden)

    Rachel P L van Swelm

    Full Text Available Drug-induced liver injury (DILI is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP. Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT values (p<0.0001. Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001, including superoxide dismutase 1 (SOD1, carbonic anhydrase 3 (CA3 and calmodulin (CaM, as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001 in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.

  11. Human Ex-Vivo Liver Model for Acetaminophen-induced Liver Damage

    Science.gov (United States)

    Schreiter, Thomas; Sowa, Jan-Peter; Schlattjan, Martin; Treckmann, Jürgen; Paul, Andreas; Strucksberg, Karl-Heinz; Baba, Hideo A.; Odenthal, Margarete; Gieseler, Robert K.; Gerken, Guido; Arteel, Gavin E.; Canbay, Ali

    2016-01-01

    Reliable test systems to identify hepatotoxicity are essential to predict unexpected drug-related liver injury. Here we present a human ex-vivo liver model to investigate acetaminophen-induced liver injury. Human liver tissue was perfused over a 30 hour period with hourly sampling from the perfusate for measurement of general metabolism and clinical parameters. Liver function was assessed by clearance of indocyanine green (ICG) at 4, 20 and 28 hours. Six pieces of untreated human liver specimen maintained stable liver function over the entire perfusion period. Three liver sections incubated with low-dose acetaminophen revealed strong damage, with ICG half-lives significantly higher than in non-treated livers. In addition, the release of microRNA-122 was significantly higher in acetaminophen-treated than in non-treated livers. Thus, this model allows for investigation of hepatotoxicity in human liver tissue upon applying drug concentrations relevant in patients. PMID:27550092

  12. Iridoid Glycosides Fraction Isolated from Veronica ciliata Fisch. Protects against Acetaminophen-Induced Liver Injury in Mice

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    Shancai Tan

    2017-01-01

    Full Text Available Veronica ciliata Fisch. has traditionally been used in Tibetan medicine for the treatment of hepatitis, cholecystitis, rheumatism, and urticaria. We analyzed the chemical composition of the iridoid glycosides fraction (IGF isolated from V. ciliata and evaluated the antioxidant and hepatoprotective properties. The IGF was separated by high-speed countercurrent chromatography (HSCCC and the main compounds were identified by ultra-performance liquid chromatography coupled to a photodiode array. We determined the in vitro antioxidant ability of the IGF through radical scavenging assays and assessed the in vivo hepatoprotective potential in an acetaminophen- (APAP- induced acute liver injury murine model. The IGF was separated by HSCCC and three major iridoid glycosides (verproside, catalposide, and amphicoside were identified as potent antioxidants and hepatoprotective compounds. Treatment with the IGF significantly suppressed the APAP-induced elevation in serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha (TNF-α; improved serum total antioxidant capacity; decreased malondialdehyde formation; elevated superoxide dismutase and glutathione activity; and decreased expression of proinflammatory factors (TNF-α, nuclear factor kappa B in the liver. Finally, we examined the histopathology of resected livers for evidence of hepatoprotection. The protection conferred by the IGF may be related to the reinforcement of antioxidant defense systems.

  13. Iridoid Glycosides Fraction Isolated from Veronica ciliata Fisch. Protects against Acetaminophen-Induced Liver Injury in Mice

    Science.gov (United States)

    Tan, Shancai; Lu, Qiuxia; Shu, Yueyue; Sun, Yiran

    2017-01-01

    Veronica ciliata Fisch. has traditionally been used in Tibetan medicine for the treatment of hepatitis, cholecystitis, rheumatism, and urticaria. We analyzed the chemical composition of the iridoid glycosides fraction (IGF) isolated from V. ciliata and evaluated the antioxidant and hepatoprotective properties. The IGF was separated by high-speed countercurrent chromatography (HSCCC) and the main compounds were identified by ultra-performance liquid chromatography coupled to a photodiode array. We determined the in vitro antioxidant ability of the IGF through radical scavenging assays and assessed the in vivo hepatoprotective potential in an acetaminophen- (APAP-) induced acute liver injury murine model. The IGF was separated by HSCCC and three major iridoid glycosides (verproside, catalposide, and amphicoside) were identified as potent antioxidants and hepatoprotective compounds. Treatment with the IGF significantly suppressed the APAP-induced elevation in serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha (TNF-α); improved serum total antioxidant capacity; decreased malondialdehyde formation; elevated superoxide dismutase and glutathione activity; and decreased expression of proinflammatory factors (TNF-α, nuclear factor kappa B) in the liver. Finally, we examined the histopathology of resected livers for evidence of hepatoprotection. The protection conferred by the IGF may be related to the reinforcement of antioxidant defense systems. PMID:28293265

  14. Predose and Postdose Blood Gene Expression Profiles Identify the Individuals Susceptible to Acetaminophen-Induced Liver Injury in Rats.

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    Xiaoyan Lu

    Full Text Available The extent of drug-induced liver injury (DILI can vary greatly between different individuals. Thus, it is crucial to identify susceptible population to DILI. The aim of this study was to determine whether transcriptomics analysis of predose and postdose rat blood would allow prediction of susceptible individuals to DILI using the widely applied analgesic acetaminophen (APAP as a model drug. Based on ranking in alanine aminotransferase levels, five most susceptible and five most resistant rats were identified as two sub-groups after APAP treatment. Predose and postdose gene expression profiles of blood samples from these rats were determined by microarray analysis. The expression of 158 genes innately differed in the susceptible rats from the resistant rats in predose data. In order to identify more reliable biomarkers related to drug responses for detecting individuals susceptibility to APAP-induced liver injury (AILI, the changes of these genes' expression posterior to APAP treatment were detected. Through the further screening method based on the trends of gene expression between the two sub-groups before and after drug treatment, 10 genes were identified as potential predose biomarkers to distinguish between the susceptible and resistant rats. Among them, four genes, Incenp, Rpgrip1, Sbf1, and Mmp12, were found to be reproducibly in real-time PCR with an independent set of animals. They were all innately higher expressed in resistant rats to AILI, which are closely related to cell proliferation and tissue repair functions. It indicated that rats with higher ability of cell proliferation and tissue repair prior to drug treatment might be more resistant to AILI. In this study, we demonstrated that combination of predose and postdose gene expression profiles in blood might identify the drug related inter-individual variation in DILI, which is a novel and important methodology for identifying susceptible population to DILI.

  15. Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

    Science.gov (United States)

    Dadhania, Vivekkumar P.; Bhushan, Bharat

    2017-01-01

    Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection. PMID:28210203

  16. TRPM2 channels mediate acetaminophen-induced liver damage.

    Science.gov (United States)

    Kheradpezhouh, Ehsan; Ma, Linlin; Morphett, Arthur; Barritt, Greg J; Rychkov, Grigori Y

    2014-02-25

    Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca(2+) homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca(2+) concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca(2+) rise. Here we report that the channel responsible for Ca(2+) entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H2O2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H2O2. In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wild-type mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

  17. Protective effect of rosiglitazone against acetaminophen-induced acute liver injury is associated with down-regulation of hepatic NADPH oxidases.

    Science.gov (United States)

    Wang, Jun-Xian; Zhang, Cheng; Fu, Lin; Zhang, Da-Gang; Wang, Bi-Wei; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Chen, Xi; Xu, De-Xiang

    2017-01-04

    The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. The aim of the present study was to investigate the effects of rosiglitazone (RSG), a synthetic PPAR-γ agonist, on acetaminophen (APAP)-induced acute liver injury. Male CD-1 mice were injected with APAP (300mg/kg). Some mice were pretreated with RSG (20mg/kg) 48, 24 and 1h before APAP injection. As expected, RSG pretreatment alleviated APAP-induced acute liver injury. Moreover, RSG pretreatment attenuated APAP-induced hepatic cell death and improved the survival. Although it did not affect hepatic cytochrome P450 (CYP)2E1 expression, RSG pretreatment attenuated reduction of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd) and glutathione S-transferase (GST) activities, inhibited upregulation of hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2 and NOX-4, and alleviated hepatic GSH depletion during APAP-induced acute liver injury. In addition, RSG pretreatment suppressed activation of hepatic nuclear factor kappa B (NF-κB) and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling during APAP-induced acute liver injury. These results provide a novel mechanistic explanation for RSG-mediated protection against APAP-induced acute liver injury. The present results suggest that synthetic PPAR-γ agonists might be effective agents for preventing the progression of APAP-induced acute liver injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex.

    Science.gov (United States)

    Onaolapo, Olakunle J; Adekola, Moses A; Azeez, Taiwo O; Salami, Karimat; Onaolapo, Adejoke Y

    2017-01-01

    We compared the relative protective abilities of silymarin and l-methionine pre-treatment in acetaminophen overdose injuries of the liver, kidney and cerebral cortex by assessing behaviours, antioxidant status, tissue histological changes and biochemical parameters of hepatic/renal function. Rats were divided into six groups of ten each; animals in five of these groups were pre-treated with oral distilled water, silymarin (25mg/kg) or l-methionine (2.5, 5 and 10mg/kg body weight) for 14days; and then administered intraperitoneal (i.p.) acetaminophen at 800mg/kg/day for 3days. Rats in the sixth group (normal control) received distilled water orally for 14days and then i.p. for 3days. Neurobehavioural tests were conducted 7days after last i.p treatment, and animals sacrificed on the 8th day. Plasma was assayed for biochemical markers of liver/kidney function; while sections of the liver, kidney and cerebral cortex were either homogenised for assay of antioxidant status or processed for histology. Acetaminophen overdose resulted in locomotor retardation, excessive self-grooming, working-memory impairment, anxiety, derangement of liver/kidney biochemistry, antioxidant imbalance, and histological changes in the liver, kidney and cerebral cortex. Administration of silymarin or increasing doses of l-methionine counteracted the behavioural changes, reversed biochemical indices of liver/kidney injury, and improved antioxidant activity. Silymarin and l-methionine also conferred variable degrees of tissue protection, on histology. Either silymarin or l-methionine can protect vulnerable tissues from acetaminophen overdose injury; however, each offers variable protection to different tissues. This study highlights an obstacle to seeking the 'ideal' protective agent against acetaminophen overdose.

  19. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

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    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  20. Hepato-protective effects of six schisandra lignans on acetaminophen-induced liver injury are partially associated with the inhibition of CYP-mediated bioactivation.

    Science.gov (United States)

    Jiang, Yiming; Fan, Xiaomei; Wang, Ying; Tan, Huasen; Chen, Pan; Zeng, Hang; Huang, Min; Bi, Huichang

    2015-04-25

    Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra fructus is widely-used traditional Chinese medicine which possesses hepato-protective potential. Schisandrin A (SinA), Schisandrin B (SinB), Schisandrin C (SinC), Schisandrol A (SolA), Schisandrol B (SolB), and Schisantherin A (SthA) are the major bioactive lignans. Most recently, we found SolB exerts significant hepato-protection against APAP-induced liver injury. In this study, the protective effects of the other five schisandra lignans against APAP-induced acute hepatotoxicity in mice were investigated and compared with that of SolB. The results of morphological and biochemical assessment clearly demonstrated significant protective effects of SinA, SinB, SinC, SolA, SolB, and SthA against APAP-induced liver injury. Among these schisandra lignans, SinC and SolB exerted the strongest hepato-protective effects against APAP-induced hepatotoxicity. Six lignans pretreatment before APAP dosing could prevent the depletions of total liver glutathione (GSH) and mitochondrial GSH caused by APAP. Additionally, the lignans treatment inhibited the enzymatic activities of three CYP450 isoforms (CYP2E1, CYP1A2, and CYP3A11) related to APAP bioactivation, and further decreased the formation of APAP toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) in mouse microsomal incubation system. This study demonstrated that SinA, SinB, SinC, SolA, SolB and SthA exhibited significant protective actions toward APAP-induced liver injury, which was partially associated with the inhibition of CYP-mediated APAP bioactivation.

  1. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity.

    Science.gov (United States)

    McGill, Mitchell R; Williams, C David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity.

  2. Hepatoprotective Effect of Polyphenol-Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen-Induced Liver Injury in Mice

    Science.gov (United States)

    Huang, Lisen; Pang, Haiyue; Zhang, Na; Chen, Yupei

    2017-01-01

    Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and α-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1–6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-β-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP-induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components. PMID:28626497

  3. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    Science.gov (United States)

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  4. Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

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    Robim M. Rodrigues

    2016-06-01

    Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

  5. Lycopene inhibits reactive oxygen species production in SK-Hep-1 cells and attenuates acetaminophen-induced liver injury in C57BL/6 mice.

    Science.gov (United States)

    Bandeira, Ana Carla Balthar; da Silva, Talita Prato; de Araujo, Glaucy Rodrigues; Araujo, Carolina Morais; da Silva, Rafaella Cecília; Lima, Wanderson Geraldo; Bezerra, Frank Silva; Costa, Daniela Caldeira

    2017-02-01

    Our aim was to investigate the antioxidant potential of lycopene in different experimental liver models: in vitro, to evaluate the influence of lycopene on reactive oxygen species (ROS) production mediated by the PKC pathway and in vivo, to evaluate the protective effects of lycopene in an experimental model of hepatotoxicity. The in vitro study assessed the lycopene antioxidant potential by the quantification of ROS production in SK-Hep-1 cells unstimulated or stimulated by an activator of the PKC pathway. The role of NADPH oxidase was evaluated by measuring its inhibition potential using an inhibitor of this enzyme. In the in vivo study, male C57BL/6 mice received lycopene (10 or 100 mg/kg by oral gavage) and 1 h later, acetaminophen (APAP) (500 mg/kg) was administrated. Lycopene decreased ROS production in SK-Hep-1 cells through inhibition of NADPH oxidase, brought about in the PKC pathway. Lycopene improved hepatotoxicity acting as an antioxidant, reduced GSSG and regulated tGSH and CAT levels, reduced oxidative damage primarily by decreasing protein carbonylation, promoted the downregulation of MMP-2 and reduced areas of necrosis improving the general appearance of the lesion in C57BL/6 mice. Lycopene is a natural compound that was able to inhibit the production of ROS in vitro and mitigate the damage caused by APAP overdose in vivo.

  6. Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

    Directory of Open Access Journals (Sweden)

    Howie Forbes

    2010-03-01

    Full Text Available Abstract Background The development of effective therapies for acute liver failure (ALF is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein. Control pigs (n = 4 survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg, increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3. Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3 observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02 and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14 coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis

  7. Use of acetylcysteine for non-acetaminophen-induced acute liver failure.

    Science.gov (United States)

    Sales, Ibrahim; Dzierba, Amy L; Smithburger, Pamela L; Rowe, Deanna; Kane-Gill, Sandra L

    2013-01-01

    The purpose of this review was to evaluate the effectiveness of acetylcysteine in the treatment of acute liver failure not related to acetaminophen. A search of MEDLINE April 2003 through May 2012 using the Pub Med database was conducted using the keywords acetylcysteine and non-acetaminophen-induced acute liver failure or acetylcysteine and liver failure. All human case reports, case series, and research articles that discussed the use of acetylcysteine for non-acetaminophen induced liver failure were evaluated. A total of 263 articles were identified during this broad search with 11 articles included for review in this article; eight case reports, two retrospective trials, and one prospective, randomized, double-blind multicenter study. In conclusion, the data suggest marginal benefit of IV acetylcysteine in NAI-ALF with coma grades I-II; however, the routine use of acetylcysteine cannot be recommended. It may be considered in non-transplant centers while awaiting referral or when transplantation is not an option. Further studies are necessary to determine optimal dosing, duration, and criteria for patient selection.

  8. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver

    Science.gov (United States)

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J.; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C.; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J.

    2017-01-01

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization. PMID:28134251

  9. Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver.

    Science.gov (United States)

    Gamal, Wesam; Treskes, Philipp; Samuel, Kay; Sullivan, Gareth J; Siller, Richard; Srsen, Vlastimil; Morgan, Katie; Bryans, Anna; Kozlowska, Ada; Koulovasilopoulos, Andreas; Underwood, Ian; Smith, Stewart; Del-Pozo, Jorge; Moss, Sharon; Thompson, Alexandra Inés; Henderson, Neil C; Hayes, Peter C; Plevris, John N; Bagnaninchi, Pierre-Olivier; Nelson, Leonard J

    2017-01-30

    Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.

  10. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  11. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    Science.gov (United States)

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  12. Targeted metabolomic study indicating glycyrrhizin’s protection against acetaminophen-induced liver damage through reversing fatty acid metabolism.

    Science.gov (United States)

    Yu, Jian; Jiang, Yang-Shen; Jiang, Yuan; Peng, Yan-Fang; Sun, Zhuang; Dai, Xiao-Nan; Cao, Qiu-Ting; Sun, Ying-Ming; Han, Jing-Chun; Gao, Ya-Jie

    2014-06-01

    The present study aimed to give a short report on a possible mechanism of glycyrrhizin to acetaminophen-induced liver toxicity. Seven-day intraperitoneal administration of glycyrrhizin (400 mg/kg/day) to 2- to 3-month-old male C57BL/6N mice (mean weight 27 g) significantly prevents acetaminophen-induced liver damage, as indicated by the activity of alanine transaminase and aspartate aminotransferase. Metabolomics analysis and principal component analysis (PCA) using ultra-fast liquid chromatography coupled to triple time-of-flight mass spectrometer were performed. PCA separated well the control, glycyrrhizin-treated, acetaminophen-treated, and glycyrrhizin+acetaminophen-treated groups. Long-chain acylcarnitines were listed as the top ions that contribute to this good separation, which include oleoylcarnitine, palmitoylcarnitine, palmitoleoylcarnitine, and myristoylcarnitine. The treatment of glycyrrhizin significantly reversed the increased levels of long-chain acylcarnitines induced by acetaminophen administration. In conclusion, this metabolomic study indicates a significant glycyrrhizin protection effect against acetaminophen-induced liver damage through reversing fatty acid metabolism.

  13. Effect of a bioflavonoid dietary supplement on acetaminophen-induced oxidative injury to feline erythrocytes.

    Science.gov (United States)

    Allison, R W; Lassen, E D; Burkhard, M J; Lappin, M R

    2000-10-15

    To determine the effect of a commercial bioflavonoid antioxidant on acetaminophen-induced oxidative injury to feline erythrocytes. Randomized controlled study. 45 healthy age-matched cats. Cats were assigned to 3 experimental groups. Groups 1 and 3 received a bioflavonoid antioxidant (10 mg/d) orally for 2 weeks. Groups 2 and 3 received an oxidative challenge with acetaminophen (90 mg/kg [41 mg/lb] of body weight, PO) on day 7. Packed cell volume, percentage of erythrocytes with Heinz bodies, blood methemoglobin concentration, and blood reduced and oxidized glutathione concentrations were determined at various times during the 2-week study period. Adverse effects were not associated with bioflavonoid antioxidant administration alone. Acetaminophen administration resulted in a significant increase in methemoglobin concentration in groups 2 and 3; differences were not detected between these groups. Heinz body concentrations in groups 2 and 3 increased after acetaminophen administration; however, the increase in cats that received the antioxidant was significantly less than in group-2 cats. Total blood glutathione concentrations did not change significantly in groups 2 and 3 after acetaminophen administration; however, ratio of reduced to oxidized glutathione concentration increased significantly after administration in group-2 cats, compared with group-3 cats. Oral administration of bioflavonoid antioxidants to cats at risk for oxidative stress may have a beneficial effect on their ability to resist oxidative injury to erythrocytes.

  14. Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

    Science.gov (United States)

    Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

    2017-04-04

    Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

  15. Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Sreenivasan Sasidharan

    2012-11-01

    Full Text Available The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05. Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

  16. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury.

    Science.gov (United States)

    Grespan, Renata; Aguiar, Rafael Pazinatto; Giubilei, Frederico Nunes; Fuso, Rafael Rocco; Damião, Marcio José; Silva, Expedito Leite; Mikcha, Jane Graton; Hernandes, Luzmarina; Bersani Amado, Ciomar; Cuman, Roberto Kenji Nakamura

    2014-01-01

    Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO), which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in mice. Their livers were then used to determine myeloperoxidase (MPO) enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•)-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice.

  17. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury

    Directory of Open Access Journals (Sweden)

    Renata Grespan

    2014-01-01

    Full Text Available Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO, which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, and alkaline phosphatase (ALP in mice. Their livers were then used to determine myeloperoxidase (MPO enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice.

  18. Artificial liver support in pigs with acetaminophen-induced acute liver failure

    Science.gov (United States)

    He, Guo-Lin; Feng, Lei; Cai, Lei; Zhou, Chen-Jie; Cheng, Yuan; Jiang, Ze-Sheng; Pan, Ming-Xin; Gao, Yi

    2017-01-01

    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. PMID:28566885

  19. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Science.gov (United States)

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-l-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800 mg/kg/day, orally) were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally). Rat hepatocyte cultures were exposed to 20 mmol/L APAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF. PMID:27782042

  20. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    Directory of Open Access Journals (Sweden)

    Herson Antonio González-Ponce

    2016-10-01

    Full Text Available Acetaminophen (APAP-induced acute liver failure (ALF is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC, the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally. Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF.

  1. [Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency].

    Science.gov (United States)

    Voloshchuk, O N; Kopylchuk, G P

    2016-01-01

    Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

  2. Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity.

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    Wang, Kun-Peng; Bai, Yu; Wang, Jian; Zhang, Jin-Zhen

    2014-05-01

    Schisandra chinensis is a well-known traditional medicinal herb. Acetaminophen is a commonly used over-the-counter analgesic and overdose of acetaminophen was the most frequent cause of acute liver failure. However, no studies have demonstrated the role of Schisandra chinensis in acetaminophen-induced acute liver failure to the best of our knowledge. In this study, an acute liver injury model was established in mice using acetaminophen. The protective role of Schisandra chinensis was detected by histopathological analysis, and measurement of the serum transaminase levels and hepatic Cyp activity levels in the mouse model. Subsequently, hepatocytes were isolated from the livers of the mouse model. The cell cycle, apoptosis, mitochondrial membrane potential and reactive oxygen species were determined using flow cytometry. Cell proliferation and 26S proteasome activity were determined using spectrophotometry. Schisandra chinensis was found to resist acetaminophen-induced hepatotoxicity by protecting mitochondria and lysosomes and inhibiting the phosphor-c-Jun N-terminal kinase signaling pathway. These findings provide a novel application of Schisandra chinensis against acetaminophen-induced acute liver failure.

  3. Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study

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    Nabi, Tauseef; Nabi, Sumaiya; Rafiq, Nadeema; Shah, Altaf

    2017-01-01

    Background/Aims: Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use. Patients and Methods: A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization. Results: The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies. Conclusion: The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe. PMID:28611340

  4. Reversal of acetaminophen induced subchronic hepatorenal injury by propolis extract in rats.

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    Bhadauria, Monika; Nirala, Satendra Kumar

    2009-01-01

    The ethanolic extract of propolis (200mg/kg, p.o.) was evaluated against acetaminophen (APAP; 20mg/kg, p.o.) induced subchronic hepatorenal injury in rats. Administration of APAP significantly increased the release of serum transaminases, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transpeptidase, bilirubin and serum proteins, whereas concomitantly decreased hemoglobin, blood sugar and albumin. Hepatorenal reduced glutathione and activities of superoxide dismutase and catalase, hepatic CYPs i.e., aniline hydroxylase and amidopyrine-N-demethylase were significantly decreased after APAP intoxication. Lipid peroxidation showed significant elevation in both organs significantly after APAP assault. Total proteins, glycogen contents and the activities of certain metabolic enzymes i.e., adenosine triphosphatase, alkaline phosphatase and acid phosphatase were altered after APAP administration. Propolis extract exhibited curative effects by reversing APAP induced alterations in blood biochemical variables, CYP enzymes and markers of oxidative stress. Histopathological analysis of liver and kidney was consistent with the biochemical findings and led us to conclude the curative potential of propolis against APAP induced hepatorenal injury. Copyright © 2008 Elsevier B.V. All rights reserved.

  5. Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Bhushan, Bharat; Poudel, Samikshya; Manley, Michael W; Roy, Nairita; Apte, Udayan

    2017-03-01

    Overdose of acetaminophen (APAP) is the leading cause of acute liver failure (ALF) in the United States. Timely initiation of compensatory liver regeneration after APAP hepatotoxicity is critical for final recovery, but the mechanisms of liver regeneration after APAP-induced ALF have not been extensively explored yet. Previous studies from our laboratory have demonstrated that activation of β-catenin signaling after APAP overdose is associated with timely liver regeneration. Herein, we investigated the role of glycogen synthase kinase 3 (GSK3) in liver regeneration after APAP hepatotoxicity using a pharmacological inhibition strategy in mice. Treatment with specific GSK3 inhibitor (L803-mts), starting from 4 hours after 600 mg/kg dose of APAP, resulted in early initiation of liver regeneration in a dose-dependent manner, without modifying the peak regenerative response. Acceleration of liver regeneration was not secondary to alteration of APAP-induced hepatotoxicity, which remained unchanged after GSK3 inhibition. Early cell cycle initiation in hepatocytes after GSK3 inhibition was because of rapid induction of cyclin D1 and phosphorylation of retinoblastoma protein. This was associated with increased activation of β-catenin signaling after GSK3 inhibition. Taken together, our study has revealed a novel role of GSK3 in liver regeneration after APAP overdose and identified GSK3 as a potential therapeutic target to improve liver regeneration after APAP-induced ALF. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  7. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Antonio Gonzalez-Ponce, Herson; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  8. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

    Science.gov (United States)

    Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Bersani-Amado, Ciomar Aparecida

    2017-01-01

    High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID:28717379

  9. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury.

    Science.gov (United States)

    Naguib, Yahya M; Azmy, Rania M; Samaka, Rehab M; Salem, Mohamed F

    2014-12-15

    Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects. Ninety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal. APAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues. We report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative

  10. Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure.

    Science.gov (United States)

    Cooper, Sheldon C; Aldridge, Roland C; Shah, Tahir; Webb, Kerry; Nightingale, Peter; Paris, Sue; Gunson, Bridget K; Mutimer, David J; Neuberger, James M

    2009-10-01

    Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated.

  11. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

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    Nélson R Carvalho

    Full Text Available The acute liver failure (ALF induced by acetaminophen (APAP is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe2 to the N-acetylcysteine (NAC during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg, (PhSe2 (15.6 mg/kg, NAC (1200 mg/kg, APAP+(PhSe2 or APAP+NAC, where the (PhSe2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe2. The effectiveness of (PhSe2 was similar at a lower dose than NAC. In summary, (PhSe2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

  12. Antioxidant and Hepatoprotective Properties of Tofu (Curdle Soymilk against Acetaminophen-Induced Liver Damage in Rats

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    Ndatsu Yakubu

    2013-01-01

    Full Text Available The antioxidant and hepatoprotective properties of tofu using acetaminophen to induce liver damage in albino rats were evaluated. Tofus were prepared using calcium chloride, alum, and steep water as coagulants. The polyphenols of tofu were extracted and their antioxidant properties were determined. The weight gain and feed intake of the rats were measured. The analysis of serum alanine aminotransferase (ALT, alkaline phosphatase (ALP, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH activities and the concentrations of albumin, total protein, cholesterol, and bilirubin were analyzed. The result reveals that the antioxidant property of both soluble and bound polyphenolic extracts was significantly higher in all tofus, but the steep water coagulated tofu was recorded higher. Rats fed with various tofus and acetaminophen had their serum ALP, ALT, AST, and LDH activities; total cholesterol; and bilirubin levels significantly (P<0.05 reduced, and total protein and albumin concentrations increased when compared with basal diet and acetaminophen administered group. Therefore, all tofus curdled with various coagulants could be used to prevent liver damage caused by oxidative stress.

  13. Hepatoprotective Effect of ψ-Glutathione in a Murine Model of Acetaminophen-Induced Liver Toxicity.

    Science.gov (United States)

    More, Swati S; Nugent, Jaime; Vartak, Ashish P; Nye, Steffan M; Vince, Robert

    2017-03-20

    Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios. While both agents appear to be equally efficacious when timely administered, ψ-GSH partly retains its efficacy even in the face of substantial delay in administration. Thus, implied is the ability of ψ-GSH to intercept secondary toxicology following APAP insult. Oral availability and complete lack of toxicity as evaluated by liver function tests and survival analysis underscored ψ-GSH as a safer and more efficacious alternative to NAC. Finally, the pharmacodynamic mimicry of GSH by ψ-GSH is illustrated through the isolation and chemical characterization of an entity that can arise only through direct encounter of ψ-GSH with N-acetyl-p-benzoquinoneimine, the primary toxic metabolite of APAP.

  14. Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice.

    Science.gov (United States)

    Ming, Ya-Nan; Zhang, Jing-Yi; Wang, Xiao-Lin; Li, Chun-Min; Ma, Si-Cong; Wang, Zheng-Yang; Liu, Xiao-Lin; Li, Xiao-Bo; Mao, Yi-Min

    2017-08-14

    Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice. A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high-throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot. Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt). Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver.

  15. NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency

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    G. P. Kopylchuk

    2015-02-01

    Full Text Available The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADН is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences­ of energy exchange in the toxic hepatitis, induced on the background of protein deficiency.

  16. Remarks on Sasidharan et al. “Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage”. Molecules 2012, 17, 13937-13947

    Directory of Open Access Journals (Sweden)

    Manu Sharma

    2013-03-01

    Full Text Available An article by Sasidharan et al. recently published in the journal Molecules [1] claimed to show the hepatoprotective effects of lantadene A against acetaminophen-induced liver damage in mice. While reading this paper, I came across certain points that need to be clarified and taken up in the interest of science and other scientists working in this area.

  17. Effects of sesame oil against after the onset of acetaminophen-induced acute hepatic injury in rats.

    Science.gov (United States)

    Chandrasekaran, Victor Raj Mohan; Chien, Se-Ping; Hsu, Dur-Zong; Chang, Yu-Chung; Liu, Ming-Yie

    2010-01-01

    Acetaminophen (APAP) is a safe and effective analgesic and antipyretic when used at therapeutic levels. However, an acute or cumulative overdose can cause severe liver injury with the potential to progress to liver failure in humans and experimental animals. Much attention has been paid to the development of an antioxidant that protects against APAP-induced acute hepatic injury. Hence, we aimed to investigate the effect of sesame oil against after the onset of acute hepatic injury in APAP-overdosed rats. Male Wistar rats were first given 2 oral doses (1,000 mg/kg each) of APAP (at 0 and 24 hours) and then 1 oral dose of sesame oil (8 mL/kg at 24 hours). After 48 hours, APAP increased aspartate and alanine aminotransferase levels in the rats' serum and centrilobular necrosis in liver tissue. In addition, APAP significantly decreased the rats' glutathione levels and mitochondrial aconitase activity, but increased superoxide anion, hydroxyl radical, and lipid peroxidation levels. Oral sesame oil (8 mL/kg, given at 24 hours) reversed all APAP-altered parameters and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil acts as a useful agent that maintains intracellular glutathione levels and inhibits reactive oxygen species, thereby protecting rats against after the onset of APAP-induced acute oxidative liver injury.

  18. A non-hepatotropic parasite infection increases mortality in the acetaminophen-induced acute liver failure murine model: possible roles for IL-5 and IL-6

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    Marco A De León-Nava

    Full Text Available We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group. Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT levels, CYP2E1 protein, interleukin (IL- 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group, whereas only one-third of uninfected animals exposed to acetaminophen (APAP group died. Uninfected (Control group and infected (Tc group mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients.

  19. A non-hepatotropic parasite infection increases mortality in the acetaminophen-induced acute liver failure murine model: possible roles for IL-5 and IL-6

    Science.gov (United States)

    De León-Nava, Marco A; Álvarez-Delgado, Carolina; Donis-Maturano, Luis; Hernández-Ruiz, Joselin; Manjarrez-Reyna, Aaron N; Cruz-Avilés, Edgar; Leon-Cabrera, Sonia; Morales-Montor, Jorge; Fragoso, José M; Escobedo, Galileo

    2016-01-01

    We evaluated the effects of a non-hepatotropic parasite infection (Taenia crassiceps) on the outcome of acetaminophen-induced acute liver failure in mice. Uninfected and T. crassiceps infected mice orally received either 300 mg/kg acetaminophen or water as vehicle (n = 5 per group). Survival analysis, hepatocyte necrosis, alanine aminotransferase (ALT) levels, CYP2E1 protein, interleukin (IL-) 5, and IL-6 were assessed for all groups. All infected mice died within 16 h after exposure to acetaminophen (Tc+APAP group), whereas only one-third of uninfected animals exposed to acetaminophen (APAP group) died. Uninfected (Control group) and infected (Tc group) mice that received the vehicle showed no liver damage. Tc+APAP mice exhibited massive liver necrosis characterised by marked balloning degeneration of hepatocytes and higher serum ALT compared to Control, Tc, and APAP animals. Liver tissue from Tc+APAP mice also displayed increased expression of CYP2E1 protein and higher mRNA and protein levels of IL-5 and IL-6 compared to the other groups. These findings suggest that non-hepatotropic parasite infections may increase mortality following acute liver failure by promoting hepatocyte necrosis via IL-5 and IL-6-dependent CYP2E1 overproduction. This study identifies new potential risk factors associated with severe acute liver failure in patients. PMID:27812602

  20. Necrostatin-1 protects against reactive oxygen species (ROS-induced hepatotoxicity in acetaminophen-induced acute liver failure

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    Kenji Takemoto

    2014-01-01

    Full Text Available Excessive acetaminophen (APAP use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK-dependent necrosis (or necroptosis, which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.

  1. Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure

    Science.gov (United States)

    Takemoto, Kenji; Hatano, Etsuro; Iwaisako, Keiko; Takeiri, Masatoshi; Noma, Naruto; Ohmae, Saori; Toriguchi, Kan; Tanabe, Kazutaka; Tanaka, Hirokazu; Seo, Satoru; Taura, Kojiro; Machida, Keigo; Takeda, Norihiko; Saji, Shigehira; Uemoto, Shinji; Asagiri, Masataka

    2014-01-01

    Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure. PMID:25349782

  2. Predicting outcome on admission and post-admission for acetaminophen-induced acute liver failure using classification and regression tree models.

    Directory of Open Access Journals (Sweden)

    Jaime Lynn Speiser

    Full Text Available Assessing prognosis for acetaminophen-induced acute liver failure (APAP-ALF patients often presents significant challenges. King's College (KCC has been validated on hospital admission, but little has been published on later phases of illness. We aimed to improve determinations of prognosis both at the time of and following admission for APAP-ALF using Classification and Regression Tree (CART models.CART models were applied to US ALFSG registry data to predict 21-day death or liver transplant early (on admission and post-admission (days 3-7 for 803 APAP-ALF patients enrolled 01/1998-09/2013. Accuracy in prediction of outcome (AC, sensitivity (SN, specificity (SP, and area under receiver-operating curve (AUROC were compared between 3 models: KCC (INR, creatinine, coma grade, pH, CART analysis using only KCC variables (KCC-CART and a CART model using new variables (NEW-CART.Traditional KCC yielded 69% AC, 90% SP, 27% SN, and 0.58 AUROC on admission, with similar performance post-admission. KCC-CART at admission offered predictive 66% AC, 65% SP, 67% SN, and 0.74 AUROC. Post-admission, KCC-CART had predictive 82% AC, 86% SP, 46% SN and 0.81 AUROC. NEW-CART models using MELD (Model for end stage liver disease, lactate and mechanical ventilation on admission yielded predictive 72% AC, 71% SP, 77% SN and AUROC 0.79. For later stages, NEW-CART (MELD, lactate, coma grade offered predictive AC 86%, SP 91%, SN 46%, AUROC 0.73.CARTs offer simple prognostic models for APAP-ALF patients, which have higher AUROC and SN than KCC, with similar AC and negligibly worse SP. Admission and post-admission predictions were developed.• Prognostication in acetaminophen-induced acute liver failure (APAP-ALF is challenging beyond admission • Little has been published regarding the use of King's College Criteria (KCC beyond admission and KCC has shown limited sensitivity in subsequent studies • Classification and Regression Tree (CART methodology allows the

  3. Reversal of bioenergetics dysfunction by diphenyl diselenide is critical to protection against the acetaminophen-induced acute liver failure.

    Science.gov (United States)

    Carvalho, Nélson R; Tassi, Cintia C; Dobraschinski, Fernando; Amaral, Guilherme P; Zemolin, Ana P; Golombieski, Ronaldo M; Dalla Corte, Cristiane L; Franco, Jeferson L; Mauriz, José L; González-Gallego, Javier; Soares, Félix A

    2017-07-01

    Physiopathological conditions such as acute liver failure (ALF) induced by acetaminophen (APAP) can often impair the mitochondrial bioenergetics. Diphenyl diselenide [(PhSe)2] has been shown protects against APAP-induced ALF. The present study aimed to clarify the signaling mechanism involved in the protection of bioenergetics dysfunction associated with ALF-induced by APAP overdose. Mice received APAP (600mg/kg) or (PhSe)2 (15.6mg/kg) alone, or APAP+(PhSe)2, all the solutions were administered by the intraperitoneal (i.p.). Samples of liver, blood and liver mitochondria were collected at 2 and 4h after APAP administration. APAP-induced ALF was able to induce ALF by means of alteration on liver injury biomarkers, increased Nitrite and Nitrate levels and the impairment of oxidative phosphorylation capacity (OXPHOS). In parallel, APAP overdose promoted activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and Heat shock protein 70 (HSP70) expression. (PhSe)2 was able to abolish the APAP-induced decline of OXPHOS and changes on the Nrf2-ARE pathway. In addition, (PhSe)2 elevated the levels of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), helping to restore the levels of nuclear respiratory factor 1 (NRF1) associated with mitochondrial biogenesis. In summary, the treatment with (PhSe)2 maintained mitochondrial function, promoted genes related to mitochondrial dynamic and demonstrating to play critical role in the modulation of cellular protective responses during ALF. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study.

    Science.gov (United States)

    Darweesh, Samar K; Ibrahim, Mona F; El-Tahawy, Mahmoud A

    2017-05-01

    Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF. In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled. NAC infusion (in empirical dose) was given as 150 mg/kg in 100 ml dextrose 5% over half an hour, then 70 mg/kg in 500 ml dextrose 5% over 4 h, then 70 mg/kg in 500 ml dextrose 5% over 16 h. Thereafter continuous infusion was administered over 24 h of 150 mg/kg in 500 ml dextrose 5% until up to two consecutive normal international normalized ratios (INRs) were obtained. Our endpoints were recovery, transplantation, or death. The primary outcome of the study was to assess reduction in mortality or liver transplantation. The secondary outcome was the evaluation of other clinical outcomes (length of ICU and hospital stays, organ system failure, and hepatic encephalopathy). The study included a total of 155 adults; the NAC group (n = 85) were given NAC between January 2011 to December 2013 and the control group (n = 70) were not given NAC and were included from files dating between 2010 and 2011. Both groups (before NAC) were comparable with regard to etiology, age, sex, smoking, presence of co-morbidities, encephalopathy, liver profile, and INR. The success rate (transplant-free survival) in the NAC group was 96.4%. While in the control group, 17 patients (23.3%) recovered and 53 (76.6%) did not recover, of these 37 (53.3%) had liver transplantation and 16 (23.3%) died (p < 0.01). The NAC group had significantly shorter hospital stays (p < 0.001), less encephalopathy (p = 0.02), and less bleeding (p < 0.01) than the control group. The control group reported a higher ICU admission (p = 0.01) rate and

  5. Toxicity monitoring with primary cultured hepatocytes underestimates the acetaminophen-induced inflammatory responses of the mouse liver.

    Science.gov (United States)

    Tachibana, Shinjiro; Shimomura, Akiko; Inadera, Hidekuni

    2011-01-01

    In vitro gene expression profiling with isolated hepatocytes has been used to assess the hepatotoxicity of certain chemicals because of animal welfare issues. However, whether an in vitro system can completely replace the in vivo system has yet to be elucidated in detail. Using a focused microarray established in our laboratory, we examined gene expression profiles in the mouse liver and primary cultured hepatocytes after treatment with different doses of acetaminophen, a widely used analgesic that frequently causes liver injury. The acute hepatotoxicity of acetaminophen was confirmed by showing the induction of an oxidative stress marker, heme oxygenase-1, elevated levels of serum transaminase, and histopathological findings. In vivo microarray and network analysis showed that acetaminophen treatment provoked alterations in relation to the inflammatory response, and that tumor necrosis factor-α plays a central role in related pathway alterations. By contrast, pathway analyses in in vitro isolated hepatocytes did not find such prominent changes in the inflammation-related networks compared with the in vivo situation. Thus, although in vitro gene expression profiles are useful for evaluating the direct toxicity of chemicals, indirect toxicities including inflammatory responses mediated by cell-cell interactions or secondary toxicity due to pathophysiological changes in the whole body may be overlooked. Our results indicate that the in vitro hepatotoxicity prediction system using isolated hepatocytes does not fully reflect the in vivo cellular response. An in vitro system may be appropriate, therefore, for high throughput screening to detect the direct hepatotoxicity of a test compound.

  6. Protective effect of pioglitazone, a PPARγ agonist against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Gupta, Gaurav; Krishna, Gopala; Chellappan, Dinesh Kumar; Gubbiyappa, Kumar Shiva; Candasamy, Mayuren; Dua, Kamal

    2014-08-01

    Acetaminophen has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Pioglitazone, PPARγ ligand, is clinically tested and used in treatment of diabetes. PPARγ is a key nuclear hormone receptor of lipid metabolisms and regulates several gene transcriptions associated with differentiation, growth arrest, and apoptosis. The aim of our study was to evaluate the hepatoprotective activity of pioglitazone on acetaminophen-induced hepatotoxicity and to understand the relationship between the PPARγ and acetaminophen-induced hepato injury. For the experiment, Sprague-Dawley rats (160-180 g) were used and divided into four groups. Groups I and II were normal and experimental controls, respectively. Groups III and IV received the pioglitazone 20 mg/kg for 10 days. Hepatotoxicity was induced in Groups II and III on the eighth day with acetaminophen (i.p. 350 mg/kg body weight). The hepatoprotective effect was evaluated by performing an assay of the total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and α-fetoprotein as well as glutathione peroxidase, lipid peroxidation, catalase, superoxide dismutase, and glutathione transferase and liver histopathology. The assay results were presented as mean and standard error of mean for each group. The study group was compared with the control group by one-way ANOVA test. A p value of hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen -induced liver pathological damage. Various biochemical estimations of different hepatic markers and antioxidant enzymes and histopathological studies of liver tissues glimpse a support to its significant hepatoprotective activity on acetaminophen -induced hepatotoxicity.

  7. Drug –induced liver injury:a review

    Directory of Open Access Journals (Sweden)

    Sreya Kosanam

    2015-03-01

    Full Text Available The incidence of drug induced liver injury (DILI is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized based on the pattern of liver enzyme alteration (hepatocellular, cholestatic or mixed pattern, the mechanism of hepatotoxicity (direct, immune mediated or idiosyncratic and histologic findings on liver biopsy (steatosis or sinusoidal obstruction syndrome. Treatment options for DILI include discontinuing the drug, conservative measurements and liver transplantation in the case of non-acetaminophen induced hepatotoxicity.

