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Sample records for tetrachloride-induced liver injury

  1. Effects of pharmaceutical formulations containing thyme on carbon tetrachloride-induced liver injury in rats.

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    Rašković, Aleksandar; Pavlović, Nebojša; Kvrgić, Maja; Sudji, Jan; Mitić, Gorana; Čapo, Ivan; Mikov, Momir

    2015-12-18

    Herbal supplements are widely used in the treatment of various liver disases, but some of them may also induce liver injuries. Regarding the infuence of thyme and its constituents on the liver, conflicting results have been reported in the literature. The objective of this study was to examine the influence of two commonly used pharmaceutical formulations containing thyme (Thymus vulgaris L.), tincture and syrup, on carbon tetrachloride-induced acute liver injury in rats. Chemical composition of investigated formulations of thyme was determined by gas chromatography and mass spectrometry. Activities of enzyme markers of hepatocellular damage in serum and antioxidant enzymes in the liver homogenates were measured using the kinetic spectrophotometric methods. Liver morphology was characterized by light microscopy using routine hematoxylin and eosin staining. Thymol was found to be predominant active constituent in both tincture and syrup. Investigated thyme preparations exerted antioxidant effects in liver by preventing carbon tetrachloride-induced increase of lipid peroxidation. Furthermore, co-treatment with thyme preparations reversed the activities of oxidative stress-related enzymes xanthine oxidase, catalase, peroxidase, glutathione peroxidase and glutathione reductase, towards normal values in the liver. Hepatotoxicity induced by carbon tetrachloride was reflected by a marked elevation of AST and ALT activities, and histopathologic alterations. Co-administration of thyme tincture resulted in unexpected exacerbation of AST and ALT values in serum, while thyme syrup managed to reduce activites of aminotransferases, in comparison to carbon tetrachloride-treated animals. Despite demonstrated antioxidant activity, mediated through both direct free radical scavenging and activation of antioxidant defense mechanisms, thyme preparations could not ameliorate liver injury in rats. Molecular mechanisms of diverse effects of thyme preparations on chemical

  2. 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.

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

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    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.

  4. Effect of unfiltered coffee on carbon tetrachloride-induced liver injury in rats.

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    Poyrazoglu, Orhan Kursat; Bahcecioglu, Ibrahim Halil; Ataseven, Huseyin; Metin, Kerem; Dagli, Adile Ferda; Yalniz, Mehmet; Ustundag, Bilal

    2008-12-01

    To assess the role of unfiltered coffee upon carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. All rats were randomly divided into control group, CCl(4)-treated, unfiltered coffee-treated and CCl(4)/unfiltered coffee-treated. Hepatic damage was induced by repeated intraperitoneal injections of CCl(4) every other day. Unfiltered coffee was given as drinking fluid for 8 days starting the day before CCl(4) administration. Liver enzymes, plasma and liver tissue malondialdehyde were analyzed. Histopathological evaluation of liver sections was performed. Serum aminotransferase level significantly increased in CCl(4)/unfiltered coffee-treated group compared to CCl(4)-treated group, as well as, lipid peroxidation products in the plasma and liver tissue. In addition, histopathological findings including inflammation and necrosis were significantly confirmed these findings. Unfiltered coffee potentiates acute liver injury in rats with CCl(4)-induced hepatotoxicity.

  5. Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

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    Shanzheng Lu

    2016-10-01

    Full Text Available Abstract Background The endometrial regenerative cell (ERC is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl4–induced acute liver injury (ALI. Methods An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl4. Transplanted ERCs were intravenously injected (1 million/mouse into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl4 induction. Results ERC treatment effectively decreased the CCl4-induced elevation of serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA was increased after ERC treatment. Furthermore, the frequency of CD4+ and CD8+ T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4+CD25+FOXP3+ regulatory T cells (Tregs was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver. Conclusions Human ERCs protect the liver from acute injury

  6. Hepatoprotective properties for Salvia cryptantha extract on carbon tetrachloride-induced liver injury.

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    Yalcin, Alper; Yumrutas, Onder; Kuloglu, Tuncay; Elibol, Ebru; Parlar, Ali; Yilmaz, İsmet; Pehlivan, Mustafa; Dogukan, Mevlut; Uckardes, Fatih; Aydin, Hasan; Turk, Ahmet; Uludag, Oznur; Sahin, İbrahim; Ugur, Kader; Aydin, Suleyman

    2017-12-30

    The present study was designed to determine the possible hepatoprotective effects of Salvia cryptantha (black weed) plant extract against carbon tetrachloride (CCl4)-induced hepatic injury in rats. Animals were grouped as follows: control group (Group I), CCl4 group (Group II), olive oil group (Group III), CCl4 + S. cryphantha 200 mg/kg group (Group IV), and CCl4 + S. cryptantha 400mg/kg group (Group V). Rats were injected intraperitoneally with CCl4 diluted in olive oil (50% v/v) at a dose of 1ml/kg body weight.  Bax and Caspase3 were determined by immunohistochemical staining, while apoptotic index was evaluated using TUNEL assay. Total mRNA was isolated from liver tissues, and the levels of BCL2, Caspase3, SOD, CAT, and glutathione peroxidase (GPx) were determined by using PCR, while MDA level were determined using a colorimetric assay. The antioxidant and anti-apoptotic gene transcripts were decreased in all of the control and treatment groups, while Caspase3 levels were not statistically different. The S. cryptantha plant extract treatment was also found to improve SOD, GPx, and catalase levels, while reducing the serum levels of MDA. The extract of S. cryptantha supplementation had a protective effect against CCl4-induced liver damage. S. cryptantha extract as a supplement may be useful as a hepato-protective agent to combat the toxic effects caused by CCl4 and other chemicals.

  7. Opuntia ficus indica (L.) Mill. fruit juice protects liver from carbon tetrachloride-induced injury.

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    Galati, E M; Mondello, M R; Lauriano, E R; Taviano, M F; Galluzzo, M; Miceli, N

    2005-09-01

    The protective effects of the juice of Opuntia ficus indica fruit (prickly pear) against carbon tetrachloride (CCl(4))-induced hepatotoxicity were examined in rats. The animals were treated orally with the juice (3 mL/rat) 2 h after administration of the hepatotoxic agent. Preventive effects were studied by giving the juice (3 mL/rat) for 9 consecutive days. On day 9 the rats received the hepatotoxic agent. Morphological and biochemical evaluations were carried out 24, 48 and 72 h after induction of the hepatic damage. Data show that O. ficus indica fruit juice administration exerts protective and curative effects against the CCl(4)-induced degenerative process in rat liver. Histology evaluation revealed a normal hepatic parenchyma at 48 h; the injury was fully restored after 72 h. Moreover, a significant reduction in CCl(4)-induced increase of GOT and GPT plasma levels is evident; these data are in agreement with the functional improvement of hepatocytes. O. ficus indica fruit juice contains many phenol compounds, ascorbic acid, betalains, betacyanins, and a flavonoid fraction, which consists mainly of rutin and isorhamnetin derivatives. Hepatoprotection may be related to the flavonoid fraction of the juice, but other compounds, such as vitamin C and betalains could, synergistically, counteract many degenerative processes by means of their antioxidant activity. Copyright 2005 John Wiley & Sons, Ltd.

  8. Involvement of TGF-β1/Smad3 Signaling in Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

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    Liman Niu

    Full Text Available Transforming growth factor-beta1 (TGF-β1 is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4 is a liver toxicant, and CCl4-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3-overexpressing mice as well. These results

  9. Inulin-type fructan and infusion of Artemisia vulgaris protect the liver against carbon tetrachloride-induced liver injury.

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    Corrêa-Ferreira, Marília Locatelli; Verdan, Maria Helena; Dos Reis Lívero, Francislaine Aparecida; Galuppo, Larissa Favaretto; Telles, José Ederaldo Queiroz; Alves Stefanello, Maria Élida; Acco, Alexandra; Petkowicz, Carmen Lúcia de Oliveira

    2017-01-15

    Infusions of aerial parts of Artemisia vulgaris L. (Asteraceae) are used in herbal medicine to treat several disorders, including hepatosis. Evaluation of in vivo hepatoprotective effects of A. vulgaris infusion (VI) and inulin (VPI; i.e., the major polysaccharide of VI). The hepatoprotective effect of A. vulgaris extracts on carbon tetrachloride (CCl 4 )-induced hepatotoxicity and the probable mechanism involved in this protection were investigated in mice. A. vulgaris infusion (VI) was prepared according to folk medicine using the aerial parts of the plant. Carbohydrate, protein, and total phenolic content was determined in VI, and its phenolic profile was determined by high-performance liquid chromatography (HPLC). Male Swiss mice were orally pretreated for 7 days with VI or VPI (once per day). On days 6 and 7 of treatment, the mice were intraperitoneally challenged with CCl 4 . Liver and blood were collected and markers of hepatic damage in plasma and oxidative stress in the liver were analyzed. Hepatic histology and inflammatory parameters were also studied in the liver. The scavenging activity of VI and VPI were evaluated in vitro using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. VI contained 40% carbohydrates, 2.9% proteins and 9.8% phenolic compounds. The HPLC fingerprint analysis of VI revealed chlorogenic, caffeic and dicaffeoylquinic acids as major low-molar-mass constituents. Oral pretreatment with VI and VPI significantly attenuated CCl 4 -induced liver damage, reduced the activity of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in plasma, and prevented reactive oxygen species accumulation and lipid peroxidation in the liver. Comparisons with the CCl 4 -treated group showed that VI and VPI completely prevented necrosis, increased the levels of reduced glutathione (GSH), and reduced tumor necrosis factor alpha (TNF-α) level in the liver. VI and VPI also exhibited high radical scavenging activity in vitro

  10. Endogenous n-3 Fatty Acids Alleviate Carbon-Tetrachloride-Induced Acute Liver Injury in Fat-1 Transgenic Mice

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    Ruibing Feng

    2016-01-01

    Full Text Available n-3 polyunsaturated fatty acids (PUFAs are beneficial for numerous models of liver diseases. The probable protective effects of n-3 PUFA against carbon-tetrachloride- (CCl4- induced acute liver injury were evaluated in a fat-1 transgenic mouse that synthesizes endogenous n-3 from n-6 PUFA. Fat-1 mice and their WT littermates were fed a modified AIN93 diet containing 10% corn oil and were injected intraperitoneally with a single dose of CCl4 or vehicle. CCl4 challenge caused severe liver injury in WT mice, as indicated by serum parameters and histopathological changes, which were remarkably ameliorated in fat-1 mice. Endogenous n-3 PUFA decreased the elevation of oxidative stress induced by CCl4 challenge, which might be attributed to the activation of Nrf2/keap1 pathway. Additionally, endogenous n-3 PUFA reduces hepatocyte apoptosis via suppressing MAPK pathway. These findings indicate that n-3 PUFA has potent protective effects against acute liver injury induced by CCl4 in mice, suggesting that n-3 PUFA can be used for the prevention and treatment of liver injury.

  11. Protective effects of baicalin on carbon tetrachloride induced liver injury by activating PPARγ and inhibiting TGFβ1.