  8. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    Directory of Open Access Journals (Sweden)

    Maria Goretti R. Queiroz

    2008-10-01

    Full Text Available Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae leaf essential oil (EOCz was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o. acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT, serum glutamate oxaloacetate transaminase (GOT activities, that were significantly (p<0.01 elevated in the acetaminophen alone treated animals. Histopathological examinations of liver tissue corroborated well with the biochemical changes. Hepatic steatosis, hydropic degeneration and necrosis were observed in the acetaminophen treated group, while these were completely absent in the standard and EOCz treated groups. In conclusion, these data suggest that the Croton zehntneri essential oil can prevent hepatic injuries from acetaminophen-induced hepatotoxicity in mice.

  9. Increased plasma levels of microparticles expressing CD39 and CD133 in acute liver injury

    DEFF Research Database (Denmark)

    Schmelzle, Moritz; Splith, Katrin; Wiuff Andersen, Lars;

    2013-01-01

    BACKGROUND: We have previously demonstrated that CD133 and CD39 are expressed by hematopoietic stem cells (HSC), which are mobilized after liver injury and target sites of injury, limit vascular inflammation, and boost hepatic regeneration. Plasma microparticles (MP) expressing CD39 can block...... endothelial activation. Here, we tested whether CD133 MP might be shed in a CD39-dependent manner in a model of liver injury and could potentially serve as biomarkers of liver failure in the clinic. METHODS: Wild-type and Cd39-null mice were subjected to acetaminophen-induced liver injury. Mice were...

  10. Elevated FABP1 serum levels are associated with poorer survival in acetaminophen-induced acute liver failure.

    Science.gov (United States)

    Karvellas, Constantine J; Speiser, Jaime L; Tremblay, Mélanie; Lee, William M; Rose, Christopher F

    2017-03-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Serum liver-type fatty acid binding protein (FABP1) early (day 1) or late (day 3-5) levels are associated with 21-day mortality in the absence of liver transplant. Serum samples from 198 APAP-ALF patients (nested case-control study with 99 survivors, 99 nonsurvivors) were analyzed by enzyme-linked immunosorbent assay with clinical data from the US Acute Liver Failure Study Group registry (1998-2014). APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 versus 690.8 ng/mL, P  350 ng/mL was associated with significantly higher risk of death at early (P = 0.0004) and late (P < 0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio = 1.31, P = 0.027) and late (log FABP1 odds ratio = 1.50, P = 0.005) were associated with significantly increased 21-day mortality after adjusting for significant covariates (Model for End-Stage Liver Disease, vasopressor use). Areas under the receiver operating characteristic curve for early and late multivariable models were 0.778 and 0.907, respectively. The area under the receiver operating characteristic curve of the King's College criteria (early, 0.552 alone, 0.711 with FABP1; late, 0.604 alone, 0.797 with FABP1) and the Acute Liver Failure Study Group prognostic index (early, 0.686 alone, 0.766 with FABP1; late, 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (P < 0.002 for all). In patients with APAP-ALF, FABP1 may have good potential to discriminate survivors from nonsurvivors and may improve models currently used in clinical practice; validation of FABP1 as a clinical prediction tool in APAP-ALF warrants further investigation. (Hepatology 2017;65:938-949). © 2016 by the American Association for the Study of Liver Diseases.

  11. The transcriptional change of mitochondrial genome in mice models for acetaminophen-induced acute liver injury and failure%对乙酰氨基酚诱导的急性肝损伤和肝衰竭模型中线粒体基因组转录改变

    Institute of Scientific and Technical Information of China (English)

    明雅南; 李春敏; 张静怡; 刘晓琳; 茅益民

    2016-01-01

    Objective To explore the relationship between transcription level of mitochondrial DNA (mtDNA ) and disease progression in the mice models of acetaminophen (APAP)‐induced acute liver injury (AILI) and acute liver failure (ALF) ,and to find the relative new biomarkers for outcome .Methods Ninety mice were randomly divided into three groups ,including control group ,AILI group (300 mg/kg) and ALF group (750 mg/kg) .After fasting 16 h ,all mice were intraperitoneally injected with same volume of saline or different doses of APAP .At different time points of 0 ,1 ,3 ,6 and 12 h , 6 mice randomly selected from each group were sacrificed for blood and liver , respectively . Plasma alanine aminotransferase (ALT ) ,aspartate aminotransferase (AST ) and reactive oxygen (ROS ) levels were detected ,and liver total RNA was extracted for RT‐PCR to detect changes in transcription of mitochondrial genome .Results Compared with the control group ,ALT and AST levels in AILI and ALF group were significantly increased .In AILI group ,ALT peaked at 6‐12 h (5000‐10000 IU/L) ,and ALT exceeded 10000 IU/L at 12 h in ALF group ,which showed significantly difference (P<0 .05) .Microbubbles steatosis in three zones was observed in both AILI and ALF groups ,and massive hepatic necrosis (MHN) were found merely in ALF group .In 1 h after APAP injection ,ROS in ALF group was about 2 .5 times as much as that in AILI group ,which significantly increased at all time points in both group .Contrasting with control and ALIF groups ,COX1 transcriptional level in AILI group increased significantly at 6 h .In AILI and ALF group ,CYTB ,COX2 and ATP8 reduced significantly at 3 h (P<0 .05) ,COX1 ,ND1 ,ND5 and ATP8 significantly decreased at 6 h (P<0 .05) ,and transcription level of other subunits of NADH significantly decreased at 12 h (P<0 .05) comparing with those in control group .Furthermore ,ATP6 at 6h in ALF group was obviously lower than that in AILI and control group (P<0 .05) .At 12 h

  12. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

    Directory of Open Access Journals (Sweden)

    Takeshi Yamamotoya

    2017-02-01

    Full Text Available Linear ubiquitin chain assembly complex (LUBAC, composed of SHARPIN (SHANK-associated RH domain-interacting protein, HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1, and HOIP (HOIL-1L interacting protein, forms linear ubiquitin on nuclear factor-κB (NF-κB essential modulator (NEMO and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4 or acetaminophen (APAP, both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

  13. Reduced SHARPIN and LUBAC Formation May Contribute to CCl₄- or Acetaminophen-Induced Liver Cirrhosis in Mice.

    Science.gov (United States)

    Yamamotoya, Takeshi; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Yamazaki, Hiroki; Kaneko, Sunao; Fujishiro, Midori; Kikuchi, Takako; Kushiyama, Akifumi; Tokunaga, Fuminori; Asano, Tomoichiro; Sakoda, Hideyuki

    2017-02-04

    Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl₄) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

  14. Reduced SHARPIN and LUBAC Formation May Contribute to CCl4- or Acetaminophen-Induced Liver Cirrhosis in Mice

    Science.gov (United States)

    Yamamotoya, Takeshi; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Yamazaki, Hiroki; Kaneko, Sunao; Fujishiro, Midori; Kikuchi, Takako; Kushiyama, Akifumi; Tokunaga, Fuminori; Asano, Tomoichiro; Sakoda, Hideyuki

    2017-01-01

    Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl4) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity. PMID:28165393

  15. Methanol extract of Dicranopteris linearis L. leaves impedes acetaminophen-induced liver intoxication partly by enhancing the endogenous antioxidant system.

    Science.gov (United States)

    Zakaria, Zainul Amiruddin; Kamisan, Farah Hidayah; Omar, Maizatul Hasyima; Mahmood, Nur Diyana; Othman, Fezah; Abdul Hamid, Siti Selina; Abdullah, Muhammad Nazrul Hakim

    2017-05-18

    The present study investigated the potential of methanolic extract of Dicranopteris linearis (MEDL) leaves to attenuate liver intoxication induced by acetaminophen (APAP) in rats. A group of mice (n = 5) treated orally with a single dose (5000 mg/kg) of MEDL was first subjected to the acute toxicity study using the OECD 420 model. In the hepatoprotective study, six groups of rats (n = 6) were used and each received as follows: Group 1 (normal control; pretreated with 10% DMSO (extract's vehicle) followed by treatment with 10% DMSO (hepatotoxin's vehicle) (10% DMSO +10% DMSO)), Group 2 (hepatotoxic control; 10% DMSO +3 g/kg APAP (hepatotoxin)), Group 3 (positive control; 200 mg/kg silymarin +3 g/kg APAP), Group 4 (50 mg/kg MEDL +3 g/kg APAP), Group 5 (250 mg/kg MEDL +3 g/kg APAP) or Group 6 (500 mg/kg MEDL +3 g/kg APAP). The test solutions pre-treatment were made orally once daily for 7 consecutive days, and 1 h after the last test solutions administration (on Day 7th), the rats were treated with vehicle or APAP. Blood were collected from those treated rats for biochemical analyses, which were then euthanized to collect their liver for endogenous antioxidant enzymes determination and histopathological examination. The extract was also subjected to in vitro anti-inflammatory investigation and, HPLC and GCMS analyses. Pre-treatment of rats (Group 2) with 10% DMSO failed to attenuate the toxic effect of APAP on the liver as seen under the microscopic examination. This observation was supported by the significant (p < 0.05) increased in the level of serum liver enzymes of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), and significant (p < 0.05) decreased in the activity of endogenous antioxidant enzymes of catalase (CAT) and superoxide dismutase (SOD) in comparison to Group 1. Pre-treatment with MEDL, at all doses, significantly (p < 0.05) reduced the level of ALT and AST while the levels of CAT and SOD was

  16. Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

    Directory of Open Access Journals (Sweden)

    Isaac Mohar

    2014-01-01

    Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

  17. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

    Science.gov (United States)

    Patterson, Andrew D; Shah, Yatrik M; Matsubara, Tsutomu; Krausz, Kristopher W; Gonzalez, Frank J

    2012-07-01

    Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.

  18. Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage.

    Science.gov (United States)

    Bachmann, Malte; Waibler, Zoe; Pleli, Thomas; Pfeilschifter, Josef; Mühl, Heiko

    2017-01-01

    Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression.

  19. Type I Interferon Supports Inducible Nitric Oxide Synthase in Murine Hepatoma Cells and Hepatocytes and during Experimental Acetaminophen-Induced Liver Damage

    Science.gov (United States)

    Bachmann, Malte; Waibler, Zoe; Pleli, Thomas; Pfeilschifter, Josef; Mühl, Heiko

    2017-01-01

    Cytokine regulation of high-output nitric oxide (NO) derived from inducible NO synthase (iNOS) is critically involved in inflammation biology and host defense. Herein, we set out to characterize the role of type I interferon (IFN) as potential regulator of hepatic iNOS in vitro and in vivo. In this regard, we identified in murine Hepa1-6 hepatoma cells a potent synergism between pro-inflammatory interleukin-β/tumor necrosis factor-α and immunoregulatory IFNβ as detected by analysis of iNOS expression and nitrite release. Upregulation of iNOS by IFNβ coincided with enhanced binding of signal transducer and activator of transcription-1 to a regulatory region at the murine iNOS promoter known to support target gene expression in response to this signaling pathway. Synergistic iNOS induction under the influence of IFNβ was confirmed in alternate murine Hepa56.1D hepatoma cells and primary hepatocytes. To assess iNOS regulation by type I IFN in vivo, murine acetaminophen (APAP)-induced sterile liver inflammation was investigated. In this model of acute liver injury, excessive necroinflammation drives iNOS expression in diverse liver cell types, among others hepatocytes. Herein, we demonstrate impaired iNOS expression in type I IFN receptor-deficient mice which associated with diminished APAP-induced liver damage. Data presented indicate a vital role of type I IFN within the inflamed liver for fine-tuning pathological processes such as overt iNOS expression. PMID:28824623

  20. 8-甲氧补骨脂素对对乙酰氨基酚致小鼠急性肝损伤的保护作用%Protective Effect of 8-Methoxypsoralen against Acetaminophen-induced Acute Hepatic Injury in Mice

    Institute of Scientific and Technical Information of China (English)

    魏鹏; 刘伟霞; 贾凤兰; 阮明; 张宝旭

    2012-01-01

    OBJECTIVE To investigate the hepatoprotective effect of 8-methoxypsoralen against acetaminophen-induced acute hepatic injury in mice. METHODS Liver injury model of mice was induced by subcutaneous injection of acetaminophen. Twenty-four hours later, the activities of serum alanine aminotransferase(ALT), aspartate aminotransferase(AST) and lactate dehydroge- nase (LDH) were determined, and the liver tissues weTe collected for histopathological assessment by HE staining under light microscope. The ratio of glutathione(GSH) and oxidized glutathione(GSSG), and the content of GSH, GSSG and malondialdehyde (MDA) in liver homogenate were also measured. RESULTS Compared with the normal control group, the model group could markedly increase serum ALT, AST and LDH activities, and the degeneration and necrosis could be observed in liver tissues. Compared with die model group, 8-methoxypsoralen could markedly decrease serum ,ALT, AST and LDH activities, reduce the MDA level in liver homogenate, and increase GSH content and the ratio of GSH/GSSG in the liver homogenate The hepatic histopathological changes in liver were also significantly ameliorated. CONCLUSION The 8-methoxypsoralen can prevent the liver from acetaminophen-induced acute hepatic injury.%目的 研究8-甲氧补骨脂素(8-methoxypsoralen,8-MOP)对对乙酰氨基酚(acetaminophen,APAP)致小鼠急性肝损伤的保护作用.方法 采用对乙酰氨基酚所致小鼠急性肝损伤模型.24 h后,检测小鼠血清中丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)和乳酸脱氢酶(LDH);留取肝脏组织,常规石蜡包埋切片,HE染色,光镜观察肝脏组织病理变化;制备肝匀浆,测定肝中还原型谷胱甘肽(GSH)、氧化型谷胱甘肽(GSSG)和丙二醛(MDA)的含量.结果 与正常对照组比较,模型组小鼠血清中ALT、AST和LDH活性明显升高,肝脏组织出现明显的肝细胞变性坏死;与模型组相比,8-甲氧补骨脂素可以明显降低小鼠血清

  1. Transcriptomic studies on liver toxicity of acetaminophen.

    Science.gov (United States)

    Toska, Endrit; Zagorsky, Robert; Figler, Bryan; Cheng, Feng

    2014-09-01

    Acetaminophen is widely used as a pain reliever and to reduce fever. At high doses, it can cause severe hepatotoxicity. Acetaminophen overdose has become the leading cause of acute liver failure in the US. The mechanisms for acetaminophen-induced liver injury are unclear. Transcriptomic studies can identify the changes in expression of thousands of genes when exposed to supratherapeutic doses of acetaminophen. These studies elucidated the mechanism of acetaminophen-induced hepatotoxicity and also provide insight into future development of diagnosis and treatment options for acetaminophen-induced acute liver failure. The following is a brief overview of some recent transcriptomic studies and gene-expression-based prediction models on liver toxicity induced by acetaminophen.

  2. Defensive nature of Sargassum polycystum (Brown alga)against acetaminophen-induced toxic hepatitis in rats: Role of drug metabolizing microsomal enzyme system, tumor necrosis factor-α and fate of liver cell structural integrity

    Institute of Scientific and Technical Information of China (English)

    H Balaji raghavendran; A Sathivel; T Devaki

    2006-01-01

    AIM: To assess the defensive nature of Sargassum polycystum (S. Polycystum) (Brown alga) against acetaminophen (AAP)-induced changes in drug metabolizing microsomal enzyme system, tumor necrosis factor (TNF-α)and fine structural features of the liver during toxic hepatitis in rats.METHODS: Male albino Wistar strain rats used for the study were randomly categorized into 4 groups. Group Ⅰ consisted of normal control rats fed with standard diet.Group Ⅱ rats were administered with acetaminophen (800 mg/kg body weight, intraperitoneally). Group Ⅲ rats were pre-treated with S. Polycystum extract alone.Group Ⅳ rats were orally pre-treated with S. Polycystum extract (200 mg/kg body weight for 21 d) prior to acetaminophen induction (800 mg/kg body weight,intraperitoneally). Serum separated and liver was excised and microsomal fraction was isolated for assaying cytochrome P450, NADPH Cyt P450 reductase and b5.Serum TNF-α was detected using ELISA. Fine structural features of liver were examined by transmission electron microscopy.RESULTS: Rats intoxicated with acetaminophen showed considerable impairment in the activities of drug metabolizing microsomal enzymes, such as cytochrome P450, NADPH Cyt P450 reductase and b5 when compared with the control rats. The rats intoxicated with acetaminophen also significantly triggered serum TNF-α when compared with the control rats. These severe alterations in the drug metabolizing enzymes were appreciably prevented in the rats pretreated with S. Polycystum. The rats pretreated with S. Polycystum showed considerable inhibition in the elevation of TNF-α compared to the rats intoxicated with acetaminophen. The electron microscopic observation showed considerable loss of structural integrity of the endoplasmic reticulum, lipid infiltration and ballooning of mitochondria in the acetaminophen-intoxicated rats,whereas the rats treated with S. Polycystum showed considerable protection against acetaminophen-induced alterations in

  3. Preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Yamada, S; Murawaki, Y; Kawasaki, H

    1993-09-14

    The preventive effect of gomisin A, a lignan component of shizandra fruits, on acetaminophen-induced hepatotoxicity in rats was examined by histological and biochemical analysis. Acetaminophen at a dose of 750 mg/kg was administered to male Wistar rats with or without pretreatment with 50 mg/kg of gomisin A. Gomisin A inhibited not only the elevation of serum aminotransferase activity and hepatic lipoperoxides content, characteristic of acetaminophen administration, but also the appearance of histological changes such as degeneration and necrosis of hepatocytes. However, gomisin A did not affect the decrease in liver glutathione content. These results suggest that gomisin A protects the liver from injury after administration of acetaminophen through the suppression of lipid peroxidation.

  4. HEPATOPROTECTIVE EFFECT OF AQUEOUS AND N-HEXANE EXTRACT OF NIGELLA SATIVA IN PARACETAMOL (ACETAMINOPHEN INDUCED LIVER DISEASES OF RATS: A HISTOPATHOLOGICAL EVALUATION

    Directory of Open Access Journals (Sweden)

    Farida Yesmin

    2013-07-01

    Full Text Available Acute over dose of paracetamol (acetaminophen causes serious hepatic necrosis. So, this study was conducted to observe the hepatoprotective activity of aqueous and n-hexane extract of Nigella sativa in paracetamol induced hepatotoxicity in rats in Dhaka, Bangladesh from 2008 to 2010. Single dose of paracetamol was administered on day one and rats were sacrificed on day three. Liver damage was evaluated by hepatic histology. Aqueous and n-hexane extract of Nigella sativa was administered orally into two other rat groups through intra-gastric tube for 28 days in which paracetamol was administered orally on day 28 and were sacrificed on day 30. Liver of all rats were excised and processed for light microscopy with a view to histopathological evaluation. The histological examination of the liver tissues in vehicle treated group and paracetamol-control group of rats showed normal hepatic architecture, centrilobular necrosis, polymorph (neutrophils infiltration and pyknosis of the hepatocytes respectively. The hepatic architecture of rats pre-treated with aqueous extract of Nigella sativa showed improvement of necrosis with very few pyknotic nuclei when compared to the paracetamol-control group. The hepatic architecture of rats pre-treated with aqueous extract as well as with the n-hexane extract of Nigella sativa did not show pyknotic nuclei and polymorph infiltration while apparently regenerating hepatocytes, visible under the microscope. Aqueous extract and n-hexane extract of Nigella sativa extended hepatoprotection by reducing oxidative stress in experimental liver damage in rats. Furthermore, the protection afforded by the n-hexane extract of Nigella sativa pre-treated group was superior to the aqueous extract of Nigella sativa pre-treated group.

  5. A Liver-centric Multiscale Modeling Framework for Xenobiotics

    Science.gov (United States)

    We describe a multi-scale framework for modeling acetaminophen-induced liver toxicity. Acetaminophen is a widely used analgesic. Overdose of acetaminophen can result in liver injury via its biotransformation into toxic product, which further induce massive necrosis. Our study foc...

  6. Hepatoprotective and antioxidant effects of Azolla microphylla based gold nanoparticles against acetaminophen induced toxicity in a fresh water common carp fish (Cyprinus carpio L.

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    Selvaraj Kunjiappan

    2015-04-01

    Conclusion: Azolla microphylla phytochemically synthesized GNaP protects liver against oxidative damage and tissue damaging enzyme activities and could be used as an effective protector against acetaminophen-induced hepatic damage in fresh water common carp fish.

  7. CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

    Science.gov (United States)

    Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

    2015-01-01

    Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients

  8. Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver.

    Science.gov (United States)

    Hu, Jiangting; Ramshesh, Venkat K; McGill, Mitchell R; Jaeschke, Hartmut; Lemasters, John J

    2016-03-01

    Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction and c-jun N-terminal kinase (JNK) activation. Because the safe limit of APAP dosing is controversial, our aim was to evaluate the role of the mitochondrial permeability transition (MPT) and JNK in mitochondrial dysfunction after APAP dosing considered nontoxic by criteria of serum alanine aminotransferase (ALT) release and histological necrosis in vivo. C57BL/6 mice were given APAP with and without the MPT inhibitor, N-methyl-4-isoleucine cyclosporin (NIM811), or the JNK inhibitor, SP600125. Fat droplet formation, cell viability, and mitochondrial function in vivo were monitored by intravital multiphoton microscopy. Serum ALT, liver histology, total JNK, and activated phospho(p)JNK were also assessed. High APAP (300 mg/kg) caused ALT release, necrosis, irreversible mitochondrial dysfunction, and hepatocellular death. By contrast, lower APAP (150 mg/kg) caused reversible mitochondrial dysfunction and fat droplet formation in hepatocytes without ALT release or necrosis. Mitochondrial protein N-acetyl-p-benzoquinone imine adducts correlated with early JNK activation, but irreversible mitochondrial depolarization and necrosis at high dose were associated with sustained JNK activation and translocation to mitochondria. NIM811 prevented cell death and/or mitochondrial depolarization after both high and low dose APAP. After low dose, SP600125 decreased mitochondrial depolarization. In conclusion, low dose APAP produces reversible MPT-dependent mitochondrial dysfunction and steatosis in hepatocytes without causing ALT release or necrosis, whereas high dose leads to irreversible mitochondrial dysfunction and cell death associated with sustained JNK activation. Thus, nontoxic APAP has the potential to cause transient mitochondrial dysfunction that may synergize with other stresses to promote liver damage and steatosis.

  9. A novel upregulation of glutathione peroxidase 1 by knockout of liver-regenerating protein Reg3β aggravates acetaminophen-induced hepatic protein nitration.

    Science.gov (United States)

    Yun, Jun-Won; Lum, Krystal; Lei, Xin Gen

    2013-12-01

    Murine regenerating islet-derived 3β (Reg3β) represents a homologue of human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein and enhances mouse susceptibility to acetaminophen (APAP)-induced hepatotoxicity. Our objective was to determine if and how knockout of Reg3β (KO) affects APAP (300 mg/kg, ip)-mediated protein nitration in mouse liver. APAP injection produced greater levels of hepatic protein nitration in the KO than in the wild-type mice. Their elevated protein nitration was alleviated by a prior injection of recombinant mouse Reg3β protein and was associated with an accelerated depletion of the peroxynitrite (ONOO(-)) scavenger glutathione by an upregulated hepatic glutathione peroxidase-1 (GPX1) activity. The enhanced GPX1 production in the KO mice was mediated by an 85% rise (pnitration and a new biosynthesis control of GPX1 by a completely "unrelated" regenerating protein, Reg3β, via transcriptional activation of Scly in coping with hepatic protein nitration. Linking selenoproteins to tissue regeneration will have profound implications in understanding the mechanism of Se functions and physiological coordination of tissue regeneration with intracellular redox control. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Hepatho-nephroprotective and antioxidant effect of stem bark of Allanblackia gabonensis aqueous extract against acetaminophen-induced liver and kidney disorders in rats

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    Theophile Dimo

    2012-08-01

    Full Text Available Objective: Allanblackia gabonensis (Guttiferae is a plant used in traditional medicine to treat some inflammatory diseases. As oxidative stress promotes the development of acetaminophen (APAP-induced hepatotoxicity, the aim of the present study was to evaluate the hepato-nephroprotective and antioxidant effect of aqueous extract of A.gabonensis on APAP-induced liver and kidney damage. Methods: A.gabonensis was given daily per os during 7 days, followed by APAP which was given 2 h after the 6th dose for preventive effect, whereas for curative testing A.gabonensis was administrated 30 min after APAP (2 g/kg. Preventive and curative effects were observed by following biochemical parameters analysis: transaminases, bilirubin, creatinine, nitric oxide, malondialdehyde (MDA, glutathione (GSH, superoxide dismutase (SOD, and catalase (CAT. Results: The aqueous extract of A.gabonensis at the dose of 100 and 200 mg/kg produced significant hepato-nephroprotective activity by reducing the serum effect of MDA while it significantly produced an increase in enzymatic antioxidant activities (SOD and CAT and non enzymatic antioxidant (GSH levels. A.gabonensis also showed a significant decrease in transaminase, bilirubin and creatinine in APAP intoxicicated rats at the doses of 100 and 200 mg/kg. Conclusion: From this study it can be concluded that aqueous extract of A.gabonensis may possess hepato-nephroprotective activities which can be partly attributed to its antioxidant properties. [J Exp Integr Med 2012; 2(4: 337-344

  11. Prophylactic and Therapeutic Potential of Acetyl-L-carnitine against Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Alotaibi, Salman A; Alanazi, Abdulrazaq; Bakheet, Saleh A; Alharbi, Naif O; Nagi, Mahmoud N

    2016-01-01

    Prophylactic and therapeutic effects of acetylcarnitine against acetaminophen-induced hepatotoxicity were studied in mice. To evaluate the prophylactic effects of acetylcarnitine, mice were supplemented with acetylcarnitine (2 mmol/kg/day per oral (p.o.) for 5 days) before a single dose of acetaminophen (350 mg/kg intraperitoneal (i.p.)). Animals were sacrificed 6 h after acetaminophen injection. Acetaminophen significantly increased the markers of liver injury, hepatic reactive oxygen species, and nitrate/nitrite, and decreased hepatic glutathione (GSH) and the antioxidant enzymes. Acetylcarnitine supplementation resulted in reversal of all biochemical parameters toward the control values. To explore the therapeutic effects of acetylcarnitine, mice were given a single dose of acetylcarnitine (0.5, 1, and 2 mmol/kg p.o.) 1.5 h after acetaminophen. Animals were sacrificed 6 h after acetaminophen. Acetylcarnitine administration resulted in partial reversal of liver injury only at 2 mmol/kg p.o. At equimolar doses, N-acetylcystiene was superior as therapeutic agent to acetylcarnitine. However, acetylcarnitine potentiated the effect of N-acetylcystiene in the treatment of acetaminophen toxicity.

  12. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

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    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.

  13. 扑热息痛肝损伤机制研究进展%Advances on mechanisms of acetaminophen-induced hepatic injury

    Institute of Scientific and Technical Information of China (English)

    顾兴丽; 孙继红; 季晖

    2009-01-01

    Acetaminophen(AAP) -induced hepatic injury is one of the common causes of drug-induced hepatic injury. Up to date, the mechanisms of AAP-induced hepatic injury are still incompletely understood. Recent advances suggest that reactive metabolite formation, glutathione depletion, alkylation of proteins, especially mitochondrial proteins and peroxynitrite formation are critical initiating events for the toxicity. This review will focus on more recent advances in mitochon- drial dysfunction after AAP overdose. Additional, oxi-dative stress and inflammatory mediators are also important for the overall outcome.%扑热息痛(AAP)肝损伤是药物性肝损伤的常见原因之一.但迄今为止,其肝损伤机制仍不完全清楚.最新研究进展指出活性代谢产物的形成、谷胱甘肽的耗竭、线粒体蛋白的烷化和过氧化亚硝酸盐的形成是主要原因.本文主要描述了AAP过量所致的线粒体功能异常的研究进展,另外也综述了氧化应激和炎症介质在扑热息痛肝损伤机制中的作用.

  14. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats

    OpenAIRE

    Daniela Rodrigues; Themis Reverbel Da Silveira; Ursula Matte

    2012-01-01

    CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7) ...

  15. Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.

    Science.gov (United States)

    Arai, Tomoya; Koyama, Ryo; Yuasa, Makoto; Kitamura, Daisuke; Mizuta, Ryushin

    2014-01-01

    Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.

  16. Hepatoprotective Potential of Prosopis farcta Beans Extracts against Acetaminophen-induced Hepatotoxicity in Wister Rats

    OpenAIRE

    Akram Asadollahi; Hadi Sarir; Arash Omidi; Mohammad Bagher Montazar Torbati

    2014-01-01

    Background: Hepatotoxicity by acetaminophen is the most frequent cause of acute liver failure in many countries. Prosopis farcta beans extract (PFE) has some antioxidant property and may alleviate hepatotoxicity. Therefore, the aim of this study was to evaluate effects of PFE against acetaminophen-induced hepatotoxicity. Methods: Thirty-six male Wistar albino rats weighing 220 ± 30 g were distributed into six groups. Two groups were pretreated with PFE (50 and 75 mg/kg) for 7 days before ...

  17. Free cholesterol accumulation in liver sinusoidal endothelial cells exacerbates acetaminophen hepatotoxicity via TLR9 signaling.

    Science.gov (United States)

    Teratani, Toshiaki; Tomita, Kengo; Suzuki, Takahiro; Furuhashi, Hirotaka; Irie, Rie; Hida, Shigeaki; Okada, Yoshikiyo; Kurihara, Chie; Ebinuma, Hirotoshi; Nakamoto, Nobuhiro; Saito, Hidetsugu; Hibi, Toshifumi; Miura, Soichiro; Hokari, Ryota; Kanai, Takanori

    2017-05-26

    Although obesity is a risk factor for acute liver failure, the pathogenic mechanisms are not yet fully understood. High cholesterol (HC) intake, which often underlies obesity, is suggested to play a role in the mechanism. We aimed to elucidate the effect of a HC diet on acetaminophen-induced acute liver injury, the most frequent cause of acute liver failure in the USA. C57BL/6 Toll-like receptor 9 (TLR9) knockout (Tlr9(-/-)) mice and their Tlr9(+/+) littermates were fed an HC diet for fourweeks and then treated with acetaminophen. Liver sinusoidal endothelial cells (LSECs) were isolated from the mice for in vivo and in vitro analyses. The HC diet exacerbated acetaminophen-induced acute liver injury in a TLR9/inflammasome pathway-dependent manner. LSECs played a major role in the cholesterol loading-induced exacerbation. The accumulation of free cholesterol in the endolysosomes in LSECs enhanced TLR9-mediated signaling, thereby exacerbating the pathology of acetaminophen-induced liver injury through the activation of the TLR9/inflammasome pathway. The accumulation of free cholesterol in LSEC endolysosomes induced a dysfunction of the Rab7 membrane trafficking recycling mechanism, thus disrupting the transport of TLR9 from late endosomes to the lysosomes. Consequently, the level of active TLR9 in the late endosomes increased, thereby enhancing TLR9 signaling in LSECs. HC intake exaggerated acetaminophen-induced acute liver injury via free cholesterol accumulation in LSECs, demonstrating a novel role of free cholesterol as a metabolic factor in TLR9 signal regulation and pathologies of acetaminophen-induced liver injury. Therapeutic approaches may target this pathway. Lay summary: High cholesterol intake exacerbated acetaminophen-induced acute liver injury via the accumulation of free cholesterol in the endolysosomes of liver sinusoidal endothelial cells. This accumulation enhanced Toll-like receptor 9 signaling via impairment of its membrane trafficking mechanism

  18. Protective Effect of Acacia nilotica (L. against Acetaminophen-Induced Hepatocellular Damage in Wistar Rats

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    Narayanan Kannan

    2013-01-01

    Full Text Available The potential biological functions of A. nilotica have long been described in traditional system of medicine. However, the protective effect of A. nilotica on acetaminophen-induced hepatotoxicity is still unknown. The present study attempted to investigate the protective effect of A. nilotica against acetaminophen-induced hepatic damage in Wistar rats. The biochemical liver functional tests Alanine transaminase (ALT, Aspartate transaminase (AST, Alkaline phosphatase (ALP, total bilirubin, total protein, oxidative stress test (Lipid peroxidation, antioxidant parameter glutathione (GSH, and histopathological changes were examined. Our results show that the pretreatment with A. nilotica (250 mg/kg·bw orally revealed attenuation of serum activities of ALT, AST, ALP, liver weight, and total bilirubin levels that were enhanced by administration of acetaminophen. Further, pretreatment with extract elevated the total protein and GSH level and decreased the level of LPO. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by acetaminophen. The present study undoubtedly provides a proof that hepatoprotective action of A. nilotica extract may rely on its effect on reducing the oxidative stress in acetaminophen-induced hepatic damage in rat model.

  19. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    Attalla Farag El-Kott, PhD; Mashael Mohammed Bin-Meferij, PhD

    2015-01-01

    Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

  20. Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice.

    Science.gov (United States)

    Kawakami, Kayoko; Moritani, Chie; Uraji, Misugi; Fujita, Akiko; Kawakami, Koji; Hatanaka, Tadashi; Suzaki, Etsuko; Tsuboi, Seiji

    2017-03-01

    Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of γ-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against acetaminophen-induced hepatotoxicity in mice.

  1. Satkara (Citrus macroptera Fruit Protects against Acetaminophen-Induced Hepatorenal Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Sudip Paul

    2016-01-01

    Full Text Available Although Citrus macroptera (Rutaceae, an indigenous fruit in Bangladesh, has long been used in folk medicine, however, there is a lack of information concerning its protective effects against oxidative damage. The protective effects of an ethanol extract of Citrus macroptera (EECM against acetaminophen-induced hepatotoxicity and nephrotoxicity were investigated in rats. Rats (treatment groups were pretreated with EECM at doses of 250, 500, and 1000 mg/kg, respectively, orally for 30 days followed by acetaminophen administration. Silymarin (100 mg/kg was administered as a standard drug over a similar treatment period. Our findings indicated that oral administration of acetaminophen induced severe hepatic and renal injuries associated with oxidative stress, as observed by 2-fold higher lipid peroxidation (TBARS compared to control. Pretreatment with EECM prior to acetaminophen administration significantly improved all investigated biochemical parameters, that is, transaminase activities, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transferase activities and total bilirubin, total cholesterol, triglyceride and creatinine, urea, uric acid, sodium, potassium and chloride ions, and TBARS levels. These findings were confirmed by histopathological examinations. The improvement was prominent in the group that received 1000 mg/kg EECM. These findings suggested that C. macroptera fruit could protect against acetaminophen-induced hepatonephrotoxicity, which might be via the inhibition of lipid peroxidation.

  2. Naproxen-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sharif Ali; Jason D Pimentel; Chan Ma

    2011-01-01

    BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. METHODS: We treated a 30-year-old woman with jaundice and intractablepruritusthatdevelopedshortlyaftertakingnaproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. RESULTS: The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. CONCLUSIONS:  Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.

  3. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted...... and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline...

  4. Preventive and curative effects of Acalypha indica on acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    M Mathew

    2011-01-01

    Full Text Available Effect of ethanol extract of the leaves of Acalypha indica (Euphorbiaceae was investigated against acetaminophen-induced hepatic damage. Acetaminophen (paracetamol at the rate of 1 g/kg produced liver damage in rats as manifested by the significant (P<0.001 rise in serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, compared to respective control values. Treatment of rats with acetaminophen led to a marked increase in lipid peroxidation as measured by malondialdehyde (MDA. This was associated with a significant reduction in superoxide dismutase (SOD and glutathione (GSH contents. Pretreatment of animals with the plant extract (100 mg/kg orally once daily for 5 days prevented (P<0.01 the acetaminophen-induced rise in serum transaminases (AST and ALT and ALP. Post treatment with five successive doses of the extract (100 mg/kg restricted the hepatic damage induced by the above said Paracetamol (P<0.001. Histological changes around the hepatic central vein were recovered by administration of the drug. Thus, it is evident that these biochemical and histological alterations resulting from acetaminophen administration were inhibited by pre and post treatment with A. indica leaf extract. One notable study of the study was the spontaneous recovery of liver damage within a week after stopping paracetamol. These results indicate that the crude ethanol extract of A. indica exhibits hepatoprotective action through antioxidant effect and validates the traditional use of the plant in hepatic dysfunction.

  5. Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

    Science.gov (United States)

    Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

    2011-12-01

    The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus.

  6. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  7. Role of Protective Effect of L-Carnitine against Acute Acetaminophen Induced Hepatic Toxicity in Adult Albino Rats

    Directory of Open Access Journals (Sweden)

    Zeinab M. Gebaly* and Gamal M. Aboul Hassan

    2012-10-01

    Full Text Available Background: Acetaminophen, a widely used analgesic and antipyretic is known to cause hepatic injury in humans and experimental animals when administered in high doses. It was reported that toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. L-carnitine is a cofactor in the transfer of long-chain fatty acid allowing to the beta-oxidation of fatty acid in the mitochondria. It is a known antioxidant with protective effects against lipid peroxidation. This study aimed to investigate the possible beneficial effect of L-carnitine as an antioxidant agent against acetaminophen induced hepatic toxicity in rats. Material and Methods: Four rat groups (N=7 in each group. Group I is the control, group II received 500 mg/kg/ body weight of L-carnitine for 7 days by oral route, group III received 640/kg/ bw of acetaminophen by oral route, group IV acute acetaminophen group pretreated with L-carnitine for 7 days by gastric tube gavage tube. The liver of all rats were removed for investigation using light and electro microscopic studies. Results: Acetaminophen caused massive centrilobular necrosis and massive degenerative changes. The electron-microscopic study showed few mitochondria, increased fat droplets and scanty smooth endoplasmic reticulum (SER, rough endoplasmic reticulum (RER.These changes were reduced by L-carnitine pretreatment. Conclusion: those results suggest that acetaminophen results damage in the liver as an acute effect and L-carnitine ameliorated the adverse effects of acetaminophen via its antioxidant role

  8. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.

    Science.gov (United States)

    Jaeschke, Hartmut; McGill, Mitchell R; Ramachandran, Anup

    2012-02-01

    Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

  9. Quercitrin from Toona sinensis (Juss. M.Roem. Attenuates Acetaminophen-Induced Acute Liver Toxicity in HepG2 Cells and Mice through Induction of Antioxidant Machinery and Inhibition of Inflammation

    Directory of Open Access Journals (Sweden)

    Van-Long Truong

    2016-07-01

    Full Text Available Quercitrin is found in many kinds of vegetables and fruits, and possesses various bioactive properties. The aim of the present study was to elucidate hepatoprotective mechanisms of quercitrin isolated from Toona sinensis (Juss. M.Roem. (syn. Cedrela sinensis Juss., using acetaminophen (APAP-treated HepG2 cell and animal models. In an in vitro study, quercitrin suppressed the production of reactive oxygen species and enhanced expression of nuclear factor E2-related factor 2 (Nrf2, activity of antioxidant response element (ARE-reporter gene, and protein levels of NADPH: quinone oxidoreductase 1 (NQO1, catalase (CAT, glutathione peroxidase (GPx, and superoxide dismutase 2 (SOD-2 in APAP-treated HepG2 cells. In an in vivo study, Balb/c mice were orally administered with 10 or 50 mg/kg of quercitrin for 7 days and followed by the injection with single dose of 300 mg/kg APAP. Quercitrin decreased APAP-caused elevation of alanine aminotransferase and aspartate aminotransferase levels, liver necrosis, the expression of pro-inflammatory factors including inducible nitric oxide synthase, cyclooxygenase 2 and inerleukin-1β, and phosphorylation of kinases including c-Jun N-terminal kinase and p38. Quercitrin restored protein levels of Nrf2, NQO1 and activities and expressions of CAT, GPx, SOD-2. The results suggested that quercitrin attenuates APAP-induced liver damage by the activation of defensive genes and the inhibition of pro-inflammatory genes via the suppressions of JNK and p38 signaling.

  10. Effect of matrine hydrochloride on liver injury

    Institute of Scientific and Technical Information of China (English)

    CHEN Li-bo; XU Feng; MA Wen-hui

    2008-01-01

    Objective Searching the function that the Injection of the matrine hydrochloride prevents and cures acute chemical liver injury of mice、 immunity liver injury of mice and chronic liver injury of rats. Methods Acute hepatic injury models of mice induced by Chemical poison carbon tetrachloride (CCl4), thioacetamide(TAA), D-galactosamine(D-GalN), immunity hepatic injury model of mice induced by BCG and fat polysaccharide (LPS), chronic liver injury model of rats induced by CCI, were introduced in the experiment. The serum ALT and AST were measured in acute hepatic injury experiments. Serum ALT, AST, AKP, ALB, TP, BiL-T, ereatinine, triglyceride, sialie acid, larninin, hyaluronic acid, type Ⅲ proeollagen and type Ⅳ collagen, hepatic hydroxyproline (HyP) of rats in chronic liver injury animals were determined after Injection of the matrine hydrochloride. Results The Injection of the matrine hydrochloride reduced serum ALT and AST level of acute chemical liver injury of mice induced by CCl4, TAA and D-GaIN. The index of the liver and the spleen of immunity liver injury of mice induced by BCG and LPS were decreased after the injection of matrine hydrochloride treatment. Compared with the model group, the injection may obviously inhibited serum ALT, AST, TP, AKP, TRI, BiL-T, creatinine, triglyceride, sialic acid, laminin , hyaluronic acid , type Ⅲ procollagen and type Ⅳ collagen activity of chronic liver injury of rats induced by CCl4, elevated ALB、A/G, reduced the liver HyP, decreased the index of the liver and the spleen. The liver visual observation, the pathology inspection and the HAI grading result showed the injection may reduce the inflammatory activity in liver tissue, restrain the liver cell damage, reduce the pseudolobuli formation. Conclusions The Injection of matrine hydrochloride had the protective function to acute chemical hepatic injury of mice induced by CCl4、TAA、D-GalN、immunity hepatic injury of mice induced by the BCG and LPS and

  11. Autophagy and Liver Ischemia-Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Raffaele Cursio

    2015-01-01

    Full Text Available Liver ischemia-reperfusion (I-R injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS, leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R.

  12. Short day photoperiod protects against acetaminophen-induced ...

    African Journals Online (AJOL)

    Prof. Ogunji

    long photoperiod while these parameters were significantly (P<0.05) reduced in rats subjected to short .... Values are mean ± SEM with n=6. *P<0.05, ... result to serious liver injury or death in humans. (Watkins ... the rate-limiting enzyme in melatonin synthesis. (Illnerova ... Day length affects immune cells numbers in deer.

  13. Sleep apnea hypopnea syndrome and liver injury

    Institute of Scientific and Technical Information of China (English)

    TIAN Jian-li; ZHANG Yun; CHEN Bao-yuan

    2010-01-01

    Objective A general review was made of studies involving: (1) the relationship between sleep apnea hypopneasyndrome/sleep apnea style intermittent hypoxia and liver injury and (2) the mechanism that causes the liver injury.Data sources The data used in this review were mainly from Medline and PubMed published in English from 1993 toFebruary 2009. The search term was "sleep apnea hypopnea syndrome".Study selection (1) Clinical and laboratory evidence that sleep apnea hypopnea syndrome and sleep apnea styleintermittent hypoxia leads to liver injury; (2) the mechanism that causes the liver injury.Results The effect of sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia on the liver functionis characterized by serum aminotransferase elevation. The liver histological injury includes hepatic steatosis, hepatocyteballooning, lobular inflammation, lobular necrosis, and liver fibrosis. Sleep apnea hypopnea syndrome and sleep apneastyle intermittent hypoxia can cause insulin resistance and oxidative stress.Conclusions Sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia can lead to chronic liverinjury, which, in most cases, is shown as nonalcoholic fatty liver disease. Insulin resistance and oxidative stress causedby sleep apnea hypopnea syndrome and sleep apnea style intermittent hypoxia play an important role in the mechanismof chronic liver disease development.

  14. Piperine, an active ingredient of black pepper attenuates acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Evan Prince Sabina; Annie Deborah Harris Souriyan; Deborah Jackline; Mahaboob Khan Rasool

    2010-01-01

    Objective: To explore the hepatoprotective and antioxidant effects of piperine against acetaminophen-induced hepatotoxicity in mice. Methods: In mice, hepatotoxicity was induced by a single dose of acetaminophen (900 mg/kg b.w. i.p.). Piperine (25 mg/kg b.w. i.p.) and standard drug silymarin (25 mg/kg b.w. i.p.) were given to mice, 30 min after the single injection of acetaminophen. After 4 h, the mice were decapitated. Activities of liver marker enzymes [(aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP)] and inflammatory mediator tumour necrosis factor-alpha (TNF-α) were estimated in serum, while lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-s-transferase and glutathione) were determined in liver homogenate of control and experimental mice. Results: Acetaminophen induction (900 mg/kg b.w. i.p.) significantly increased the levels of liver marker enzymes, TNF-α, and lipid peroxidation, and caused the depletion of antioxidant status. Piperine and silymarin treatment to acetaminophen challenged mice resulted in decreased liver marker enzymes activity, TNF-α and lipid peroxidation levels with increase in antioxidant status. Conclusions: The results clearly demonstrate that piperine shows promising hepatoprotective effect as comparable to standard drug silymarin.

  15. Protective effect of glycine on liver injury during liver transplantation

    Institute of Scientific and Technical Information of China (English)

    WANG Yao-sheng; YAN Ye-hong; ZOU Xun-feng

    2010-01-01

    @@ Multiple procedures of liver transplantation bring conditions producing cold ischemia-reperfusion (I/R) injury. During cold storage, the graft organ is subjected to cold ischemia, also known as hypoxia injury. After reperfusion, although hypoxic condition has been ameliorated, reoxygenation of the graft liver can produce not only reperfusion injury including generation of oxygen free radical, lipoperoxidation and calcium overload, but also aggravate the hypoxia damage, involving endothelial cell (EC) damage, Kupffer cell (KC) activation, and adherence of neutrophils and platelets to Ecs. Clinically, I/R injury is one of the major problems complicating liver transplantation, and can ultimately result in serious complications such as primary nonfunction and delayed graft function, which may lead to the need of urgent retransplantation. Therefore, the therapeutic strategies of attenuating graft I/R injury are clinically significant and might improve overall graft function and survival.

  16. Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices.

    Science.gov (United States)

    Ash, Stephen R; Caldwell, Cary A; Singer, Greg G; Lowell, Jeff A; Howard, Todd K; Rustgi, Vinod K

    2002-01-01

    When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.

  17. Antioxidant and hepatoprotective potential of Pouteria campechiana on acetaminophen-induced hepatic toxicity in rats.

    Science.gov (United States)

    Aseervatham, G Smilin Bell; Sivasudha, T; Sasikumar, J M; Christabel, P Hephzibah; Jeyadevi, R; Ananth, D Arul

    2014-03-01

    Pouteria campechiana (Kunth) Baehni. is used as a remedy for coronary trouble, liver disorders, epilepsy, skin disease, and ulcer. Therefore, the present study aims to investigate the antioxidant and hepatoprotective effect of polyphenolic-rich P. campechiana fruit extract against acetaminophen-intoxicated rats. Total phenolic and flavonoid contents of egg fruit were estimated followed by the determination of antioxidant activities. Treatment with P. campechiana fruit extract effectively scavenged the free radicals in a concentration-dependent manner within the range of the given concentrations in all antioxidant models. The presence of polyphenolic compounds were confirmed by high-performance thin-layer chromatography (HPTLC). The animals were treated with acetaminophen (250 mg/kg body weight; p.o.) thrice at the interval of every 5 days after the administration of P. campechiana aqueous extract and silymarin (50 mg/kg). Acetaminophen treatment was found to trigger an oxidative stress in liver, leading to an increase of serum marker enzymes. However, treatment with P. campechiana fruit extract significantly reduced the elevated liver marker enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase) and increased the antioxidant enzymes (viz., superoxide dismutase and catalase) and glutathione indicating the effect of the extract in restoring the normal functional ability of hepatocytes. These results strongly suggest that P. campechiana fruit extract has strong antioxidant and significant hepatoprotective effect against acetaminophen-induced hepatotoxicity.

  18. Liver injury from herbal and dietary supplements.

    Science.gov (United States)

    Navarro, Victor J; Khan, Ikhlas; Björnsson, Einar; Seeff, Leonard B; Serrano, Jose; Hoofnagle, Jay H

    2017-01-01

    Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

  19. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-04-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content.

  20. Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats

    Science.gov (United States)

    Baali, Nacera; Belloum, Zahia; Baali, Samiya; Chabi, Beatrice; Pessemesse, Laurence; Fouret, Gilles; Ameddah, Souad; Benayache, Fadila; Benayache, Samir; Feillet-Coudray, Christine; Cabello, Gérard; Wrutniak-Cabello, Chantal

    2016-01-01

    Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5–2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content. PMID:27043622

  1. Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Nesreen E.M. Mohammed

    2016-11-01

    Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

  2. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Science.gov (United States)

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  3. Drug-induced liver injuries

    African Journals Online (AJOL)

    most clinicians and is synonymous with drug-induced hepatotoxicity. A succinct ... or herbal medicine resulting in liver test abnormalities or liver dysfunction with a ... and exclusion of other common aetiological factors, e.g. viral hepatitis. .... chronic alcohol use and hepatitis B or C infection. As a combination of drugs is used.

  4. Acetaminophen Induced Hepatotoxicity in Wistar Rats--A Proteomic Approach.

    Science.gov (United States)

    Ilavenil, Soundharrajan; Al-Dhabi, Naif Abdullah; Srigopalram, Srisesharam; Ock Kim, Young; Agastian, Paul; Baru, Rajasekhar; Choi, Ki Choon; Valan Arasu, Mariadhas

    2016-01-28

    Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP) effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups--control, nontoxic (150 mg/kg) and toxic dose (1500 mg/kg) of APAP--were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD's PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%), immunity (14%), neurological related (12%) and transporter proteins (2%), whereas in non-toxic dose-induced rats they were oxidative stress (9%), immunity (6%), neurological (14%) and transporter proteins (9%). It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  5. Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

    Directory of Open Access Journals (Sweden)

    Soundharrajan Ilavenil

    2016-01-01

    Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

  6. Aspirin-Induced Acute Liver Injury

    Science.gov (United States)

    Satoskar, Rohit

    2014-01-01

    Aspirin is thought to be a relatively safe drug in adults. The association of aspirin and Reye syndrome in children is well documented. We report a 41-year-old female with pericarditis who was treated with high-dose aspirin and developed subsequent acute liver injury. After discontinuation of aspirin, liver enzyme elevation and right upper quadrant pain both resolved. We conclude that high-dose aspirin should be considered as a potentially hepatotoxic agent. PMID:26157904

  7. Prevention of grafted liver from reperfusive injury

    Institute of Scientific and Technical Information of China (English)

    Kai Ma; Yang yu; Xian-Min Bu; Yan-Jun Li; Xian-Wei Dai; Liang Wang; Yang Dai; Hai-Ying Zhao; Xiang-Hong Yang

    2001-01-01

    @@ INTRODUCTIONThe incidence of primary non-function(PNF)of grafted liver in the early postoperative stage is 2%-23%[1-4],its main cause is the ischemic-rechemic injure[5,6].In this experiment,anisodamine was added into the preserving fluid and the grafted liver was rewarmed at different temperatures to protect the cell membranc and prevent ischemic-reperfusive injury.

  8. Drug –induced liver injury:a review

    OpenAIRE

    Sreya Kosanam; Revathi Boyina; Lakshmi Prasanthi N

    2015-01-01

    The incidence of drug induced liver injury (DILI) is about 1/1000 to 1/10000 among patients who receive therapeutic drug doses. Drug induced hepatotoxicity is a major cause of acute and chronic liver disease. The severity of liver damage ranges from nonspecific changes in liver structure to acute liver failure, cirrhosis and liver cancer. Some common agents that can cause liver injury are acetaminophen, antibiotics, statins, INH and herbal drugs.Drug-induced hepatotoxicity can be categorized ...

  9. Protective effects of pterostilbene against acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    El-Sayed, El-Sayed M; Mansour, Ahmed M; Nady, Mohamed E

    2015-01-01

    The present study was undertaken to evaluate the protective effect of pterostilbene against acetaminophen-induced hepatotoxicity. Silymarin was used as a standard hepatoprotective agent. A single dose of acetaminophen (800 mg/kg i.p.), injected to male rats, caused significant increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, total cholesterol, triglycerides, tumor necrosis factor alpha, and hepatic contents of malondialdehyde, nitric oxide, caspase-3, hydroxyproline, with significant decreases in serum HDL-cholesterol, total proteins, albumin, and hepatic activities of reduced glutathione, superoxide dismutase and catalase as compared with the control group. On the other hand, administration of each of pterostilbene (50 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) for 15 days before acetaminophen ameliorated liver function and oxidative stress parameters. Histopathological evidence confirmed the protection offered by pterostilbene from the tissue damage caused by acetaminophen. In conclusion, pterostilbene possesses multimechanistic hepatoprotective activity that can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

  10. Antcin H Protects Against Acute Liver Injury Through Disruption of the Interaction of c-Jun-N-Terminal Kinase with Mitochondria.

    Science.gov (United States)

    Huo, Yazhen; Win, Sanda; Than, Tin Aung; Yin, Shutao; Ye, Min; Hu, Hongbo; Kaplowitz, Neil

    2017-02-10

    Antrodia Camphorate (AC) is a mushroom that is widely used in Asian countries to prevent and treat various diseases, including liver diseases. However, the active ingredients that contribute to the biological functions remain elusive. The purpose of the present study is to test the hepatoprotective effect of Antcin H, a major triterpenoid chemical isolated from AC, in murine models of acute liver injury. We found that Antcin H pretreatment protected against liver injury in both acetaminophen (APAP) and galactosamine/tumor necrosis factor (TNF)α models. More importantly, Antcin H also offered a significant protection against acetaminophen-induced liver injury when it was given 1 h after acetaminophen. The protection was verified in primary mouse hepatocytes. Antcin H prevented sustained c-Jun-N-terminal kinase (JNK) activation in both models. We excluded an effect of Antcin H on acetaminophen metabolism and TNF receptor signaling and excluded a direct effect as a free radical scavenger or JNK inhibitor. Since the sustained JNK activation through its interaction with mitochondrial Sab, leading to increased mitochondrial reactive oxygen species (ROS), is pivotal in both models, we examined the effect of Antcin H on p-JNK binding to mitochondria and impairment of mitochondrial respiration. Antcin H inhibited the direct effect of p-JNK on isolated mitochondrial function and binding to isolated mitochondria. Innovation and Conclusion: Our study has identified Antcin H as a novel active ingredient that contributes to the hepatoprotective effect of AC, and Antcin H protects against liver injury through disruption of the binding of p-JNK to Sab, which interferes with the ROS-dependent self-sustaining activation of MAPK cascade. Antioxid. Redox Signal. 26, 207-220.

  11. Acetaminophen-Induced Acute Pancreatitis. A Case Report

    Directory of Open Access Journals (Sweden)

    Hisato Igarashi

    2009-09-01

    Full Text Available Context Drug-induced acute pancreatitis is rare but should not be overlooked in a patient who presents with idiopathic acute pancreatitis. More than 100 drugs have been implicated in causing the disease: acetaminophen has been associated with acute pancreatitis in cases where there has been an overdose of drugs; however, the frequency is rare. Case report We report the case of a 35-year-old woman who presented with acute pancreatitis and severe metabolic acidosis after overdosing on a drug containing acetaminophen. She improved dramatically after intensive care; however, she showed recurrent episodes after re-overdosing on the same drug. With her self re-challenge test, she was diagnosed as having acetaminophen-induced pancreatitis and metabolic acidosis. A review of the relevant literature is also presented. Conclusions Drug-induced acute pancreatitis is often challenging for clinicians and a detailed mechanism is unknown. It is very important to rule out drug-induced pancreatitis when treating pancreatitis with an unknown etiology.

  12. Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization.

    Science.gov (United States)

    Park, Woo-Jae; Park, Joo-Won; Erez-Roman, Racheli; Kogot-Levin, Aviram; Bame, Jessica R; Tirosh, Boaz; Saada, Ann; Merrill, Alfred H; Pewzner-Jung, Yael; Futerman, Anthony H

    2013-10-25

    Very long chain (C22-C24) ceramides are synthesized by ceramide synthase 2 (CerS2). A CerS2 null mouse displays hepatopathy because of depletion of C22-C24 ceramides, elevation of C16-ceramide, and/or elevation of sphinganine. Unexpectedly, CerS2 null mice were resistant to acetaminophen-induced hepatotoxicity. Although there were a number of biochemical changes in the liver, such as increased levels of glutathione and multiple drug-resistant protein 4, these effects are unlikely to account for the lack of acetaminophen toxicity. A number of other hepatotoxic agents, such as d-galactosamine, CCl4, and thioacetamide, were also ineffective in inducing liver damage. All of these drugs and chemicals require connexin (Cx) 32, a key gap junction protein, to induce hepatotoxicity. Cx32 was mislocalized to an intracellular location in hepatocytes from CerS2 null mice, which resulted in accelerated rates of its lysosomal degradation. This mislocalization resulted from the altered membrane properties of the CerS2 null mice, which was exemplified by the disruption of detergent-resistant membranes. The lack of acetaminophen toxicity and Cx32 mislocalization were reversed upon infection with recombinant adeno-associated virus expressing CerS2. We establish that Gap junction function is compromised upon altering the sphingolipid acyl chain length composition, which is of relevance for understanding the regulation of drug-induced liver injury.

  13. Effects of erdosteine on acetaminophen-induced hepatotoxicity in rats.

    Science.gov (United States)

    Kuvandik, Guven; Duru, Mehmet; Nacar, Ahmet; Yonden, Zafer; Helvaci, Rami; Koc, Ahmet; Kozlu, Tolunay; Kaya, Hasan; Sogüt, Sadik

    2008-07-01

    We investigated the effects of erdosteine on acetaminophen (APAP)-induced hepatotoxicity in rats. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), AST (aspartate aminotransferase), and ALT (alanine transaminase) activities, and malonyldialdehyde (MDA) and nitric oxide levels as oxidant/antioxidant biochemical parameters were investigated with light microscopic evaluation in adult female Wistar Albino rats. APAP administration produced a decrease in hepatic SOD, CAT, and GSH-Px activities, and coadministration of erdosteine (150 and 300 mg/kg) resulted in increases in the activities. MDA and NO levels increased in the APAP group, and erdosteine treatments prevented these increases. Significant elevations in serum AST and ALT levels were observed in the APAP group, and when erdosteine and APAP were coadministered, their serum levels were close to those in the control group. Light microscopic evaluation of livers showed that there were remarkable centrilobular (zone III) hepatic necrosis and mild to moderate sinusoidal congestion in the APAP group, whereas in the erdosteine group, cellular necrosis was minimal and the hepatocytes maintained a better morphology when compared to the APAP group. Erdosteine prevented APAP-induced liver injury and toxic side effects probably through the antioxidant and radical scavenging effects of erdosteine.

  14. Lysosomal iron mobilization and induction of the mitochondrial permeability transition in acetaminophen-induced toxicity to mouse hepatocytes.

    Science.gov (United States)

    Kon, Kazuyoshi; Kim, Jae-Sung; Uchiyama, Akira; Jaeschke, Hartmut; Lemasters, John J

    2010-09-01

    Acetaminophen induces the mitochondrial permeability transition (MPT) in hepatocytes. Reactive oxygen species (ROS) trigger the MPT and play an important role in AAP-induced hepatocellular injury. Because iron is a catalyst for ROS formation, our aim was to investigate the role of chelatable iron in MPT-dependent acetaminophen toxicity to mouse hepatocytes. Hepatocytes were isolated from fasted male C3Heb/FeJ mice. Necrotic cell killing was determined by propidium iodide fluorometry. Mitochondrial membrane potential was visualized by confocal microscopy of tetramethylrhodamine methylester. Chelatable ferrous ion was monitored by calcein quenching, and 70 kDa rhodamine-dextran was used to visualize lysosomes. Cell killing after acetaminophen (10mM) was delayed and decreased by more than half after 6 h by 1mM desferal or 1mM starch-desferal. In a cell-free system, ferrous but not ferric iron quenched calcein fluorescence, an effect reversed by dipyridyl, a membrane-permeable iron chelator. In hepatocytes loaded with calcein, intracellular calcein fluorescence decreased progressively beginning about 4 h after acetaminophen. Mitochondria then depolarized after about 6 h. Dipyridyl (20mM) dequenched calcein fluorescence. Desferal and starch-desferal conjugate prevented acetaminophen-induced calcein quenching and mitochondrial depolarization. As calcein fluorescence became quenched, lysosomes disappeared, consistent with release of iron from ruptured lysosomes. In conclusion, an increase of cytosolic chelatable ferrous iron occurs during acetaminophen hepatotoxicity, which triggers the MPT and cell killing. Disrupted lysosomes are the likely source of iron, and chelation of this iron decreases acetaminophen toxicity to hepatocytes.

  15. Acute liver injury secondary to sertraline.

    Science.gov (United States)

    Suen, Christopher F D Li Wai; Boyapati, Ray; Simpson, Ian; Dev, Anouk

    2013-09-26

    Sertraline is widely prescribed to treat depression and anxiety disorders. However, hepatitis secondary to its use is a rare entity. We report the case of a 26-year-old woman in her 20th week of pregnancy presented with nausea, vomiting, malaise and dark urine. This occurred 6 months after sertraline 50 mg daily was started for the treatment of depression. Three weeks prior to her presentation, the dose of sertraline was increased to 100 mg daily. The patient's liver biochemical profile demonstrated increased transaminases. The biopsy of the liver showed lobular hepatitis, with a mild prominence of eosinophils, suggestive of a drug-induced or toxin-induced aetiology. Extensive biochemical work-up failed to show any other pathology to account for her hepatitis. Liver function tests normalised after cessation of sertraline, indicating a probable association between sertraline use and acute hepatocellular injury in our patient.

  16. In vivo antioxidant activity of bark extract of Bixa orellana L. against acetaminophen- induced oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Smilin Bell Aseervatham G; Shamna R; Sangeetha B; Sasikumar JM

    2012-01-01

    Objective: To evaluate the in vivo activity of bark extract of Bixa orellana L. (B. orellana) against acetaminophen induced oxidative stress. Methods: In the present study, antioxidant activity ofB. orellana was evaluated by using normal and acetaminophen induced oxidative stressed rats at the dose of 100 mg/kg and 200 mg/kg p.o. oraly daily for 20 days. The animal's body weight was checked before and after treatment. Different biochemical parameters such as serum glutamate pyruvate transaminases, serum glutamate oxalo transaminases, alkaline phosphatase, total bilirubin, cholesterol, protein, lactate dehydrogenase, superoxide dismutase, catalase, ascorbic acid, lipid peroxide was performed. Histopathological analysis of the control and the hepatotoxicity induced rats were performed. Results: It was observed that the B. orellana bark extract showed significant protective activity against acetaminophen induced damage at 200 mg/kg dose level, while the 100 mg/kg dose showed moderate activity. Conclusions: From the result obtained in the present study suggest that B. orellana bark extract elicit protective activity through antioxidant activity on acetaminophen induced hepatic damage in rats.

  17. Croton zehntneri Essential oil prevents acetaminophen-induced acute hepatotoxicity in mice

    OpenAIRE

    Maria Goretti R. Queiroz; José Henrique L. Cardoso; Tomé, Adriana R; Roberto C. P. Lima Jr.; Jamile M. Ferreira; Daniel F. Sousa; Felipe C. Lima; Campos, Adriana R.

    2008-01-01

    Hepatoprotective activity of Croton zehntneri Pax & Hoffman (Euphorbiaceae) leaf essential oil (EOCz) was evaluated against single dose of acetaminophen-induced (500 mg/kg, p.o.) acute hepatotoxicity in mice. EOCz significantly protected the hepatotoxicity as evident from the activities of serum glutamate pyruvate transaminase (GPT), serum glutamate oxaloacetate transaminase (GOT) activities, that were significantly (p

  18. Elemental characterization of injuries in fish liver

    Energy Technology Data Exchange (ETDEWEB)

    Stori, E.M., E-mail: elistori@gmail.com [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Post-Graduation Program on Science Materials – PGCIMAT, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, CEP 91501-970 Porto Alegre, RS (Brazil); Rocha, M.L.C.F.; Dias, J.F. [Oceanographic Institute, University of São Paulo, Praça do Oceanográfico, 191 Butantã, CEP 05508-120 São Paulo, SP (Brazil); Santos, C.E.I. dos [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Souza, C.T. de; Amaral, L; Dias, J.F. [Ion Implantation Laboratory, Physics Institute, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, P.O. Box 15051, CEP 91501-970 Porto Alegre, RS (Brazil); Post-Graduation Program on Science Materials – PGCIMAT, Federal University of Rio Grande do Sul, Av. Bento Gonçalves 9500, CEP 91501-970 Porto Alegre, RS (Brazil)

    2014-01-01

    Fish liver is the primary organ related to the biotransformation of organic contaminants and metals. This organ is very sensitive to organic and inorganic contaminants and can accumulate them in higher amounts relative to the environment itself and to other organs. One of the most common injuries is a histopathology called melanomacrophage centers, characterized as modifications of the cellular structure of the tissue and usually accompanied by pigmented cells. The aim of this study is to apply micro-PIXE in combination with conventional PIXE as a qualitative and quantitative analysis of elements to characterize histopathologies in the liver of fishes. Micro-PIXE results show that there is a higher concentration of Fe, P, K, Ti, Cr, Ni, Cu and Zn in melanomacrophage centers. On healthy tissue, the distribution of these elements is homogeneous. In cases where the histopathological study showed injuries without melanomacrophage centers, the micro-PIXE analysis showed much smaller clusters with higher concentrations of these elements, suggesting the presence of melanomacrophage centers which are too small to be detected by histopathological conventional methods. Broad PIXE results showed that the concentration of Si, Cl, K, Ti, Fe and Cu are directly related to the presence of melanomacrophage centers. Moreover, it could be observed that the concentration of Cr, Mn and Ni is directly related to the injuries but not to melanomacrophage centers.

  19. Effect of sesame oil against acetaminophen-induced acute oxidative hepatic damage in rats.

    Science.gov (United States)

    Chandrasekaran, Victor Raj Mohan; Wan, Chang-Hsin; Liu, Li-Lian; Hsu, Dur-Zong; Liu, Ming-Yie

    2008-08-01

    Acetaminophen (APAP) overdose causes acute liver injury or even death in both humans and experimental animals. We investigated the effect of sesame oil on APAP-induced acute liver injury. Male Wistar rats were given APAP (1,000 mg/kg; orally) to induce acute liver injury. Acetaminophen significantly increased aspartate transaminase, alanine transaminase, lipid peroxidation, and superoxide anion and hydroxyl radical generation levels; it also induced glutathione depletion. Sesame oil (8 mL/kg; orally) did not alter the gastric absorption of APAP, but it inhibited all the parameters altered by APAP and protected the rats against APAP-induced acute liver injury. We hypothesize that sesame oil maintained the intracellular glutathione levels, reduced reactive oxygen species levels, and inhibited lipid peroxidation in rats with APAP-induced acute liver injury.

  20. Autophagy and ethanol-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Terrence M Donohue Jr

    2009-01-01

    The majority of ethanol metabolism occurs in the liver. Consequently, this organ sustains the greatest damage from ethanol abuse. Ethanol consumption disturbs the delicate balance of protein homeostasis in the liver, causing intracellular protein accumulation due to a disruption of hepatic protein catabolism.Evidence indicates that ethanol or its metabolism impairs trafficking events in the liver, including the process of macroautophagy, which is the engulfment and degradation of cytoplasmic constituents by the lysosomal system. Autophagy is an essential, ongoing cellular process that is highly regulated by nutrients,endocrine factors and signaling pathways. A great number of the genes and gene products that govern the autophagic response have been characterized and the major metabolic and signaling pathways that activate or suppress autophagy have been identified. This review describes the process of autophagy, its regulation and the possible mechanisms by which ethanol disrupts the process of autophagic degradation. The implications of autophagic suppression are discussed in relation to the pathogenesis of alcohol-induced liver injury.

  1. 题目:CYP450代谢酶和一些抗氧化信号参与调控了绿原酸抑制对乙酰氨基酚的肝毒性%Chlorogenic acid prevents acetaminophen-induced liver injury:the involvement of CYP450 metabolic enzymes and some antioxidant signals

    Institute of Scientific and Technical Information of China (English)

    Chun PANG; Yu-chen SHENG; Ping JIANG; Hai WEI; Li-li JI

    2015-01-01

    目的:本研究旨在观察绿原酸对乙酰氨基酚诱导肝损伤的解毒作用及其机理。创新点:发现CYP450代谢酶和一些重要的抗氧化信号分子(如Prx家族蛋白等)参与调控了绿原酸抑制对乙酰氨基酚的肝毒性。方法:检测小鼠血清转氨酶含量,检测体外 CYP2E1、CYP3A4和CYP1A2酶活性,检测肝组织中丙二醛(MDA)、谷胱甘肽(GSH)和活性氧(ROS)含量,用实时聚合酶链反应(real-time PCR)检测肝组织中Prx1-6、Ephx2、Polr2k、Fmo5、Nrf2等的mRNA表达情况。结论:绿原酸可以明显抑制对乙酰氨基酚造成的急性肝损伤。给药组小鼠血清中的转氨酶与模型组相比均有显著下降,绿原酸在体外可以微弱抑制CYP2E1和CYP1A2代谢酶的活性,通过MDA、GSH和 ROS分析发现绿原酸可以抑制对乙酰氨基酚造成的氧化应激损伤。通过real-time PCR分析发现对乙酰氨基酚降低了抗氧化酶 Prx家族、Ephx2、Polr2k和 Nrf2的基因表达,而绿原酸可以逆转对乙酰氨基酚降低的这些基因的表达。%Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cel viability induced by AP in L-02 celsin vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST)in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin

  2. Acute alcohol-induced liver injury

    Directory of Open Access Journals (Sweden)

    Gavin Edward Arteel

    2012-06-01

    Full Text Available Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, that also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

  3. Acute liver injury induced by weight-loss herbal supplements.

    Science.gov (United States)

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  4. Liver Injury Induced by Anticancer Chemotherapy and Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Y. Maor

    2013-01-01

    Full Text Available Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies.

  5. A review of drug-induced liver injury databases.

    Science.gov (United States)

    Luo, Guangwen; Shen, Yiting; Yang, Lizhu; Lu, Aiping; Xiang, Zheng

    2017-07-17

    Drug-induced liver injuries have been a major focus of current research in drug development, and are also one of the major reasons for the failure and withdrawal of drugs in development. Drug-induced liver injuries have been systematically recorded in many public databases, which have become valuable resources in this field. In this study, we provide an overview of these databases, including the liver injury-specific databases LiverTox, LTKB, Open TG-GATEs, LTMap and Hepatox, and the general databases, T3DB, DrugBank, DITOP, DART, CTD and HSDB. The features and limitations of these databases are summarized and discussed in detail. Apart from their powerful functions, we believe that these databases can be improved in several ways: by providing the data about the molecular targets involved in liver toxicity, by incorporating information regarding liver injuries caused by drug interactions, and by regularly updating the data.

  6. Alcoholic liver injury:Influence of gender and hormones

    Institute of Scientific and Technical Information of China (English)

    Patricia; K; Eagon

    2010-01-01

    This article discusses several subjects pertinent to a consideration of the role of gender and hormones in alcoholic liver injury (ALI). Beginning with an overview of factors involved in the pathogenesis of ALI, we review changes in sex hormone metabolism resulting from alcohol ingestion, summarize research that points to estrogen as a cofactor in ALI, consider evidence that gut injury is linked to liver injury in the setting of alcohol, and briefly review the limited evidence regarding sex hormones and gut...

  7. Review of liver injury associated with dietary supplements.

    Science.gov (United States)

    Stickel, Felix; Kessebohm, Kerstin; Weimann, Rosemarie; Seitz, Helmut K

    2011-05-01

    Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms 'dietary/nutritional supplements', 'adverse hepatic reactions', 'liver injury'; 'hepatitis', 'liver failure', 'vitamin A' and 'retinoids', and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.

  8. 5-Lipoxygenase Deficiency Reduces Acetaminophen-Induced Hepatotoxicity and Lethality

    Directory of Open Access Journals (Sweden)

    Miriam S. N. Hohmann

    2013-01-01

    Full Text Available 5-Lipoxygenase (5-LO converts arachidonic acid into leukotrienes (LTs and is involved in inflammation. At present, the participation of 5-LO in acetaminophen (APAP-induced hepatotoxicity and liver damage has not been addressed. 5-LO deficient (5-LO-/- mice and background wild type mice were challenged with APAP (0.3–6 g/kg or saline. The lethality, liver damage, neutrophil and macrophage recruitment, LTB4, cytokine production, and oxidative stress were assessed. APAP induced a dose-dependent mortality, and the dose of 3 g/kg was selected for next experiments. APAP induced LTB4 production in the liver, the primary target organ in APAP toxicity. Histopathological analysis revealed that 5-LO-/- mice presented reduced APAP-induced liver necrosis and inflammation compared with WT mice. APAP-induced lethality, increase of plasma levels of aspartate aminotransferase and alanine aminotransferase, liver cytokine (IL-1β, TNF-α, IFN-γ, and IL-10, superoxide anion, and thiobarbituric acid reactive substances production, myeloperoxidase and N-acetyl-β-D-glucosaminidase activity, Nrf2 and gp91phox mRNA expression, and decrease of reduced glutathione and antioxidant capacity measured by 2,2′-azinobis(3-ethylbenzothiazoline 6-sulfonate assay were prevented in 5-LO-/- mice compared to WT mice. Therefore, 5-LO deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage, suggesting 5-LO is a promising target to reduce APAP-induced lethality and liver inflammatory/oxidative damage.

  9. Platelet-activating factor in liver injury: A relational scope

    Institute of Scientific and Technical Information of China (English)

    Nikolaos P Karidis; Gregory Kouraklis; Stamatios E Theocharis

    2006-01-01

    The hepatocyte, the main cellular component of the liver, exhibits variable susceptibility to different types of injury induced by endogenous or exogenous factors.Hepatocellular dysfunction or death and regeneration are dependent upon the complicated interactions between numerous biologically active molecules. Plateletactivating factor (PAF) seems to play a pivotal role as the key mediator of liver injury in the clinical and experimental setting, as implied by the beneficial effects of its receptor antagonists. A comprehensive up-todate overview of the specific functional and regulatory properties of PAF in conditions associated with liver injury is attempted in this review.

  10. Severe liver injury induced by repeated use of hair dye

    Institute of Scientific and Technical Information of China (English)

    HOU Feng-qin; LIN Xiao-hong; YU Yan-yan; WANG Tai-ling; WANG Gui-qiang

    2009-01-01

    @@ Asignificant number of drugs has been proven,or at least suggested,to cause hepatotoxicity.1-3 Liver injury due to herbal medicines,chemicals or natural toxins also occur from household,occupational,or environmental exposure.4,5 However,liver toxicity due to hair dyes now is rarely recognized.Only in 2003,Tokumoto et al6 reported a case of hair dye-induced hepatitis,which presented a comparatively mild liver lesion.Here we described a case had more severe liver injury.

  11. PPAR and Liver Injury in HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Maud Lemoine

    2009-01-01

    Full Text Available Due to the introduction of active HIV antiretroviral treatment, AIDS-related morbidity and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV-infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug-related toxicity, and NASH. HIV-infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1 the liver injuries in HIV-infected patients; (2 both the current experimental and human data regarding PPAR and liver diseases; (3 the interactions between HIV and PPAR; (4 the potential use of PPAR agonists for the management of HIV-related liver diseases.

  12. Chimeric mice with a humanized liver as an animal model of troglitazone-induced liver injury.

    Science.gov (United States)

    Kakuni, Masakazu; Morita, Mayu; Matsuo, Kentaro; Katoh, Yumiko; Nakajima, Miki; Tateno, Chise; Yokoi, Tsuyoshi

    2012-10-02

    Troglitazone (Tro) is a thiazolidinedione antidiabetic drug that was withdrawn from the market due to its association with idiosyncratic severe liver injury. Tro has never induced liver injury in experimental animals in vivo. It was assumed that the species differences between human and experimental animals in the pharmaco- or toxicokinetics of Tro might be associated with these observations. In this study, we investigated whether a chimeric mouse with a humanized liver that we previously established, whose replacement index with human hepatocytes is up to 92% can reproduce Tro-induced liver injury. When the chimeric mice were orally administered Tro for 14 or 23 days (1000mg/kg/day), serum alanine aminotransferase (ALT) was significantly increased by 2.1- and 3.6-fold, respectively. Co-administration of l-buthionine sulfoximine (10mM in drinking water), an inhibitor of glutathione (GSH) synthesis, unexpectedly prevented the Tro-dependent increase of ALT, which suggests that the GSH scavenging pathway will not be involved in Tro-induced liver injury. To elucidate the mechanism of the onset of liver injury, hepatic GSH content, the level of oxidative stress markers and phase I and phase II drug metabolizing enzymes were determined. However, these factors were not associated with Tro-induced liver injury. An immune-mediated reaction may be associated with Tro-induced liver toxicity in vivo, because the chimeric mouse is derived from an immunodeficient SCID mouse. In conclusion, we successfully reproduced Tro-induced liver injury using chimeric mice with a humanized liver, which provides a new animal model for studying idiosyncratic drug-induced liver injury. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  13. Role of IRAK-M in alcohol induced liver injury.

    Directory of Open Access Journals (Sweden)

    Yipeng Wang

    Full Text Available Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR signaling pathways and interleukin receptor-associated kinase-M (IRAK-M in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT, more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68(+ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.

  14. Postoperative acute kidney injury in living donor liver transplantation recipients.

    Science.gov (United States)

    Atalan, Hakan K; Gucyetmez, Bulent; Aslan, Serdar; Yazar, Serafettin; Polat, Kamil Y

    2017-09-05

    There are many risk factors for postoperative acute kidney injury in liver transplantation. The aim of this study is to investigate the risk factors for postoperative acute kidney injury in living donor liver transplantation recipients. 220 living donor liver transplantation recipients were retrospectively evaluated in the study. According to the Kidney Disease Improving Global Outcomes Guidelines, acute kidney injury in postoperative day 7 was investigated for all patients. The patient's demographic data, preoperative and intraoperative parameters, and outcomes were recorded. Acute kidney injury was found in 27 (12.3%) recipients. In recipients with acute kidney injury, female population, model for end-stage liver disease score, norepinephrine requirement, duration of mean arterial pressure less than 60 mmHg, the usage of gelatin and erythrocyte suspension and blood loss were significantly higher than recipients with nonacute kidney injury (for all p5 mL kg-1 and duration of MAP less than 60 mmHg ≥5.5 minutes respectively (for all p<0.05). In living donor liver transplantation recipients, serum tacrolimus levels, intraoperative blood loss, hypotension period and the usage of gelatin may be risk factors for acute kidney injury in the early postoperative period.

  15. Role of stem cells during diabetic liver injury

    OpenAIRE

    Wan, Ying; Garner, Jessica; Wu, Nan; Phillip, Levine; Han, Yuyan; McDaniel, Kelly; Annable, Tami; Zhou, Tianhao; Francis, Heather; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco; Meng, Fanyin

    2015-01-01

    Abstract Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non‐alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic r...

  16. Pathomorphological changes after liver impact injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    麻晓林; 杨志焕; 王正国; 朱佩芳; 李晓炎; 王东

    2002-01-01

    Objective: To investigate the histopathological changes in the liver and other organs after impact injury. Methods: The rabbits were impacted with a BIM-IV biological impacting machine at the xiphoid process. The severity of liver injury was graded and scored through gross anatomy. At the same time, the pathological changes in the liver, heart, and lung were observed by light and electron microscopes. Results: Light microscopy showed that the pathological changes in the liver were: 1) loss of normal structure, hemorrhage and distortion of hepatic lobules; 2) cloudy swelling, degeneration, vacuolation and necrosis of liver cells; 3) infiltration of neutrophils. The lungs were injured and there were liver cell emboli in the small pulmonary arteries. Electron microscopy showed that the ultrastructure of the liver cells was severely damaged and the cells had significant features of necrosis. Conclusions: The major pathomorphological changes in the liver after impact injury are hemorrhage and necrosis. They may be complicated by exfoliation of liver cells to hepatic sinusoids. These cells circulate with the blood to form emboli in the pulmonary blood vessels.

  17. Gastric emptying in rats with acetaminophen-induced hepatitis

    Directory of Open Access Journals (Sweden)

    Hessel G.

    1998-01-01

    Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

  18. Genetic association studies in drug-induced liver injury.

    Science.gov (United States)

    Daly, Ann K; Day, Chris P

    2009-11-01

    Genetic studies on drug-induced liver injury (DILI) have proved challenging, both because of their rarity and their difficulty in replicating observed effects. However, significant progress has now been achieved by both candidate-gene and genome-wide association studies. These two approaches are considered in detail, together with examples of DILI due to specific drugs where consistent associations have been reported. Particular consideration is given to associations between antituberculosis drug-related liver injury and the "slow acetylator" genotype for N-acetyltransferase 2, amoxicillin/clavulanate-related liver injury, and the human leukocyte antigen (HLA) class II DRB1*1501 allele and flucloxacillin-related injury and the HLA class I B*5701 allele. Although these associations are drug-specific, the possibility that additional, more general susceptibility genes for DILI exist requires further investigation, ideally by genome-wide association studies involving international collaboration. The possibility of interethnic variation in susceptibility to DILI also requires further study.

  19. Effect of IL-10 mRNA expression in acetaminophen-induced hepatotoxicity%白细胞介素-10mRNA表达在对乙酰氨基酚所致肝损害中的作用

    Institute of Scientific and Technical Information of China (English)

    田丰; 解莹; 张亚杰

    2012-01-01

    Objective To investigate the role of interleukin-10( IL-10 ) in acetaminophen-induced hepatotoxic-ity. Methods To establish the model of acetaminophen-induced hepatotoxicity in SD rats. The levels of serum ALT of AAP group and control group were measured by radioimmunoassay. Hepatic tissue samples were taken to evaluate pathological changes by HE staining and the IL-10 mRNA expression was detected by RT-PCR. Results Compared to control group, serum ALT( nKat/L )were progressively increased after acetaminophen administration( P < 0. 01 )in different time periods; Liver pathological damage were progressively exacerbated; The expression of IL-10 mRNA in liver tissue increased significantly( P <0. 01 ),and reached a peak at 12 h. Conclusion IL-10 has a strong inhibitory effect on pro-inflammatory cytokine expression, which may play a protective role in acetaminophen-induced hepatotoxicity.%目的 探讨白细胞介素-10(IL-10)在AAP肝损害中的作用.方法 应用对乙酰氨基酚(AAP)建立SD大鼠肝损害模型;AAP组和对照组分别测定血清ALT水平,HE染色观察肝脏病理变化,RT-PCR方法检测大鼠肝组织中IL-10 mRNA的表达.结果 AAP组和对照组相比,各时间点血清ALT水平均显著升高(P<0.01);肝脏病理损伤进行性加剧;肝组织IL-10 mRNA表达显著升高(P<0.01),于12 h达高峰.结论 IL-10可能具有抑制促炎因子表达作用,在AAP引起的肝损害中可能起到肝脏保护作用.

  20. Liver transplantation in the mouse: Insights into liver immunobiology, tissue injury, and allograft tolerance.

    Science.gov (United States)

    Yokota, Shinichiro; Yoshida, Osamu; Ono, Yoshihiro; Geller, David A; Thomson, Angus W

    2016-04-01

    The surgically demanding mouse orthotopic liver transplant model was first described in 1991. It has proved to be a powerful research tool for the investigation of liver biology, tissue injury, the regulation of alloimmunity and tolerance induction, and the pathogenesis of specific liver diseases. Liver transplantation in mice has unique advantages over transplantation of the liver in larger species, such as the rat or pig, because the mouse genome is well characterized and there is much greater availability of both genetically modified animals and research reagents. Liver transplant experiments using various transgenic or gene knockout mice have provided valuable mechanistic insights into the immunobiology and pathobiology of the liver and the regulation of graft rejection and tolerance over the past 25 years. The molecular pathways identified in the regulation of tissue injury and promotion of liver transplant tolerance provide new potential targets for therapeutic intervention to control adverse inflammatory responses/immune-mediated events in the hepatic environment and systemically. In conclusion, orthotopic liver transplantation in the mouse is a valuable model for gaining improved insights into liver biology, immunopathology, and allograft tolerance that may result in therapeutic innovation in the liver and in the treatment of other diseases.

  1. Role of stem cells during diabetic liver injury.

    Science.gov (United States)

    Wan, Ying; Garner, Jessica; Wu, Nan; Phillip, Levine; Han, Yuyan; McDaniel, Kelly; Annable, Tami; Zhou, Tianhao; Francis, Heather; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco; Meng, Fanyin

    2016-02-01

    Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non-alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic reticulum stress. The realization that these factors are important in hepatocyte damage and lack of donor livers has led to studies concentrating on the role of stem cells (SCs) in the prevention and treatment of liver injury. Possible avenues that the application of SCs may improve liver injury include but are not limited to: the ability to differentiate into pancreatic β-cells (insulin producing cells), the contribution for hepatocyte regeneration, regulation of lipogenesis, glucogenesis and anti-inflammatory actions. Once further studies are performed to explore the underlying protective mechanisms of SCs and the advantages and disadvantages of its application, there will be a greater understand of the mechanism and therapeutic potential. In this review, we summarize the findings regarding the role of SCs in diabetic liver diseases.