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    Qiao, Hongxiang; Han, Hongcan; Hong, Dongsheng; Ren, Zihua; Chen, Yan; Zhou, Changxin

    2011-01-01

    Traditional Chinese herbal medicines have attracted considerable attention in many countries with treatment of several end-stage liver diseases. The present study investigated the protective effects of baicalin on hepatotoxicity and hepatic fibrosis and explored the role of transforming growth factor β1 (TGFβ1) and peroxisome proliferator activated receptors γ (PPARγ) on the rat liver injury model. The rat liver injury model was introduced by subcutaneous injection of carbon tetrachloride (CCl(4)) for 8 weeks. At week 5, rats were treated with baicalin of different doses or silymarin. Detection of biochemical indicators, histological analysis, and enzyme-linked immunosorbent assays were employed to evaluate severity of liver inflammation, and western blotting and RT-PCR assay were performed to evaluate TGFβ1 and PPARγ pathway related proteins and gene expression. The administration of baicalin could significantly improve histological changes of CCl(4) treated rat livers and return biochemical indicators for liver injury to nearly baseline level. In addition, the increased expression of TGFβ1 was markedly suppressed by baicalin, and decreased expression of PPARγ was also dramatically elevated by baicalin as well. The hepatoprotective effects of baicalin may be conferred by elevating the level of PPARγ contributing to down-regulation of TGFβ1 signaling pathway and suppression of hepatic stellate cell activation. The studies demonstrated that baicalin is a potent and promising antifibrotic drug in the treatment of hepatic fibrosis.

  12. Reduction of carbon tetrachloride-induced rat liver injury by IRFI 042, a novel dual vitamin E-like antioxidant.

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    Campo, G M; Squadrito, F; Ceccarelli, S; Calò, M; Avenoso, A; Campo, S; Squadrito, G; Altavilla, D

    2001-04-01

    Carbon tetrachloride (CCl4 )-induced hepatotoxicity is likely the result of a CCl4 -induced free radical production which causes membrane lipid peroxidation and activation of transcription factors regulating both the TNF-alpha gene and the early-immediate genes involved in tissue regeneration. IRFI 042 is a novel vitamin E-like compound having a masked sulphydryl group in the aliphatic side chain. We studied the effect of IRFI 042 on CCl4 -induced liver injury. Liver damage was induced in male rats by an intraperitoneal injection of CCl4 (1 ml/kg in vegetal oil). Serum alanine aminotransferase (ALT) activity, liver malondialdehyde (MAL), hydroxyl radical formation (OH*), calculated indirectly by a trapping agent, hepatic reduced glutathione (GSH) concentration, plasma TNF-alpha, liver histology and hepatic mRNA levels for TNF-alpha were evaluated 48 h after CCl4 administration. Hepatic vitamin E (VE) levels were evaluated, in a separate group of animals, 2 h after CCl4 injection. A control group with vitamin E (100 mg/kg) was also treated in order to evaluate the differences versus the analogue treated groups. Intraperitoneal injection of carbon tetrachloride produced a marked increase in serum ALT activity (CCl4 = 404.61 +/- 10.33 U/L; Controls= 28.54 +/- 4.25 U/L), liver MAL (CCl4 = 0.67 +/- 0.16 nmol/mg protein; Controls= 0.13 +/- 0.06 nmol/mg protein), OH(7) levels assayed as 2,3-DHBA (CCl4 = 8.73 +/- 1.46 microM; Controls= 0.45 +/- 0.15 microM) and 2,5-DHBA (CCl4 = 24.61 +/- 3.32 microM; Controls= 2.75 +/- 0.93 microM), induced a severe depletion of GSH (CCl4 = 3.26 +/- 1.85 micromol/g protein; Controls= 17.82 +/- 3.13 micromol/g protein) and a marked decrease in VE levels (CCl4 = 5.67 +/- 1.22 nmol/g tissue; Controls= 13.47 +/- 3.21 nmol/g tissue), caused liver necrosis, increased plasma TNF-alpha levels (CCl4 = 57.36 +/- 13.24 IU/ml; Controls= 7.26 +/- 2.31 IU/ml) and enhanced hepatic mRNA for TNF-alpha (CCl4 = 19.22 +/- 4.38 a.u.; Controls= 0.76 +/- 0.36 a

  13. Antioxidant and Hepatoprotective Activity of Veronica ciliata Fisch. Extracts Against Carbon Tetrachloride-Induced Liver Injury in Mice

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    Li Yin

    2014-06-01

    Full Text Available Veronica ciliata Fisch. has been traditionally used in Traditional Chinese Medicine prescriptions due to its curative effects for hepatitis, cholecystitis, rheumatism, and urticaria. The present study was focused on investigating the role of ethyl acetate and aqueous extracts of Veronica ciliata Fisch. Furthermore, in vitro antioxidant activity (scavenging of DPPH, ABTS, superoxide, and nitrite radicals; reducing power; β-carotene bleaching and the hepatoprotective effect of the ethyl acetate extract by means of CCl4-induced oxidative stress in mice were investigated. The ethyl acetate extract of Veronica ciliata Fisch. displayed more noteworthy in vitro antioxidant activities than the aqueous extract. Moreover, it significantly prevented the increase in serum T-AOC, ALT, AST and ALP level in acute liver damage induced by CCl4, decreased the extent of MDA formation in liver and elevated the activities of SOD and GSH in liver. This activity was found to be comparable to that of bifendate. Histopathological observation of the liver was also performed to further support the evidence from the biochemical analysis. The results indicated that strong antioxidant activities and a significant protective effect against acute hepatotoxicity induced by CCl4 of Veronica ciliata Fisch. were concentrated in the ethyl acetate extract. The results suggested that this activity may be due to free radical-scavenging and antioxidant properties.

  14. S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury.

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    Corrales, F; Giménez, A; Alvarez, L; Caballería, J; Pajares, M A; Andreu, H; Parés, A; Mato, J M; Rodés, J

    1992-10-01

    Administration of carbon tetrachloride to rats resulted in induction of hepatic fibrosis and a 60% reduction of hepatic S-adenosylmethionine synthetase activity without producing any significant modification of hepatic levels of S-adenosylmethionine synthetase messenger RNA. The reduction of S-adenosylmethionine synthetase activity was corrected by treatment with S-adenosylmethionine (3 mg/kg/day, intramuscularly). Administration of carbon tetrachloride also produced a 45% depletion of liver glutathione (reduced form) that was corrected by S-adenosylmethionine treatment. After the rats received carbon tetrachloride, a 2.3-fold increase in liver collagen was observed; prolyl hydroxylase activity was 2.5 times greater than that seen in controls. These increases were attenuated in animals treated with carbon tetrachloride and S-adenosylmethionine. The attenuation by S-adenosylmethionine treatment of the fibrogenic effect of carbon tetrachloride was associated with a decrease in the number of rats in which cirrhosis developed.