  2. Isolated liver gunshot injuries: nonoperative management is feasible?

    Directory of Open Access Journals (Sweden)

    SIZENANDO VIEIRA STARLING

    2015-08-01

    Full Text Available ABSTRACTObjective:to evaluate the safety and effectiveness of non-operative management (NOM of liver injury, being the only abdominal injury, from gunshot wounds to the abdomen.Methods:patients who had liver damage diagnosed as single abdominal injury caused by PAF in the right thoracoabdominal region, hemodynamically stable were studied. All underwent examination with computed tomography. Were analyzed: age, gender, levels of trauma, hemodynamic condition and the abdominal examination on admission, the results of the CT scan, the extra-abdominal lesions found, the serum levels of hemoglobin, clinical course, complications, length of hospital stay, outpatient treatment and death.Results:during the study period 169 patients, treated non-operatively, presented liver gunshot wounds. Of these, only 28 patients (16.6% had liver injury as the only abdominal injury and consequently met the inclusion criteria for this study. The average age was 27.7 years and 25 patients (89.2% were male. The overall average of verified trauma scores were: RTS 7.45, ISS 10.9, and TRISS 98.7%. The most frequent injuries were grade II and grade III (85.7%. Complications occurred in only one patient who presented a progressive decline in hemoglobin. He underwent a CT scan which showed blush in the liver parenchyma. An arteriography was performed, which showed a successfully embolized arteriovenous fistula. There were no deaths in the patient sample. The average hospital stay was 5.3 days.Conclusion:isolated hepatic injury in gunshot abdominal trauma is uncommon. However, the NOM protocol for this type of injury is safe and has low morbidity. This approach should only be followed in institutions with adequate infrastructure, where an experienced and cohesive team is able to follow a specific protocol, with rigorous periodic evaluation of its results.

  3. Congenital biliary atresia: liver injury begins at birth

    DEFF Research Database (Denmark)

    Makin, Erica; Quaglia, Alberto; Kvist, Nina

    2009-01-01

    -note review for infants with definite BA who underwent laparotomy within first week of life. RESULTS: Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial. CONCLUSION: This suggests......BACKGROUND: The timing of onset of liver injury in biliary atresia (BA) is not known, although in approximately 10% of cases, biliary pathologic condition associated with the biliary atresia splenic malformation syndrome must begin well before birth. METHODS: The study involved retrospective case...... that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory...

  4. Liver injury suppressing compounds from avocado (Persea americana).

    Science.gov (United States)

    Kawagishi, H; Fukumoto, Y; Hatakeyama, M; He, P; Arimoto, H; Matsuzawa, T; Arimoto, Y; Suganuma, H; Inakuma, T; Sugiyama, K

    2001-05-01

    To evaluate the protective activity of fruits against liver injury, 22 different fruits were fed to rats with liver damage caused by D-galactosamine, a powerful liver toxin. As measured by changes in the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), avocado showed extraordinarily potent liver injury suppressing activity. Five active compounds were isolated and their structures determined. These were all fatty acid derivatives, of which three, namely, (2E,5E,12Z,15Z)-1-hydroxyheneicosa-2,5,12,15-tetraen-4-one, (2E,12Z,15Z)-1-hydroxyheneicosa-2,12,15-trien-4-one, and (5E,12Z)-2-hydroxy-4-oxoheneicosa-5,12-dien-1-yl acetate, were novel.

  5. Genetic tracing of hepatocytes in liver homeostasis, injury, and regeneration.

    Science.gov (United States)

    Wang, Yue; Huang, XiuZhen; He, Lingjuan; Pu, Wenjuan; Li, Yan; Liu, Qiaozhen; Li, Yi; Zhang, Libo; Yu, Wei; Zhao, Huan; Zhou, Yingqun; Zhou, Bin

    2017-05-26

    The liver possesses a remarkable capacity to regenerate after damage. There is a heated debate on the origin of new hepatocytes after injuries in adult liver. Hepatic stem/progenitor cells have been proposed to produce functional hepatocytes after injury. Recent studies have argued against this model and suggested that pre-existing hepatocytes, rather than stem cells, contribute new hepatocytes. This hepatocyte-to-hepatocyte model is mainly based on labeling of hepatocytes with Cre-recombinase delivered by the adeno-associated virus. However, the impact of virus infection on cell fate determination, consistency of infection efficiency, and duration of Cre-virus in hepatocytes remain confounding factors that interfere with the data interpretation. Here, we generated a new genetic tool Alb-DreER to label almost all hepatocytes (>99.5%) and track their contribution to different cell lineages in the liver. By "pulse-and-chase" strategy, we found that pre-existing hepatocytes labeled by Alb-DreER contribute to almost all hepatocytes during normal homeostasis and after liver injury. Virtually all hepatocytes in the injured liver are descendants of pre-existing hepatocytes through self-expansion. We concluded that stem cell differentiation is unlikely to be responsible for the generation of a substantial number of new hepatocytes in adult liver. Our study also provides a new mouse tool for more precise in vivo genetic study of hepatocytes in the field. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Saponins (Ginsenosides) from the Leaves of Panax quinquefolius Ameliorated Acetaminophen-Induced Hepatotoxicity in Mice.

    Science.gov (United States)

    Xu, Xing-Yue; Hu, Jun-Nan; Liu, Zhi; Zhang, Rui; He, Yu-Fang; Hou, Wei; Wang, Zhi-Qing; Yang, Ge; Li, Wei

    2017-05-10

    Acetaminophen (APAP) overdose is one of the most common inducements of drug-induced liver injury (DILI) in the world. The main purpose of this paper was to investigate the liver protection activity of saponins (ginsenosides) from the leaves of Panax quinquefolius (PQS) against APAP-induced hepatotoxicity, and the involved mechanisms were demonstrated for the first time. Mice were pretreated with PQS (150 and 300 mg/kg) by oral gavage for 7 days before being treated with 250 mg/kg APAP. Severe liver injury was exerted at 24 h post-APAP, and hepatotoxicity was assessed. Our results showed that pretreatment with PQS significantly decreased the serum alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β) levels in a dose-dependent manner as compared to the APAP administration. Meanwhile, compared with that in the APAP group, PQS decreased hepatic malondialdehyde (MDA) contents and 4-hydroxynonenal (4-HNE) expression and restored reduced glutathione (GSH) content and superoxide dismutase (SOD) activity in livers of mice. PQS inhibited the overexpression of pro-inflammatory factors cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the liver tissues. Furthermore, Western blotting analysis revealed that PQS pretreatment inhibited the activation of apoptotic signaling pathways via increase of Bcl-2 and decrease of Bax and caspase-3 protein expression levels. Liver histopathological observation provided further evidence that PQS pretreatment significantly inhibited APAP-induced hepatocyte necrosis, inflammatory cell infiltration, and congestion. Biological indicators of nitrative stress such as 3-nitrotyrosine (3-NT) were inhibited after PQS pretreatment, compared to the APAP group. The present study clearly demonstrates that PQS exerts a protective effect against APAP-induced hepatic injury because of its antioxidant, anti-apoptotic, and anti-inflammatory activities. The findings from

  7. The role of oxidative stress in alcoholic liver injury

    Directory of Open Access Journals (Sweden)

    Radosavljević Tatjana

    2009-01-01

    Full Text Available Introduction. Oxidative stress plays an important role in pathogenesis of alcoholic liver injury. The main source of free oxygen species is cytochrome P450-dependent monooxygenase, which can be induced by ethanol. Role of cytochrome P4502E1 in ethanol-induced oxidative stress. Reactive oxygen species produced by this enzyme are more important in intracellular oxidative damage compared to species derived from activated phagocytes. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in alcohol-induced oxidative stress. Production of mitochondrial reactive oxygen species is increased, and glutathione content is decreased in chronically ethanolfed animals. Oxidative stress in mitochondria leads to mitochondrial DNA damage and has a dual effect on apoptosis. Role of Kupffer cells in alcohol-induced liver injury. Chronic ethanol consumption is associated with increased release of endotoxin from gut lumen into portal circulation. Endotoxin activates Kupffer cells, which then release proinflammatory cytokines and oxidants. Role of neutrophils in alcohol-induced liver injury. Alcoholic liver injury leads to the accumulation of neutrophils, which release reactive oxygen species and lysosomal enzymes and contribute to hepatocyte damage and necrosis. Role of nitric oxide in alcohol-induced oxidative stress. High amounts of nitric oxide contribute to the oxidative damage, mainly by generating peroxynitrites. Role of antioxidants in ethanol-induced oxidative stress. Chronic ethanol consumption is associated with reduced liver glutathione and α-tocopherol level and with reduced superoxide dismutase, catalase and glutathione peroxidase activity. Conclusion. Oxidative stress in alcoholic liver disease is a consequence of increased production of oxidants and decreased antioxidant defense in the liver.

  8. Liver injury induced by herbal complementary and alternative medicine.

    Science.gov (United States)

    Navarro, Victor J; Seeff, Leonard B

    2013-11-01

    Herbal and dietary supplement use is common. Most marketed products consist of complex mixtures. Although they are perceived as safe, instances of hepatotoxicity attributable to these products underscore their potential for injury, but the exact component that is responsible for injury is difficult to discern. The lenient regulatory environment in the United States, which opens the possibility of adulteration and contamination, adds to the challenge of disease attribution. Although many different herbal and dietary supplements have been reported to cause liver injury, in the United States, products used for bodybuilding and weight loss are the most commonly implicated.

  9. Novel insight into mechanisms of cholestatic liver injury

    Institute of Scientific and Technical Information of China (English)

    Benjamin L Woolbright; Hartmut Jaeschke

    2012-01-01

    Cholestasis results in a buildup of bile acids in serum and in hepatocytes.Early studies into the mechanisms of cholestatic liver injury strongly implicated bile acidinduced apoptosis as the major cause of hepatocellular injury.Recent work has focused both on the role of bile acids in cell signaling as well as the role of sterile inflammation in the pathophysiology.Advances in modern analytical methodology have allowed for more accurate measuring of bile acid concentrations in serum,liver,and bile to very low levels of detection.Interestingly,toxic bile acid levels are seemingly far lower than previously hypothesized.The 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 injury.This 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.

  10. Effects ofSalmonella infection on hepatic damage following acute liver injury in rats

    Institute of Scientific and Technical Information of China (English)

    Yong-Tao Li; Cheng-Bo Yu; Dong Yan; Jian-Rong Huang; Lan-Juan Li

    2016-01-01

    BACKGROUND: Acute liver injury is a common clinical disor-der associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The pur-pose of this study was to address this unanswered question using a rat model. METHODS: Oral supplementation withSalmonella enterica serovar enteritidis (S. enteritidis) was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the con-centrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver injury. RESULTS: The levels of liver damage and endotoxin were sig-niifcantly increased in theSalmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury (P CONCLUSIONS: OralS. enteritidis administration exacer-bates acute liver injury, especially when injury was severe. Major factors of the exacerbation include inlfammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver.

  11. Hepatoprotective effect of kaempferol against alcoholic liver injury in mice.

    Science.gov (United States)

    Wang, Meng; Sun, Jianguo; Jiang, Zhihui; Xie, Wenyan; Zhang, Xiaoying

    2015-01-01

    Kaempferol is a biologically active component present in various plants. The hepatoprotective effect of kaempferol in drug-induced liver injury has been proven, while its effect against alcoholic liver injury (ALI) remains unclear. Hence, the present study aimed to evaluate the effect of kaempferol against ALI in mice. The experimental ALI mice model was developed and the mice were treated with different doses of kaempferol for 4 weeks. The liver functions were observed by monitoring the following parameters: Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) levels in serum; histopathological studies of liver tissue; oxidative stress by hydrogen peroxide (H2O2), superoxide dismutase (SOD) and glutathione (GSH); the lipid peroxidation status by malondialdehyde (MDA) and lipid accumulation by triglyceride (TG) level in serum; and the expression levels and activities of a key microsomal enzyme cytochrome 2E1 (CYP2E1), by both in vitro and in vivo methods. The ALI mice (untreated) showed clear symptoms of liver injury, such as significantly increased levels of oxidative stress, lipid peroxidation and excessive CYP2E1 expression and activity. The mice treated with different kaempferol dosages exhibited a significant decrease in the oxidative stress as well as lipid peroxidation, and increased anti-oxidative defense activity. The kaempferol treatment has significantly reduced the expression level and activity of hepatic CYP2E1, thus indicating that kaempferol could down regulate CYP2E1. These findings show the hepatoprotective properties of kaempferol against alcohol-induced liver injury by attenuating the activity and expression of CYP2E1 and by enhancing the protective role of anti-oxidative defense system.

  12. Intestinal microflora in rats with ischemia/reperfusion liver injury

    Institute of Scientific and Technical Information of China (English)

    XING Hui-chun; LI Lan-juan; XU Kai-jin; SHEN Tian; CHEN Yun-bo; SHENG Ji-fang; YU Yun-song; CHEN Ya-gang

    2005-01-01

    Objectives: To investigate the intestinal microflora status related to ischemia/reperfusion (I/R) liver injury and explore the possible mechanism. Methods: Specific pathogen free grade Sprague-Dawley rats were randomized into three groups: Control group (n=8), sham group (n=6) and I/R group (n=10). Rats in the control group did not receive any treatment, rats in the I/R group were subjected to 20 min of liver ischemia, and rats in the sham group were only subjected to sham operation. Twenty-two hours later, the rats were sacrificed and liver enzymes and malondialdehyde (MDA), superoxide dismutase (SOD), serum endotoxin,intestinal bacterial counts, intestinal mucosal histology, bacterial translocation to mesenteric lymph nodes, liver, spleen, and kidney were studied. Results: Ischemia/reperfusion increased liver enzymes, MDA, decreased SOD, and was associated with plasma endotoxin elevation in the I/R group campared to those in the sham group. Intestinal Bifidobacteria and Lactobacilli decreased and intestinal Enterobacterium and Enterococcus, bacterial translocation to kidney increased in the I/R group compared to the sham group. Intestinal microvilli were lost, disrupted and the interspace between cells became wider in the I/R group.Conclusion: I/R liver injury may lead to disturbance of intestinal microflora and impairment of intestinal mucosal barrier function,which contributes to endotoxemia and bacterial translocation to kidney.

  13. Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today?

    Science.gov (United States)

    Teschke, Rolf; Frenzel, Christian

    For the pathologist, the diagnosis of drug induced liver injury (DILI) is challenging, because histopathological features mimic all primary hepatic and biliary diseases, lacking changes that are specific for DILI. Therefore, in any patient of suspected DILI who underwent liver biopsy, the pathologist will assure the clinician that the observed hepatic changes are compatible with DILI, but this information is less helpful due to lack of specificity. Rather, the pathologist should assess liver biopsies blindly, without knowledge of prior treatment by drugs. This will result in a detailed description of the histological findings, associated with suggestions for potential causes of these hepatic changes. Then, it is up to the physician to reassess carefully the differential diagnoses, if not done before. At present, liver histology is of little impact establishing the diagnosis of DILI with the required degree of certainty, and this shortcoming also applies to herb induced liver injury (HILI). To reach at the correct diagnoses of DILI and HILI, clinical and structured causality assessments are therefore better approaches than liver histology results obtained through liver biopsy, an invasive procedure with a low complication rate.

  14. Ginseng for Liver Injury: Friend or Foe?

    Directory of Open Access Journals (Sweden)

    Tae-Woo Kim

    2016-12-01

    Full Text Available Panax sp., including Panax ginseng Meyer, Panax quiquifolius L., or Panax notoginseng (Burk. FH Chen, have been used as functional foods or for traditional Chinese medicine for diabetes, inflammation, stress, aging, hepatic injury, and cancer. In recent decades, a number of both in vitro and in vivo experiments as well as human studies have been conducted to investigate the efficacy and safety of various types of ginseng samples and their components. Of these, the hepatoprotective and hepatotoxic effects of ginseng and their ginsenosides and polysaccharides are reviewed and summarized.

  15. Clozapine-induced liver injury and pleural effusion

    Directory of Open Access Journals (Sweden)

    Joseph P.M. Kane

    2014-09-01

    Full Text Available Clozapine, whilst associated commonly with a transient and benign increase in liver enzymes, has also been associated with varying presentations of hepatitis in existing case reports. This report describes what we believe to be the first documented case of acute liver injury and pleural effusion associated with clozapine, resolving after cessation of the agent. The case supports existing literature in advocating a high index of suspicion, particularly in the 4-5 weeks following clozapine initiation, when considering nonspecific clinical symptoms and signs.

  16. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography

    NARCIS (Netherlands)

    Stravitz, R. Todd; Lisman, Ton; Luketic, Velimir A.; Sterling, Richard K.; Puri, Puneet; Fuchs, Michael; Ibrahim, Ashraf; Lee, William M.; Sanyal, Arun J.

    2012-01-01

    Background & Aims: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. Methods: Fifty-one pa

  17. Normothermic acellular ex vivo liver perfusion reduces liver and bile duct injury of pig livers retrieved after cardiac death.

    Science.gov (United States)

    Boehnert, M U; Yeung, J C; Bazerbachi, F; Knaak, J M; Selzner, N; McGilvray, I D; Rotstein, O D; Adeyi, O A; Kandel, S M; Rogalla, P; Yip, P M; Levy, G A; Keshavjee, S; Grant, D R; Selzner, M

    2013-06-01

    We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

  18. Drug-induced liver injury: Is it somehow foreseeable?

    Institute of Scientific and Technical Information of China (English)

    Giovanni Tarantino; Matteo Nicola Dario Di Minno; Domenico Capone

    2009-01-01

    The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes -450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

  19. Identification of early biomarkers during acetaminophen-induced hepatotoxicity by fourier transform infrared microspectroscopy.

    Directory of Open Access Journals (Sweden)

    Rekha Gautam

    Full Text Available Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2(-/- mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2(-/- mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.

  20. Ebselen prevents early alcohol-induced liver injury in rats.

    Science.gov (United States)

    Kono, H; Arteel, G E; Rusyn, I; Sies, H; Thurman, R G

    2001-02-15

    Oxidants have been shown to be involved in alcohol-induced liver injury. Moreover, 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), an organoselenium compound and glutathione peroxidase mimic, decreases oxidative stress and protects against stroke clinically. This study was designed to test the hypothesis that ebselen protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g/kg/d) continuously for up to 4 weeks using the intragastric enteral feeding protocol developed by Tsukamoto and French. Ebselen (50 mg/kg twice daily, intragastrically) or vehicle (1% tylose) was administered throughout the experiment. Mean urine ethanol concentrations were not significantly different between treatment groups, and ebselen did not affect body weight gains or cyclic patterns of ethanol concentrations in urine. After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (37 +/- 5 IU/l) by enteral ethanol (112 +/- 7 IU/l); ebselen blunted this increase significantly (61 +/- 8 IU/l). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver (pathology score: 4.3 +/- 0.3). In contrast, these pathological changes were blunted significantly by ebselen (pathology score: 2.5 +/- 0.4). While there were no significant effects of either ethanol or ebselen on glutathione peroxidase activity in serum or liver tissue, ebselen blocked the increase in serum nitrate/nitrite caused by ethanol. Furthermore, ethanol increased the activity of NF-kappaB over 5-fold, the number of infiltrating neutrophils 4-fold, and the accumulation of 4-hydroxynonenal over 5-fold. Ebselen blunted all of these effects significantly. These results indicate that ebselen prevents early alcohol-induced liver injury, most likely by preventing oxidative stress, which decreases inflammation.

  1. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  2. Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

    Science.gov (United States)

    Vliegenthart, Adb; Kimmitt, R A; Seymour, J H; Homer, N Z; Clarke, J I; Eddleston, M; Gray, A; Wood, D M; Dargan, P I; Cooper, J G; Antoine, D J; Webb, D J; Lewis, S C; Bateman, D N; Dear, J W

    2017-04-01

    Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  3. Acute kidney injury in acute liver failure: a review.

    Science.gov (United States)

    Moore, Joanna K; Love, Eleanor; Craig, Darren G; Hayes, Peter C; Simpson, Kenneth J

    2013-11-01

    Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review.

  4. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Yuchao; McGill, Mitchell R.; Dorko, Kenneth [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2014-09-15

    Acetaminophen (APAP) overdose is the most prevalent cause of drug-induced liver injury in western countries. Numerous studies have been conducted to investigate the mechanisms of injury after APAP overdose in various animal models; however, the importance of these mechanisms for humans remains unclear. Here we investigated APAP hepatotoxicity using freshly isolated primary human hepatocytes (PHH) from either donor livers or liver resections. PHH were exposed to 5 mM, 10 mM or 20 mM APAP over a period of 48 h and multiple parameters were assessed. APAP dose-dependently induced significant hepatocyte necrosis starting from 24 h, which correlated with the clinical onset of human liver injury after APAP overdose. Interestingly, cellular glutathione was depleted rapidly during the first 3 h. APAP also resulted in early formation of APAP-protein adducts (measured in whole cell lysate and in mitochondria) and mitochondrial dysfunction, indicated by the loss of mitochondrial membrane potential after 12 h. Furthermore, APAP time-dependently triggered c-Jun N-terminal kinase (JNK) activation in the cytosol and translocation of phospho-JNK to the mitochondria. Both co-treatment and post-treatment (3 h) with the JNK inhibitor SP600125 reduced JNK activation and significantly attenuated cell death at 24 h and 48 h after APAP. The clinical antidote N-acetylcysteine offered almost complete protection even if administered 6 h after APAP and a partial protection when given at 15 h. Conclusion: These data highlight important mechanistic events in APAP toxicity in PHH and indicate a critical role of JNK in the progression of injury after APAP in humans. The JNK pathway may represent a therapeutic target in the clinic. - Highlights: • APAP reproducibly causes cell death in freshly isolated primary human hepatocytes. • APAP induces adduct formation, JNK activation and mitochondrial dysfunction in PHH. • Mitochondrial adducts and JNK translocation are delayed in PHH compared to

  5. Hyperhomocysteinemia,endoplasmic reticulum stress,and alcoholic liver injury

    Institute of Scientific and Technical Information of China (English)

    Cheng Ji; Neil Kaplowitz

    2004-01-01

    Deficiencies in vitamins or other factors (B6, B12, folic acid,betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (Hhcy). Hhcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. Hhcy unleashes mediators of inflammation such as NFκB, IL-1β, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis,fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of Hhcy. ER stress may also be involved in other liver diseases such as α1-antitrypsin (α1-AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans,and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of Hhcy and liver disease.

  6. Macrophages and dendritic cells in the development of liver injury leading to liver failure.

    Science.gov (United States)

    Ananiev, J; Penkova, M; Tchernev, G; Chokoeva, A A; Philipov, S; Tana, C; Gulubova, M; Wollina, U

    2014-01-01

    Liver failure (LF) continues to be a serious problem due to different underlying disorders. Not only hepatocytes but Kupffer cells (KCs) and dendritic cells (DCs) are of importance in this instance. We wanted to investigate the possible role of KCs and liver DCs in the development of liver injury in patients with liver failure. Liver specimens from 23 patients who died after liver failure were examined for the presence and distribution of CD68-positive KCs and CD83-positive DCs by immunohistochemistry. The distribution of the CD83-positive DC in the sinusoidal and the periportal spaces was not even. While 39.1% of patients had a high sinusoidal density of CD83-positive cells, 60.9% demonstrated a high density of CD83-positive cells in the periportal tract. The number of CD83-positive DCs in periportal tracts in patients with advanced liver fibrosis (n=5) were high, while those with mild liver fibrosis (n=18) had low numbers of mature dendritic cells (χ2=4.107; p=0.043). In addition, all patients with intensive fibrosis had low counts of CD68-positive KC’s in portal tracts vs patients with mild fibrosis of which 67% had high counts (χ2=6.97; p=0.008). In seven of the patients with moderate steatosis (87.5%) low numbers of CD68-positive KCs were found in sinusoids, in contrast to those with severe steatosis, where 12 patients (80%) had high KC counts (χ2=13.4; p less than 0.001). The distribution and number of CD68-positive KC and CD83-positive DC reflect the progression of liver fibrosis leading to liver failure.

  7. Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

    Science.gov (United States)

    Lin, Christine

    2016-01-01

    Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans. PMID:27725933

  8. The protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    Nnodim Johnkennedy; Emejulu Adamma

    2011-01-01

    Objective: To evaluate the protective effect of leaf extract of Gongronema latifolium (G. latifolium) against acute acetaminophen induced hepatic toxicity in Wistar rats. Methods:Thirty six Wistar rats were divided into 6 groups with 6 rats in each group. Animals in group 1 and 2 were administered with 600 mg/kg b.w. of acetaminophen only and acetaminophen plus 100 mg/kg b.w. of caffeine by oral gavages, respectively. Experimental groups 3 and 4 were treated as in group 1 but in addition received 200 and 400 mg/kg b.w., respectively of the leaf extract of G. latifolium by oral gavages. The experimental groups 5 and 6 were treated as in group 2 and in addition received 200 and 400 mg/kg b.w. of leaf extract of G. latifolium, respectively. The treatment lasted for 14 days. Results: The results obtained showed that the serum glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) and alkaline phosphatase (ALP) levels had a greater increase in group 2 than in group 1 but dropped marginally in groups 3 and 4. However, in groups 5 and 6, AST, ALT and ALP were significantly reduced (P<0.05). Similarly, serum protein levels were significantly increased in groups 3, 4, 5 and 6 when compared with group 1 and 2. Conclusions: It can be concluded that extract of G. latifolium offers protection against acetaminophen and caffeinated acetaminophen toxicity in Wistar rats.

  9. A case of acetaminophen-induced acute tubulointerstitial nephritis in adult.

    Science.gov (United States)

    Inoue, Dan; Usui, Ryosuke; Nitta, Kosaku; Koike, Minako

    2017-08-11

    We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi-pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN.

  10. Melatonin protects liver from intestine ischemia reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Jian-Yi Li; Hong-Zhuan Yin; Xi Gu; Yong Zhou; Wen-Hai Zhang; Yi-Min Qin

    2008-01-01

    AIM:To investigate the protective effect of melatonin on liver after intestinal ischemia-reperfusion injury in rats.METHODS:One hundred and fifty male Wistar rats,weighing 190-210 g,aged 7 wk,were randomly divided into melatonin exposure group,alcohol solvent control group and normal saline control group.Rats in the melatonin exposure group received intraperitoneal (IP) melatonin (20 mg/kg) 30 min before intestinal ischemia-reperfusion (IR),rats in the alcohol solvent control group received the same concentration and volume of alcohol,and rats in the normal saline control group received the same volume of normal saline.Serum samples were collected from each group 0.5,1,6,12,and 24 h after intestinal IR.Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured with an auto-biochemical analyzer.Serum TNF-a was tested by enzyme-linked immunosorbent assay (ELISA).Malondialdehyde (MDA) in liver was detected by colorimetric assay.Pathological changes in liver and immunohistochemical straining of ICAM-1 were observed under an optical microscope.RESULTS:The levels of ALT measured at various time points after intestinal IR in the melatonin exposure group were significantly lower than those in the other two control groups (P<0.05).The serum AST levels 12 and 24 h after intestinal IR and the ICAM-1 levels (%) 6,12 and 24 h after intestinal IR in the melatonin exposure group were also significantly lower than those in the other two control groups (P<0.05).CONCLUSION:Exotic melatonin can inhibit the activity of ALT,AST and TNF-a decrease the accumulation of MDA,and depress the expression of ICAM-1 in liver after intestinal IR injury,thus improving the liver function.

  11. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  12. Acute liver failure and acute kidney injury: Definitions, prognosis, and outcome

    NARCIS (Netherlands)

    Włodzimirow, K.A.

    2013-01-01

    The objective of this thesis was to investigate definitions, prognostic indicators and their association with adverse events, mainly mortality for acute liver failure (ALF), acute-on-chronic liver failure (ACLF) and acute kidney injury (AKI).

  13. Preventive effect of zinc on nickel-induced oxidative liver injury in rats

    African Journals Online (AJOL)

    MIDOU

    2013-12-18

    Dec 18, 2013 ... exposure of rats to nickel sulfate for 21 days resulted in a significant decrease in body weight gain and absolute liver weight ... Nickel treatment also produced oxidative liver injury ..... Biochemical toxicology of arsenic. Rev.

  14. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.

    Science.gov (United States)

    Cotter, David G; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M; d'Avignon, D André; Graham, Mark J; Dietzen, Dennis J; Brunt, Elizabeth M; Patti, Gary J; Crawford, Peter A

    2014-12-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.

  15. Albendazole-induced liver injury: a case report

    Directory of Open Access Journals (Sweden)

    David Ríos

    2013-05-01

    Full Text Available We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a “likely” correlation between hepatocellular damage and drug toxicity etiology. 

  16. Albendazole-induced liver injury: a case report.

    Science.gov (United States)

    Ríos, David; Restrepo, Juan C

    2013-04-01

    We report a case of a 47-year-old male, who was referred to the clinical hepatology services at Pablo Tobón Uribe Hospital for evaluation of a jaundice syndrome. After undergoing several exams, we diagnosed hepatic hydatidosis and the patient was treated with albendazole; however, after five months of uninterrupted treatment the patient again consulted and his liver test showed marked hepatocellular damage. This time, the patient was diagnosed with drug-induced liver injury due to albendazole, based on information from the clinical record, history of drug consumption, clinical and laboratory tests improved after discontinuing the medication and after discarding other possible causes; this diagnosis was supported by the CIOMS/RUCAM scale, which showed a "likely" correlation between hepatocellular damage and drug toxicity etiology.

  17. Drug-induced liver injury and drug development: industry perspective.

    Science.gov (United States)

    Regev, Arie

    2014-05-01

    Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development.

  18. Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats.

    Science.gov (United States)

    Pradhan, Shrabani; Mandal, Shreya; Roy, Suchismita; Mandal, Arpita; Das, Koushik; Nandi, Dilip K

    2013-04-01

    Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control - receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.

  19. CXCL16 participates in pathogenesis of immunological liver injury by regulating T lymphocyte infiltration in liver tissue

    Institute of Scientific and Technical Information of China (English)

    Huan-Bin Xu; Yan-Ping Gong; Jin Cheng; Yi-Wei Chu; Si-Dong Xiong

    2005-01-01

    AIM: To investigate the role of CXCL16 in the pathogenesis of immunological liver injury and to explore the possible mechanism of T lymphocyte infiltration requlated by CXCL16.METHODS: Immunological liver injury in murine model was induced by Bacille Calmette-Guerin and lipopolysaccharide.Expression pattem and distribution of CXCL16 were examined by real-time quantitative RT-PCR and immunohistochemical analysis. Anti-CXCL16 antibody was administrated in vivo to investigate its effect on T-cell recruitment and acute hepatic necrosis. The survival of murine model was also evaluated.RESULTS: The murine immunological liver injury model was successfully established. CXCL16 expression increased and predominantly distributed in periportal areas and vascular endothelia in injured liver tissues. Administration of anti-CXCL16 Ab protected the mice from death and acute liver damage. Approximately 70% of the mice survived for 72 h in the anti-CXCL16 Ab treatment group, whereas 80% died within 72 h in control Ab group. The number of liver-infiltrating T lymphocytes was significantly reduced from 1.01×L07 to 3.52x 106/liver, compared with control Ab treatment.CONCLUSION: CXCL16 is involved in immunological liver injury by regulating T lymphocyte infiltration in liver tissue.

  20. Metabolomics evaluation of the effects of green tea extract on acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Lu, Yihong; Sun, Jinchun; Petrova, Katya; Yang, Xi; Greenhaw, James; Salminen, William F; Beger, Richard D; Schnackenberg, Laura K

    2013-12-01

    Green tea has been purported to have beneficial health effects including protective effects against oxidative stress. Acetaminophen (APAP) is a widely used analgesic drug that can cause acute liver injury in overdose situations. These studies explored the effects of green tea extract (GTE) on APAP-induced hepatotoxicity in liver tissue extracts using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance spectroscopy. Mice were orally administered GTE, APAP or GTE and APAP under three scenarios. APAP alone caused a high degree of hepatocyte necrosis associated with increases in serum transaminases and alterations in multiple metabolic pathways. The time of GTE oral administration relative to APAP either protected against or potentiated the APAP-induced hepatotoxicity. Dose dependent decreases in histopathology scores and serum transaminases were noted when GTE was administered prior to APAP; whereas, the opposite occurred when GTE was administered after APAP. Similarly, metabolites altered by APAP alone were less changed when GTE was given prior to APAP. Significantly altered pathways included fatty acid metabolism, glycerophospholipid metabolism, glutathione metabolism, and energy pathways. These studies demonstrate the complex interaction between GTE and APAP and the need to employ novel analytical strategies to understand the effects of dietary supplements on pharmaceutical compounds.

  1. Antioxidant and Hepatoprotective Efficiency of Selenium Nanoparticles Against Acetaminophen-Induced Hepatic Damage.

    Science.gov (United States)

    Amin, Kamal Adel; Hashem, Khalid Shaban; Alshehri, Fawziah Saleh; Awad, Said T; Hassan, Mohammed S

    2017-01-01

    Overdoses of acetaminophen (APAP), a famous and widely used drug, may have hepatotoxic effects. Nanoscience is a novel scientific discipline that provides specific tools for medical science problems including using nano trace elements in hepatic diseases. Our study aimed to assess the hepatoprotective role of selenium nanoparticles (Nano-Se) against APAP-induced hepatic injury. Twenty-four male rats were classified into three equal groups: a control group that received 0.9 % NaCl, an APAP-treated group (oral administration), and a group treated with Nano-Se (10-20 nm, intraperitoneal (i.p.) injection) and APAP (oral administration). APAP overdose induced significant elevations in liver function biomarkers, hepatic lipid peroxidation, hepatic catalase, and superoxide dismutase (SOD), decreased the reduced glutathione (GSH) content and glutathione reductase (GR) activity, and stimulated significant DNA damage in hepatocytes, compared to control rats. Nano-Se administration improved the hepatic antioxidant protection mechanism and decreased cellular sensitivity to DNA fragmentation. Nano-Se exhibits a protective effect against APAP-induced hepatotoxicity through improved liver function and oxidative stress mediated by catalase, SOD, and GSH and decreases hepatic DNA fragmentation, a hepatic biomarker of cell death. Nano-Se could be a novel hepatoprotective strategy to inhibit oxidative stress.

  2. Hepatoprotective effects of Paeonia anomala against acetaminophen-induced cell damage through activation of anti-oxidant system

    Directory of Open Access Journals (Sweden)

    O Sarangerel

    2014-10-01

    Full Text Available Overdose of the analgesic and anti-pyretic acetaminophen causes a potentially fatal hepatic necrosis due to a high toxicity and depletion of cellular defense mechanisms. In the present work, the potential hepatoprotective effect of the fruit extract of Paeonia anomala against acetaminophen induced cell damages was evaluated in cultured HepG2 cells and compared to the root extract. The fruit extract showed a potent protection against acetaminophen induced cell death, while the root extract showed a weak protection. Particularly, the pre-treatment of lower doses of the fruit extract, 10 μg/ mL and 20 μg/mL, significantly enhanced cell viability. The level of total glutathione in HepG2 cells treated with the fruit extract prior to the treatment of 40 mM acetaminophen was enhanced, however, the root extract failed for this activity. In addition, activities of quinone reductase, glutathione peroxidase and glutathione reductase were increased and protein levels of glutathione peroxidase 1 and superoxide dismutase 1 were enhanced in the cells treated with 10-20 μg/mL of the fruit extract. Furthermore, the protein level of Nrf2, a crucial regulator for detoxifying and antioxidant systems, was increased by the fruit extract treatment. These results suggest that the fruit extract of P. anomala exerts protective effects against acetaminophen-induced toxicity through activation of key antioxidant systems.DOI: http://dx.doi.org/10.5564/mjc.v14i0.190 Mongolian Journal of Chemistry 14 (40, 2013, p.5-11

  3. Desferrioxamine attenuates minor lung injury following surgical acute liver failure.

    Science.gov (United States)

    Kostopanagiotou, G G; Kalimeris, K A; Arkadopoulos, N P; Pafiti, A; Panagopoulos, D; Smyrniotis, V; Vlahakos, D; Routsi, C; Lekka, M E; Nakos, G

    2009-06-01

    Acute liver failure (ALF) can be complicated by lung dysfunction. The aim of this study was to test the hypothesis that inhibition of oxidative stress through iron chelation with desferrioxamine (DFX) attenuates pulmonary injury caused by ALF. 14 adult female domestic pigs were subjected to surgical devascularisation of the liver and were randomised to a study group (DFX group, n = 7), which received post-operative intravenous infusion of DFX (14.5 mg x kg(-1) x h(-1) for the first 6 h post-operatively and 2.4 mg x kg(-1) x h(-1) until completion of 24 h), and a control group (n = 7). Post-operative lung damage was evaluated by histological and bronchoalveolar lavage fluid (BALF) analysis. DFX resulted in reduced BALF protein levels and tissue phospholipase (PL)A(2) activity. Plasma malondialdehyde and BALF nitrate and nitrite concentrations were lower, while catalase activity in the lung was higher after DFX treatment. PLA(2), platelet-activating factor acetylhydrolase and total cell counts in BALF did not differ between groups. Histological examination revealed reduced alveolar collapse, pneumonocyte necrosis and total lung injury in the DFX-treated animals. DFX reduced systemic and pulmonary oxidative stress during ALF. The limited activity of PLA(2) and the attenuation of pneumonocyte necrosis could represent beneficial mechanisms by which DFX improves alveolar-capillary membrane permeability and prevents alveolar space collapse.

  4. Ischemia-Reperfusion Injury and Ischemic-Type Biliary Lesions following Liver Transplantation

    Directory of Open Access Journals (Sweden)

    Raffaele Cursio

    2012-01-01

    Full Text Available Ischemia-reperfusion (I-R injury after liver transplantation (LT induces intra- and/or extrahepatic nonanastomotic ischemic-type biliary lesions (ITBLs. Subsequent bile duct stricture is a significant cause of morbidity and even mortality in patients who underwent LT. Although the pathogenesis of ITBLs is multifactorial, there are three main interconnected mechanisms responsible for their formation: cold and warm I-R injury, injury induced by cytotoxic bile salts, and immunological-mediated injury. Cold and warm ischemic insult can induce direct injury to the cholangiocytes and/or damage to the arterioles of the peribiliary vascular plexus, which in turn leads to apoptosis and necrosis of the cholangiocytes. Liver grafts from suboptimal or extended-criteria donors are more susceptible to cold and warm I-R injury and develop more easily ITBLs than normal livers. This paper, focusing on liver I-R injury, reviews the risk factors and mechanisms leading to ITBLs following LT.

  5. [The Correlation Between MicroRNAs in Serum and the Extent of Liver Injury].

    Science.gov (United States)

    Zuo, Yi-Nan; He, Xue-Ling; Shi, Xue-Ni; Wei, Shi-Hang; Yin, Hai-Lin

    2017-05-01

    To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS). The acute liver injury model in rat by CCl4 (1.5 mL/kg), and the acute liver injury model in mice by APAP (160 mg/kg) were established. The serum at different time points on both models were collected respectively. The absolute quantification of microRNAs in serum were detected by using MiRbay(TM) SV miRNA Assay kit. Meanwhile, the pathological sections of liver tissue of the mice at each time point were collected to analyze the correlation between microRNAs and the degree of liver injury. In CCl4-induced rat acute liver injury model and APAP induced mouse acute liver injury, miR-122 and miR-192 appeared to be rising significantly, which remained the highest level at 24 h after treatment, and declined to the normal level after 72 h. In CCl4-induced rat acute liver injury model, the change of miR-92a was fluctuated and had no apparent rules, miR-451 declined gradually, but not obviously. In mice acute liver injury model induced by APAP, miR-92a and miR-451 in the progress of liver injury declined gradually, reached the lowest point at 48 h, and then recovered. The result of correlation analysis indicated that miR-122 and miR-192 presented a good positive correlation with the DILI-PSS ( r=0.741 3, Pcorrelation with DILI-PSS in APAP-induced liver injury models.

  6. Effect of leflunomide on immunological liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hong-Wei Yao; Jun Li; Yong Jin; Yun-Fang Zhang; Chang-Yu Li; Shu-Yun Xu

    2003-01-01

    AIM: To study the effect of leflunomide on immunologicalliver injury (ILI) in mice.METHODS: ILI was induced by tail vein injection of 2.5 mgBacilluS Calmette-Guerin (BCG), and 10 d later with :L0 μglipopolysaccharide (LPS) in 0.2 mL saline (BCG+LPS). Thealanine aminotransferase (ALT), aspartate aminotransferase(ASr), nitric oxide (NO) level in plasma and molondiadehyde(MDA), glutathione peroxidase (GSHpx) in liver homogenatewere assayed by spectroscopy. The serum content of tumornecrosis factors-α (TNF-α) was determined by ELISA.Interleukin-1 (IL-1), interleukin-2 (IL-2) and ConcanavalinA (ConA)-induced splenocyte proliferation response weredetermined by methods of 3H-infiltrated cell proliferation.RESULTS: Leflunomide (4, 12, 36 mg@kg-1) was found tosignificantly decrease the serum transaminase (ALT, AST)activity and MDA content in liver homogenate, and improvereduced GSHpx level of liver homogenate. Leflunomide (4,12, 36 mg@kg-1) significantly lowered TNF-α and NO level inserum, and IL-1 produced by intraperitoneal macrophagesinduced splenocyte proliferation response were furtherinhibited.CONCLUSION: These findings suggested that leflunomidehad significant protective action on ILI in mice.

  7. NRF2 Protection against Liver Injury Produced by Various Hepatotoxicants

    Directory of Open Access Journals (Sweden)

    Jie Liu

    2013-01-01

    Full Text Available To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd and Keap1-hepatocyte knockout (Keap1-HKO mice were used as a “graded Nrf2 activation” model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant. Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, bromobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1β, IL-6, and TNFα, oxidative stress genes (Ho-1, Egr1, ER stress genes (Gadd45 and Gadd153, and genes encoding cell death (Noxa, Bax, Bad, and caspase3. Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.

  8. Normothermic machine perfusion reduces bile duct injury and improves biliary epithelial function in rat donor livers.

    Science.gov (United States)

    Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

    2016-07-01

    Bile duct injury may occur during liver procurement and transplantation, especially in livers from donation after circulatory death (DCD) donors. Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury compared to static cold storage (SCS). However, it is unknown whether NMP provides better preservation of bile ducts. The aim of this study was to determine the impact of NMP on bile duct preservation in both DCD and non-DCD livers. DCD and non-DCD livers obtained from Lewis rats were preserved for 3 hours using either SCS or NMP, followed by 2 hours ex vivo reperfusion. Biomarkers of bile duct injury (gamma-glutamyltransferase and lactate dehydrogenase in bile) were lower in NMP-preserved livers compared to SCS-preserved livers. Biliary bicarbonate concentration, reflecting biliary epithelial function, was 2-fold higher in NMP-preserved livers (P < 0.01). In parallel with this, the pH of the bile was significantly higher in NMP-preserved livers (7.63 ± 0.02 and 7.74 ± 0.05 for non-DCD and DCD livers, respectively) compared with SCS-preserved livers (7.46 ± 0.02 and 7.49 ± 0.04 for non-DCD and DCD livers, respectively). Scanning and transmission electron microscopy of donor extrahepatic bile ducts demonstrated significantly decreased injury of the biliary epithelium of NMP-preserved donor livers (including the loss of lateral interdigitations and mitochondrial injury). Differences between NMP and SCS were most prominent in DCD livers. Compared to conventional SCS, NMP provides superior preservation of bile duct epithelial cell function and morphology, especially in DCD donor livers. By reducing biliary injury, NMP could have an important impact on the utilization of DCD livers and outcome after transplantation. Liver Transplantation 22 994-1005 2016 AASLD.