  15. Curcumin Attenuates on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Modulation of the Nrf2/HO-1 and TGF-β1/Smad3 Pathway

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    Xinyan Peng

    2018-01-01

    Full Text Available This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4 exposure. At 24 h, curcumin-attenuated CCl4 induced elevated serum transaminase activities and histopathological damage in the mouse’s liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA formations, and increased superoxide dismutase (SOD, catalase (CAT activities and glutathione (GSH content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-β1 and Smad3 mRNAs (both p < 0.01, and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2 and HO-1 mRNA (both p < 0.01 in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-β1/Smad3 pathways.

  16. Schisandra Lignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

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    Qingshan Chen

    2017-01-01

    Full Text Available Schisandra chinensis (S. chinensis is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans in S. chinensis remain unclear. This study aimed to investigate the protective effect and related molecular mechanism of Schisandra lignan extract (SLE against carbon tetrachloride- (CCl4- induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4 treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways.

  17. Antioxidant and hepatoprotective effects of Lithocarpus polystachyus against carbon tetrachloride-induced injuries in rat

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    Shenghua Li

    2013-12-01

    Full Text Available The present study aims to investigate the hepatoprotective and antioxidant effects of the total flavonoid of Lithocarpus polystachyus Rehd.(LP-F in vitro and in vivo. The in vitro antioxidant property of total flavonoids was investigated by employing various established systems. Rats with carbon tetrachloride-induced liver injury were used to assess the hepatoprotective and antioxidant effect of total flavonoids in vivo. The level of activity of glutamate pyruvate transaminase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase, total bilirubin, total cholesterol, triglycerides total protein and albumin contents in the serum and malondialdehyde, superoxide dismutase, catalase, and glutathione in the liver and kidney of the rats were assayed using standard procedures. The results showed the total flavonoids of L. polystachyus has strong hepatoprotective and antioxidant activity in vitro and in vivo. These data were supplemented with histopathological studies of rat liver sections. This suggests that the hepatoprotective activity of formulation is possibly attributed to its free radical scavenging properties.

  18. Effect of melatonin on carbon tetrachloride- induced kidney injury in ...

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    Exposure to carbon tetrachloride (CCl4) induces acute and chronic renal injuries as well as oxidative stress in rats. The aim of this study was to evaluate the effect of exogenous melatonin (MEL) treatment on CCl4-induced oxidative stress and nephrotoxicity in rats using histopathological and biochemical parameters. Serum ...

  19. Epidermal growth factor protects against carbon tetrachloride-induced hepatic injury.

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    Berlanga, J; Caballero, M E; Ramirez, D; Torres, A; Valenzuela, C; Lodos, J; Playford, R J

    1998-03-01

    1. Epidermal growth factor (EGF) is known to protect the gastrointestinal tract against various noxious agents. Its potential value in preventing/ treating hepatic injury is, however, largely unexplored. We therefore examined whether EGF could influence CCl4-induced hepatic injury. 2. Female Sprague-Dawley rats (8 per group) received saline or recombinant EGF (500 or 750 micrograms/kg, intraperitoneal) 30 min before CCl4 (20% v/v, in olive oil, intraperitoneal). Eighteen hours later, animals were killed, serum was collected for assay of biochemical markers of hepatic injury and livers were removed for histological analyses. 3. Administration of CCl4 resulted in severe hepatic necrosis and caused a 10-fold rise in plasma alanine aminotransferase levels compared with levels seen in control animals (218 +/- 15 compared with 23 +/- 9 mumol/l in controls, mean +/- SEM, P < 0.01). Serum malondialdehyde levels, used as a marker of lipid peroxidation, showed a 2-fold rise in response to CCl4 treatment (median 4.0, quartile range 3.3-5.8 units/l compared with median 2.3, quartile range 2.1-2.5 units/l in controls, P < 0.05). Administration of EGF at 500 micrograms/kg, before the CCl4, did not protect against injury, as assessed by histology or rise in plasma alanine aminotransferase levels. In contrast, animals given EGF at 750 micrograms/kg, before the CCl4, had only minimal changes in histology, with only a minor rise in alanine aminotransferase levels (37 +/- 4 compared with 23 +/- 9 mumol/l in animals not given CCl4) and had no significant rise in malondialdehyde levels. 4. EGF protects against CCl4-induced hepatic injury and may provide a novel approach to the treatment of liver damage.

  20. Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats.

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    El-Agroudy, Nermeen N; El-Naga, Reem N; El-Razeq, Rania Abd; El-Demerdash, Ebtehal

    2016-11-01

    Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects. Male Sprague-Dawley rats were treated with either CCl4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring α-SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF-κB, TNF-α, COX-2, IL-1β), TGF-β1 and Hh signalling markers (Ptch-1, Smo, Gli-2) were also assessed. Hepatic fibrosis induced by CCl4 was significantly reduced by forskolin, as indicated by decreased α-SMA expression and collagen deposition. Forskolin co-treatment significantly attenuated oxidative stress and inflammation, reduced TGF-β1 levels and down-regulated mRNA expression of Ptch-1, Smo and Gli-2 through cAMP-dependent PKA activation. In our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti-inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP-dependent activation of PKA. © 2016 The British Pharmacological Society.