  9. Normothermic Machine Perfusion Reduces Bile Duct Injury and Improves Biliary Epithelial Function in Rat Donor Livers

    NARCIS (Netherlands)

    Op den Dries, Sanna; Karimian, Negin; Westerkamp, Andrie C; Sutton, Michael E; Kuipers, Michiel; Wiersema-Buist, Janneke; Ottens, Petra J; Kuipers, Jeroen; Giepmans, Ben N; Leuvenink, Henri G D; Lisman, Ton; Porte, Robert J

    BACKGROUND: Bile duct injury may occur during liver procurement and transplantation, especially in livers donated after circulatory death (DCD). Normothermic machine perfusion (NMP) has been shown to reduce hepatic injury, compared to static cold storage (SCS). However, it is unknown whether NMP

  10. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    Science.gov (United States)

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  11. Signaling mechanisms in alcoholic liver injury: Role of transcription factors,kinases and heat shock proteins

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Alcoholic liver injury comprises of interactions of various intracellular signaling events in the liver. Innate immune responses in the resident Kupffer cells of the liver, oxidative stress-induced activation of hepatocytes,fibrotic events in liver stellate cells and activation of liver sinusoidal endothelial cells all contribute to alcoholic liver injury. The signaling mechanisms associated with alcoholic liver injury vary based on the cell type involved and the extent of alcohol consumption. In this review we will elucidate the oxidative stress and signaling pathways affected by alcohol in hepatocytes and Kupffer cells in the liver by alcohol. The toll-like receptors and their down-stream signaling events that play an important role in alcohol-induced inflammation will be discussed. Alcohol-induced alterations of various intracellular transcription factors such as NFκB, PPARs and AP-1, as well as MAPK kinases in hepatocytes and macrophages leading to induction of target genes that contribute to liver injury will be reviewed. Finally, we will discuss the significance of heat shock proteins as chaperones and their functional regulation in the liver that could provide new mechanistic insights into the contributions of stress-induced signaling mechanisms in alcoholic liver injury.

  12. Accuracy of the AAST organ injury scale for CT evaluation of traumatic liver and spleen injuries

    Directory of Open Access Journals (Sweden)

    Homann Georg

    2014-02-01

    Full Text Available 【Abstract】Objective: Detection of abdominal injury is a very important component in trauma management, so a precise assessment of liver and spleen injuries including their severity degree is necessary. There is a good case to believe that in emergency situations the radiologists’ performance may profit from a systematic approach using established scoring systems. Score systems as the organ injury scale (OIS drawn up by the American Association for the Surgery of Trauma are a valuable guidance for objective trauma assessment. Aim of this study was to evaluate retrospectively whether a structured approach using the OIS may help improve trauma assessment. Methods: Fifty-three patients, 38 male and 15 female who underwent CT and laparotomy after abdominal trauma were included in this study. The laparotomy was performed by experienced surgeons with a minimum experience of 6 years. While the original CT reports were written by different radiologists with a minimum experience of 3 years, and then a radiologist with experience of 4 years reviewed the same original CT pictures, resulting in the structured report. Both the original and structured CT results on liver and spleen injuries were transferred into OIS grades. Finally, the initial and structured CT results were compared with the intraoperative findings gathered from the surgery report. Results: Regarding the original CT report we found a mean divergence of 0.68±0.8 (r=0.45 to the OIS finding in the surgery report for liver injuries (0.69±1.17 for spleen injuries; r=0.69. In comparison with the structured approach, where we detected a divergence of 0.8±0.68; r=0.63 (0.47±0.77 for spleen injuries; r=0.91, there was no significant difference. However we detected a lower rate of over-diagnosis in structured approaches. Conclusion: Our study shows that a structured approach to triage abdominal trauma using an imaging check- list does not lead to a significantly higher detection rate, but a

  13. A monkey model of acetaminophen-induced hepatotoxicity; phenotypic similarity to human.

    Science.gov (United States)

    Tamai, Satoshi; Iguchi, Takuma; Niino, Noriyo; Mikamoto, Kei; Sakurai, Ken; Sayama, Ayako; Shimoda, Hitomi; Takasaki, Wataru; Mori, Kazuhiko

    2017-01-01

    Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

  14. Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.

    Science.gov (United States)

    Tran, A; Tréluyer, J M; Rey, E; Barbet, J; Ferracci, G; d'Athis, P; Vincent, J; Pons, G

    2001-02-01

    Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.

  15. Apoptotic cell death as a target for the treatment of acute and chronic liver injury

    NARCIS (Netherlands)

    Schoemaker, Marieke Henriëtte

    2004-01-01

    Acute liver failure can develop as a consequence of viral hepatitis, drug- or toxin-induced toxicity or rejection after liver transplantation, whereas chronic liver injury can be due to long-term exposure to alcohol, chemicals, chronic viral hepatitis, metabolic or cholestatic disorders. During acut

  16. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity.

    Science.gov (United States)

    Jin, Fen; Wan, Chunpeng; Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity.

  17. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity

    Science.gov (United States)

    Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity. PMID:28234915

  18. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

    Energy Technology Data Exchange (ETDEWEB)

    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya; Okada, Norihiko; Yoshida, Saori; Yamamoto, Junya; Ohkubo, Rika [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Abiko, Yumi [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Yamada, Hidenori [Jobu Hospital for Respiratory Diseases, Maebashi 371-0048 (Japan); Akahoshi, Noriyuki [Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543 (Japan); Kasahara, Tadashi [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan); Kumagai, Yoshito [Environmental Biology Laboratory, School of Medicine, University of Tsukuba, Ibaraki 305-8575 (Japan); Ishii, Isao, E-mail: isao-ishii@umin.ac.jp [Department of Biochemistry, Keio University School of Pharmaceutical Sciences, Tokyo 105-8512 (Japan)

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/−}, and

  19. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein

    Directory of Open Access Journals (Sweden)

    Kopylchuk G.P.

    2015-09-01

    Full Text Available Background. Acetaminophen is known as inducer of acute hepatotoxicity. Extrahepatic manifestations of acetaminophen toxicity are poorly understood in particular its nephrotoxicity. Objective. The purpose of this study was the morphological characteristic of rat kidneys under the conditions of acetaminophen-induced nephrotoxicity on the background of alimentary deprivation of protein. Methods. Аfter administration of the toxic dose of acetaminophen and maintenance of rats on a different regimen of protein nutrition their kidneys were sectioned and stained with hematoxylin and eosin according to a standard technique. Results. It was estimated, that in rats maintained during long period of time under the conditions of alimentary deprivation of protein, and in rats injected with toxic dose of acetaminophen morphological changes of kidney were not observed. Administration of acetaminophen on the background of previous protein deficiency causes the pathological changes of kidney morphology with papillary necrosis as a key sign. Conclusion. Alimentary deprivation of protein in case of acetaminophen injection is the critical factor for the impairment of structural integrity of kidney tissue with its subsequent dysfunction. Citation: Kopylchuk GP, Voloshchuk ON, Buchkovskaia IM, Davydenko IS. [Morphological characteristic of rats’ kidneys under the conditions of acetaminophen-induced nephrotoxicity against the background alimentary deprivation of protein]. Morphologia. 2015;9(3:28-30. Russian.

  20. Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G.

    Science.gov (United States)

    Abdelaziz, Heba A; Shaker, Mohamed E; Hamed, Mohamed F; Gameil, Nariman M

    2017-06-05

    The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Revisiting acute liver injury associated with herbalife products.

    Science.gov (United States)

    Appelhans, Kristy; Smith, Casey; Bejar, Ezra; Henig, Y Steve

    2011-10-27

    In the November 27, 2010 issue of the World Journal of Hepatology (WJH), three case reports were published which involved patients who had consumed various dietary supplements and conventional foods generally marketed as weight loss products. The reference to Herbalife products as contaminated and generally comparable to all dietary supplements or weight loss products is not scientifically supported. The authors provided an insufficient amount of information regarding patient histories, concomitant medications and other compounds, dechallenge results, and product specifications and usage. This information is necessary to fully assess the association of Herbalife products in the WJH case reports. Therefore, the article does not objectively support a causal relationship between the reported cases of liver injury and Herbalife products or ingredients.

  2. HIFU Hemostasis of Liver Injuries Enhanced by Ultrasound Contrast Agents

    Science.gov (United States)

    Zderic, Vesna; Vaezy, Shahram; Brayman, Andrew A.; Matula, Thomas J.; O'Keefe, Grant E.; Crum, Lawrence A.

    2005-03-01

    Our objective was to investigate whether High-Intensity Focused Ultrasound (HIFU) hemostasis can be achieved faster in the presence of ultrasound contrast agents (UCA). Incisions (3 cm long and 0.5 cm deep) were made in surgically exposed rabbit liver. Optison at a concentration of 0.18 ml/kg was injected into the mesenteric vein, immediately before the incision was made. The HIFU applicator (frequency of 5.5 MHz, and intensity of 3,700 W/cm2) was scanned manually over the incision (at an approximate rate of 1 mm/s) until hemostasis was achieved. The times to complete hemostasis were measured and normalized with the initial blood loss. The hemostasis times were 59±23 s in the presence of Optison and 70±23 s without Optison. The presence of Optison produced a 37% reduction in the normalized hemostasis times (phemostasis of internal organ injuries.

  3. Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen-induced toxicity in humans.

    Science.gov (United States)

    Thiel, C; Cordes, H; Baier, V; Blank, L M; Kuepfer, L

    2017-02-01

    Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level. The results provide new insights into the inhibitory and stimulatory effects of CAF on APAP-induced hepatotoxicity for crucially affected key cellular processes and individual genes at the patient level. This study might facilitate the risk assessment of drug combination therapies in humans and thus may improve patient safety in clinical practice. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  4. The Molecular Circadian Clock and Alcohol-Induced Liver Injury.

    Science.gov (United States)

    Udoh, Uduak S; Valcin, Jennifer A; Gamble, Karen L; Bailey, Shannon M

    2015-10-14

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  5. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  6. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  7. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Hadi, Mackenzie; Laarakkers, Coby M. M.; Masereeuw, Rosalinde; Groothuis, Geny M. M.; Russel, Frans G. M.

    2014-01-01

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker ide

  8. Hepatic pseudoaneurysm after traumatic liver injury; is CT follow-up warranted?

    DEFF Research Database (Denmark)

    Østerballe, Lene; Helgstrand, Frederik; Axelsen, Thomas

    2014-01-01

    INTRODUCTION: Hepatic pseudoaneurysm (HPA) is a rare complication after liver trauma, yet it is potentially fatal, as it can lead to sudden severe haemorrhage. The risk of developing posttraumatic HPA is one of the arguments for performing follow-up CT of patients with liver injuries. The aim...... no treatment failures. There was no correlation between the severity of the liver injury and development of HPA. 5 out of 7 patients were asymptomatic and would have been discharged without treatment if the protocol did not include a default follow-up CT. CONCLUSIONS: In conclusion, this study shows that HPA...... is not correlated to the severity of liver injury and it develops in 4% of patients after traumatic liver injury. In order to avoid potentially life-threatening haemorrhage from a post trauma hepatic pseudoaneurysm, it seems appropriate to do follow-up CT as part of the conservative management of blunt...

  9. Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Mei Liu

    2014-01-01

    Full Text Available Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by D-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.

  10. Freshly isolated hepatocyte transplantation in acetaminophen-induced hepatotoxicity model in rats Transplante de hepatócitos recém-isolados em um modelo de hepatotoxicidade induzida por acetaminofeno em ratos

    Directory of Open Access Journals (Sweden)

    Daniela Rodrigues

    2012-12-01

    Full Text Available CONTEXT: Hepatocyte transplantation is an attractive therapeutic modality for liver disease as an alternative for orthotopic liver transplantation. OBJECTIVE: The aim of the current study was to investigate the feasibility of freshly isolated rat hepatocyte transplantation in acetaminophen-induced hepatotoxicity model. METHODS: Hepatocytes were isolated from male Wistar rats and transplanted 24 hours after acetaminophen administration in female recipients. Female rats received either 1x10(7 hepatocytes or phosphate buffered saline through the portal vein or into the spleen and were sacrificed after 48 hours. RESULTS: Alanine aminotransferase levels measured within the experiment did not differ between groups at any time point. Molecular analysis and histology showed presence of hepatocytes in liver of transplanted animals injected either through portal vein or spleen. CONCLUSION: These data demonstrate the feasibility and efficacy of hepatocyte transplantation in the liver or spleen in a mild acetaminophen-induced hepatotoxicity model.CONTEXTO: O transplante de hepatócitos é uma modalidade terapêutica atrativa para doenças hepáticas como alternativa ao transplante hepático ortotópico. OBJETIVO: Investigar a factibilidade do uso de hepatócitos frescos isolados de ratos em um modelo de hepatotoxicidade induzida por paracetamol. MÉTODOS: Hepatócitos foram isolados de ratos Wistar machos e transplantados 24 horas após a administração de paracetamol em receptores fêmeas. As ratas receberam 1x10(7 hepatócitos ou tampão salina fosfato pela veia porta ou no baço e foram sacrificadas após 48 horas. RESULTADOS: Os níveis de alanina aminotransferase medidos durante o experimento não diferiram entre os grupos em nenhum momento. Análises moleculares e histológicas demonstraram a presença de hepatócitos no fígado dos animais transplantados pelo baço ou pela veia porta. CONCLUSÃO: Os dados indicam a factibilidade e eficácia do

  11. Role of transcription factor Egr-1 in liver injury following hemorrhagic shock and resuscitation

    Institute of Scientific and Technical Information of China (English)

    MEI Jian-min; Timothy R. Billiar; YU Cong-hui; David J. Gallo; YANG Rong-hua; LIU Sha-lei

    2005-01-01

    Objective: To investigate the role of transcription factor Egr-1 in liver injury following hemorrhagic shock (HS) /resuscitation (R). Methods: Both Egr-1 knockout (KO) and wild-type (WT) mice were subjected to HS and HSR injuries. The expressions of TNF-α, IL-6, G-CSF and ICAM-1 mRNAs in the liver were examined by RT-PCR, and their serum levels were measured by ELISA. The liver inflammatory infiltration and liver injury in both Egr-1 WT and KO mice following HS/R were evaluated by liver MPO content, serum ALT level and histological examination. Results: Egr-1 inhibition resulted in less mRNA expression of TNF-α, IL-6 , G-CSF and ICAM-1 in the liver, and lower serum levels of TNF-α, IL-6, G-CSF and ICAM-1 antigens in Egr-1 KO mice following HS/R. The liver inflammatory infiltration and liver injury were less severe in Egr-1 KO mice following HS/R, as evidenced by lower serum ALT level, lower hepatic MPO content and histological manifestations. Conclusion: Our data suggest that transcription factor Egr-1 is involved in regulating the expression of inflammatory response genes and plays a role in liver injury following HS/R.

  12. Characterization of chemically induced liver injuries using gene co-expression modules.

    Directory of Open Access Journals (Sweden)

    Gregory J Tawa

    Full Text Available Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20% genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.

  13. Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

    Science.gov (United States)

    Tawa, Gregory J.; AbdulHameed, Mohamed Diwan M.; Yu, Xueping; Kumar, Kamal; Ippolito, Danielle L.; Lewis, John A.; Stallings, Jonathan D.; Wallqvist, Anders

    2014-01-01

    Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules) specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1) known biochemical pathways associated with liver injuries and 2) clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20%) genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects. PMID:25226513

  14. Warm ischemic injury is reflected in the release of injury markers during cold preservation of the human liver.

    Directory of Open Access Journals (Sweden)

    Bote G Bruinsma

    Full Text Available Liver transplantation plays a pivotal role in the treatment of patients with end-stage liver disease. Despite excellent outcomes, the field is strained by a severe shortage of viable liver grafts. To meet high demands, attempts are made to increase the use of suboptimal livers by both pretransplant recovery and assessment of donor livers. Here we aim to assess hepatic injury in the measurement of routine markers in the post-ischemic flush effluent of discarded human liver with a wide warm ischemic range.Six human livers discarded for transplantation with variable warm and cold ischemia times were flushed at the end of preservation. The liver grafts were flushed with NaCl or Lactated Ringer's, 2 L through the portal vein and 1 L through the hepatic artery. The vena caval effluent was sampled and analyzed for biochemical markers of injury; lactate dehydrogenase (LDH, alanine transaminase (ALT, and alkaline phosphatase (ALP. Liver tissue biopsies were analyzed for ATP content and histologically (H&E examined.The duration of warm ischemia in the six livers correlated significantly to the concentration of LDH, ALT, and ALP in the effluent from the portal vein flush. No correlation was found with cold ischemia time. Tissue ATP content at the end of preservation correlated very strongly with the concentration of ALP in the arterial effluent (P<0.0007, R2 = 0.96.Biochemical injury markers released during the cold preservation period were reflective of the duration of warm ischemic injury sustained prior to release of the markers, as well as the hepatic energy status. As such, assessment of the flush effluent at the end of cold preservation may be a useful tool in evaluating suboptimal livers prior to transplantation, particularly in situations with undeterminable ischemic durations.

  15. Moringa oleifera hydroethanolic extracts effectively alleviate acetaminophen-induced hepatotoxicity in experimental rats through their antioxidant nature.

    Science.gov (United States)

    Fakurazi, Sharida; Sharifudin, Syazana Akmal; Arulselvan, Palanisamy

    2012-07-10

    The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO) extracts and its curative role in acetaminophen (APAP)-induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p) were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT) and the levels of oxidative damage markers including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) protein adduct, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05) reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use.

  16. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury.

    Science.gov (United States)

    Schaub, Johanna R; Malato, Yann; Gormond, Coralie; Willenbring, Holger

    2014-08-21

    Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  17. Evidence against a Stem Cell Origin of New Hepatocytes in a Common Mouse Model of Chronic Liver Injury

    Directory of Open Access Journals (Sweden)

    Johanna R. Schaub

    2014-08-01

    Full Text Available Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.

  18. Protective effect of salvianolate on lung injury induced by ischemia reperfusion injury of liver in mice

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

    Full Text Available Objective To evaluate the protective effect of salvianolate on lung injury induced by hepatic ischemia reperfusion(IR injury in mice and its underlying mechanisms.Methods A hepatic IR model of mice was reproduced,and 24 animals were assigned into 3 groups(8 each: sham operation(SO group,control group and salvianolate(SV group.Just before ischemia induction,animals in SV group received salvianolate injection at a dose of 60 mg/kg via tail vein,while in control group the mice received normal saline with an equal volume,and in SO group the mice received the same operation as in SV group but without producing liver ischemia.Four hours after reperfusion,the serum,liver and lung tissue were collected.The alanine aminotransferase(ALT and aspartate aminotransferase(AST levels in serum were detected and the histological changes in liver and lung were examined.The wet-to-dry weight ratio of pulmonary tissue was measured.The contents of tumor necrosis factor α(TNF-α,interleukin(IL-6,IL-1β and IL-10 in bronchoalveolar lavage fluid(BALF were detected by enzyme linked immunosorbent assay(ELISA,and the relative mRNA levels of TNF-α,IL-6,IL-1β and IL-10 in pulmonary tissue were analyzed by real-time reverse transcription PCR(RT-PCR.The activaty of transcription factor NF-κB was measured with Western blotting analysis.Results No significant pathologic change was found in mice of SO group.Compared with the mice in control group,those in SV group exhibited lower levels of ALT and AST(P < 0.01,lighter histological changes in liver and lung(P < 0.05,lower levels of wet-to-dry weight ratio of lung tissue(P < 0.05,lower expression levels of TNF-α,IL-6,IL-1β and IL-10 in BALF and lung tissue(P < 0.05 or P < 0.01.Further examination demonstrated that the activity of NF-κB in SV group was significantly down-regulated as compared with that in control group.Conclusion Salvianolate can attenuate lung injury induced by hepatic IR in mice,the mechanism may inclade

  19. Bupivacaine drug-induced liver injury: a case series and brief review of the literature.

    Science.gov (United States)

    Chintamaneni, Preethi; Stevenson, Heather L; Malik, Shahid M

    2016-08-01

    Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaine-induced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic.

  20. Acute Liver Injury with Severe Coagulopathy in Marasmus Caused by a Somatic Delusional Disorder

    Directory of Open Access Journals (Sweden)

    Lance L. Stein

    2011-01-01

    Full Text Available Marasmus is a severe form of protein-calorie malnutrition characterized by the depletion of fat stores, muscle wasting, and the lack of edema. In developed countries, marasmus is often the result of anorexia nervosa. Abnormal transaminases with liver synthetic dysfunction have rarely been reported with anorexia nervosa. To our knowledge, we report the first detailed case of acute liver injury with severe coagulopathy (INR>1.5 in a patient with marasmus due to self-induced calorie restriction caused by a somatic delusional disorder. This case highlights the severity of liver injury that may occur with significant weight loss from self-induced calorie restriction and the rapid normalization of this injury with treatment. It is important for clinicians to be aware of patterns of acute liver injury in patients with severe protein-calorie malnutrition, regardless of the underlying cause.

  1. anti-retroviral therapy related liver injury (arli): a series of 11 cases

    African Journals Online (AJOL)

    2013-12-02

    Dec 2, 2013 ... Risk factors for liver injury should be evaluated ... Weight (Kg) using a Salter weighing scale and height (Cms) ... ascertain other risk factors which affect ART related ..... associated with an increased propensity to develop.

  2. Liver Injury from Herbal, Dietary, and Weight Loss Supplements: a Review.

    Science.gov (United States)

    Zheng, Elizabeth X; Navarro, Victor J

    2015-06-28

    Herbal and dietary supplement usage has increased steadily over the past several years in the United States. Among the non-bodybuilding herbal and dietary supplements, weight loss supplements were among the most common type of HDS implicated in liver injury. While drug induced liver injury is rare, its consequences are significant and on the rise. The purpose of this review is to highlight case reports of weight loss products such as Hydroxycut and OxyElite Pro as one form of HDS that have hepatotoxic potential and to characterize its clinical effects as well as pattern of liver injury. We also propose future strategies in the identification and study of potentially hepatotoxic compounds in an effort to outline a diagnostic approach for identifying any drug induced liver injury.

  3. Pretreatment with TCDD exacerbates liver injury from Concanavalin A: critical role for NK cells.

    Science.gov (United States)

    Fullerton, Aaron M; Roth, Robert A; Ganey, Patricia E

    2013-11-01

    For many liver diseases, including viral and autoimmune hepatitis, immune cells play an important role in the development and progression of liver injury. Concanavalin A (Con A) administration to rodents has been used as a model of immune-mediated liver injury resembling human autoimmune hepatitis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to alter the development of immune-mediated diseases. Mice pretreated with TCDD developed exacerbated liver injury in response to administration of a mild dose (6 mg/kg) of Con A. In the present study, we tested the hypothesis that TCDD pretreatment exacerbates Con A-induced liver injury by enhancing the activation and recruitment of accessory cell types including neutrophils, macrophages, and natural killer (NK) cells. Mice were treated with 0, 0.3, 3, or 30 μg/kg TCDD and 4 days later with Con A or saline. TCDD pretreatment with doses of 3 and 30 μg/kg significantly increased liver injury from Con A administration. The plasma concentrations of neutrophil chemokines were significantly increased in TCDD-pretreated mice after Con A administration. NKT cell-deficient (CD1d KO) mice were used to examine whether NKT cells were required for TCDD/Con A-induced liver injury. CD1d KO mice were completely protected from liver injury induced by treatment with Con A alone, whereas the injury from TCDD/Con A treatment was reduced but not eliminated. However, T-cell deficient (RAG1 KO) mice were protected from liver injury induced by Con A irrespective of pretreatment with TCDD. TCDD/Con A treatment increased the percentage of NK cells expressing the activation marker CD69. Depletion of NK cells prior to treatment resulted in significant reductions in plasma interferon-γ and liver injury from TCDD/Con A treatment. In summary, exposure to TCDD exacerbated the immune-mediated liver injury induced by Con A, and our findings suggest that NK cells play a critical role in this response.

  4. Interaction between nitric oxide synthase and cyclooxygenase in the development of acetaminophen-induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Meltem Kolgazi

    2015-03-01

    Results: AG and KET prevented the increase in liver malondialdehyde levels due to APAP toxicity. Decreased liver glutathione in APAP group was prevented by all treatments except NIM. Stimulated liver myeloperoxidase activity in APAP group was attenuated by all treatments except INDO and NIM. Elevation of liver chemiluminescence, nuclear factor (NF- and #61547;B expression and serum alanine transferase level due to APAP overdose were also suppressed by all treatments. Conclusions: NOS and COX pathways interact in the development of hepatotoxicity due to APAP overdose. [J Exp Integr Med 2015; 5(1.000: 16-22

  5. Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR.

    Science.gov (United States)

    Kanno, Syu-ichi; Tomizawa, Ayako; Yomogida, Shin

    2016-01-01

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Drug-induced liver injury from agents such as APAP is known to vary between individuals within a species. To avoid liver injury and ensure the proper use of pharmaceutical products, it is important to be able to predict such risks using genetic information. This study evaluated the use of quantitative real-time polymerase chain reaction (RT-qPCR) to identify mRNAs (carried in the blood of male ddY mice) capable of predicting susceptibility to APAP-induced hepatotoxicity. Screening was performed on samples obtained at 18 h after treatment from mice that had been orally treated with 500 mg/kg APAP. APAP-induced hepatotoxicity was seen in 60% of the mice, and the mortality rate was 12%. Blood APAP concentration did not differ significantly between mice with and without APAP-induced hepatotoxicity. We compared blood mRNA expression levels between mice with (positive, serious or lethal injury) and without hepatotoxicity in the APAP-treated group. The transcript levels of interleukin-encoding loci Il1β, Il10, and tumor necrosis factor (Tnf) were increased in the lethal injury group. Transcripts of the loci encoding transthyretin (Ttr) and metallothionein 1 (Mt1) showed increases in the liver injury group, while those of the glutathione peroxidase 3-encoding locus (Gpx3) were decreased. APAP hepatotoxicity was potentiated in fasted animals, although fasting did not appear to affect the level of expression of these genes. These results indicate that mRNA expression of Il1β, Il10, Tnf, Ttr, Mt1, and Gpx3 in mouse blood may provide useful surrogate markers of APAP-induced hepatotoxicity.

  6. Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh

    Directory of Open Access Journals (Sweden)

    Grace Guzman

    2009-01-01

    Full Text Available There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa, an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease. Their liver biopsies showed a component of centrilobular necrosis consistent with severe drug-induced liver injury. In addition, the biopsies showed characteristics of autoimmune-like liver injury with an interface hepatitis dominated by plasma cells. Although serum markers for autoimmune hepatitis were not particularly elevated, both patients responded to corticosteroids, supporting an immune-mediated component to the liver injury. Liver injury following the use of black cohosh should be included in the list of differential diagnoses for chronic hepatitis with features mimicking autoimmune hepatitis.

  7. Expression and significance of SOCS3 in liver tissue of rats with severe acute pancreatitis complicated by liver injury

    Directory of Open Access Journals (Sweden)

    Bin WANG

    2012-11-01

    Full Text Available Objective  To investigate the expression and mechanism of action of suppressor of cytokine signaling 3 (SOCS3 in liver tissue of rats with experimental severe acute pancreatitis (SAP concurring with liver injury. Methods  The rat model of SAP was reproduced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. Thirty-two male SD rats were randomly assigned into 4 groups (8 each: normal control group (NC, SAP 6h, 12h, and 18h groups. The levels of serum amylase (AMY, alanine aminotransferase (ALT and aspartate aminotransferase (AST were measured dynamically. The concentrations of IL -6 and IL -18 were determined by ELISA. The localization and expression of SOCS3 protein in liver were determined by immunohistochemical staining and Western blotting. Results  Compared with NC group, the serum levels of AMY, ALT and AST increased significantly in SAP groups (P < 0.05, and there was significant difference among SAP groups. The serum concentrations of IL-6 and IL-18 increased significantly in the SAP groups than in NC group (P < 0.05, and there was significant difference among SAP groups. Compared with NC group, the concentration of SOCS3 protein increased significantly in SAP groups, and increased gradually along with the increased duration of pancreatitis (P < 0.05. A minor expression of SOCS3 protein was found in NC group. The change in SOCS3 protein concentration was consistent with the severity of liver injury as well as the serum concentrations of IL-6 and IL-18. Conclusions  The inflammatory action induced by SAP concurring with liver injury may induce the expression of SOCS3 in liver tissue, and it may increase in intensity along with the severity of liver injury and inflammatory reaction. The mechanism may be attributed to a negative feedback regulation of the inflammatory action mediated by JAK/STAT pathway.

  8. The Roles of Innate Immune Cells in Liver Injury and Regeneration

    Institute of Scientific and Technical Information of China (English)

    Zhongjun Dong; Haiming Wei; Rui Sun; Zhigang Tian

    2007-01-01

    For predominant abundance with liver-specific Kupffer cells, natural killer (NK) cells, and natural killer T (NKT)cells and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features.In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A (Con A), lipopolysaccharide (LPS), or polyinosinic-polycytidylic acid (Poly I:C)-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.

  9. Low-dose ATRA Supplementation Abolishes PRM Formation in Rat Liver and Ameliorates Ethanol-induced Liver Injury

    Institute of Scientific and Technical Information of China (English)

    PAN Zhihong; DAN Zili; FU Yu; TANG Wangxian; LIN Jusheng

    2006-01-01

    The effects of all-trans-retinoic acid (ATRA) in low doses supplementation on concentrations of polar retinoid metabolites (PRM) and retinoids in the ethanol-fed rat liver, and on hepatocyte injury were investigated. The rat model of alcoholic liver disease (ALD) was induced by intragastric infusion of ethanol, and then the rats were administrated with ATRA in two different doses (150 μg/kg body weight and 1.5 mg/kg body weight) for 4 weeks. Concentrations of retinoids in rat liver and plasma were determined by using HPLC. Liver tissues pathologic changes were observed under the light microscopy and electron microscopy. The serum transaminases concentrations were measured. The results showed that the HPLC analysis of retinoids revealed that retinoids (vitamin A,RA, retinyl palmitate) concentrations in ethanol-fed rat liver and RA concentration in ethanol-fed rat plasma were markedly diminished (P<0.01) after ethanol feeding for 12 weeks. Furthermore, obvious peaks of PRM were formed in livers of ethanol-fed rats. ATRA 150 μg/kg supplementation in ethanol-fed rats for 4 weeks raised RA concentration in both liver and plasma, and also raised vitamin A concentration in liver to control levels, partially restored retinyl palmitate concentration (P<0.05) in liver. ATRA 1.5 mg/kg supplementation raised not only RA concentrations in liver and plasma but also retinyl palmitate concentrations in liver. However, the vitamin A concentration in liver of ATRA-supplemented rats (1.5 mg/kg) was higher than that of controls (P<0.05). The histologic observation of liver tissues indicated that ATRA treatment notably alleviated hepatocellular swelling,steatosis, the swelling of mitochondria and proliferation of smooth endoplasmic reticulum (SER).ATRA treatment greatly decreased levels of serum transaminases as compared with the only ethanol-fed group (P<0.05). It was concluded that low-dose ATRA treatment could restore retinoids concentrations and abolish the PRM formation

  10. Decoy receptor 3 analogous supplement protects steatotic rat liver from ischemia–reperfusion injury

    Directory of Open Access Journals (Sweden)

    Tzu-Hao Li

    2017-07-01

    Conclusion: Using multimodal in vivo and in vitro approaches, we found that DcR3a analogue was a potential agent to protect steatotic liver against IR injury by simultaneous blockade of the multiple IR injury-related pathogenic changes.

  11. Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model

    NARCIS (Netherlands)

    B.H.M. Heijnen; I.H. Straatsburg; N.D. Padilla; G.J. Mierlo; C.E. Hack; T.M. van Gulik

    2006-01-01

    Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 10

  12. Immune-mediated Liver Injury in Hepatitis B Virus Infection

    National Research Council Canada - National Science Library

    In Soo Oh; Su-Hyung Park

    2015-01-01

    Hepatitis B virus (HBV) is responsible for approximately 350 million chronic infections worldwide and is a leading cause of broad-spectrum liver diseases such as hepatitis, cirrhosis and liver cancer...

  13. Effect of adoptive transfer or depletion of regulatory T cells on triptolide-induced liver injury

    Directory of Open Access Journals (Sweden)

    Xinzhi eWang

    2016-04-01

    Full Text Available ObjectiveThe aim of this study is to clarify the role of regulatory T cell (Treg in triptolide (TP-induced hepatotoxicity. MethodsFemale C57BL/6 mice received either adoptive transfer of Tregs or depletion of Tregs, then underwent TP administration and were sacrificed 24 hours after TP administration. Liver injury was determined according to ALT and AST levels in serum and histopathological change in liver tissue. Hepatic frequencies of Treg cells and the mRNA expression levles of transcription factor FoxP3 and RORγt, IL-10, SOCS and Notch/Notch ligand were investigated.ResultsDuring TP-induced liver injury, hepatic Treg and IL-10 decreased, while Th17 cell transcription factor RORγt, SOCS signaling and Notch signaling increased, accompanied with liver inflammation. Adoptive transfer of Tregs ameliorated the severity of TP-induced liver injury, accompanied with increased levels of hepatic Treg and IL-10. Adoptive transfer of Tregs remarkably inhibited the expression of RORγt, SOCS3, Notch1 and Notch3. On the contrary, depletion of Treg cells in TP-administered mice resulted in a notable increase of RORγt, SOCS1, SOCS3 and Notch3, while the Treg and IL-10 of liver decreased. Consistent with the exacerbation of liver injury, higher serum levels of ALT and AST were detected in Treg-depleted mice. ConclusionsThese results showed that adoptive transfer or depletion of Tregs attenuated or aggravated TP-induced liver injury, suggesting that Tregs could play important roles in the progression of liver injury. SOCS proteins and Notch signaling affected Tregs, which may contribute to the pathogenesis of TP-induced hepatotoxicity.

  14. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jie, E-mail: JLiu@kumc.edu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Lu, Yuan-Fu [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Zunyi Medical College, Zunyi 563003 (China); Zhang, Youcai; Wu, Kai Connie [University of Kansas Medical Center, Kansas City, KS 66160 (United States); Fan, Fang [Cytopathology, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Klaassen, Curtis D. [University of Kansas Medical Center, Kansas City, KS 66160 (United States)

    2013-11-01

    Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential. - Highlights: • Oleanolic acid at higher doses and long-term use may produce liver injury. • Oleanolic acid increased serum ALT, ALP, bilirubin and bile acid concentrations. • OA produced feathery degeneration, inflammation and cell death in the liver. • OA altered bile acid homeostasis, affecting bile acid synthesis and transport.

  15. Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients.

    Science.gov (United States)

    Kondo, Kazuma; Yamada, Naohito; Suzuki, Yusuke; Toyoda, Kaoru; Hashimoto, Tatsuji; Takahashi, Akemi; Kobayashi, Akio; Shoda, Toshiyuki; Kuno, Hideyuki; Sugai, Shoichiro

    2012-01-01

    Acetaminophen (APAP) is a commonly used and effective analgesic and antipyretic agent. However, some patients encounter hepatotoxicity after repeated APAP dosing at therapeutic doses. In the present study, we focused on the nutritional state as one of the risk factors of APAP-induced chronic hepatotoxicity in humans and investigated the contribution of undernourishment to susceptibility to APAP-induced chronic hepatotoxicity using an animal model mimicking undernourished patients. Rats were divided into 2 groups: the ad libitum fed (ALF) and the restricted fed (RF) rats and were assigned to 3 groups (n = 8/group) for each feeding condition. The animals were given APAP at 0, 300 and 500mg/kg for 99 days under each feeding condition. Plasma and urinary glutathione-related metabolites and liver function parameters were measured during the dosing period and hepatic glutathione levels were measured at the end of the dosing period. In the APAP-treated ALF rats hepatic glutathione levels were increased and hepatic function parameters were not changed, but in the APAP-treated RF rats hepatic glutathione levels were decreased at 500mg/kg and hepatic function parameters were increased at 300 and 500mg/kg. Moreover the urinary endogenous metabolite profile after long-term treatment with APAP in the ALF and RF rats was similar to that in human non-responders and responders to APAP-induced chronic hepatotoxicity, respectively. In conclusion, the RF rats were more sensitive to APAP-induced chronic hepatotoxicity than the ALF rats and were considered to be a useful model to estimate the contribution of the nutritional state of patients to APAP-induced chronic hepatotoxicity.

  16. Injurious effect on rat liver mitochondria by lymphocytes from patients with primary biliary cirrhosis.

    Science.gov (United States)

    Bootello, A; Fernandez-Cruz, E; Escartin, P; Blanco, M F; Gosalvez, M; Segovia De Arana, J M

    1976-01-01

    Lymphocytes from primary biliary cirrhosis (PBC) patients were shown to have an injurious effect on rat liver mitochondria, as was demonstrated by the inhibition of mitochondrial respiratory control by these cells. The incubation of the PBC patients' lymphocytes with isolated rat liver mitochondria produced a significant inhibition of mitochondrial respiration in the presence of ADP. However, no significant effect on respiration was seen with control lymphocytes of normal persons or with lymphocytes from patients with alcoholic cirrhosis and miscellaneous liver diseases. The results suggest that this injurious effect of PBC lymphocytes on mitochondria might be a consequence of sensitization in vivo of the PBC patients' lymphocytes by the mitochondrial antigens. PMID:1277585

  17. Protective effects of ω-3 PUFA on the second liver injury in rats with traumatic brain injury and hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    许会彬

    2014-01-01

    Objective To investigate the effects of preconditioning withω-3 polyunsaturated fatty acid(ω-3 PUFA)on the second liver injury in rats with traumatic brain injury and hemorrhagic shock(TBIS)and explore the underlying mechanism.Methods Total of 36 male Wistar rats were assigned randomly(random number)into 3 groups(n=12 in each):sham

  18. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats.

    Science.gov (United States)

    Hanafy, Abeer; Aldawsari, Hibah M; Badr, Jihan M; Ibrahim, Amany K; Abdel-Hady, Seham El-Sayed

    2016-01-01

    The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  19. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Abeer Hanafy

    2016-01-01

    Full Text Available The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

  20. Acute kidney injury in acute on chronic liver failure.

    Science.gov (United States)

    Maiwall, Rakhi; Sarin, S K; Moreau, Richard

    2016-03-01

    Acute on chronic liver failure (ACLF) is a distinct clinical entity; however, there is still debate in the way it is defined in the East as compared to the West, especially with respect to incorporation of kidney dysfunction or failure in the definition of ACLF. Kidney dysfunction is defined as serum creatinine between 1.5 and 1.9 mg/dl and kidney failure as serum creatinine of more than 2 mg/dl or requirement of renal replacement therapy according to the EASL-CLIF Consortium. Kidney dysfunction or failure is universally present in patients with ACLF according to the definition by the EASL-CLIF Consortium while on the contrary the APASL definition of ACLF does not incorporate kidney dysfunction or failure in its definition. Recently, both the diagnosis and management of renal failure in patients with cirrhosis has changed with the advent of the acute kidney injury (AKI) criteria defined as an abrupt decline in renal functions, characterized by an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or an increase of more than 50 % from baseline, which is known or presumed to have occurred in the previous 7 days. Further, recent studies in patients with cirrhosis have shown the utility of biomarkers for the diagnosis of AKI. The present review covers the pathogenetic mechanisms, diagnosis, prognosis as well as management of AKI in patients with ACLF from both a Western as well as an Eastern perspective. The review identifies an unmet need to diagnose AKI and prevent this ominous complication in patients with ACLF.

  1. Internal vacuum-assisted closure device in the swine model of severe liver injury

    Directory of Open Access Journals (Sweden)

    Everett Christopher B

    2012-12-01

    Full Text Available Abstract Objectives The authors present a novel approach to nonresectional therapy in major hepatic trauma utilizing intraabdominal perihepatic vacuum assisted closure (VAC therapy in the porcine model of Grade V liver injury. Methods A Grade V injury was created in the right lobe of the liver in a healthy pig. A Pringle maneuver was applied (4.5 minutes total clamp time and a vacuum assisted closure device was placed over the injured lobe and connected to suction. The device consisted of a perforated plastic bag placed over the liver, followed by a 15 cm by 15cm VAC sponge covered with a nonperforated plastic bag. The abdomen was closed temporarily. Blood loss, cardiopulmonary parameters and bladder pressures were measured over a one-hour period. The device was then removed and the animal was euthanized. Results Feasibility of device placement was demonstrated by maintenance of adequate vacuum suction pressures and seal. VAC placement presented no major technical challenges. Successful control of ongoing liver hemorrhage was achieved with the VAC. Total blood loss was 625 ml (20ml/kg. This corresponds to class II hemorrhagic shock in humans and compares favorably to previously reported estimated blood losses with similar grade liver injuries in the swine model. No post-injury cardiopulmonary compromise or elevated abdominal compartment pressures were encountered, while hepatic parenchymal perfusion was maintained. Conclusion These data demonstrate the feasibility and utility of a perihepatic negative pressure device for the treatment of hemorrhage from severe liver injury in the porcine model.

  2. Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

    Directory of Open Access Journals (Sweden)

    Antonios Douros

    2016-01-01

    Full Text Available Herb-induced liver injury (HILI has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once. Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

  3. Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

    Science.gov (United States)

    Douros, Antonios; Bronder, Elisabeth; Andersohn, Frank; Klimpel, Andreas; Kreutz, Reinhold; Garbe, Edeltraut; Bolbrinker, Juliane

    2016-01-01

    Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed. PMID:26784183

  4. The Effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yu-Jie Zhang

    2016-09-01

    Full Text Available Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. The animals were treated daily with alcohol and fruit juices for fifteen days. Chronic treatment with alcohol increased the levels of aspartate transaminase (AST, alanine transaminase (ALT, total bilirubin (TBIL, triglyceride (TG, malondialdehyde (MDA, and decreased total protein (TP. Histopathological evaluation also showed that ethanol induced extensive fat droplets in hepatocyte cytoplasm. Syzygium samarangense and Passiflora edulis normalized various biochemical parameters. Solanum muricatum increased the level of ALT and induced infiltration of inflammatory cells in the liver. These results strongly suggest that treatment with Syzygium samarangense and Passiflora edulis could protect liver from the injury of alcohol, while Solanum muricatum could aggravate the damage.

  5. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.

    Science.gov (United States)

    Deutsch, M; Graffeo, C S; Rokosh, R; Pansari, M; Ochi, A; Levie, E M; Van Heerden, E; Tippens, D M; Greco, S; Barilla, R; Tomkötter, L; Zambirinis, C P; Avanzi, N; Gulati, R; Pachter, H L; Torres-Hernandez, A; Eisenthal, A; Daley, D; Miller, G

    2015-05-07

    Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

  6. Small-for-Size Liver Transplantation Increases Pulmonary Injury in Rats: Prevention by NIM811

    Directory of Open Access Journals (Sweden)

    Qinlong Liu

    2012-01-01

    Full Text Available Pulmonary complications after liver transplantation (LT often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 μM for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG and quarter-size grafts (QSG, respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5–18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1β mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT.