  1. Ameliorative effect of Ganoderma lucidum on carbon tetrachloride-induced liver fibrosis in rats

    Science.gov (United States)

    Lin, Wen-Chuan; Lin, Wei-Lii

    2006-01-01

    AIM: To investigate the effects of Reishi mushroom, Ganoderma lucidum extract (GLE), on liver fibrosis induced by carbon tetrachloride (CCl4) in rats. METHODS: Rat hepatic fibrosis was induced by CCl4. Forty Wistar rats were divided randomly into 4 groups: control, CCl4, and two GLE groups. Except for rats in control group, all rats were administered orally with CCl4 (20%, 0.2 mL/100 g body weight) twice a week for 8 weeks. Rats in GLE groups were treated daily with GLE (1 600 or 600 mg/kg) via gastrogavage throughout the whole experimental period. Liver function parameters, such as ALT, AST, albumin, and albumin/globulin (A/G) ratio, spleen weight and hepatic amounts of protein, malondiladehyde (MDA) and hydroxyproline (HP) were determined. Histochemical staining of Sirius red was performed. Expression of transforming growth factor β1 (TGF-β1), methionine adenosyltransferase (MAT1) 1A and MAT2A mRNA were detected by using RT-PCR. RESULTS: CCl4 caused liver fibrosis, featuring increase in plasma transaminases, hepatic MDA and HP contents, and spleen weight; and decrease in plasma albumin, A/G ratio and hepatic protein level. Compared with CCl4 group, GLE (600, 1 600 mg/kg) treatment significantly increased plasma albumin level and A/G ratio (P  < 0.05) and reduced the hepatic HP content (P < 0.01). GLE (1 600 mg/kg) treatment markedly decreased the activities of transaminases (P  < 0.05), spleen weight (P  < 0.05) and hepatic MDA content (P  < 0.05); but increased hepatic protein level (P  < 0.05). Liver histology in the GLE (1 600 mg/kg)-treated rats was also improved (P  < 0.01). RT-PCR analysis showed that GLE treatment decreased the expression of TGF-β1 (P  < 0.05-0.001) and changed the expression of MAT1A (P  < 0.05-0.01) and MAT2A (P  < 0.05-0.001). CONCLUSION: Oral administration of GLE significantly reduces CCl4-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular

  2. [Chinese herbal medicine Xiayuxue Decoction inhibits liver angiogenesis in rats with carbon tetrachloride-induced liver fibrosis].

    Science.gov (United States)

    Du, Jin-xing; Liu, Ping; Sun, Ming-yu; Tao, Qing; Zhang, Li-jun; Chen, Gao-feng; Hu, Yi-yang; Liu, Cheng-hai; Xu, Lie-ming

    2011-08-01

    To evaluate the effects of Xiayuxue Decoction, a compound traditional Chinese medicine, on liver angiogenesis in rats with carbon tetrachloride (CCl(4))-induced liver fibrosis. Liver cirrhosis was induced by intraperitoneal injection of 50% CCl(4)-olive oil solution at the dose of 1 mL/kg body weight, twice per week for 9 consecutive weeks. After 3- and 6-week injection, 6 rats in the normal group and 6 rats in the model group were randomly sacrificed for dynamic observation. The survival rats of model group were randomly divided into model group (n=15) and Xiayuxue Decoction group (n=11). Six normal rats were used as a normal control. Xiayuxue Decoction was administered orally starting from the 7th week for 3 weeks. At the end of the ninth week, animals were sacrificed and liver tissues were harvested to measure histological changes, activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 and protein expressions of platelet endothelial cell adhesion molecule-1 (CD31), von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR2), complement decay-accelerating factor (DAF) and α-smooth muscle actin (α-SMA) in the liver tissues. Compared with the normal group, liver injury, fatty degeneration and collagen deposition were evidently observed in the model group and protein expressions of CD31, vWF, VEGF, VEGFR2, DAF and α-SMA were gradually increased. In addition, the activities of MMP-2 and MMP-9 in liver tissues were enhanced in the model group (Pliver injury, fatty degeneration and collagen deposition were markedly inhibited by Xiayuxue Decoction; protein expressions of CD31, vWF, VEGF, VEGFR2,α-SMA and DAF and activities of MMP-2 and MMP-9 in the liver tissues were decreased in the Xiayuxue Decoction group (Pliver cirrhosis induced by CCl(4). Xiayuxue Decoction inhibits the angiogenesis by decreasing the activities of MMP-2 and MMP-9, inhibiting the activation of hepatic stellate cells, and

  3. Antioxidant and Hepatoprotective Activities of Ethanolic Extracts of Leaves of Premna esculenta Roxb. against Carbon Tetrachloride-Induced Liver Damage in Rats

    OpenAIRE

    Mahmud, ZA; Bachar, SC; Qais, N

    2012-01-01

    Premna esculenta Roxb. (family Verbenaceae) is a shrub used by the ethnic people of Chittagong Hill Tracts of Bangladesh for the treatment of hepatocellular jaundice. The present study was done to evaluate the hepatoprotective and the in vivo antioxidant activity of ethanolic extracts of leaves of the plant in carbon tetrachloride-induced liver damage in rats. Hepatotoxicity was induced in rats by i.p. injection of CCl4 diluted with olive oil (1:1 v/v; 1 mL/kg body weight) on alternate days f...

  4. Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: Protection by melatonin and cranberry flavonoids

    Energy Technology Data Exchange (ETDEWEB)

    Cheshchevik, V.T. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Lapshina, E.A.; Dremza, I.K.; Zabrodskaya, S.V. [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Reiter, R.J. [Department of Cellular and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229–3900 (United States); Prokopchik, N.I. [Grodno State Medical University, Gorkogo - 80, 230015 Grodno (Belarus); Zavodnik, I.B., E-mail: zavodnik_il@mail.ru [Institute for Pharmacology and Biochemistry, National Academy of Sciences of Belarus, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus); Department of Biochemistry, Yanka Kupala Grodno State University, Len. Kom. Blvd. - 50, 230017 Grodno (Belarus)