  7. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai Nguyen Thanh; Hue Pham Thi Minh; Tuan Anh Le; Huong Duong Thi Ly; Tung Nguyen Huu; Loi Vu Duc; Thu Dang Kim; Tung Bui Thanh

    2015-01-01

    To investigated the protective potential of ethanol extracts of Scutellaria baicalensis (S. baicalensis ) against lipopolysaccharide (LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS (5 mg/kg of body weight, intraperitoneal injection). Both protein and mRNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. Cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS significantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice. Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  8. Ethanol extracts of Scutellaria baicalensis protect against lipopolysaccharide-induced acute liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Hai; Nguyen; Thanh; Hue; Pham; Thi; Minh; Tuan; Anh; Le; Huong; Duong; Thi; Ly; Tung; Nguyen; Huu; Loi; Vu; Duc; Thu; Dang; Kim; Tung; Bui; Thanh

    2015-01-01

    Objective: To investigated the protective potential of ethanol extracts of Scutellaria baicalensis(S. baicalensis) against lipopolysaccharide(LPS)-induced liver injury. Methods: Dried roots of S. baicalensis were extracted with ethanol and concentrated to yield a dry residue. Mice were administered 200 mg/kg of the ethanol extracts orally once daily for one week. Animals were subsequently administered a single dose of LPS(5 mg/kg of body weight, intraperitoneal injection). Both protein and m RNA levels of cytokines, such as tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in liver tissues were evaluated by ELISA assay and quantitative PCR. C yclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB protein levels in liver tissues were analyzed by western blotting. Results: Liver injury induced by LPS signifi cantly increased necrosis factor alpha, interleukin-1β, interleukin-6, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor-κB in liver tissues. Treatment with ethanol extracts of S. baicalensis prevented all of these observed changes associated with LPS-induced injury in liver mice.Conclusions: Our study showed that S. baicalensis is potentially protective against LPS-induced liver injury in mice.

  9. Apocynin reduced doxycycline-induced acute liver injury in ovariectomized mice

    Directory of Open Access Journals (Sweden)

    Satoru Mitazaki

    2016-01-01

    Full Text Available To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx mice against doxycycline (DOXY-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip 8 weeks after the operation, 30 min after apocynin (5 mg/kg or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.

  10. The hypertension drug, verapamil, activates Nrf2 by promoting p62-dependent autophagic Keap1 degradation and prevents acetaminophen-induced cytotoxicity.

    Science.gov (United States)

    Lee, Da Hyun; Park, Jeong Su; Lee, Yu Seol; Sung, Su Haeng; Lee, Yong-Ho; Bae, Soo Han

    2017-02-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamilinduced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity. [BMB Reports 2017; 50(2): 91-96].

  11. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    Science.gov (United States)

    Khurana, Sandeep; Jadeja, Ravirajsinh; Twadell, William; Cheng, Kunrong; Rachakonda, Vikrant; Saxena, Neeraj; Raufman, Jean-Pierre

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced survival and increased liver nodularity and fibrosis. We next assessed AOM-induced liver injury in mice treated with a selective M3R agonist, pilocarpine. After pilocarpine treatment, stimulation of post-M3R signaling in the liver was evidenced by ERK and AKT activation. In contrast to the damaging effects of the M3R antagonist, administering pilocarpine to AOM-treated mice significantly attenuated hepatic stellate cell activation, collagen deposition, bile ductule proliferation, and liver fibrosis and nodularity. As anticipated from these findings, livers from pilocarpine-treated mice exhibited reduced expression of key players in fibrosis (α1 collagen, α-smooth muscle actin, TGF-β1, PGDF, TGF-β1R, PGDFR) and decreased mRNA levels for molecules that regulate extracellular matrix formation (TIMP-1, TIMP-2, MMP-2, MMP-13). Cleaved caspase-3, nitrotyrosine and BrdU immunostaining provided evidence that pilocarpine treatment reduced hepatocyte apoptosis and oxidative stress, while increasing hepatocyte proliferation. Collectively, these findings identify several downstream mechanisms whereby M3R activation ameliorates toxic liver injury. These novel observations provide a proof-of-principle that selectively stimulating M3R activation to prevent or diminish liver injury is a therapeutic strategy worthy of further investigation. PMID:23707755

  12. Impact of asialoglycoprotein receptor deficiency on the development of liver injury

    Institute of Scientific and Technical Information of China (English)

    Serene ML Lee; Carol A Casey; Benita L McVicker

    2009-01-01

    The asialoglycoprotein (ASGP) receptor is a wellcharacterized hepatic receptor that is recycled via the common cellular process of receptor-mediated endocytosis (RME). The RME process plays an integral part in the proper trafficking and routing of receptors and ligands in the healthy cell. Thus, the missorting or altered transport of proteins during RME is thought to play a role in several diseases associated with hepatocyte and liver dysfunction. Previously,we examined in detail alterations that occur in hepatocellular RME and associated receptor functions as a result of one particular liver injury, alcoholic liver disease (ALD). The studies revealed profound ethanolmediated impairments to the ASGP receptor and the RME process, indicating the importance of this receptor and the maintenance of proper endocytic events in normal tissue. To further clarify these observations,studies were performed utilizing knockout mice (lacking a functional ASGP receptor) to which were administered several liver toxicants. In addition to alcohol, we examined the effects following administration of anti-Fas (CD95) antibody, carbon tetrachloride (CCl4) and lipopolysaccharide (LPS)/galactosamine. The results of these studies demonstrated that the knockout mice sustained enhanced liver injury in response to all of the treatments, as shown by increased indices of liver damage, such as enhancement of serum enzyme levels,histopathological scores, as well as hepatocellular death.Overall, the work completed to date suggests a possible link between hepatic receptors and liver injury. In particular, adequate function and content of the ASGP receptor may provide protection against various toxinmediated liver diseases.

  13. A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury

    National Research Council Canada - National Science Library

    Hide, Diana; Ortega-Ribera, Martí; Fernández-Iglesias, Anabel; Fondevila, Constantino; Salvadó, M Josepa; Arola, Lluís; García-Pagán, Juan Carlos; Mancini, Aldo; Bosch, Jaime; Gracia-Sancho, Jordi

    2014-01-01

    ...), liver grafts from healthy and steatotic rats, and human liver samples, we aimed to characterize the effects of a new recombinant form of human manganese superoxide dismutase (rMnSOD) on hepatic CS+WR injury. After CS...

  14. The role of hepatic ischemia-reperfusion injury and liver parenchymal quality on cancer recurrence.

    Science.gov (United States)

    Orci, Lorenzo A; Lacotte, Stéphanie; Oldani, Graziano; Morel, Philippe; Mentha, Gilles; Toso, Christian

    2014-09-01

    Hepatic ischemia/reperfusion (I/R) injury is a common clinical challenge. Despite accumulating evidence regarding its mechanisms and potential therapeutic approaches, hepatic I/R is still a leading cause of organ dysfunction, morbidity, and resource utilization, especially in those patients with underlying parenchymal abnormalities. In the oncological setting, there are growing concerns regarding the deleterious impact of I/R injury on the risk of post-surgical tumor recurrence. This review aims at giving the last updates regarding the role of hepatic I/R and liver parenchymal quality injury in the setting of oncological liver surgery, using a "bench-to-bedside" approach. Relevant medical literature was identified by searching PubMed and hand scanning of the reference lists of articles considered for inclusion. Numerous preclinical models have depicted the impact of I/R injury and hepatic parenchymal quality (steatosis, age) on increased cancer growth in the injured liver. Putative pathophysiological mechanisms linking I/R injury and liver cancer recurrence include an increased implantation of circulating cancer cells in the ischemic liver and the upregulation of proliferation and angiogenic factors following the ischemic insult. Although limited, there is growing clinical evidence that I/R injury and liver quality are associated with the risk of post-surgical cancer recurrence. In conclusion, on top of its harmful early impact on organ function, I/R injury is linked to increased tumor growth. Therapeutic strategies tackling I/R injury could not only improve post-surgical organ function, but also allow a reduction in the risk of cancer recurrence.

  15. S-nitroso-N-acetylcysteine ameliorates ischemia-reperfusion injury in the steatotic liver

    Directory of Open Access Journals (Sweden)

    Wellington Andraus

    2010-01-01

    Full Text Available BACKGROUND: Steatosis is currently the most common chronic liver disease and it can aggravate ischemia-reperfusion (IR lesions. We hypothesized that S-nitroso-N-acetylcysteine (SNAC, an NO donor component, can ameliorate cell damage from IR injury. In this paper, we report the effect of SNAC on liver IR in rats with normal livers compared to those with steatotic livers. METHODS: Thirty-four rats were divided into five groups: I (n=8, IR in normal liver; II (n=8, IR in normal liver with SNAC; III (n=9, IR in steatotic liver; IV (n=9, IR in steatotic liver with SNAC; and V (n=10, SHAN. Liver steatosis was achieved by administration of a protein-free diet. A SNAC solution was infused intraperitoneally for one hour, beginning 30 min. after partial (70% liver ischemia. The volume of solution infused was 1 ml/100 g body weight. The animals were sacrificed four hours after reperfusion, and the liver and lung were removed for analysis. We assessed hepatic histology, mitochondrial respiration, oxidative stress (MDA, and pulmonary myeloperoxidase. RESULTS: All groups showed significant alterations compared with the group that received SHAN. The results from the steatotic SNAC group revealed a significant improvement in liver mitochondrial respiration and oxidative stress compared to the steatotic group without SNAC. No difference in myeloperoxidase was observed. Histological analysis revealed no difference between the non-steatotic groups. However, the SNAC groups showed less intraparenchymal hemorrhage than groups without SNAC (p=0.02. CONCLUSION: This study suggests that SNAC effectively protects against IR injury in the steatotic liver but not in the normal liver.

  16. Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM: To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions. METHODS: Abdominal injection of CCl4 was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was function-ally examined by depletion experiment using ...

  17. Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS: Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d.UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment.RESULTS: At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ± 35.5 U/L, respectively, P < 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION: The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.

  18. xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway.

    Science.gov (United States)

    Kang, Eun Sil; Lee, Jaeyong; Homma, Takujiro; Kurahashi, Toshihiro; Kobayashi, Sho; Nabeshima, Atsunori; Yamada, Sohsuke; Seo, Han Geuk; Miyata, Satoshi; Sato, Hideyo; Fujii, Junichi

    2017-01-01

    Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the transsulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine γ-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT(-/-) mice was increased to a greater extent than that for the xCT(+/+) mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT(+/+) and xCT(-/-) mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems.

  19. Evaluation of liver function and electroacupuncture efficacy of animals with alcoholic liver injury by the novel imaging methods.

    Science.gov (United States)

    Zhang, Dong; Song, Xiao-Jing; Li, Shun-Yue; Wang, Shu-You; Chen, Bing-Jun; Bai, Xiao-Dong; Tang, Li-Mei

    2016-07-22

    Imaging methods to evaluate hepatic microcirculation (HM) and liver function (LF) by directly monitoring overall liver tissue remain lacking. This study establish imaging methods for LF that combines Laser speckle perfusion imaging (LSPI) and in vivo optical imaging (IVOI) technologies to investigate changes of hepatic microcirculation and reserve function in the animals gavaged with 50% ethanol (15 ml/kg·bw) for a model of acute alcoholic liver injury (ALI), and for evaluation of electroacupuncture (EA) effect. The liver blood perfusion and indocyanine green (ICG) distribution were observe by LSPI and IVOI separately. After EA, the livers were collected to measure the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), thromboxane A (TXA2), prostacyclin (PGI2) and endothelin (ET). The acquisitions of newly established LSPI of liver and ICG in vivo fluorescence imaging (ICG-IVFI), combining the results of other indexes showed: hepatic microcirculation perfusion (HMP) significantly reduced, ICG metabolism reduced, and ALT/AST increased in animal model with acute ALI. EA can reverse these changes. The use of LSPI of liver and ICG-IVFI, which was novel imaging methods for LF established in this study, could display the LF characteristics of ALI and the EA efficacy.

  20. Complications of high grade liver injuries: management and outcomewith focus on bile leaks

    Directory of Open Access Journals (Sweden)

    Bala Miklosh

    2012-03-01

    Full Text Available Abstract Background Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to expect an increased risk of hepatic complications following trauma. The aim of the current study was to define hepatic related morbidity in patients sustaining high-grade hepatic injuries that could be safely managed non-operatively. Patients and methods This is a retrospective study of patients with liver injury admitted to Hadassah-Hebrew University Medical Centre over a 10-year period. Grade 3-5 injuries were considered to be high grade. Collected data included the number and types of liver-related complications. Interventions which were required for these complications in patients who survived longer than 24 hours were analysed. Results Of 398 patients with liver trauma, 64 (16% were found to have high-grade liver injuries. Mechanism of injury was blunt trauma in 43 cases, and penetrating in 21. Forty patients (62% required operative treatment. Among survivors 22 patients (47.8% developed liver-related complications which required additional interventional treatment. Bilomas and bile leaks were diagnosed in 16 cases post-injury. The diagnosis of bile leaks was suspected with abdominal CT scan, which revealed intraabdominal collections (n = 6, and ascites (n = 2. Three patients had continuous biliary leak from intraabdominal drains left after laparotomy. Nine patients required ERCP with biliary stent placement, and 2 required percutaneous transhepatic biliary drainage. ERCP failed in one case. Four angioembolizations (AE were performed in 3 patients for rebleeding. Surgical treatment was found to be associated with higher complication rate. AE at admission was associated with a significantly higher rate of biliary complications. There were 24 deaths (37%, the majority from uncontrolled haemorrhage (18 patients. There were only 2 hepatic-related mortalities due to liver failure

  1. Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases

    Science.gov (United States)

    Wunsch, Ewa; Krawczyk, Marcin; Milkiewicz, Malgorzata; Trottier, Jocelyn; Barbier, Olivier; Neurath, Markus F.; Lammert, Frank; Kremer, Andreas E.; Milkiewicz, Piotr

    2016-01-01

    Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival. PMID:27506882

  2. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

    Energy Technology Data Exchange (ETDEWEB)

    Massey, Veronica L. [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Stocke, Kendall S. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Schmidt, Robin H.; Tan, Min [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Ajami, Nadim [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Neal, Rachel E. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Petrosino, Joseph F. [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Barve, Shirish [Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)

    2015-05-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria.

  3. The protective effect of niacinamide on ischemia-reperfusion-induced liver injury.

    Science.gov (United States)

    Chen, C F; Wang, D; Hwang, C P; Liu, H W; Wei, J; Lee, R P; Chen, H I

    2001-01-01

    Reperfusion of ischemic liver results in the generation of oxygen radicals, nitric oxide (NO) and their reaction product peroxynitrite, all of which may cause strand breaks in DNA, which activate the nuclear enzyme poly(ADP ribose)synthase (PARS). This results in rapid depletion of intracellular nicotinamide adenine dinucleotide and adenosine 5'-triphosphate (ATP) and eventually induces irreversible cytotoxicity. In this study, we demonstrated that niacinamide, a PARS inhibitor, attenuated ischemia/reperfusion (I/R)-induced liver injury. Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 min. Thereafter, flow was restored and the liver was reperfused for 90 min. Blood samples collected prior to I and after R were analyzed for methyl guanidine (MG), NO, tumor necrosis factor (TNF-alpha) and ATP. Blood levels of aspartate transferase (AST), alanine transferase (ALT) and lactate dehydrogenase (LDH) which served as indexes of liver injury were measured. This protocol resulted in elevation of the blood NO level (p niacinamide (10 mM), liver injury was significantly attenuated, while blood ATP content was reversed. In addition, MG, TNF-alpha and NO release was attenuated. These results indicate that niacinamide, presumably by acting with multiple functions, exerts potent anti-inflammatory effects in I/R-induced liver injury.

  4. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  5. Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy

    Science.gov (United States)

    Guo, Rui; Lin, Bin; Pan, Jing Fei; Liong, Emily C.; Xu, Ai Min; Youdim, Moussa; Fung, Man Lung; So, Kwok Fai; Tipoe, George L.

    2016-01-01

    Acute liver disease is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long term clinical outcome and lead to liver failure or cancer. Here, we initially demonstrated the beneficial role of caspase-9-dependent autophagy in acute liver injury. Treatment with caspase-9 inhibitor z-LEHD-FMK in HepG2 cells, AML12 cells and C57BL/b6N mice exacerbated CCl4-induced acute hepatocellular damage, and also down-regulated autophagy markers expression levels, indicating that caspase-9 inhibition may aggravate acute liver damage by suppressing cytoprotective autophagy. CCl4 was used as an acute liver injury inducer which caused oxidative stress and apoptosis through up-regulation of HIF-1α, as well as triggered hepatic inflammation and necroptosis via TLR4/NF-κB pathway. Caspase-9 Thr125 site was firstly phosphorylated by ERK1/2 which subsequently activated the cytoprotective autophagy process to attenuate acute CCl4 injury. Caspase-9 inhibition further aggravated hepatic necroptosis through NF-κB expression, leading to increased pro-inflammatory mediators levels, suggesting a protective role of caspase-9-dependent autophagy in the inflammatory process as well as its possibility being a new therapeutic target for the treatment of acute liver injury. PMID:27580936

  6. Total Flavonoids from Mimosa Pudica Protects Carbon Tetrachloride -Induced Acute Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Zhen-qin QIU

    2015-03-01

    Full Text Available Objective: To observe the protective effect of total flavonoids from Mimosa pudica on carbon tetrachloride (CCl4-induced acute liver injury in mice. Methods: CCl4-induced acute liver injury model in mice was established. The activity of ALT and AST, the content of serum albumin (Alb and total antioxidant capacity (T-AOC were determined. The content of malondiadehyde (MDA was measured and the activity of superoxide dismutase (SOD was determined. The histopathological changes of liver were observed.Results: Compared with CCl4 modle group, each dose group of total flavonouida from Mimosa pudica couldreduced the activity of ALT and AST in mice obviously (P<0.01, indicating they had remarkably protective effect on CCl4-induced acute liver injury in mice. high and middle dose groups of total flavonouida from Mimosa pudica couldincrease the content of Alb in mice (P<0.01. Each dose group of total flavonouida from Mimosa pudica could enhance the level of T-AOC (P<0.01. each dose group of total flavonouida from Mimosa pudica could lower the content of liver homogenate MDA but enhance the activity of SOD in a dose-depended manner (P<0.01. Conclusion: Total flavones from Mimosa Pudica have obvious protective effect on CCl4-induced acute liver injury in mice.

  7. Interleukin-23 mediates the pathogenesis of LPS/GalN-induced liver injury in mice.

    Science.gov (United States)

    Bao, Suxia; Zhao, Qiang; Zheng, Jianming; Li, Ning; Huang, Chong; Chen, Mingquan; Cheng, Qi; Zhu, Mengqi; Yu, Kangkang; Liu, Chenghai; Shi, Guangfeng

    2017-05-01

    Interleukin-23 (IL-23) is required for T helper 17 (Th17) cell responses and IL-17 production in hepatitis B virus infection. A previous study showed that the IL-23/IL-17 axis aggravates immune injury in patients with chronic hepatitis B virus infection. However, the role of IL-23 in acute liver injury remains unclear. The purpose of this study was to determine the role of the inflammatory cytokine IL-23 in lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury in mice. Serum IL-23 from patients with chronic hepatitis B virus (CHB), acute-on-chronic liver failure (ACLF) and healthy individuals who served as healthy controls (HCs) was measured by ELISA. An IL-23p19 neutralizing antibody or an IL-23p40 neutralizing antibody was administered intravenously at the time of challenge with LPS (10μg/kg) and GalN (400mg/kg) in C57BL/6 mice. Hepatic pathology and the expression of Th17-related cytokines, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and the stabilization factor Csf3 were assessed in liver tissue. Serum IL-23 was significantly upregulated in ACLF patients compared with CHB patients and HCs (Pliver tissue histopathology and significant reductions in the expression of Th17-related inflammatory cytokine, including IL-17 and TNF-α; neutrophil chemoattractants, including Cxcl1, Cxcl2, Cxcl9, and Cxcl10; and stabilization factors Csf3 within the liver tissue compared with LPS/GalN mice (Pliver injury in mice. IL-23 neutralizing antibodies attenuated liver injury by reducing the expression of Th17-related inflammatory cytokines, neutrophil chemoattractants and stabilization factors within the liver tissue, which indicated that IL-23 likely functions upstream of Th17-related cytokine and chemokine expression to recruit inflammatory cells into the liver. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Protective effect of nitric oxide induced by ischemic preconditioning on reperfusion injury of rat liver graft

    Institute of Scientific and Technical Information of China (English)

    Jian-Ping Gong; Bing Tu; Wei Wang; Yong Peng; Shou-Bai Li; Lu-Nan Yan

    2004-01-01

    AIM: Ischemic preconditioning (IP) is a brief ischemic episode,which confers a state of protection against the subsequent long-term ischemia-reperfusion injuries. However, little is known regarding the use of IP before the sustained cold storage and liver transplantation. The present study was designed to evaluate the protective effect of IP on the long-term preservation of liver graft and the prolonged anhepatic-phase injury.METHODS: Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation. All livers underwent 10 min of ischemia followed by 10 min of reperfusion before harvest. Rat liver transplantation was performed with the portal vein clamped for 25 min. Tolerance of transplanted liver to the reperfusion injury and liverdamage were investigated. The changes in adenosineconcentration in hepatic tissue and those of nitric oxide (NO)and tumor necrosis factor (TNF) in serum were also assessed.RESULTS: Recipients with IP significantly improved theirone-week survival rate and liver function, they had increasedlevels of circulating NO and hepatic adenosine, and a reducedlevel of serum TNF, as compared to controls. Histologicalchanges indicating hepatic injuries appeared improved in theIP group compared with those in control group. The protectiveeffect of IP was also obtained by administration of adenosine,while blockage of the NO pathway using Nω-nitro-L-argininemethyl ester abolished the protective effect of IRCONCLUSION: IP appears to have a protective effect onthe long-term preservation of liver graft and the prolongedanhepatic-phase injuries. NO may be involved in this process.

  9. The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

    Directory of Open Access Journals (Sweden)

    Jun Ho Shin

    2013-03-01

    Full Text Available The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC on acetaminophen (APAP-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH production and glutathione peroxidase (GSH-px activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

  10. Obesity Increases Sensitivity to Endotoxin Liver Injury: Implications for the Pathogenesis of Steatohepatitis

    Science.gov (United States)

    Yang, Shi Qi; Zhi Lin, Hui; Lane, M. Daniel; Clemens, Mark; Diehl, Anna Mae

    1997-03-01

    Genetically obese fatty/fatty rats and obese/obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor α (TNFα ), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon γ , which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.

  11. The protection of meloxicam against chronic aluminium overload-induced liver injury in rats.

    Science.gov (United States)

    Yang, Yang; He, Qin; Wang, Hong; Hu, Xinyue; Luo, Ying; Liang, Guojuan; Kuang, Shengnan; Mai, Shaoshan; Ma, Jie; Tian, Xiaoyan; Chen, Qi; Yang, Junqing

    2017-04-04

    The present study was designed to observe the protective effect and mechanisms of meloxicam on liver injury caused by chronic aluminium exposure in rats. The histopathology was detected by hematoxylin-eosin staining. The levels of prostaglandin E2, cyclic adenosine monophosphate and inflammatory cytokines were detected by enzyme linked immunosorbent assay. The expressions of cyclooxygenases-2, prostaglandin E2 receptors and protein kinase A were measured by western blotting and immunohistochemistry. Our experimental results showed that aluminium overload significantly damaged the liver. Aluminium also significantly increased the expressions of cyclooxygenases-2, prostaglandin E2, cyclic adenosine monophosphate, protein kinase A and the prostaglandin E2 receptors (EP1,2,4) and the levels of inflammation and oxidative stress, while significantly decreased the EP3 expression in liver. The administration of meloxicam significantly improved the impairment of liver. The contents of prostaglandin E2 and cyclic adenosine monophosphate were significantly decreased by administration of meloxicam. The administration of meloxicam also significantly decreased the expressions of cyclooxygenases-2 and protein kinase A and the levels of inflammation and oxidative stress, while significantly increased the EP1,2,3,4 expressions in rat liver. Our results suggested that the imbalance of cyclooxygenases-2 and downstream prostaglandin E2 signaling pathway is involved in the injury of chronic aluminium-overload rat liver. The protective mechanism of meloxicam on aluminium-overload liver injury is attributed to reconstruct the balance of cyclooxygenases-2 and downstream prostaglandin E2 signaling pathway.

  12. Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats

    Science.gov (United States)

    Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

    2016-01-01

    Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti-inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)-induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN-induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor-α, interferon-γ and granulocyte/macrophage colony-stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN-induced liver injury. Therefore, Centella asiatica may be useful in preventing liver damage. PMID:27748812

  13. Innate immune recognition and regulation in liver injury: A brief report from a series of studies

    Institute of Scientific and Technical Information of China (English)

    TIAN ZhiGang

    2009-01-01

    The discovery of innate immune receptors and the emergence of liver Immunology (high content of NK and NKT cells in liver) led to the second research summit in innate immunity since the finding of NK cells in the middle 1970s. Liver disease is one of the most dangerous threats to humans, and the pro-gress in innate immunology and liver immunology made it possible to re-explain the cellular end too-lecular immune mechanisms of liver disease. In the past ten years, we have found that innate recogni-tion of hepatic NK and NKT subsets were involved in murine liver injury. We established a novel NK cell-dependent acute murine hepatitis model by activating Toll-like receptor-3 (TLR-3) with an injection of poly I:C, which may mimic mild viral hepatitis (such as Chronic Hepatitis B). We observed that a network of innate immune cells including NK, NKT and Kupffer cells is involved in liver immune injury in our established NK cell-dependent murine model. We noted that TLR-3 on Kupffer ceils activated by pretreatment with poly I:C might protect against bacterial toxin (LPS)-induced fuIminant hepatitis by down-regulating TLR-4 function, while TLR-3 pre-activation of NK cells might reduce Con A-induced NKT cell-mediated fulminant hepatitis by blocking NKT cell recruitment to the liver. We also found that the oversensitivity to injury by immune stimulation in HBV (hepatitis B virus) transgenic mice (full HBV gene-tg or HBs-tg) correlated to the over-expression of Real, an NKG2D (natural killer cell group 2D) ligand of NK cells or CDld, a ligand of TCR-V14 of NKT cells, on HBV+ hepatocytes, which leads to an innate immune response against hepatocytes and is critical in liver immune injury and regeneration.

  14. Liver manipulation causes hepatocyte injury and precedes systemic inflammation in patients undergoing liver resection.

    NARCIS (Netherlands)

    Poll, M.C. van de; Derikx, J.P.M.; Buurman, W.A.; Peters, W.H.M.; Roelofs, H.M.J.; Wigmore, S.J.; Dejong, C.H.

    2007-01-01

    BACKGROUND: Liver failure following liver surgery is caused by an insufficient functioning remnant cell mass. This can be due to insufficient liver volume and can be aggravated by additional cell death during or after surgery. The aim of this study was to elucidate the causes of hepatocellular injur

  15. Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice.

    Science.gov (United States)

    Salama, Mohamed; Elgamal, Mohamed; Abdelaziz, Azza; Ellithy, Moataz; Magdy, Dina; Ali, Lina; Fekry, Emad; Mohsen, Zinab; Mostafa, Mariam; Elgamal, Hoda; Sheashaa, Hussein; Sobh, Mohamed

    2015-07-01

    Acetaminophen (APAP, 4-hydroxyacetanilide) is the most common cause of acute liver failure in the United States. In addition to exhibiting hepatotoxicity, APAP exerts a nephrotoxic effect may be independent of the induced liver damage. Toll-like receptors (TLRs) have been suggested as a potential class of novel therapeutic targets. The aim of the present study was to investigate the potential of the TLR-4 blocker TAK-242 in the prevention of APAP-induced hepato-renal failure. Four groups of C57BL mice were studied: Vehicle-treated/control (VEH), APAP-treated (APAP), N-acetyl cysteine (NAC)-pretreated plus APAP (APAP + NAC) and TAK-242-pretreated plus APAP (APAP + TAK) groups. Mice were clinically assessed then perfused 4 h later. Liver and kidney tissues were collected and examined histologically using basic hematoxylin and eosin staining to detect signs of necrosis and inflammation. Plasma samples were collected to measure the levels of alanine transaminase, aspartate transaminase and serum creatinine. In addition, liver and kidney tissues were assayed to determine the levels of reduced glutathione. The results of the present study indicate the potential role of TLR-4 in APAP-induced organ toxicity. In the APAP + TAK and APAP + NAC groups, histopathological examination indicated that pretreatment with TAK-242 or NAC afforded protection against APAP-induced injury. However, this protective effect was more clinically evident in the APAP + TAK group compared with the APAP + NAC group. The various biochemical parameters (serum enzymes and reduced glutathione) revealed no significant protection in either of the pretreated groups. Therefore, the present study indicated that the TLR-4 blocker had protective effects against acute APAP toxicity in liver and kidney tissues. These effects were identified clinically, histologically and biochemically. Furthermore, the TLR-4 blocker TAK-242 exhibited antioxidant properties in addition to anti-inflammatory effects.

  16. Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.

    Directory of Open Access Journals (Sweden)

    Yumin Xu

    Full Text Available BACKGROUND: Acute-on-chronic liver failure (ACLF is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor/TNFR (tumor necrosis factor receptor 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor: IgG Fc [sTNFR:IgG-Fc] prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55 pathway. However, it is still unclear if sTNFR:IgG-Fc can inhibit hepatocyte damage during development of ACLF. METHODOLOGY: Chronic liver disease (liver fibrosis/cirrhosis was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA, and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN/lipopolysaccharide (LPS i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. PRINCIPAL FINDINGS: Reduced mortality was observed in sTNFR:IgG-Fc treated ACLF rats, consistent with reduced interleukin (IL-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFR:IgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA. This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFR:IgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFR:IgG-Fc treated ACLF rats. CONCLUSIONS: sTNFR:IgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.

  17. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital

    Science.gov (United States)

    Mrzljak, Anna; Kosuta, Iva; Skrtic, Anita; Kanizaj, Tajana Filipec; Vrhovac, Radovan

    2013-01-01

    Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement. PMID:23467452

  18. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital.

    Science.gov (United States)

    Mrzljak, Anna; Kosuta, Iva; Skrtic, Anita; Kanizaj, Tajana Filipec; Vrhovac, Radovan

    2013-01-01

    Noni (Morinda citrifolia) juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months) anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.

  19. Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia Juice and Phenobarbital

    Directory of Open Access Journals (Sweden)

    Anna Mrzljak

    2013-01-01

    Full Text Available Noni (Morinda citrifolia juice is a popular herbal dietary supplement globally used for preventive or therapeutic purposes in a variety of ailments, claiming to exhibit hepatoprotective properties as well. Herein we present the case of a 38-year-old woman who developed acute liver injury associated with noni juice consumption on a long-term (9 months anticonvulsant therapy. Clinical presentation and liver biopsy were consistent with severe, predominantly hepatocellular type of injury. Both agents were stopped and corticosteroids were initiated. Five months later the patient had fully recovered. Although in the literature the hepatotoxicity of noni juice remains speculative, sporadic but emerging cases of noni juice-associated liver injury address the need to clarify and investigate potential harmful effects associated with this supplement.

  20. Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity.

    Science.gov (United States)

    Uysal, Hilal Bektas; Dağlı, Bekir; Yılmaz, Mustafa; Kahyaoğlu, Fadime; Gökçimen, Alparslan; Ömürlü, İmran Kurt; Demirci, Buket

    2016-01-01

    The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 ± 0.210, 0.213 ± 0.004, 0.194 ± 0.001, 0.197 ± 0.06, 0.199 ± 0.008 and 0.173 ± 0.010 μmol/g protein, respectively. Total glutathione levels were 7.787 ± 0.395, 14.925 ± 0.932, 13.200 ± 0.984, 13.162 ± 0.486, 13.287 ± 0.787 and 13.500 ± 0.891 μm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP-induced hepatotoxicity.

  1. Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

    OpenAIRE

    Abeer Hanafy; Aldawsari, Hibah M; Badr, Jihan M.; Amany K. Ibrahim; Seham El-Sayed Abdel-Hady

    2016-01-01

    The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae) was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophe...

  2. Glutathione peroxidase 3 is a protective factor against acetaminophen-induced hepatotoxicity in vivo and in vitro

    Science.gov (United States)

    Kanno, Syu-Ichi; Tomizawa, Ayako; Yomogida, Shin; Hara, Akiyoshi

    2017-01-01

    Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP-induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP-induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2-fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β-estradiol, a major female hormone, decreased APAP-induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP-induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA-GPx3 or a GPx3 expression vector on NAPQI-induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh-7 or K562). NAPQI-induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP-induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP-induced liver damage. PMID:28677736

  3. Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Yue-Ying He; Bao-Xu Zhang; Feng-Lan Jia

    2011-01-01

    AIM: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP)- induced hepatotoxicity in C57BL/6J mice. METHODS: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined. RESULTS: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously. CONCLUSION: BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism.

  4. Sirtuin 1 modulation in rat model of acetaminophen-induced hepatotoxicity.

    Science.gov (United States)

    Wojnarová, L; Kutinová Canová, N; Farghali, H; Kučera, T

    2015-01-01

    Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

  5. Sesamin ameliorates oxidative liver injury induced by carbon tetrachloride in rat.

    Science.gov (United States)

    Lv, Dan; Zhu, Chang-Qing; Liu, Li

    2015-01-01

    Sesamin is naturally occurring lignan from sesame oil with putative antioxidant property. The present study was designed to investigate the protective role of sesamin against carbon tetrachloride induced oxidative liver injury. Male Wistar albino rats (180-200 g) were divided in to 5 groups (n=6). Hepatotoxicity was induced by the administration of CCl4 (0.1 ml/100 g bw., 50% v/v with olive oil) intraperitoneally. Sesamin was administered in two different dose (5 and 10 ml/kg bw) to evaluate the hepatoprotective activity. Sesamin significantly reduced the elevated serum liver marker enzymes (Psesamin treated groups shows the amelioration of oxidative stress induced by CCl4. Histopathological report also supported the hepatoprotection offered by sesamin. Sesamin effects in both the dose were in comparable to reference standard drug silymarin. From these above findings it has been concluded that sesamin ameliorate the oxidative liver injury in terms of reduction of lipid peroxidation and enhancement of liver antioxidant enzymes.

  6. Hepatoprotective effects of Sapium sebiferum in paracetamol-induced liver injury

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    Liaqat Hussain

    2015-06-01

    Full Text Available Sapium sebiferum leaves were used to determine its hepatoprotective effects against paracetamol-induced hepatotoxicity in mice. A dose dependent study was conducted using two different doses (200 mg/kg and 400 mg/kg of the extract of S. sebiferum against toxic effects of paracetamol (500 mg/kg in experimental animal model. Silymarin (50 mg/kg was used as standard drug to compare therapeutic effects of S. sebiferum with control and paracetamol-treated groups. Paracetamol significantly increased the serum levels of liver enzyme markers like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin. The extract showed protective effects by normalizing the liver enzymes markers in a dose dependent manner. Histopathological results confirmed the hepatoprotective effects of leaves of S. sebiferum. We conclude that leaves of S. sebiferum have strong hepatoprotective effects against paracetamol-induced liver injury and can be used in liver injuries caused by drug-induced toxicity.

  7. Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.

    Science.gov (United States)

    Liu, Jie; Lu, Yuan-Fu; Zhang, Youcai; Wu, Kai Connie; Fan, Fang; Klaassen, Curtis D

    2013-11-01

    Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential.

  8. Co-administration of cyclosporine A alleviates thioacetamide-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sabrina Fan; Ching-Feng Weng

    2005-01-01

    AIM: To investigate the effects of cyclosporine A (CsA)on thioacetamide (TAA)-induced liver injury.METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group shows higher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4)in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section,TGFβ-R1 and FGFR4 are more concentrated in rat liver after CsA plus TAA injury.CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.

  9. Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway

    Science.gov (United States)

    Jiang, Yi-ming; Wang, Ying; Tan, Hua-sen; Yu, Tao; Fan, Xiao-mei; Chen, Pan; Zeng, Hang; Huang, Min; Bi, Hui-chang

    2016-01-01

    Aim: The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect. Methods: Male C57BL/6 mice were treated with SolB (200 mg·kg−1·d−1, ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay. Results: SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5–20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells. Conclusion: SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity. PMID:26806302

  10. Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Edith Hochhauser

    2015-07-01

    Full Text Available Background/Aims: Ischemia/reperfusion (I/R injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC, a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70% ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway, the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation. This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. Conclusion: A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.

  11. Effects of cefodizime on chemokines of liver tissues in mice with immunological hepatic injury

    Institute of Scientific and Technical Information of China (English)

    WANG Peng; KAN Quan-cheng; YU Zu-jiang; LI Ling; PAN Xue

    2011-01-01

    Background Chronic hepatic inflammation is characterized by the accumulation of lymphocytes as a consequence of increased recruitment from the blood and retention within the tissue at sites of infection. CXC chemokine ligand 16 (CXCL16) mRNA has been detected in both inflamed and normal liver tissues and is strongly upregulated in the injured liver tissues in a murine model. The aim of this study was to investigate the effect of cefodizime on CXCL16 mRNA of liver tissues in mice with immunological hepatic injury.Methods The murine model of immunological hepatic injury was induced by Bacillus Calmette Guerin and Lipoposaccharide. The mice with immunological hepatic injury were randomly assigned to the model group, the cefodizime group and the ceftriaxone group. The three groups were continuously given agents for seven days and CXCL16 mRNA of liver tissue was determined and contrasted with the control group treated by normal saline. Reverse transcription-polymerase chain reaction was used to assay CXCL16 mRNA levels in liver tissues.Results The expressions of CXCL16 mRNA were significantly higher in the model group and the ceftriaxone group than in the control group and the cefodizime group (P <0.05), indicating the mice in the model group and the ceftriaxone group were immunodeficient. There was no statistical difference in the expressions of CXCL16 mRNA between the control group and the cefodizime group. Similarly, no statistical difference in the expressions of CXCL16 mRNA between the model group and the ceftriaxone group was detected (P >0.05).Conclusion Cefodizime effectively reduces the infiltration of lymphocytes into liver tissues and alleviates the liver damage by decreasing CXCL16 mRNA in liver tissues in mice with immunological hepatic injury.

  12. Role of Hydrogen Sulfide on Autophagy in Liver Injuries Induced by Selenium Deficiency in Chickens.

    Science.gov (United States)

    Wenzhong, Wang; Tong, Zhang; Hongjin, Lin; Ying, Chang; Jun, Xing

    2017-01-01

    Selenium (Se) is an indispensable trace mineral that was associated with liver injuries in animal models. Hydrogen sulfide (H2S) is involved in many liver diseases, and autophagy can maintain liver homeostasis with a stress stimulation. However, little is known about the correlation between H2S and autophagy in the liver injury chicken models induced by Se deficiency. In this study, we aimed to investigate the correlation between H2S and autophagy in the liver injury chicken models. We randomly divided 120 1-day-old chickens into two equal groups. The control group was fed with complete food with a Se content of 0.15 mg/kg, and the Se-deficiency group (lab group) was fed with a Se-deficient diet with a Se content of 0.033 mg/kg. When the time comes to 15, 25, and 35 days, the chickens were sacrificed (20 each). The liver tissues were gathered and examined for pathological observations, the mRNA and protein levels of H2S synthases (CSE, CBS, and 3-MST) and the mRNA and protein levels of autophagy-related genes. The results showed that the expression of CSE, CBS, and 3-MST and H2S production were higher in the lab group than in the control group. Swellings, fractures, and vacuolizations were visible in the mitochondria cristae in the livers of the lab group and autophagosomes were found as well. In addition, the expression of autophagy-related genes (ATG5, LC3-I, LC3-II, Beclin1, and Dynein) was higher in the lab group than in the control group (p liver injury chicken models, and H2S was correlated with autophagy.

  13. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury

    Directory of Open Access Journals (Sweden)

    Henning W Zimmermann

    2012-10-01

    Full Text Available Different etiologies such as drug toxicity, acute viral hepatitis B or acetaminophen poisoning can cause acute liver injury (ALI or even acute liver failure (ALF. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF, interleukin-6 (IL-6, IL-1-beta or monocyte chemoattractant protein 1 (MCP-1, CCL2 as well as activating other non-parenchymal liver cells, e.g. endothelial or hepatic stellate cells (HSC. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g. via caspase activation, but also activate protective signaling pathways, e.g. via nuclear factor kappa B (NF-kB. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+ monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1 are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.

  14. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

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    Maria Ausiliatrice Puglisi

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs, represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

  15. Mitochondrial Roles and Cytoprotection in Chronic Liver Injury

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    Davide Degli Esposti

    2012-01-01

    Full Text Available The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.

  16. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q.H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y.X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X.M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-03-03

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  17. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    L. Zong

    2014-03-01

    Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  18. A fatal case of air-bag-mediated liver injury in an unrestrained driver.

    Science.gov (United States)

    Uemura, Koichi; Uchida, Kyoko; Nara, Akina; Ochiai, Eriko

    2009-04-01

    A middle-aged man, who drove a small vehicle while drunken and not wearing a seat belt, crashed head on into a pier wall at a high speed. The rapid air-bag deployment caused abdominal compression of the driver, who was found dead 2 m away from the car. There were facial front-glass injuries and multiple rib fractures, but no head injury. Autopsy disclosed liver laceration with intra-abdominal hemorrhage (2,000 mL), resulting in hemorrhagic shock. This is the first autopsy report of liver laceration caused by the rapid expansion of an air-bag during an automobile crash.

  19. Effects of Modulating M3 Muscarinic Receptor Activity on Azoxymethane-Induced Liver Injury in Mice

    OpenAIRE

    2013-01-01

    Previously, we reported that azoxymethane (AOM)-induced liver injury is robustly exacerbated in M3 muscarinic receptor (M3R)-deficient mice. We used the same mouse model to test the hypothesis that selective pharmacological modulation of M3R activity regulates the liver injury response. Initial experiments confirmed that giving a selective M3R antagonist, darifenacin, to AOM-treated mice mimicked M3R gene ablation. Compared to vehicle controls, mice treated with the M3R antagonist had reduced...

  20. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

    OpenAIRE

    Cotter, David G.; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M.; d’Avignon, D. André; Graham, Mark J.; Dietzen, Dennis J.; Brunt, Elizabeth M; Patti, Gary J.; Crawford, Peter A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohe...

  1. Pistacia Terebinthus Coffee Protects against Thioacetamide-Induced Liver Injury in Rats

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    Ibrahim Halil Bahcecioglu

    2015-08-01

    Full Text Available Aim/background: Pistacia terebinthus is used as a coffee substitute in the East and Southern Anatolia regions of Turkey. It contains unsaturated fatty acids, tocopherols, polyphenols and carotenoids. P. terebinthus has anti-inflammatory and potential antioxidant activity. In this study we evaluated the protective effects of P. terebinthus coffee (PTC on thioacetamide (TAA-induced liver injury in rats. Materials and methods: Twenty-eight male Sprague-Dawley rats were equally randomized into four groups. Chronic liver injury was induced with TAA (100 mg/kg i.p. three times weekly. The first group of rats served as control and received only tap water (G1, and the remaining groups of rats received PTC, p.o (G2; TAA (G3; TAA plus PTC, p.o (G4, respectively. Results: After 8 weeks, PTC intake significantly reduced fibrosis/ inflammation scores (p < 0.05 in the livers of TAA-treated group. Compared to control group, PTC intake reduced transforming growth factor beta (TGF-β concentrations in the liver (p < 0.05. Compared to the TAA group, TGF-β, nuclear factor kappa B (NF-κB (p < 0.05, tumor necrosis factor alpha (TNF-α concentrations in the liver tissue were reduced by PTC intake. Discussion and conclusion: PTC intake provided beneficial effects against TAA-induced liver injury in rats. PTC probably suppresses the proinflammatory cytokines through NF-κB signaling pathway.

  2. Baicalein and its underlying mechanism as a protector against liver injury induced by cisplatin in mice

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    Chengwei Niu

    2017-01-01

    Full Text Available Cisplatin is widely used for the treatment of a variety of cancers but with a high incidence of hepatotoxicity. Baicalein is originally isolated from the root of Scutellaria baicalensis Georgi with broad bioactivities. The present study aims to investigate the protective effect of baicalein against cisplatin-induced acute liver injury and the underlying mechanism of this protective effect. Administration of cisplatin (40 mg/kg for 24 h increased the serum alanine and aspartate aminotransferases and alkaline phosphatase levels, while baicalein could reverse all those changes induced by cisplatin. Liver histological analysis further evidenced the protection of baicalein against cisplatin-induced liver injury. Baicalein counteracted the increased liver malondialdehyde (amount induced by cisplatin, while baicalein could further increase the cisplatin-induced elevation of the amount of reduced glutathione in the liver. Further results showed that baicalein reversed the cisplatin-induced decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S transferase and glutathione reductase. On the other hand, baicalein alleviated the increase in the serum levels of tumour necrosis factor alpha and interleukin 6 induced by cisplatin. Taken together, our results demonstrate that baicalein can inhibit cisplatin-induced hepatic oxidative stress and inflammation, which contributes greatly to the amelioration of cisplatin-induced liver injury.

  3. Surgical intervention for paediatric liver injuries is almost history - a 12-year cohort from a major Scandinavian trauma centre.

    Science.gov (United States)

    Koyama, Tomohide; Skattum, Jorunn; Engelsen, Peder; Eken, Torsten; Gaarder, Christine; Naess, Pål Aksel

    2016-11-29

    Although nonoperative management (NOM) has become standard care, optimal treatment of liver injuries in children is still challenging since many of these patients have multiple injuries. Moreover, the role of angiography remains poorly defined, and a high index of suspicion of complications is warranted. This study reviews treatment and outcomes in children with liver injuries at a major Scandinavian trauma centre over a 12-year period. Patients trauma registry and medical records. A total of 66 children were included. The majority was severely injured as reflected by a median injury severity score of 20.5 (mean 22.2). NOM was attempted in 60 (90.9%) patients and was successful in 57, resulting in a NOM success rate of 95.0% [95% CI 89.3 to 100]. Only one of the three NOM failures was liver related, occurred in the early part of the study period, and consisted in operative placement of drains for bile leak. Two (3.0%) patients underwent angiographic embolization (AE). Complications occurred in 18 (27.3% [95 % CI 16.2 to 38.3]) patients. Only 2 (3.0%) patients had liver related complications, in both cases bile leak. Six (9.1%) patients underwent therapeutic laparotomy for non-liver related injuries. Two (3.0%) patients died secondary to traumatic brain injury. This single institution paediatric liver injury cohort confirms high attempted NOM and NOM success rates even in patients with high grade injuries and multiple accompanying injuries. AE can be a useful NOM adjunct in the treatment of paediatric liver injuries, but is seldom indicated. Moreover, bile leak is the most common liver-related complication and the need for liver-related surgery is very infrequent. NOM is the treatment of choice in almost all liver injuries in children, with operative management and interventional radiology very infrequently indicated.

  4. OLIGOFRUCTOSE PROTECTS AGAINST ARSENIC-INDUCED LIVER INJURY IN A MODEL OF ENVIRONMENT/OBESITY INTERACTION

    Science.gov (United States)

    Massey, Veronica L; Stocke, Kendall S; Schmidt, Robin H.; Tan, Min; Ajami, Nadim; Neal, Rachel E.; Petrosino, Joseph F; Barve, Shirish; Arteel, Gavin E.

    2015-01-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 wks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. PMID:25759243

  5. Antibiotic-Induced Liver Injury in Paediatric Outpatients: A Case-Control Study in Primary Care Databases

    NARCIS (Netherlands)

    C. Ferrajolo (Carmen); K.M.C. Verhamme (Katia); G. Trifirò (Gianluca); ‘T Jong, G.W. (Geert W.); G. Picelli (Gino); C. Giaquinto (Carlo); G. Mazzaglia (Giampiero); B.H.Ch. Stricker (Bruno); F. Rossi (Francesco); A. Capuano (Annalisa); M.C.J.M. Sturkenboom (Miriam)

    2016-01-01

    textabstractIntroduction: Antibiotics are the most commonly prescribed drug class in children. Real-world data mining on the paediatric population showed potential associations between antibiotic use and acute liver injury. Objective: We assessed risk estimates of liver injury associated with antibi

  6. Biliary tract injury caused by different relative warm ischemia time in liver transplantation in rats

    Institute of Scientific and Technical Information of China (English)

    Hong-Feng Zhao; Guo-Wei Zhang; Jie Zhou; Jian-Hua Lin; Zhong-Lin Cui; Xiang-Hong Li

    2009-01-01

    BACKGROUND: There is a controversy over the degree of liver and biliary injury caused by the period of secondary warm ischemia. A liver autotransplantation model was adopted because it excludes the effects of infection and immunological rejection on bile duct injury. This study was undertaken to assess biliary tract injury caused by relative warm ischemia (secondary warm ischemia time in the biliary tract) and reperfusion. METHODS: One hundred and two rats were randomly divided into 5 groups: groupⅠ (control); groupsⅡ toⅤ, relative warm ischemia times of 0 minute, 30 minutes, 1 hour and 2 hours. In addition to the levels of serum alkaline phosphatase, and total bilirubin, pathomorphology assessment and TUNEL assay were performed to evaluate biliary tract damage. RESULTS: Under the conditions that there were no signiifcant differences in warm ischemia time, cold perfusion time and anhepatic phase, group comparisons showed statistically signiifcant differences. The least injury occurred in groupⅡ (portal vein and hepatic artery reperfused simultaneously) but the most severe injury occurred in groupⅤ (biliary tract relative warm ischemia time 2 hours). CONCLUSIONS: Relative warm ischemia is one of the factors that result in bile duct injury, and the relationship between relative warm ischemia time the bile injury degree is time-dependent. Simultaneous arterial and portal reperfusion is the best choice to avoid the bile duct injury caused by relative warm ischemia.

  7. Subnormothermic ex vivo liver perfusion reduces endothelial cell and bile duct injury after donation after cardiac death pig liver transplantation.

    Science.gov (United States)

    Knaak, Jan M; Spetzler, Vinzent N; Goldaracena, Nicolas; Boehnert, Markus U; Bazerbachi, Fateh; Louis, Kristine S; Adeyi, Oyedele A; Minkovich, Leonid; Yip, Paul M; Keshavjee, Shaf; Levy, Gary A; Grant, David R; Selzner, Nazia; Selzner, Markus

    2014-11-01

    An ischemic-type biliary stricture (ITBS) is a common feature after liver transplantation using donation after cardiac death (DCD) grafts. We compared sequential subnormothermic ex vivo liver perfusion (SNEVLP; 33°C) with cold storage (CS) for the prevention of ITBS in DCD liver grafts in pig liver transplantation (n = 5 for each group). Liver grafts were stored for 10 hours at 4°C (CS) or preserved with combined 7-hour CS and 3-hour SNEVLP. Parameters of hepatocyte [aspartate aminotransferase (AST), international normalized ratio (INR), factor V, and caspase 3 immunohistochemistry], endothelial cell (EC; CD31 immunohistochemistry and hyaluronic acid), and biliary injury and function [alkaline phosphatase (ALP), total bilirubin, and bile lactate dehydrogenase (LDH)] were determined. Long-term survival (7 days) after transplantation was similar between the SNEVLP and CS groups (60% versus 40%, P = 0.13). No difference was observed between SNEVLP- and CS-treated animals with respect to the peak of serum INR, factor V, or AST levels within 24 hours. CD31 staining 8 hours after transplantation demonstrated intact EC lining in SNEVLP-treated livers (7.3 × 10(-4) ± 2.6 × 10(-4) cells/μm(2)) but not in CS-treated livers (3.7 × 10(-4) ± 1.3 × 10(-4) cells/μm(2) , P = 0.03). Posttransplant SNEVLP animals had decreased serum ALP and serum bilirubin levels in comparison with CS animals. In addition, LDH in bile fluid was lower in SNEVLP pigs versus CS pigs (14 ± 10 versus 60 ± 18 μmol/L, P = 0.02). Bile duct histology revealed severe bile duct necrosis in 3 of 5 animals in the CS group but none in the SNEVLP group (P = 0.03). Sequential SNEVLP preservation of DCD grafts reduces bile duct and EC injury after liver transplantation. © 2014 American Association for the Study of Liver Diseases.

  8. Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications.

    Science.gov (United States)

    Gordon, D W; Rosenthal, G; Hart, J; Sirota, R; Baker, A L

    1995-02-08

    Unconventional medical practices, including the use of herbal remedies, are prevalent in the United States. Chaparral is an herbal preparation made from a desert shrub and used for its antioxidant properties. We report the case of a 60-year-old woman who took chaparral for 10 months and developed severe hepatitis for which no other cause could be found. Despite aggressive supportive therapy, the patient deteriorated and required orthotopic liver transplantation. She is now well, more than 1 year after her transplant. This case suggests that chaparral can cause serious liver injury and fulminant hepatic failure. Herbal medications should be considered as potential causes of liver toxicity.

  9. Evaluation of nephroprotective, diuretic, and antioxidant activities of plectranthus amboinicus on acetaminophen-induced nephrotoxic rats.

    Science.gov (United States)

    Palani, S; Raja, S; Naresh, R; Kumar, B Senthil

    2010-05-01

    Plectranthus amboinicus (PA), commonly known as country borage, is a folkoric medicinal plant. Juice from its leaves is commonly used for illnesses including liver and renal conditions in the Asian sub-continent. Acetaminophen (APAP), used as an analgesic, produces liver and kidney necrosis in mammals at high doses. The aim of this study was to investigate the nephroprotective, diuretic, and antioxidant activities of the ethanol extract of PA at two doses of 250 and 500 mg/kg bw on APAP-induced toxicity in rats. This study shows that APAP significantly increases the levels of serum urea (UR), hemoglobin (Hb), total leukocyte count, creatinine, raised body weight, and reduced levels of neutrophils, granulocytes, uric acid, and platelet concentration. Ethanol extract of PA rescued these phenotypes by increasing anti-oxidative responses as assessed by biochemistry and histopathology. In addition, the ethanol extract of PA at two doses showed a significant diuretic activity by increased levels of total urine output and urinary elerolytes such as sodium and potassium. In conclusion, these data suggest that the ethanol extract of PA possess nephroprotective and antioxidant effects against APAP-induced nephrotoxicity and strong diuretics effect in rats.

  10. Propolis reverses acetaminophen induced acute hepatorenal alterations: a biochemical and histopathological approach.

    Science.gov (United States)

    Nirala, Satendra Kumar; Bhadauria, Monika

    2008-04-01

    The present study has been conducted to evaluate the curative effect of propolis extract, a honey bee-hive product, against acetaminophen (APAP) induced oxidative stress and dysfunction in liver and kidney. Animals were challenged with APAP (2 g/kg, p.o.) followed by treatment of propolis extract (100 and 200 mg/kg, p.o.) once only after 24 h. Release of transaminases, alkaline phosphatase, lactate dehydrogenase, and serum bilirubin were increased, whereas hemoglobin and blood sugar were decreased after APAP administration. Antioxidant status in both the liver and kidney tissues were estimated by determining the glutathione, malondialdehyde content and activities of the CYP enzymes, which showed significant alterations after APAP intoxication. In addition, activities of adenosine triphosphatase, acid phosphatase, alkaline phosphatase, and major cell contents (total protein, glycogen and cholesterol) were also altered due to APAP poisoning. Propolis extract successfully reversed the alterations of these biochemical variables at higher dose. Improvements in hepatorenal histoarchitecture were also consistent with biochemical observations. The results indicated that ethanolic extract of propolis has ability to reverse APAP-induced hepatorenal biochemical and histopathological alterations probably by increasing the antioxidative defense activities due to various phenolic compounds present in it.

  11. Effects of quercetin on polychlorinated biphenyls-induced liver injury in rats

    Directory of Open Access Journals (Sweden)

    Cléia Rocha de Oliveira

    2014-05-01

    Full Text Available Introduction: Polychlorinated biphenyls (PCBs, used as pesticides in agriculture, can lead to irreversible injuries in living organisms, particularly in liver. Oxidative stress has been implicated in the liver pathogenesis induced by different molecules, including PCBs. It has been demonstrated that quercetin, an antioxidant flavonoid found in the diet, exhibits a potent antioxidant effect in different liver pathologies. Objective: To evaluate oxidative stress caused by PCBs in liver and the antioxidant activity of quercetin. Methodology: We used male Wistar rats (n = 36, divided in 4 groups: control, quercetin (50 mg/kg/day, PCBs (0.4 ml/kg/day, and rats treated with both PCBs and quercetin. On day 25 blood was collected to assess liver integrity (enzymes AST, ALT and ALP, and liver samples to measure oxidative stress (TBARS, activity of antioxidant enzymes (SOD, CAT, GPx and DNA damage (micronucleus assay, and histological damage. Results: TBARS concentration and SOD activity were significantly higher in PCBs animals as compared to the PCB group receiving quercetin. CAT and GPx decreased in PCBs and increased when quercetin was added. The histological analysis showed damage to hepatocytes in PCBs, but quercetin was able to afford protection against such damage. The micronucleus test showed there was an increase in the production of microclenucleus compared to control, and quercetin was able to reduce this effect. Conclusion: Contamination with PCBs led to increased lipid peroxidation and DNA damage, and the use of antioxidant quercetin was effective in reducing PCBs-induced liver injury.

  12. U-74389G PRETREATMENT ATTENUATING WARM ISCHEMIA INJURY IN LIVER TRANSPLANTATION

    Institute of Scientific and Technical Information of China (English)

    严佶祺; 李宏为; 张明钧; 杨卫平; 蔡伟耀; 林言箴

    2002-01-01

    Objective To investigate the protective role of lazaroid U-74389G pretreatment against warm ischemia injury of rat liver transplantation from non-heart-beating donors. Methods Rat othortopic liver transplantation was perfomed in 4 groups (N-45, N-60 , pN-45 and pN-60 ), according to pretreatrnent with U-74389G or not, and the non-heart-beating time 45min or 60min before donor liver harvested. Survival rates, liver functions, MDA values and graft pathology of each group were compared. Results The oneweek survival rates ofGroupN-45, N-60 , pN-45 and pN-60 were25% (2/8), 0% (0/8), 58.3% (7/12)and 33.3% ( 4/12 ), respectively. U-74389G pretreatment significantly increased survival rate of rat liver transplantation from non-heart-beating donors, but also improved liver functions atd graft pathologies, as well as decreased MDA expression. Conclusion U-74389G pretreatment could attenuate warm ischemia reperfusion injury of rat liver transplantation from non-heart-beating donors.

  13. [Method of treatment of combined injuries of the liver and spleen in children].

    Science.gov (United States)

    Babich, I I; Matveev, O L; Panchenko, S N; Poliakova, L P

    2008-01-01

    Since 1980 operations for combined injuries of the liver and spleen have been made on 57 children aged from 5 through 16 years. Autografting of splenic tissue into the liver wound was performed in 17 (29.8%) patients using an original technique developed in experiments. The novelty of the suggested technique is that autografting of splenic tissue into the liver wound was followed by fixing the fragments with Pi-like stitches through the spleen transplant capsule. It ensures the impermeability of the liver wound, adequate hemostasis without applying artificial hemostatic materials and helps to avoid alloplastic materials for additional drainage of the subhepatic space, provides a direct physiological contact between the splenoid and liver tissue that is effective for prevention of hyposplenism following spleenectomy.

  14. TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.

    Directory of Open Access Journals (Sweden)

    Susanne Nicole Weber

    Full Text Available The development of hepatocellular carcinoma (HCC is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN, with HCC formation depending amongst others on interleukin (IL 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6 as well as hepatic apoptosis (TUNEL and proliferation (Ki67 rates.Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.This study demonstrates that liver injury upon DEN challenge

  15. [A clinicopathological study of primary liver cancer associated with alcoholic liver injury].

    Science.gov (United States)

    Kohgo, Y; Ohhira, M; Ono, M

    1996-04-01

    We described a clinicopathological study of primary hepatoma associated with alcoholic liver diseases without viral liver diseases. In 150 patients with primary hepatoma, 6 patients (4%) have hepatoma associated with pure alcoholic liver disease, although 143 hepatoma were associated with chronic viral liver diseases and one was with primary biliary cirrhosis. All patients were male. The diagnosis of hepatoma was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Three cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in 3 cases and liver cirrhosis was in 3 cases. Chronic infections of hepatitis B and C viruses were ruled out by assaying serum virus markers. Autoimmune hepatitis and primary biliary cirrhosis were neglected by serum autoantibody. Hemochromatosis and Wilson's disease were also excluded. Hepatocellular carcinoma was diagnosed histologically in all the cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced hepatocellular carcinoma. In cases with small hepatoma, the tumor was resected surgically in two cases and percutaneous ethanol injection against hepatoma was performed in one case. In these cases with small hepatoma, the patients were alive without tumor recurrence during observation period. In advanced hepatoma, transcatheter arterial infusion of anticancer agent was performed in two cases and no therapy was performed due to poor general condition in one case. One case was alive with recurrent hepatoma for 27 months, during which a therapy was repeated five times. Other 2 cases were died. The clinicopathological features of hepatoma associated with alcoholic liver disease were essentially same as those associated with chronic viral infection, although the incidence of hepatoma in alcoholic liver disease was lower than in viral liver disease. The mechanism of hepatocarcinogenesis in alcoholic liver disease was unclear and, therefore

  16. Drug-Induced Liver Injury Is a Major Risk for New Drugs.

    Science.gov (United States)

    Seeff, Leonard B

    2015-01-01

    Drug-induced liver injury (DILI), a relatively rare condition, is nevertheless a major reason for not approving a drug in development or for removing one already marketed. With a specific diagnostic biomarker lacking, finding elevated serum enzyme [alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase] activities remains an initial signal for incipient liver injury. Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called 'Hy's law') there is a high possibility of serious DILI. In 1997 several drugs were approved by the Food and Drug Administration (FDA) of the USA that were later withdrawn from the market for serious liver toxicity. New drugs in development are now required to be monitored for liver injury, and the data is to be considered in the approval decision. A program called e-DISH (evaluation of drug-induced serious hepatotoxicity) was introduced in 2004 to aid medical reviewers to select from all subjects studied those few who show nontrivial liver injury and estimate the most likely cause. The threshold of enzyme elevation comprising a warning for possibly serious DILI is uncertain, although generally accepted as 3-5 times the 'upper limit of normal'. The new direct-acting antiviral agents for treating chronic hepatitis C virus, which often lead to a reduction of elevated ALTs, mandate that a later increase without viral breakthrough be compared to the new on-treatment level of values. The drug may be discontinued or interrupted for evaluation to exclude other possible causes of liver injury. The FDA has approved no drug since 1997 that has been withdrawn later because of serious hepatotoxicity.

  17. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

    Science.gov (United States)

    Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel

    2014-06-01

    Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury.

  18. Xanthohumol suppresses inflammatory response to warm ischemia-reperfusion induced liver injury.

    Science.gov (United States)

    Dorn, Christoph; Massinger, Sabine; Wuzik, Andreas; Heilmann, Jörg; Hellerbrand, Claus

    2013-02-01

    Liver ischemia/reperfusion (I/R) leads to formation of reactive oxygen species (ROS), which cause hepatic injury and initiate an inflammatory response, which is a critical problem after liver surgery and transplantation. Xanthohumol, the major prenylated chalcone found in hops, has been discussed for its anti-inflammatory and ROS-scavenging properties, and thus, we aimed to investigate the effect of xanthohumol in a model of warm I/R liver injury. Xanthohumol was applied to BALB/c mice orally at a dose of 1 mg/g body weight for 5 days before I/R-injury was induced by clamping the vascular blood supply to the median and left lateral liver lobe for 1 h followed by a 6 h period of reperfusion. At this time, HPLC analysis revealed hepatic xanthohumol levels of approximately 2 μM, a concentration which has been shown to inhibit inflammatory effects in vitro. Assessment of hepatic HMOX1 expression, hepatic glutathione content and immunohistochemical analysis for proteins conjugated with the reactive aldehyde 4-hydroxynonenal indicated that I/R-induced oxidative stress was significantly inhibited in xanthohumol-fed compared to control mice. Histological analysis, TUNEL staining and determination of transaminase serum levels revealed no significant effects of xanthohumol on acute hepatocellular injury. However, at the same time point, pretreatment with xanthohumol almost completely blunted the I/R-induced AKT and NFκB activation and the expression of the proinflammatory genes IL-1alpha, IL-6, MCP-1 and ICAM-1, which are known to play a crucial role in the subacute phase of I/R-induced liver damage. In conclusion, these data indicate the potential of xanthohumol application to prevent adverse inflammatory responses to I/R-induced liver damage such as after surgical liver resection or transplantation.

  19. Ciprofloxacin-induced cholestatic liver injury – A case report

    Directory of Open Access Journals (Sweden)

    Miroslav Vujasinović

    2012-09-01

    Case report: A 19year old man has been treated with ciprofloxacin at a daily dose of 500 mg twice a day due to a mild respiratory infection. After twenty days he was admitted to hospital because of jaundice. Laboratory findings showed a typical pattern of acute cholestatic liver failure, which was additionally confirmed by the liver biopsy. The patient was treated symptomatically. Ten months later the patient’s clinical status is stabile with a normal bilirubin level and mildly elevated alkaline phosphatase and gamma-glutamyltransferase. Conclusion: Although severe hepatotoxicity after the administration of ciprofloxacin is rare, physicians should be cautious and alert to its side-effects.

  20. Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera Extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N-acetylcysteine.

    Science.gov (United States)

    Fan, Xiaomei; Chen, Pan; Jiang, Yiming; Wang, Ying; Tan, Huasen; Zeng, Hang; Wang, Yongtao; Qu, Aijuan; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2015-03-01

    Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.

  1. Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene.

    Science.gov (United States)

    Mojena, M; Hortelano, S; Castrillo, A; Diaz-Guerra, M J; Garcia-Barchino, M J; Saez, G T; Bosca, L

    2001-03-01

    The effect of pre-existent hepatic NO synthesis on liver injury induced by lipopolysaccharide was studied in animals carrying a nitric oxide synthase-2 (NOS-2) transgene under the control of the phosphoenolpyruvate carboxykinase (PEPCK) promoter. These animals expressed NOS-2 in liver cells under fasting conditions. Lipopolysaccharide-induced liver injury in D-galactosamine-conditioned mice, which enhanced notably the effect of the endotoxin on the liver, was impaired in animals expressing NOS-2. This protection against inflammatory liver damage was dependent on NO synthesis and was caused by an inhibition of nuclear factor kB (NF-kB) activity and an impairment of the synthesis of the proinflammatory cytokines tumor necrosis factor a and interleukin 1b. These data indicate that intrahepatic synthesis of NO protects liver by inhibiting the release of cascades of proinflammatory mediators and suggest a beneficial role for local delivery of NO in the control of liver injury.

  2. Therapeutic potential of alpha-ketoglutarate against acetaminophen-induced hepatotoxicity in rats

    Directory of Open Access Journals (Sweden)

    Lalita Mehra

    2016-01-01

    Full Text Available Objective: Alpha-ketoglutarate (α-KG is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP induced toxicity in rats. Materials and Methods: Animals were divided into three groups of six animals each. Group I (Vehicle control: Normal Saline, Group II (APAP: A single intraperitoneal injection of 0.6 g/kg, Group III (APAP + α-KG: APAP as in Group II with α-KG treatment at a dose of 2 g/kg, orally for 5 days. Then the levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and alkaline phosphatase (ALP with oxidative stress markers including malondialdehyde (MDA, reduced glutathione (GSH, superoxide dismutase (SOD, catalase (CAT, and histopathology were analyzed. Results: The results indicate that APAP caused significant elevations in ALT, AST, ALP, and MDA levels, while GSH, SOD, and CAT were significantly depleted while co-administration of α-KG showed a significant (P < 0.05 reduction in the severity of these damages. Histologically, the liver showed inflammation and necrosis after APAP treatment, which were significantly restored with co-administration of α-KG. Conclusion: These results indicate the possible therapeutic potential of α-KG in protecting liver damage by APAP in rats.

  3. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  4. Influence of zinc sulfate intake on acute ethanol-induced liver injury in rats

    Institute of Scientific and Technical Information of China (English)

    Sema Bolkent; Pelin Arda-Pirincci; Sehnaz Bolkent; Refiye Yanardag; Sevim Tunali; Sukriye Yildirim

    2006-01-01

    AIM: To investigate the role of metallothionein and proliferating cell nuclear antigen (PCNA) on the morphological and biochemical effects of zinc sulfate in ethanol-induced liver injury.METHODS: Wistar albino rats were divided into four groups. Group I; intact rats, group Ⅱ; control rats given only zinc, group Ⅲ; animals given absolute ethanol, group Ⅳ; rats given zinc and absolute ethanol.Ethanol-induced injury was produced by the 1 mL of absolute ethanol, administrated by gavage technique to each rat. Animals received 100 mg/kg per day zinc sulfate for 3 d 2 h prior to the administration of absolute ethanol.RESULTS: Increases in metallothionein immunoreactivity in control rats given only zinc and rats given zinc and ethanol were observed. PCNA immunohistochemistry showed that the number of PCNA-positive hepatocytes was increased significantly in the livers of rats administered ethanol + zinc sulfate. Acute ethanol exposure caused degenerative morphological changes in the liver. Blood glutathione levels decreased, serum alkaline phosphatase and aspartate transaminase activities increased in the ethanol group when compared to the control group. Liver glutathione levels were reduced, but lipid peroxidation increased in the livers of the group administered ethanol as compared to the other groups. Administration of zinc sulfate in the ethanol group caused a significant decrease in degenerative changes, lipid peroxidation, and alkaline phosphatase and aspartate transaminase activities, but an increase in liver glutathione.CONCLUSION: Zinc sulfate has a protective effect on ethanol-induced liver injury. In addition, cell proliferation may be related to the increase in metallothionein immunoreactivity in the livers of rats administered ethanol + zinc sulfate.

  5. Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion

    Science.gov (United States)

    Yazdani, Hamza O.; Sud, Vikas; Goswami, Julie; Loughran, Patricia; Huang, Hai; Simmons, Richard L.; Tsung, Allan

    2017-01-01

    Introduction Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Methods Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. Results After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines

  6. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats

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    Sayed M. Mizar

    2015-03-01

    Full Text Available Oxidative stress plays a key role in the pathogenesis of hepatic ischemia/reperfusion (I/R-induced injury, one of the leading causes of liver damage post-surgical intervention, trauma and transplantation. This study aimed to evaluate the protective effect of nebivolol and chrysin against I/R-induced liver injury via their vasodilator and antioxidant effects, respectively. Adult male Wister rats received nebivolol (5 mg/kg and/or chrysin (25 mg/kg by oral gavage daily for one week then subjected to ischemia via clamping the portal triad for 30 min then reperfusion for 30 min. Liver function enzymes, alanine transaminase (ALT and aspartate transaminase (AST, as well as hepatic Myeloperoxidase (MPO, total nitrate (NOx, glutathione (GSH and liver malondialdehyde (MDA were measured at the end of the experiment. Liver tissue damage was examined by histopathology. In addition, the expression levels of nitric oxide synthase (NOS subtypes, endothelial (eNOS and inducible (iNOS in liver samples were assessed by Western blotting and confirmed by immunohistochemical analysis. Both chrysin and nebivolol significantly counteracted I/R-induced oxidative stress and tissue damage biomarkers. The combination of these agents caused additive liver protective effect against I/R-induced damage via the up regulation of nitric oxide expression and the suppression of oxidative stress. Chrysin and nebivolol combination showed a promising protective effect against I/R-induced liver injury, at least in part, via decreasing oxidative stress and increasing nitric oxide levels.

  7. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen.

    Science.gov (United States)

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-02-26

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA(-/-)). We found that MsrA(-/-) mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA(+/+)). The central lobule area of the MsrA(-/-) liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA(-/-) than in MsrA(+/+) mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA(-/-) than in MsrA(+/+) livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA(-/-) than in MsrA(+/+) livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion.

    Science.gov (United States)

    Tohme, Samer; Kameneva, Marina V; Yazdani, Hamza O; Sud, Vikas; Goswami, Julie; Loughran, Patricia; Huang, Hai; Simmons, Richard L; Tsung, Allan

    2017-08-29

    Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines. DRPs significantly attenuated

  9. Hepatoprotective Effect of Trigona spp. Bee Propolis against Carbon Tetrachloride-Induced Liver Injury in Rat

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    Rachel Amelia

    2016-06-01

    Full Text Available Background: Oxidative stress reaction can cause liver injury. This process can be prevented by antioxidant activities which can break the destructive chain caused by free radical substances in the liver. Propolis produced by Trigona spp. bee is known to have a high level of antioxidant. The aim of this study was to examine the effect of Trigona spp. bee propolis on liver histological toxicity caused by carbon tetrachloride-induced oxidative stress. Methods:This experimental study was conducted in September 2013 at the Animal Laboratory of Departement of Pharmacology and Therapy, Faculty of Medicine Universitas Padjadjaran. Twenty-four healthy male Wistar rats as objects were adapted for one week and randomly divided into 3 groups. Group I was the control negative, group II was given carbon tetrachloride on day 14, group III was given Trigona spp. bee propolis on day 1-14. On day 14, group III was injected CCl4 intraperitoneally. The quantitative data were statistically analyzed using the one way ANOVA and Tukey test with p value < 0.05. Results: Group I showed the liver contained normal cells, without significant injury of the membrane, round and complete nucleus. The average number of liver cell was 464 ± 9.59281 cells/field; group II underwent necrosis and the average of the cells was 146 ± 7.56885 cells/field; group III showed some normal liver cells, and some necrotic area with the normal liver cells average was 263 ± 14.10860 cells/field. The p-value=0.00. Conclusions: Trigona spp. bee propolis has a hepatoprotective effect against CCl4-induced liver injury histologically.

  10. Pharmaco-epidemiological, clinical and laboratory characteristics of drug-induced liver injury in tuberculosis

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    M. V. Koroleva

    2015-01-01

    Full Text Available Objective: improving the efficiency of pharmacotherapy of drug-induced liver injury in tuberculosis by clarifying pharmaco-epidemiological, clinical and laboratory features.Materials and Methods: A retrospective analysis of primary medical records of 250 patients with pulmonary tuberculosis, patients «Volgograd Regional Clinical TB Dispensary № 1». We evaluated the dynamics of biochemical parameters characterizing the development of hepatic cytolytic syndrome, examined the impact of gender and age on the incidence of liver damage, we investigated the relationship of clinical tuberculosis and chemotherapy regimen with the incidence of drug-induced liver injury, examined the clinical manifestations of liver disease.Results: Drug-induced liver injury as a complication of a specific anti-TB treatment was diagnosed in 67 patients (26,8%. In 170 patients (68,0% showed increase in alanine aminotransferase and asparaginaminotrasferazy. Hepatotoxicity significantly more common in patients with disseminated tuberculosis with the collapse of the lung tissue, smear, and a high degree of disease severity. Risk factors for drug liver damage were female gender and age older than 50 years. Women develop liver disease at an earlier date, and displays it harder than men. The earliest and most informative routine biochemical tests, reflecting the state of the liver in the dynamics are ALT and AST. It was found that the mode of the standard anti-TB treatment determines the type of liver injury: the first, 2a and 3rd modes prevails cytolytic hepatocellular type, with 2b mode – combined (mixed type 4th – type of cholestatic liver damage. It was found that repeated, after the development of hepatotoxic reactions, the appointment of anti-TB drugs without gepatoprotektsii in 94% of patients leads to repeated drug-induced liver damage. Cancel specific therapy against the background of cytolytic syndrome promotes the formation of

  11. Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat.

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    Ismail Ben Mosbah

    Full Text Available Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP, a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging

  12. Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury.

    Science.gov (United States)

    Irvine, Katharine M; Clouston, Andrew D; Gadd, Victoria L; Miller, Gregory C; Wong, Weng-Yew; Melino, Michelle; Maradana, Muralidhara Rao; MacDonald, Kelli; Lang, Richard A; Sweet, Matthew J; Blumenthal, Antje; Powell, Elizabeth E

    2015-01-01

    Macrophages play critical roles in liver regeneration, fibrosis development and resolution. They are among the first responders to liver injury and are implicated in orchestrating the fibrogenic response via multiple mechanisms. Macrophages are also intimately associated with the activated hepatic progenitor cell (HPC) niche or ductular reaction that develops in parallel with fibrosis. Among the many macrophage-derived mediators implicated in liver disease progression, a key role for macrophage-derived Wnt proteins in driving pro-regenerative HPC activation towards a hepatocellular fate has been suggested. Wnt proteins, in general, however, have been associated with both pro- and anti-fibrogenic activities in the liver and other organs. We investigated the role of macrophage-derived Wnt proteins in fibrogenesis and HPC activation in murine models of chronic liver disease by conditionally deleting Wntless expression, which encodes a chaperone essential for Wnt protein secretion, in LysM-Cre-expressing myeloid cells (LysM-Wls mice). Fibrosis and HPC activation were exacerbated in LysM-Wls mice compared to littermate controls, in the absence of an apparent increase in myofibroblast activation or interstitial collagen mRNA expression, in both the TAA and CDE models of chronic liver disease. Increased Epcam mRNA levels paralleled the increased HPC activation and more mature ductular reactions, in LysM-Wls mice. Increased Epcam expression in LysM-Wls HPC was also observed, consistent with a more cholangiocytic phenotype. No differences in the mRNA expression levels of key pro-inflammatory and pro-fibrotic cytokines or the macrophage-derived HPC mitogen, Tweak, were observed. LysM-Wls mice exhibited increased expression of Timp1, encoding the key Mmp inhibitor Timp1 that blocks interstitial collagen degradation, and, in the TAA model, reduced expression of the anti-fibrotic matrix metalloproteinases, Mmp12 and Mmp13, suggesting a role for macrophage-derived Wnt proteins

  13. Expression of nitric oxide synthase in T-cell-dependent liver injury initiated by ConA in Kunming mice

    Institute of Scientific and Technical Information of China (English)

    张修礼; 曲建慧; 万谟彬; 权启镇; 孙自勤; 王要军; 江学良; 李文波

    2004-01-01

    Objective: To investigate whether nitric oxide synthase (NOS) is expressed in T-cell-dependent liver injury initiated by concanavalin A (ConA) in Kunming mice and study the possible effect of nitric oxide(NO) on liver injury models. Methods: Liver injury in Kunming mice was induced by administration of ConA through tail vein. Expression of NOS in the liver was detected by NADPH diaphorase staining method. The possible effect of NO on liver injury models was obtained by L-NAME injection to suppress synthesis of NO. Results: NOS has a strong expression in hepatocytes after ConA injection, especially in those close to the central vein, while only a weak expression was found in the epithelial cells in control group. Liver injury became more serious when NO synthesis was inhibited by L-NAME, accompanied by great malondialdehyde(MDA) increase in serum and severe intrahepatic vascular thrombosis. Conclusion: NOS markedly expressed in ConAinduced liver injury, which may subsequently promote nitric oxide synthesis. Increasement of nitric oxide has a protective effect on ConA-induced liver injury.

  14. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.; Schlienger, R.; Reynolds, R.; Klungel, O.

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods T

  15. Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

    Science.gov (United States)

    Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

    2014-05-01

    Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response.

  16. Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.

    Science.gov (United States)

    Shin, So Youn; Jeong, Sook-Hyang; Sung, Pil Soo; Lee, Jino; Kim, Hyung Joon; Lee, Hyun Woong; Shin, Eui-Cheol

    2016-05-01

    Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

  17. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.|info:eu-repo/dai/nl/313936455; Schlienger, R.; Reynolds, R.; Klungel, O.|info:eu-repo/dai/nl/181447649

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods T

  18. Application of urine proteomics for biomarker discovery in drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Kramers, Cornelis; Masereeuw, R.; Russel, Frans G M

    2014-01-01

    Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker cand

  19. Ascertainment of acute liver injury in two European primary care databases

    NARCIS (Netherlands)

    Ruigómez, A.; Brauer, R.; Rodríguez, L. A García; Huerta, C.; Requena, G.; Gil, M.; de Abajo, Francisco; Downey, G.; Bate, A.; Tepie, M. Feudjo; de Groot, M.C.H.|info:eu-repo/dai/nl/313936455; Schlienger, R.; Reynolds, R.; Klungel, O.|info:eu-repo/dai/nl/181447649

    2014-01-01

    Purpose The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. Methods

  20. Methylene blue attenuates acute liver injury induced by paraquat in rats.

    Science.gov (United States)

    Chen, Jun-Liang; Dai, Li; Zhang, Peng; Chen, Wei; Cai, Gao-Shan; Qi, Xiao-Wei; Hu, Ming-Zhu; Du, Bin; Pang, Qing-Feng

    2015-09-01

    Paraquat (PQ) poisoning often leads to severe oxidative liver injury. Recent studies have reported that methylene blue (MB) can prevent oxidative stress-induced diseases. This study tested the hypothesis that MB treatment reduced acute liver injury induced by PQ in rats. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: (1) normal group, (2) MB group (2mg/kg i.p.), (3) PQ group (35 mg/kg i.p.) and (4) PQ+MB group (MB 2mg/kg i.p. administrated 2h after PQ). We evaluated the changes of liver histopathology, serum liver enzymatic activities, oxidative stress, heme oxygenase-1 expression, and mitochondrial permeability transition. The rats were injected with PQ produced liver injury, evidenced by histological changes and elevated serum alkaline phosphatase and alanine transaminase levels; PQ also led to oxidative stress, an increase of malondialdehyde content and mitochondrial permeability transition pore opening. Pathological damage and all of the above mentioned markers were reversed in the animals treated with MB than in those who received PQ alone. Meanwhile, MB significantly increased the contents of superoxide dismutase, adenosine triphosphate and the expression of heme oxygenase-1. In conclusion, MB had a protective effect against PQ-induced hepatic damage in rats. The mechanisms of the protection seem to be the inhibition of mitochondrial permeability transition opening and the increase of heme oxygenase-1 expression.

  1. Hepatoprotective effect of Matricaria chamomilla.L in paraquat induced rat liver injury.

    Science.gov (United States)

    Tavakol, H S; Farzad, K; Fariba, M; Abdolkarim, C; Hassan, G; Seyed-Mostafa, H Z; Akram, R

    2015-02-01

    Paraquat (PQ), an effective and widely used herbicide, has been proven to be safe when appropriately applied to eliminate weeds. However, PQ poisoning is an extremely frustrating clinical condition with a high mortality and with a lack of effective treatments in humans. PQ is known to induce injury via a redox cyclic reaction. The purpose of this study was to investigate the effect of aqueous extract Matricaria chamomilla.L (M. chamomilla) against PQ-induced liver injury in association with its antioxidant activity.The male rats were treated by gastric gavage daily with PQ (5 mg/kg/day) and M. chamomilla (50 mg/kg/day) were administered alone or in combination for 7 days. After treatments, total antioxidant capacity (TAC), total thiol molecules (TTG) levels and catalase (CAT) activity in liver tissue were measured. At the end of the experiment, plasma and lung tissue of the animals was separated. The activity of enzymatic scavengers such as CAT, TAC and TTG were measured in liver homogenate.In this sample, the TAC and TTG were lower in the PQ group as compared with control group. Co-administration of PQ with M. chamomilla extract increased TAC and TTG in liver tissue as compared with PQ group.In conclusion, M. chamomilla as natural antioxidant may be considered beneficial for the protection oxidative liver injury in PQ poisoning.

  2. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury.

    Science.gov (United States)

    Frazier, Thomas H; DiBaise, John K; McClain, Craig J

    2011-09-01

    Obesity and its metabolic complications are major health problems in the United States and worldwide, and increasing evidence implicates the microbiota in these important health issues. Indeed, it appears that the microbiota function much like a metabolic "organ," influencing nutrient acquisition, energy homeostasis, and, ultimately, the control of body weight. Moreover, alterations in gut microbiota, increased intestinal permeability, and metabolic endotoxemia likely play a role in the development of a chronic low-grade inflammatory state in the host that contributes to the development of obesity and associated chronic metabolic diseases such as nonalcoholic fatty liver disease. Supporting these concepts are the observations that increased gut permeability, low-grade endotoxemia, and fatty liver are observed in animal models of obesity caused by either high-fat or high-fructose feeding. Consistent with these observations, germ-free mice are protected from obesity and many forms of liver injury. Last, many agents that affect gut flora/permeability, such as probiotics/prebiotics, also appear to affect obesity and certain forms of liver injury in animal model systems. Here the authors review the role of the gut microbiota and metabolic endotoxemia-induced inflammation in the development of obesity and liver injury, with special reference to the intensive care unit setting.

  3. Difficulties in diagnosing acute kidney injury post liver transplantation using serum creatinine based diagnostic criteria

    Institute of Scientific and Technical Information of China (English)

    Banwari; Agarwal; Andrew; Davenport

    2014-01-01

    Renal function in patients with advanced cirrhosis is an important prognostic factor for survival both prior to and following liver transplantation. The importance of renal function is reflected by the introduction of the model for end stage liver disease(MELD) score, which includes serum creatinine. The MELD score has been shown to predict the short term risk of death for transplant wait listed patients and is currently used by many countries to allocate liver transplants on the basis of severity of underlying illness. Changes in serum creatinine are also used to stage acute kidney injury. However prior to liver transplantation the serum creatinine typically over estimates underlying renal function, particularly when a colorimetric Jaffe based assay is used, and paradoxically then under estimates renal function post liver transplantation, particularly when immunophyllins are started early as part of transplant immunosuppression. As acute kidney injury is defined by changes in serum creatinine, this potentially leads to over estimation of the incidence and severity of acute kidney injury in the immediate post-operative period.

  4. Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion.

    Directory of Open Access Journals (Sweden)

    Bin Liu

    Full Text Available Hepatic ischemia/reperfusion (I/R injury is an unavoidable consequence of major liver surgery, especially in liver transplantation with bowel congestion, during which endotoxemia is often evident. The inflammatory response aggravated by endotoxin after I/R contributes to liver dysfunction and failure. The purpose of the present study was to investigate the protective effect of butyrate, a naturally occurring four-carbon fatty acid in the body and a dietary component of foods such as cheese and butter, on hepatic injury complicated by enterogenous endotoxin, as well as to examine the underlying mechanisms involved. SD rats were subjected to a total hepatic ischemia for 30 min after pretreatment with either vehicle or butyrate, followed by 6 h and 24 h of reperfusion. Butyrate preconditioning markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathological changes. The inflammatory factors levels, macrophages activation, TLR4 expression, and neutrophil infiltration in live were attenuated by butyrate. Butyrate also maintained the intestinal barrier structures, reversed the aberrant expression of ZO-1, and decreased the endotoxin translocation. We conclude that butyrate inhibition of endotoxin translocation, macrophages activation, inflammatory factors production, and neutrophil infiltration is involved in the alleviation of total hepatic I/R liver injury in rats. This suggests that butyrate should potentially be utilized in liver transplantation.