    2012-06-15

    In current societies, the risk of toxic liver damage has markedly increased. The aim of the present work was to carry out further research into the mechanism(s) of liver mitochondrial damage induced by acute (0.8 g/kg body weight, single injection) or chronic (1.6 g/ kg body weight, 30 days, biweekly injections) carbon tetrachloride – induced intoxication and to evaluate the hepatoprotective potential of the antioxidant, melatonin, as well as succinate and cranberry flavonoids in rats. Acute intoxication resulted in considerable impairment of mitochondrial respiratory parameters in the liver. The activity of mitochondrial succinate dehydrogenase (complex II) decreased (by 25%, p < 0.05). Short-term melatonin treatment (10 mg/kg, three times) of rats did not reduce the degree of toxic mitochondrial dysfunction but decreased the enhanced NO production. After 30-day chronic intoxication, no significant change in the respiratory activity of liver mitochondria was observed, despite marked changes in the redox-balance of mitochondria. The activities of the mitochondrial enzymes, succinate dehydrogenase and glutathione peroxidase, as well as that of cytoplasmic catalase in liver cells were inhibited significantly. Mitochondria isolated from the livers of the rats chronically treated with CCl{sub 4} displayed obvious irreversible impairments. Long-term melatonin administration (10 mg/kg, 30 days, daily) to chronically intoxicated rats diminished the toxic effects of CCl{sub 4}, reducing elevated plasma activities of alanine aminotransferase and aspartate aminotransferase and bilirubin concentration, prevented accumulation of membrane lipid peroxidation products in rat liver and resulted in apparent preservation of the mitochondrial ultrastructure. The treatment of the animals by the complex of melatonin (10 mg/kg) plus succinate (50 mg/kg) plus cranberry flavonoids (7 mg/kg) was even more effective in prevention of toxic liver injury and liver mitochondria damage

  5. Hepatoprotective effect of grape seed oil against carbon tetrachloride induced oxidative stress in liver of γ-irradiated rat.

    Science.gov (United States)

    Ismail, Amel F M; Salem, Asmaa A M; Eassawy, Mamdouh M T

    2016-07-01

    Carbon tetrachloride (CCl4) and ionizing radiation are well known environmental pollutants that generate free radicals and induce oxidative stress. The liver is the primary and major target organ responsible for the metabolism of drugs, toxic chemicals and affected by irradiation. This study investigated the effect of grape seed oil (GSO) on acute liver injury induced by carbon tetrachloride (CCl4) in γ-irradiated rats (7Gy). CCl4-intoxicated rats exhibited an elevation of ALT, AST activities, IL-6 and TNF-α level in the serum. Further, the levels of MDA, NO, NF-κB and the gene expression of CYP2E1, iNOS and Caspase-3 were increased, and SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Furthermore, silent information regulator protein 1 (SIRT1) gene expression was markedly down-regulated. Additionally, alterations of the trace elements; copper, manganese, zinc and DNA fragmentation was observed in the hepatic tissues of the intoxicated group. These effects were augmented in CCl4-intoxicated-γ-irradiated rats. However, the administration of GSO ameliorated these parameters. GSO exhibit protective effects on CCl4 induced acute liver injury in γ-irradiated rats that could be attributed to its potent antioxidant, anti-inflammatory and anti-apoptotic activities. The induction of the antioxidant enzymes activities, down-regulation of the CYP2E1, iNOS, Caspase-3 and NF-κB expression, up-regulation of the trace elements concentration levels and activation of SIRT1 gene expression are responsible for the improvement of the antioxidant and anti-inflammatory status in the hepatic tissues and could be claimed to be the hepatoprotective mechanism of GSO. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Folic acid and melatonin ameliorate carbon tetrachloride-induced hepatic injury, oxidative stress and inflammation in rats

    Directory of Open Access Journals (Sweden)

    Ebaid Hossam

    2013-02-01

    Full Text Available Abstract This study investigated the protective effects of melatonin and folic acid against carbon tetrachloride (CCl4-induced hepatic injury in rats. Oxidative stress, liver function, liver histopathology and serum lipid levels were evaluated. The levels of protein kinase B (Akt1, interferon gamma (IFN-γ, programmed cell death-receptor (Fas and Tumor necrosis factor-alpha (TNF-α mRNA expression were analyzed. CCl4 significantly elevated the levels of lipid peroxidation (MDA, cholesterol, LDL, triglycerides, bilirubin and urea. In addition, CCl4 was found to significantly suppress the activity of both catalase and glutathione (GSH and decrease the levels of serum total protein and HDL-cholesterol. All of these parameters were restored to their normal levels by treatment with melatonin, folic acid or their combination. An improvement of the general hepatic architecture was observed in rats that were treated with the combination of melatonin and folic acid along with CCl4. Furthermore, the CCl4-induced upregulation of TNF-α and Fas mRNA expression was significantly restored by the three treatments. Melatonin, folic acid or their combination also restored the baseline levels of IFN-γ and Akt1 mRNA expression. The combination of melatonin and folic acid exhibited ability to reduce the markers of liver injury induced by CCl4 and restore the oxidative stability, the level of inflammatory cytokines, the lipid profile and the cell survival Akt1 signals.

  7. Investigation of the hepatoprotective effects of Sesame (Sesamum indicum L.) in carbon tetrachloride-induced liver toxicity.

    Science.gov (United States)

    Cengiz, Nureddin; Kavak, Servet; Güzel, Ali; Ozbek, Hanefi; Bektaş, Hava; Him, Aydın; Erdoğan, Ender; Balahoroğlu, Ragıb

    2013-01-01

    More than 600 chemicals can cause damage in liver, one of which is carbon tetrachloride (CCl₄). Hepatoprotective agents could prevent tissue damage and reduce morbidity and mortality rates; such agents may include alternative or folkloric treatments. We investigated sesame (Sesamum indicum L.) for its hepatoprotective effect in CCl₄-induced experimental liver damage. To this end, 0.8 mg/kg of sesame fixed oil was provided intraperitoneally to rats whose livers were damaged by CCl₄. Tissue and blood samples were taken at the end of the experiments and evaluated histologically and biochemically. Ballooning degenerations and an increase in lipid droplets in liver parenchyma and increases in serum alanine transaminase, aspartate transaminase, and bilirubin were found in the CCl₄ group. Biochemical and histopathological findings in the sesame fixed oil treated group were not significantly different from the CCl₄ group. Sesame did not show a hepatoprotective effect in CCl₄-induced liver toxicity.