  5. Epigenetic effects of ethanol on liver and gastrointestinal injury

    Institute of Scientific and Technical Information of China (English)

    Shivendra D Shukla; Annayya R Aroor

    2006-01-01

    Alcohol consumption causes cellular injury. Recent developments indicate that ethanol induces epigenetic alterations, particularly acetylation, methylation of histones, and hypo- and hypermethylation of DNA. This has opened up a new area of interest in ethanol research and is providing novel insight into actions of ethanol at the nucleosomal level in relation to gene expression and patho-physiological consequences. The epigenetic effects are mainly attributable to ethanol metabolic stress (Emess), generated by the oxidative and non-oxidative metabolism of ethanol, and dysregulation of methionine metabolism. Epigenetic changes are important in ethanol-induced hepatic steatosis, fibrosis, carcinoma and gastrointestinal injury. This editorial highlights these new advances and its future potential.

  6. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice.

    Science.gov (United States)

    van der Geest, Rick; Ouweneel, Amber B; van der Sluis, Ronald J; Groen, Albert K; Van Eck, Miranda; Hoekstra, Menno

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; Phypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Intermittent Ischemia but Not Ischemic Preconditioning Is Effective in Restoring Bile Flow After Ischemia Reperfusion Injury in the Livers of Aged Rats

    NARCIS (Netherlands)

    Schiesser, Marc; Wittert, Anna; Nieuwenhuijs, Vincent B.; Morphett, Arthur; Padbury, Robert T. A.; Barritt, Greg J.

    2009-01-01

    BackgroundlAims. Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of t

  8. Protective Effect of Sundarban Honey against Acetaminophen-Induced Acute Hepatonephrotoxicity in Rats

    Directory of Open Access Journals (Sweden)

    Rizwana Afroz

    2014-01-01

    Full Text Available Honey, a supersaturated natural product of honey bees, contains complex compounds with antioxidant properties and therefore has a wide a range of applications in both traditional and modern medicine. In the present study, the protective effects of Sundarban honey from Bangladesh against acetaminophen- (APAP- induced hepatotoxicity and nephrotoxicity in experimental rats were investigated. Adult male Wistar rats were pretreated with honey (5 g/kg for 4 weeks, followed by the induction of hepatotoxicity and nephrotoxicity via the oral administration of a single dose of APAP (2 g/kg. Organ damage was confirmed by measuring the elevation of serum alkaline phosphatase (ALP, alanine transaminase (ALT, aspartate transaminase (AST, total protein (TP, total bilirubin (TB, urea, creatinine, and malondialdehyde (MDA. Histopathological alterations observed in the livers and the kidneys further confirmed oxidative damage to these tissues. Animals pretreated with Sundarban honey showed significantly markedly reduced levels of all of the investigated parameters. In addition, Sundarban honey ameliorated the altered hepatic and renal morphology in APAP-treated rats. Overall, our findings indicate that Sundarban honey protects against APAP-induced acute hepatic and renal damage, which could be attributed to the honey’s antioxidant properties.

  9. Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice.

    Science.gov (United States)

    Alanazi, Abdulrazaq; Algfeley, Saleh G; Al-Hosaini, Khaled A; Korashy, Hesham M; Imam, Faisal; Nagi, Mahmoud N

    2017-04-01

    Overdose of acetaminophen (APAP) is often associated with hepatotoxicity. Carfilzomib (CFZ) shows multiple pharmacological activities including anti-inflammatory potential. Therefore, this study was undertaken to evaluate the possible therapeutic effects of CFZ against APAP-induced hepatotoxicity. Hepatotoxicity was induced by administration of APAP (350 mg/kg, intraperitoneal). Mice were given CFZ (0.125, 0.25, or 0.5 mg/kg, intraperitoneal) 1.5 h after APAP administration. Animals were sacrificed on 6 h and blood and liver tissue samples were collected for analysis. In CFZ-post-treated group, there was significant and dose-dependent decrease in serum alanine aminotransferase levels. The level of tumor necrosis factor-α (TNF-α), reactive oxygen species, and NO decreased, whereas glutathione increased significantly by CFZ post-treatment. Upregulated mRNA expression of COX-II and iNOS were significantly downregulated by CFZ post-treatment. CFZ may exert its hepatoprotective action by alleviating inflammatory, oxidative, and nitrosative stress via inhibition of TNF-α, COX-II, and iNOS. © 2016 Wiley Periodicals, Inc.

  10. Acetaminophen-induced anion gap metabolic acidosis secondary to 5-oxoproline: a case report.

    Science.gov (United States)

    Abkur, Tarig Mohammed; Mohammed, Waleed; Ali, Mohamed; Casserly, Liam

    2014-12-06

    5-oxoproline (pyroglutamic acid), an organic acid intermediate of the gamma-glutamyl cycle, is a rare cause of high anion gap metabolic acidosis. Acetaminophen and several other drugs have been implicated in the development of transient 5-oxoprolinemia in adults. We believe that reporting all cases of 5-oxoprolinemia will contribute to a better understanding of this disease. Here, we report the case of a patient who developed transient 5-oxoprolinemia following therapeutic acetaminophen use. A 75-year-old Caucasian woman was initially admitted for treatment of an infected hip prosthesis and subsequently developed transient high anion gap metabolic acidosis. Our patient received 40 g of acetaminophen over a 10-day period. After the more common causes of high anion gap metabolic acidosis were excluded, a urinary organic acid screen revealed a markedly increased level of 5-oxoproline. The acidosis resolved completely after discontinuation of the acetaminophen. 5-oxoproline acidosis is an uncommon cause of high anion gap metabolic acidosis; however, it is likely that it is under-diagnosed as awareness of the condition remains low and testing can only be performed at specialized laboratories. The diagnosis should be suspected in cases of anion gap metabolic acidosis, particularly in patients with recent acetaminophen use in combination with sepsis, malnutrition, liver disease, pregnancy or renal failure. This case has particular interest in medicine, especially for the specialties of nephrology and orthopedics. We hope that it will add more information to the literature about this rare condition.

  11. Hepatoprotective Effect of Pretreatment with Thymus vulgaris Essential Oil in Experimental Model of Acetaminophen-Induced Injury

    National Research Council Canada - National Science Library

    Grespan, Renata; Aguiar, Rafael Pazinatto; Giubilei, Frederico Nunes; Fuso, Rafael Rocco; Damião, Marcio José; Silva, Expedito Leite; Mikcha, Jane Graton; Hernandes, Luzmarina; Bersani Amado, Ciomar; Cuman, Roberto Kenji Nakamura

    2014-01-01

    .... This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO), which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects...

  12. Protective effect of mycelial polysaccharides from Cordyceps sinensis on immunological liver injury in mice

    Directory of Open Access Journals (Sweden)

    Kai-zhong DONG

    2016-04-01

    Full Text Available Objective  To explore the protective effects of mycelial polysaccharides from Cordyceps sinensis (MPCS on BCG+LPS-induced liver injury in mice. Methods  The immunological liver injury mice model was reproduced by giving bacillus Calmette-Guerin (BCG and lipopolysaccharide (LPS. Sixty NIH mice were randomly assigned into 6 groups (10 each: normal control group, model group, mycelium polysaccharide in high (100mg/kg, medium (50mg/kg and low (25mg/kg dose group, and bifendate (150mg/kg treatment group. The serum transaminase levels of alanine ALT and AST were assayed with ELISA, nitric oxide (NO in serum was measured by nitrate reductase method, and the liver homogenate was prepared for the determination of the contents of interleukin-1β(IL-1β and tumor necrosis factor-α(TNF-α. The mRNA expression levels of IL-6 and iNOS in hepatic tissue were assessed using RT-PCR . Results  In the mice of immunological liver injury, mycelial polysaccharides from Cordyceps sinensis obviously lowered the serum ALT and AST levels (P<0.01, high dose MPCS significantly reduced the serum NO and liver tissue IL-1βand TNF-αlevels (P<0.01. Compared with the model group, high and medium dose MPCS significantly reduced the expression levels of IL-6 and iNOS mRNA in hepatic tissues (P<0.01. Conclusion  MPCS shows a certain protective effect on immunological liver injury induced by BCG plus LPS in mice. DOI: 10.11855/j.issn.0577-7402.2016.04.05

  13. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  14. Ischemia and reperfusion injury of the rat liver: the role of nimodipine.

    Science.gov (United States)

    Chávez-Cartaya, R E; Pino DeSola, G; Ramirez-Romero, P; Calne, R Y; Jamieson, N V

    1996-01-01

    The protective effect of the calcium channel blocker nimodipine on liver ischemia and reperfusion was studied in the rat. The homeostasis of intracellular calcium ions seems to be a determinant factor in the cell injury that appears after ischemia and reperfusion. Nimodipine was used to downregulate the calcium levels in the cytosol of the ischemic cell, the hypothetical role of Ca2+ in the pathogenesis of ischemia and reperfusion injury. The experimental procedure consisted of the temporary interruption of blood flow to the left lateral and medial lobes of the rat liver and subsequent reperfusion after a period of 45 min of ischemia. Nimodipine (10 micrograms/kg body wt) was administered either before or after the onset of ischemia. The postischemic liver blood flow and liver oxyhemoglobin saturation were recorded using a He-Ne laser Doppler flowmeter and photometer, which showed, in the pretreated group, a recovery of reperfusion blood flow (58.1%) and liver reflectance (85.5%) significantly better (P flow (32.8%) and reflectance (70.5%). In the group that received nimodipine after ischemia, the recovery of the blood flow and the postreperfusion liver reflectance were not significantly better than those in the untreated control group. ALT levels (P < 0.05), galactose elimination capacity (P < 0.001), and histological studies also showed a protective effect of calcium antagonist nimodipine when administered before ischemia.

  15. Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury

    Institute of Scientific and Technical Information of China (English)

    Lauren M Aleksunes; Michael Goedken; José E Manautou

    2006-01-01

    AIM: To investigate the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in human liver specimens obtained from patients with liver damage due to acetaminophen (APAP) overdose or primary biliary cirrhosis (PBC).METHODS: NQO1 activity was determined in cytosol from normal, APAP and PBC liver specimens. Western blot and immunohistochemical staining were used to determine patterns of NQO1 expression using a specific antibody against NQO1.RESULTS: NQO1 protein was very low in normal human livers. In both APAP and PBC livers, there was strong induction of NQO1 protein levels on Western blot.Correspondingly, significant up-regulation of enzyme activity (16- and 22-fold, P< 0.05) was also observed in APAP and PBC livers, respectively. Immunohistochemical analysis highlighted injury-specific patterns of NQO1 staining in both APAP and PBC livers.CONCLUSION: These data demonstrate that NQO1 protein and activity are markedly induced in human livers during both APAP overdose and PBC. Up-regulation of this cytoprotective enzyme may represent an adaptive stress response to limit further disease progression by detoxifying reactive species.

  16. Lupeol protects against acetaminophen-induced oxidative stress and cell death in rat primary hepatocytes.

    Science.gov (United States)

    Kumari, Archana; Kakkar, Poonam

    2012-05-01

    Drug induced hepatotoxicity is a major problem where phytochemicals hold promise for its abrogation. This study was carried out to explore cytoprotective potential of lupeol, a triterpene, against acetaminophen (AAP)-induced toxicity in rat hepatocytes. AAP exposure significantly (p<0.05) reduced cell viability, disturbed Bcl-2 family pro/anti-apoptotic protein balance, increased ROS production and altered redox homeostasis. It also induced mitochondria-mediated hepatocellular injury by significant mitochondrial depolarization, caspase-9/3 activation and subsequent DNA fragmentation. Our results suggest that lupeol pre-treatment effectively restored antioxidant enzyme levels, decreased lipid peroxidation, inhibited ROS generation and depolarization of mitochondria. Lupeol also attenuated mitochondria-mediated signaling pathway and DNA damage as evident from TUNEL assay and cell cycle studies leading to prevention of cytotoxicity. This study confirms the efficacy of lupeol, a food derived antioxidant, in abrogating ROS generation, maintaining redox balance and providing significant protection against mitochondria-mediated cell death during AAP-induced toxicity.

  17. Effect of fasting on the metabolic response of liver to experimental burn injury.

    Directory of Open Access Journals (Sweden)

    Mehmet A Orman

    Full Text Available Liver metabolism is altered after systemic injuries such as burns and trauma. These changes have been elucidated in rat models of experimental burn injury where the liver was isolated and perfused ex vivo. Because these studies were performed in fasted animals to deplete glycogen stores, thus simplifying quantification of gluconeogenesis, these observations reflect the combined impact of fasting and injury on liver metabolism. Herein we asked whether the metabolic response to experimental burn injury is different in fed vs. fasted animals. Rats were subjected to a cutaneous burn covering 20% of the total body surface area, or to similar procedures without administering the burn, hence a sham-burn. Half of the animals in the burn and sham-burn groups were fasted starting on postburn day 3, and the others allowed to continue ad libitum. On postburn day 4, livers were isolated and perfused for 1 hour in physiological medium supplemented with 10% hematocrit red blood cells. The uptake/release rates of major carbon and nitrogen sources, oxygen, and carbon dioxide were measured during the perfusion and the data fed into a mass balance model to estimate intracellular fluxes. The data show that in fed animals, injury increased glucose output mainly from glycogen breakdown and minimally impacted amino acid metabolism. In fasted animals, injury did not increase glucose output but increased urea production and the uptake of several amino acids, namely glutamine, arginine, glycine, and methionine. Furthermore, sham-burn animals responded to fasting by triggering gluconeogenesis from lactate; however, in burned animals the preferred gluconeogenic substrate was amino acids. Taken together, these results suggest that the fed state prevents the burn-induced increase in hepatic amino acid utilization for gluconeogenesis. The role of glycogen stores and means to increase and/or maintain internal sources of glucose to prevent increased hepatic amino acid

  18. Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation

    Directory of Open Access Journals (Sweden)

    Xiaxia Cai

    2016-03-01

    Full Text Available Background: Previous studies suggested that nucleotides were beneficial for liver function, lipid metabolism and so on. The present study aimed to investigate the metabolic response of dietary nucleotides supplementation in alcohol-induced liver injury rats. Methods: Five groups of male Wistar rats were used: normal control group (basal diet, equivalent distilled water, alcohol control group (basal diet, 50% alcohol (v/v, dextrose control group (basal diet, isocaloric amount of dextrose, and 0.04% and 0.16% nucleotides groups (basal diet supplemented with 0.4 g and 1.6 g nucleotides kg−1 respectively, 50% alcohol (v/v. The liver injury was measured through traditional liver enzymes, expression of oxidative stress markers and histopathological examination. Ultra-performance liquid chromatography quadrupole-time-flight mass spectrometry (UPLC-Q-TOF-MS was applied to identify liver metabolite profiles. Results: Nucleotides supplementation prevented the progression of hepatocyte steatosis. The levels of total proteins, globulin, alanine aminotransferase, aspartate aminotransferase, total cholesterol triglyceride, as well as the oxidative stress markers altered by alcohol, were improved by nucleotides supplementation. Elevated levels of liver bile acids (glycocholic acid, chenodeoxyglycocholic acid, and taurodeoxycholic acid, as well as lipids (stearic acid, palmitic acid, oleic acid, phosphatidylcholine, and lysophosphatidylethanolamine in alcohol-treated rats were reversed by nucleotides supplementation. In addition, supplementation with nucleotides could increase the levels of amino acids, including valyl-Leucine, l-leucine, alanyl-leucine and l-phenylalanine. Conclusion: These data indicate potential biomarkers and confirm the benefit of dietary nucleotides on alcoholic liver injury.

  19. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

    Directory of Open Access Journals (Sweden)

    Peter Onody

    Full Text Available INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment or 24 hours (late pretreatment before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005, AST (p early = 0.02; p late = 0.004 and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034 and PAR positivity (p early = 0.02; p late = 0.04. Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

  20. A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.

    Directory of Open Access Journals (Sweden)

    Sinem Perk

    Full Text Available With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD. A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD, recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP, and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE as log(SPE >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

  1. A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.

    Science.gov (United States)

    Perk, Sinem; Izamis, Maria-Louisa; Tolboom, Herman; Uygun, Basak; Berthiaume, Francois; Yarmush, Martin L; Uygun, Korkut

    2011-01-01

    With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

  2. Resistance to acetaminophen-induced hepatotoxicity in glutathione S-transferase Mu 1-null mice.

    Science.gov (United States)

    Arakawa, Shingo; Maejima, Takanori; Fujimoto, Kazunori; Yamaguchi, Takashi; Yagi, Masae; Sugiura, Tomomi; Atsumi, Ryo; Yamazoe, Yasushi

    2012-01-01

    We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3β and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity.

  3. Implication of altered proteasome function in alcoholic liver injury

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The proteasome is a major protein-degrading enzyme,which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels: low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation.Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins.Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. In addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling (Ⅰ-κB and SOCS), thereby blocking cytokine signal transduction.Finally, ethanol-elicited blockade of interferon type 1 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class Ⅰ-restricted antigen presentation.

  4. HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

    Directory of Open Access Journals (Sweden)

    Manuela G. Neuman

    2012-01-01

    Full Text Available The present paper describes possible connections between antiretroviral therapies (ARTs used to treat human immunodeficiency virus (HIV infection and adverse drug reactions (ADRs encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication.

  5. A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury.

    Science.gov (United States)

    Kohonen, Pekka; Parkkinen, Juuso A; Willighagen, Egon L; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C

    2017-07-03

    Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 10(8) data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments. Analysing 68 DILI-annotated drugs, the PTGS tool outperforms and complements existing tests, leading to a hereto-unseen level of DILI prediction accuracy.

  6. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Science.gov (United States)

    Ishida, Tokiko; Kotani, Hirokazu; Miyao, Masashi; Kawai, Chihiro; Jemail, Leila; Abiru, Hitoshi; Tamaki, Keiji

    2016-01-01

    The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of

  7. Renal Impairment with Sublethal Tubular Cell Injury in a Chronic Liver Disease Mouse Model.

    Directory of Open Access Journals (Sweden)

    Tokiko Ishida

    Full Text Available The pathogenesis of renal impairment in chronic liver diseases (CLDs has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy, autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the

  8. Intravenous administration of glutathione protects parenchymal and non-parenchymal liver cells against reperfusion injury following rat liver transplantation

    Institute of Scientific and Technical Information of China (English)

    Rolf J. Schauer; Sinan Kalmuk; Alexander L. Gerbes; Rosemarie Leiderer; Herbert Meissner; Friedrich W. Schildberg; Konrad Messmer; Manfred Bilzer

    2004-01-01

    AIM: To investigate the effects of intravenous administration of the antioxidant glutathione (GSH) on reperfusion injury following liver transplantation.METHODS: Livers of male Lewis rats were transplantedafter 24 h of hypothermic preservation in University of Wisconsin solution in a syngeneic setting. During a 2-h reperfusion period either saline (controls, n=8) or GSH administered via the jugular vein.RESULTS: Two hours after starting reperfusion plasma ALT increased to 1 457±281 U/L (mean±SE) in controls but to only 908±187 U/L (P<0.05) in animals treated with morphological findings on electron microscopy: GSH treatment prevented detachment of sinusoidal endothelial cells (SECs) as well as loss of microvilli and mitochondrial swelling of hepatooytes. Accordingly, postischemic bile flow increased 2-fold. Intravital fluorescence microscopy revealed a nearly complete restoration of sinusoidal blood flow and a significant reduction of leukocyte adherence to sinusoids and postsinusoidal venules. Following infusion of 50 μmol and and 97±18 mol/L, but to only 20±3 mol/L in untreated recipients. Furthermore, plasma glutathione disulfide (GSSG) increased untreated controls (1.8±0.5 mol/L vs 2.2±0.2 mol/L).CONCLUSION: Plasma GSH levels above a critical level may act as a "sink" for ROS produced in the hepatic vasculature during reperfusion of liver grafts. Therefore, GSH can be considered a candidate antioxidant for the prevention of reperfusion injury after liver transplantation, in particular since it has a low toxicity in humans.

  9. Dynamical changing pattems of glycogen and enzyme histochemical activities in rat liver graft undergoing warm ischemia injury

    Institute of Scientific and Technical Information of China (English)

    Xiao-Shun He; Yi Ma; Lin-Wei Wu; Jin-Lang Wu; Rui-De Hu; Gui-Hua Chen; Jie-Fu Huang

    2005-01-01

    AIM: To investigate the changing patterns of glycogen and enzyme histochemical activities in rat liver graft under a dif ferent warm ischemia time (WIT) and to predict the tolerant time limitation of the liver graft to warm ischemia injury.METHODS: The rats were randomized into five groups, WTT was 0, 15, 30, 45, 60 min, respectively, and histochemical staining of liver graft specimens was observed. The recovery changes of glycogen and enzyme histochemistry activities were measured respectively 6 and 24 h following liver graft implantation.RESULTS: The activities of succinic dehydrogenase, cytochrome oxidase, apyrase (Mg++-ATPase) and content of glycogen were decreased gradually after different WIT in a time-dependent manner. The changes were significant when WIT was over 30 min.CONCLUSION: Hepatic injury is reversible within 30 min of warm ischemia injury. Glycogen and enzyme histochemistry activities of liver grafts and their recovery potency after reperfusion may serve as criteria to evaluate the quality of liver grafts.

  10. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    OpenAIRE

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in...

  11. Epigallocatechin-3-Gallate Ameliorates Alcohol-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Xi Li

    2006-07-01

    Full Text Available Endotoxemia is a common event in alcoholic liver disease. Elevated intestinalpermeability is the major factor involved in the mechanism of alcoholic endotoxemia andthe pathogenesis of alcoholic liver disease. This study examined the effect ofepigallocatechin-3-gallate (EGCG on alcohol-induced gut leakiness, and explored therelated mechanisms involved in its protection against alcohol-induced liver injury in rats.Four groups of female Sprague-Dawley rats were studied. Alcohol and alcohol/EGCGgroups rats received fish oil along with alcohol daily via gastrogavage for 6 weeks, anddextrose and dextrose/EGCG groups rats were given fish oil along with isocaloric dextroseinstead of alcohol. The dextrose/EGCG and alcohol/EGCG groups received additionaltreatment of EGCG (100mg.kg-1 body weight daily intragastrically by gavage. Intestinalpermeability was assessed by urinary excretion of lactulose and mannitol (L/M ratio. Liverinjury was evaluated histologically and by serum alanine aminotransferase (ALT. Plasmaendotoxin and serum tumor necrosis factor-α (TNF-α levels were assayed; livermalondialdehyde (MDA contents determined. CD14 and inflammatory factors, such asTNF-α, cyclooxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS mRNAs inthe liver were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR. Ratsgiven fish oil plus alcohol had gut leakiness (L/M ratio was increased, which wasassociated with both endotoxemia and liver injury. The above responses were accompaniedby increased CD14, TNF-α, COX-2 and iNOS mRNA expressions in the liver. EGCGsupplementation partly blocked the gut leakiness, reduced endotoxemia and lipidperoxidation, and blunted the elevated expressions of CD14, TNF-α, COX-2 and iNOS, allof which were associated with improved liver injury. These results show that EGCG can block alcohol-induced gut leakiness, reduce endotoxemia, and inhibit inflammatory factors expressions in

  12. Effect of WeiJia on carbon tetrachloride induced chronic liver injury

    Institute of Scientific and Technical Information of China (English)

    Pik-Yuen Cheung; Jay Chun; Hsiang-Fu Kung; Meng-su Yang; Qi Zhang; Ya-Ou Zhang; Gan-Rong Bai; Marie Chia-Mi Lin; Bernard Chan; Chi-Chun Fong; Lin Shi; Yue-Feng Shi

    2006-01-01

    AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model.METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week,Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type Ⅳ collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed.RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV,ALT, AST and Y-GT levels after eight weeks of treatment for Group C rats were 58±22 μg/L (P0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in a-SMA expression level was also observed.CONCLUSION: WeiJia could improve liver function and reduce liver fibrosis

  13. Proteomic analysis of protective effects of polysaccharides from Salvia miltiorrhiza against immunological liver injury in mice.

    Science.gov (United States)

    Sun, Xue-Gang; Fu, Xiu-Qiong; Cai, Hong-Bing; Liu, Qiang; Li, Chun-Hua; Liu, Ya-Wei; Li, Ying-Jia; Liu, Zhi-Feng; Song, Yu-Hong; Lv, Zhi-Ping

    2011-07-01

    This study was designed to investigate mechanisms of the protective effects of Salvia miltiorrhiza polysaccharide (SMPS) against lipopolysaccharide (LPS)-induced immunological liver injury (ILI) in Bacille Calmette-Guérin (BCG)-primed mice. Two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis showed that three proteins are down-regulated and six proteins are up-regulated by SMPS. SMPS reduces the degree of liver injury by up-regulating the enzymes of the citric acid cycle, namely malate dehydrogenase (MDH) and 2-oxoglutarate dehydrogenase complex. LPS significantly increases nuclear factor kappa B (NF-κB) activation, inducible nitric oxide synthase (iNOS) expression and MDA level in BCG primed mice liver, whereas SMPS treatment protects against the immunological liver injury through inhibition of the NF-κB activation by up-regulation of PRDX6 and the subsequent attenuation of lipid peroxidation, iNOS expression and inflammation. Copyright © 2011 John Wiley & Sons, Ltd.

  14. Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Yun-Hee Lee

    2016-07-01

    Full Text Available It has been reported that barley leaves possess beneficial properties such as antioxidant, hypolipidemic, antidepressant, and antidiabetic. Interestingly, barley sprouts contain a high content of saponarin, which showed both anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of barley sprouts on alcohol-induced liver injury mediated by inflammation and oxidative stress. Raw barley sprouts were extracted, and quantitative and qualitative analyses of its components were performed. The mice were fed a liquid alcohol diet with or without barley sprouts for four weeks. Lipopolysaccharide (LPS-stimulated RAW 264.7 cells were used to study the effect of barley sprouts on inflammation. Alcohol intake for four weeks caused liver injury, evidenced by an increase in serum alanine aminotransferase and aspartate aminotransferase activities and tumor necrosis factor (TNF-α levels. The accumulation of lipid in the liver was also significantly induced, whereas the glutathione (GSH level was reduced. Moreover, the inflammation-related gene expression was dramatically increased. All these alcohol-induced changes were effectively prevented by barley sprouts treatment. In particular, pretreatment with barley sprouts significantly blocked inducible nitric oxide synthase (iNOS and cyclooxygenase (COX-2 expression in LPS-stimulated RAW 264.7. This study suggests that the protective effect of barley sprouts against alcohol-induced liver injury is potentially attributable to its inhibition of the inflammatory response induced by alcohol.

  15. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

    Institute of Scientific and Technical Information of China (English)

    Ignazio Grattagliano; Leonilde Bonfrate; Catia V Diogo; Helen H Wang; David QH Wang; Piero Portincasa

    2009-01-01

    Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O_2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca~(2+)-dependent ATPase, reduced capability to sequester Ca~(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

  16. The protective effect of Nigella sativa against liver injury: a review

    Directory of Open Access Journals (Sweden)

    Hamid Mollazadeh

    2015-12-01

    Full Text Available Nigella sativa (Family Ranunculaceae is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.

  17. Hepatoprotective effect of apple polyphenols against concanavalin A-induced immunological liver injury in mice.

    Science.gov (United States)

    Wang, Fang; Xue, Yang; Yang, Jingyu; Lin, Fang; Sun, Ying; Li, Ting; Wu, Chunfu

    2016-10-25

    Apple polyphenols (AP), a polyphenol extracted from the unripe apple, has been reported to improve acute hepatotoxicity induced by CCl4 in mice due to its significant antioxidant activity. In this study, the hepatoprotective effect of AP against concanavalin A (Con A)-induced immunological liver injury in mice was investigated. Mice were treated with AP daily for seven days prior to a single intravenous administration of Con A. The serum levels of AST, ALT, TP, Alb and histopathological changes were determined and the A/G ratio was calculated. Potential mechanisms were further explored by measuring TNF-α and IFN-γ levels, NO content as well as changes in the levels of endogenous oxidants and antioxidants. AP significantly improved the abnormal levels of ALT, AST, TP and Alb, and the A/G ratio. AP was also associated with improvement of liver histopathological changes after Con A-induced liver injury. Moreover, AP reduced serum levels of TNF-α and IFN-γ, decreased serum NO content, inhibited oxidative DNA single-strand breaks, and improved the abnormalities of MDA content, SOD activity and GSH level. These results suggest that AP exerts a protective effect against Con A-induced immunological liver injury through suppressing pro-inflammatory cytokines and activating the antioxidant system.

  18. The traditional ayurvedic medicine, Eugenia jambolana (Jamun fruit), decreases liver inflammation, injury and fibrosis during cholestasis.

    Science.gov (United States)

    Donepudi, Ajay C; Aleksunes, Lauren M; Driscoll, Maureen V; Seeram, Navindra P; Slitt, Angela L

    2012-04-01

    Cholestasis is a common disease of the liver. Chronic cholestasis eventually leads to hepatic cirrhosis and fibrosis, and rodent chronic cholestasis models are used to study aspects of fibrosis and cirrhosis. Cholestasis-induced liver injury and fibrosis are associated with increased oxidative stress and inflammation. Few pharmacological therapies exist for treatment of cholestasis or cirrhosis, but it is known that humans with better nutritional intake are less likely to develop certain types of cirrhosis. Eugenia jambolana (Jamun) is a tropical berry fruit rich in antioxidant anthocyanin compounds. As anthocyanins decrease cellular lipid peroxidation and oxidative stress, it was hypothesized that Jamun fruit extract (JFE) administration could protect against cholestatic liver injury and inflammation in mice. Starting 24 h after sham or bile-duct ligation (BDL) surgery, male C57Bl/6 mice were administered vehicle or JFE (100 mg/kg, po) for 10 days. Mice that underwent BDL had elevated serum ALT levels, which were reduced to 60% by JFE treatment. Likewise, BDL caused hepatic inflammation, macrophage infiltration, fibrosis and necrosis, all of which were largely improved by JFE. Interestingly, hepatoprotection was observed in JFE-treated BDL mice, despite suppressed transporter expression and increased hepatic bile acid concentrations. Jamun fruit phytochemicals decreased hepatic inflammation and oxidative stress, and protected against hepatocellular injury in mice. Jamun warrants further investigation as a potential antioxidant/anti-inflammatory therapy not only to treat cholestasis but also other liver diseases with an inflammatory component. © 2011 John Wiley & Sons A/S.

  19. Protective effects of apocynin and allopurinol on ischemia/reperfusion-induced liver injury in mice

    Institute of Scientific and Technical Information of China (English)

    Ping-Guo Liu; Song-Qing He; Yan-Hong Zhang; Jian Wu

    2008-01-01

    AIM: To determine the effects of allopurinol, an inhibitor of xanthine oxidase, and apocynin, an inhibitor of NADPH oxidase, on oxidant stress and liver injury caused by hepatic ischemia/reperfusion (I/R) procedure in mice. METHODS: Nice were pretreated with a xanthine oxidase inhibitor, allopurinol, or NADPH oxidase (NOX)inhibitor, apocynin before the hepatic I/R procedure. Then treated or untreated mice underwent the hepatic I/R procedure. The effects on hepatic injury and superoxide anions were determined after starting reperfusion. RESULTS: A standard warm hepatic I/R procedure led to a marked increase in superoxide anion production as indicated by a superoxide anion tracer, MCLA. At the same time, the procedure caused profound acute liver injury, as indicated by elevated serum alanine aminotransferase and tumor necrosis factor-αlevels, reduced liver glutathione levels and elevated malondialdehyde contents, as well as a high apoptotic cell count. All these changes were reversed by the use of apocynin or allopurinol prior to the hepatic I/R procedure. CONCLUSION: AIIopurinol and apocynin exerted protective effects on hepatic ischemia/reperfusion injury. The protection is associated with blocking the generation of superoxide anions during the hepatic I/R procedure by inhibiting xanthine oxidase and NADPH oxidase activity.

  20. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Zhou, Lili; Shu, Xugang [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Sun, Xiaohong [College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Mi, Shumei; Yang, Yuhui [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Yin, Yulong, E-mail: yinyulong@isa.ac.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125 (China)

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  1. Adenovirus-mediated eNOS expression augments liver injury after ischemia/reperfusion in mice.

    Directory of Open Access Journals (Sweden)

    Arun P Palanisamy

    Full Text Available Hepatic ischemia/reperfusion (l/R injury continues to be a critical problem. The role of nitric oxide in liver I/R injury is still controversial. This study examines the effect of endothelial nitric oxide synthase (eNOS over-expression on hepatic function following I/R. Adenovirus expressing human eNOS (Ad-eNOS was administered by tail vein injection into C57BL/6 mice. Control mice received either adenovirus expressing LacZ or vehicle only. Sixty minutes of total hepatic ischemia was performed 3 days after adenovirus treatment, and mice were sacrificed after 6 or 24 hrs of reperfusion to assess hepatic injury. eNOS over expression caused increased liver injury as evidenced by elevated AST and ALT levels and decreased hepatic ATP content. While necrosis was not pervasive in any group, TUNEL demonstrated significantly increased apoptosis in Ad-eNOS infected livers. Western blotting demonstrated increased levels of protein nitration and upregulation of the pro-apoptotic proteins bax and p53. Our data suggest that over-expression of eNOS is detrimental in the setting of hepatic I/R.

  2. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2

    Science.gov (United States)

    Ma, Linglan; Zhao, Jinfang; Wang, Jue; Liu, Jie; Duan, Yanmei; Liu, Huiting; Li, Na; Yan, Jingying; Ruan, Jie; Wang, Han; Hong, Fashui

    2009-11-01

    Although it is known that nano-TiO2 or other nanoparticles can induce liver toxicities, the mechanisms and the molecular pathogenesis are still unclear. In this study, nano-anatase TiO2 (5 nm) was injected into the abdominal cavity of ICR mice for consecutive 14 days, and the inflammatory responses of liver of mice was investigated. The results showed the obvious titanium accumulation in liver DNA, histopathological changes and hepatocytes apoptosis of mice liver, and the liver function damaged by higher doses nano-anatase TiO2. The real-time quantitative RT-PCR and ELISA analyses showed that nano-anatase TiO2 can significantly alter the mRNA and protein expressions of several inflammatory cytokines, including nucleic factor-κB, macrophage migration inhibitory factor, tumor necrosis factor-α, interleukin-6, interleukin-1β, cross-reaction protein, interleukin-4, and interleukin-10. Our results also implied that the inflammatory responses and liver injury may be involved in nano-anatase TiO2-induced liver toxicity.

  3. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J. [Institute of Microcirculation, Hebei North University, Zhangjiakou, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

    2014-02-17

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na{sup +}-K{sup +}-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na{sup +}-K{sup +}-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na{sup +}-K{sup +}-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  4. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    Directory of Open Access Journals (Sweden)

    Z.G. Zhao

    2014-02-01

    Full Text Available The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL on lipopolysaccharide (LPS-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1, myeloperoxidase (MPO, and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  5. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis.

    Science.gov (United States)

    Hirsova, Petra; Ibrahim, Samar H; Bronk, Steven F; Yagita, Hideo; Gores, Gregory J

    2013-01-01

    Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol) diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.

  6. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Petra Hirsova

    Full Text Available Hedgehog signaling pathway activation has been implicated in the pathogenesis of NASH. Despite this concept, hedgehog pathway inhibitors have not been explored. Thus, we examined the effect of vismodegib, a hedgehog signaling pathway inhibitor, in a diet-induced model of NASH. C57BL/6 mice were placed on 3-month chow or FFC (high saturated fats, fructose, and cholesterol diet. One week prior to sacrifice, mice were treated with vismodegib or vehicle. Mice fed the FFC diet developed significant steatosis, which was unchanged by vismodegib therapy. In contrast, vismodegib significantly attenuated FFC-induced liver injury as manifested by reduced serum ALT and hepatic TUNEL-positive cells. In line with the decreased apoptosis, vismodegib prevented FFC-induced strong upregulation of death receptor DR5 and its ligand TRAIL. In addition, FFC-fed mice, but not chow-fed animals, underwent significant liver injury and apoptosis following treatment with a DR5 agonist; however, this injury was prevented by pre-treatment with vismodegib. Consistent with a reduction in liver injury, vismodegib normalized FFC-induced markers of inflammation including mRNA for TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and a variety of macrophage markers. Furthermore, vismodegib in FFC-fed mice abrogated indices of hepatic fibrogenesis. In conclusion, inhibition of hedgehog signaling with vismodegib appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition may be salutary in human NASH.

  7. Cholesterol and sphingolipids in alcohol-induced liver injury.

    Science.gov (United States)

    Fernández, Anna; Colell, Anna; Garcia-Ruiz, Carmen; Fernandez-Checa, José C

    2008-03-01

    The pathogenesis of alcohol-induced liver disease (ALD) is still poorly understood. One of the clues to its progression relates to the alcohol-mediated susceptibility of hepatocytes to cell death by reactive oxygen species (ROS) and inflammatory cytokines. Tumor necrosis factor alpha (TNF) has been considered a key ALD mediator with acidic sphingomyelinase (ASMase)-mediated ceramide generation playing a critical role. TNF receptor 1 and 2 knock-out mice or ASMase(-/-) mice exhibit resistance to alcohol-mediated fatty liver and cell death. Furthermore, alcohol feeding has been shown to sensitize hepatocytes to TNF due to the limitation of mitochondrial glutathione (mGSH) through impaired import of GSH from the cytosol due to altered membrane order parameter caused by mitochondrial cholesterol increase. Selective pharmacological depletion of mGSH sensitizes hepatocytes to TNF-mediated cell death, which reproduces the observations found with alcohol feeding. TNF signaling analyses in hepatocytes with or without mGSH depletion indicate that mGSH prevents cardiolipin peroxidation (CLOOH) formation by TNF-induced ROS via ASMase and that CLOOH cooperates with oligomerized Bax to cause mitochondrial outer membrane permeabilization through destabilization of the lipid bilayer via increased bilayer-to-inverted hexagonal phase transitions. Thus, activation of ASMase and cholesterol-mediated mGSH depletion both collaborate to promote alcohol-induced TNF-mediated hepatocellular damage, suggesting novel therapeutic opportunities in ALD.

  8. Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Jain

    2014-01-01

    Full Text Available Total parenteral nutrition (TPN, a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD. PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR in the gut and enhance fibroblast growth factor 19 (FGF19 level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA. Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs. GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.

  9. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Akiko Kojima-Yuasa

    2016-12-01

    Full Text Available Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme’s activity and reduced intracellular thiobarbituric acid reactive substances (TBARS levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

  10. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats.

    Science.gov (United States)

    Kojima-Yuasa, Akiko; Goto, Mayu; Yoshikawa, Eri; Morita, Yuri; Sekiguchi, Hirotaka; Sutoh, Keita; Usumi, Koji; Matsui-Yuasa, Isao

    2016-12-19

    Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM) on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl₄)-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl₄-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl₄-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1)-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl₄-treated rats increased significantly, but DNSM-treatment suppressed the enzyme's activity and reduced intracellular thiobarbituric acid reactive substances (TBARS) levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

  11. Troxerutin protects the mouse liver against oxidative stress-mediated injury induced by D-galactose.

    Science.gov (United States)

    Zhang, Zi-feng; Fan, Shao-hua; Zheng, Yuan-lin; Lu, Jun; Wu, Dong-mei; Shan, Qun; Hu, Bin

    2009-09-01

    Troxerutin, a trihydroxyethylated derivative of rutin, has been well-demonstrated to exert hepatoprotective properties. In the present study, we attempted to explore whether the antioxidant and anti-inflammatory mechanisms were involved in troxerutin-mediated protection from D-gal-induced liver injury. The effects of troxerutin on liver lipid peroxidation, antioxidant enzymatic activities, and the expression of inflammatory mediator were investigated in D-gal-treated mice. The results showed that troxerutin largely attenuated the D-gal-induced TBARS content increase and also markedly renewed the activities of Cu, Zn-SOD, CAT, and GPx in the livers of D-gal-treated mice. Furthermore, troxerutin inhibited the upregulation of the expression of NF-kappaB p65, iNOS, and COX-2 induced by D-gal. D-Gal-induced tissue architecture changes and serum ALT and AST increases were effectively suppressed by troxerutin. In conclusion, these results suggested that troxerutin could protect the mouse liver from D-gal-induced injury by attenuating lipid peroxidation, renewing the activities of antioxidant enzymes and suppressing inflammatory response. This study provided novel insights into the mechanisms of troxerutin in the protection of the liver.

  12. Liver regeneration - The best kept secret: A model of tissue injury response

    Directory of Open Access Journals (Sweden)

    Javier A. Cienfuegos

    2014-03-01

    Full Text Available Liver regeneration (LR is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades. LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness and explains the difficulties of reshaping it with therapeutic goals. TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes -cell-cycle transition G0-G1-, and a second phase of proliferation -cell-cycle S/M phases- which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines (TNF-α, IL-1β, IL-6, growth factors (HGF, EGF, VGF and anti-inflammatory factors (IL-10, TGF-β. Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation. The recent induced pluripotential cells (iPS description and the mesenchymal stem cell (CD133+ plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration.

  13. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model

    Directory of Open Access Journals (Sweden)

    Banu Taskin

    2017-01-01

    Full Text Available The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days. The rats were then sacrificed to harvest blood and liver tissue samples in order to determine blood and tissue MDA, serum ALT, plasma TNF-α, TGF-β, and PTX3 levels. Histological specimens were examined via light microscopy. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by relatively worse histopathological scores and increased biochemical marker levels. Lactulose treatment significantly reduced the liver enzyme ALT, plasma TNF-α, TGF-β, PTX3, and MDA levels and also decreased histological changes in the liver tissue with MTX-induced hepatotoxicity in the rat model. We suggest that lactulose has anti-inflammatory and antifibrotic effects on an MTX-induced liver injury model. These effects can be due to the impact of intestinal microbiome.

  14. Oleanolic acid attenuates liver ischemia reper-fusion injury by HO-1/Sesn2 signaling pathway

    Institute of Scientific and Technical Information of China (English)

    Bao-Bin Hao; Xiong-Xiong Pan; Ye Fan; Ling Lu; Xiao-Feng Qian; Xue-Hao Wang; Feng Zhang; Jian-Hua Rao

    2016-01-01

    BACKGROUND: Ischemia reperfusion injury (IRI) is unavoid-able in liver transplantation and hepatectomy. The present study aimed to explore the possible mechanism and the effect of oleanolic acid (OA) in hepatic IRI. METHODS: Mice were randomly divided into 6 groups based on different treatment. IRI model: The hepatic artery, portal vein, and bile duct to the left and median