  8. Antioxidant and hepatoprotective activity of punicalagin and punicalin on carbon tetrachloride-induced liver damage in rats.

    Science.gov (United States)

    Lin, C C; Hsu, Y F; Lin, T C; Hsu, F L; Hsu, H Y

    1998-07-01

    Punicalagin and punicalin, isolated from the leaves of Terminalia catappa L., are used to treat dermatitis and hepatitis. Both compounds have strong antioxidative activity. The antihepatotoxic activity of punicalagin and punicalin on carbon tetrachloride (CCl4)-induced toxicity in the rat liver was evaluated. Levels of serum glutamate-oxalate-transaminase and glutamate-pyruvate-trans-aminase were increased by administration of CCl4 and reduced by drug treatment. Histological changes around the liver central vein and oxidation damage induced by CCl4 also benefited from drug treatment. The results show that both punicalagin and punicalin have anti-hepatotoxic activity but that the larger dose of punicalin induced liver damage. Thus even if tannins have strong antioxidant activity at very small doses, treatment with a larger dose will induce cell damage.

  9. Transplanted human amniotic membrane-derived mesenchymal stem cells ameliorate carbon tetrachloride-induced liver cirrhosis in mouse.

    Directory of Open Access Journals (Sweden)

    DingGuo Zhang

    Full Text Available BACKGROUND: Human amniotic membrane-derived mesenchymal stem cells (hAMCs have the potential to reduce heart and lung fibrosis, but whether could reduce liver fibrosis remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Hepatic cirrhosis model was established by infusion of CCl₄ (1 ml/kg body weight twice a week for 8 weeks in immunocompetent C57Bl/6J mice. hAMCs, isolated from term delivered placenta, were infused into the spleen at 4 weeks after mice were challenged with CCl₄. Control mice received only saline infusion. Animals were sacrificed at 4 weeks post-transplantation. Blood analysis was performed to evaluate alanine aminotransferase (ALT and aspartate aminotransferase (AST. Histological analysis of the livers for fibrosis, hepatic stellate cells activation, hepatocyte apoptosis, proliferation and senescence were performed. The donor cell engraftment was assessed using immunofluorescence and polymerase chain reaction. The areas of hepatic fibrosis were reduced (6.2%±2.1 vs. control 9.6%±1.7, p<0.05 and liver function parameters (ALT 539.6±545.1 U/dl, AST 589.7±342.8 U/dl,vs. control ALT 139.1±138.3 U/dl, p<0.05 and AST 212.3±110.7 U/dl, p<0.01 were markedly ameliorated in the hAMCs group compared to control group. The transplantation of hAMCs into liver-fibrotic mice suppressed activation of hepatic stellate cells, decreased hepatocyte apoptosis and promoted liver regeneration. More interesting, hepatocyte senescence was depressed significantly in hAMCs group compared to control group. Immunofluorescence and polymerase chain reaction revealed that hAMCs engraftment into host livers and expressed the hepatocyte-specific markers, human albumin and α-fetoproteinran. CONCLUSIONS/SIGNIFICANCE: The transplantation of hAMCs significantly decreased the fibrosis formation and progression of CCl₄-induced cirrhosis, providing a new approach for the treatment of fibrotic liver disease.

  10. New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage

    Energy Technology Data Exchange (ETDEWEB)

    Hamdy, Nadia [Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt); El-Demerdash, Ebtehal, E-mail: ebtehal_dm@yahoo.com [Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo (Egypt)

    2012-06-15

    Portal hypertension is a common complication of chronic liver diseases associated with liver fibrosis and cirrhosis. At present, beta-blockers such as carvedilol remain the medical treatment of choice for protection against variceal bleeding and other complications. Since carvedilol has powerful antioxidant properties we assessed the potential antifibrotic effects of carvedilol and the underlying mechanisms that may add further benefits for its clinical usefulness using a chronic model of carbon tetrachloride (CCl4)-induced hepatotoxicity. Two weeks after CCl4 induction of chronic hepatotoxicity, rats were co-treated with carvedilol (10 mg/kg, orally) daily for 6 weeks. It was found that treatment of animals with carvedilol significantly counteracted the changes in liver function and histopathological lesions induced by CCl4. Also, carvedilol significantly counteracted lipid peroxidation, GSH depletion, and reduction in antioxidant enzyme activities; glutathione-S-transferase and catalase that was induced by CCl4. In addition, carvedilol ameliorated the inflammation induced by CCl4 as indicated by reducing the serum level of acute phase protein marker; alpha-2-macroglobulin and the liver expression of nuclear factor-kappa B (NF-κB). Finally, carvedilol significantly reduced liver fibrosis markers including hydroxyproline, collagen accumulation, and the expression of the hepatic stellate cell (HSC) activation marker; alpha smooth muscle actin. In conclusion, the present study provides evidences for the promising antifibrotic effects of carvedilol that can be explained by amelioration of oxidative stress through mainly, replenishment of GSH, restoration of antioxidant enzyme activities and reduction of lipid peroxides as well as amelioration of inflammation and fibrosis by decreasing collagen accumulation, acute phase protein level, NF-κB expression and finally HSC activation. -- Highlights: ► Carvedilol is a beta blocker with antioxidant and antifibrotic

  11. Gypenosides Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the Differentiation of Hepatic Progenitor Cells into Myofibroblasts.

    Science.gov (United States)

    Chen, Jiamei; Li, Xuewei; Hu, Yonghong; Liu, Wei; Zhou, Qun; Zhang, Hua; Mu, Yongping; Liu, Ping

    2017-01-01

    Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.

  12. Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor β Secretion

    Science.gov (United States)

    Muñoz-Ortega, Martin Humberto; Llamas-Ramírez, Raúl Wiliberto; Romero-Delgadillo, Norma Isabel; Elías-Flores, Tania Guadalupe; de Jesus Tavares-Rodríguez, Edgar; del Rosario Campos-Esparza, María; Cervantes-García, Daniel; Muñoz-Fernández, Luis; Gerardo-Rodríguez, Martin; Ventura-Juárez, Javier

    2016-01-01

    Background/Aims The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. Methods Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor β (TGF-β) immunohistochemistry was analyzed. Results Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-β-secreting cells. Conclusions Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-β via the blockage of α1- and β-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved. PMID:26573293

  13. The involvement of sirtuin 1 and heme oxygenase 1 in the hepatoprotective effects of quercetin against carbon tetrachloride-induced sub-chronic liver toxicity in rats.

    Science.gov (United States)

    Kemelo, Mighty Kgalalelo; Pierzynová, Aneta; Kutinová Canová, Nikolina; Kučera, Tomáš; Farghali, Hassan

    2017-05-01

    The present study was designed to evaluate the therapeutic potential of quercetin in a sub-chronic model of hepatotoxicity. The roles of putative antioxidant enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1), in hepatoprotection were also addressed. Sub-chronic liver injury was induced in rats by intraperitoneal administration of 0.5 ml/kg carbon tetrachloride (CTC), once every 3 days, for 2 weeks. Some CTC rats were concurrently treated with 100 mg/kg quercetin, intragastrically, once every day, for 2 weeks. The effects of these drugs in the liver were evaluated by biochemical, histological, immunohistochemical and molecular biological studies. CTC triggered oxidative damage to the liver as unanimously shown by altered biochemical parameters and liver morphology. Furthermore, CTC highly upregulated HO-1 and SIRT1 expression levels. Concomitant treatment of rats with quercetin downregulated SIRT1 expression and ameliorated the hepatotoxic effects of CTC. However, quercetin did not have any significant effect on HO-1 expression and bilirubin levels. Collectively, these results suggest that the antioxidant and cytoprotective effects of quercetin in CTC treated rats were SIRT1 mediated and less dependent on HO-1. Thus, pharmacologic modulation of SIRT1 could provide a logic therapeutic approach in sub-chronic hepatotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Mistletoe alkaloid fractions alleviates carbon tetrachloride-induced liver fibrosis through inhibition of hepatic stellate cell activation via TGF-β/Smad interference.

    Science.gov (United States)

    Jiang, Ying; Wang, Chi; Li, Ying-Ying; Wang, Xue-Cong; An, Jian-Duo; Wang, Yun-Jiao; Wang, Xue-Jiang

    2014-12-02

    Mistletoe (Viscum coloratum (Kom.) Nakai) has long been categorized as a traditional herbal medicine in Asia. In addition to its application in cancer therapy, mistletoe has also been used in the treatment of chronic hepatic disorders in China. In the present study, we investigated the antifibrotic effect and mechanisms of action of mistletoe extracts in a rat model of carbon tetrachloride (CCl4)-induced hepatotoxicity. An experimental model of hepatic fibrosis was established by intraperitoneal injection of rats with CCl4 for 8 weeks. Rats were subsequently treated with a mistletoe alkaloid fraction preparation via oral administration (120mg/kg daily for 8 weeks) or with distilled water as a control. Histopathological changes were observed by hematoxylin and eosin staining and Masson׳s trichrome staining. The expression of markers relevant to hepatic stellate cell (HSC) activation in the liver was assessed by real-time reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The anti-fibrosis activity and mechanisms of action of mistletoe alkaloid fractions were further investigated in the HSC-T6 HSC line, following treatment with mistletoe alkaloid fractions (12mg/ml) for 48h. Hepatic fibrosis decreased markedly in CCl4-treated animals following treatment with mistletoe alkaloid fractions, compared to controls. The mRNA levels of transforming growth factor-β1 (TGF-β1), procollagen I and tissue inhibitors of metalloproteinases (TIMPs) were significantly downregulated, by about 40%, 40% and 45%, respectively, in liver tissues from rats treated with mistletoe alkaloid fractions. Furthermore, significant downregulation of TGF-β1, TGF-β1 receptor, phosphorylated Smad 2 and alpha smooth muscle actin (α-SMA) proteins, by about 45%, 30% and 40%, respectively, was also observed in liver tissues from mistletoe alkaloid fractions-treated rats. In contrast, Smad 7 levels were significantly increased by about 30% in mistletoe alkaloid

  15. Sesamol loaded solid lipid nanoparticles: a promising intervention for control of carbon tetrachloride induced hepatotoxicity.

    Science.gov (United States)

    Singh, Neha; Khullar, Neeraj; Kakkar, Vandita; Kaur, Indu Pal

    2015-05-03

    Sesamol, a component of sesame seed oil, exhibited significant antioxidant activity in a battery of in vitro and ex vivo tests including lipid peroxidation induced in rat liver homogenates. Latter established its potential for hepatoprotection. However, limited oral bioavailability, fast elimination (as conjugates) and tendency towards gastric irritation/toxicity (especially forestomach of rodents) may limit its usefulness. Presently, we packaged sesamol into solid lipid nanoparticles (S-SLNs) to enhance its biopharmaceutical performance and compared the efficacy with that of free sesamol and silymarin, a well established hepatoprotectant, against carbon tetrachloride induced hepatic injury in rats, post induction. A self recovery group in which no treatment was given was used to observe the self-healing capacity of liver. S-SLNs prepared by microemulsification method were administered to rats post-treatment with CCl4 (1 ml/kg body weight (BW) twice weekly for 2 weeks, followed by 1.5 ml/kg BW twice weekly for the subsequent 2 weeks). Liver damage and recovery on treatment was assessed in terms of histopathology, serum injury markers (alanine aminotransferase, aspartate aminotransferase), oxidative stress markers (lipid peroxidation, superoxide dismutase, and reduced glutathione) and a pro-inflammatory response marker (tumor necrosis factor alpha). S-SLNs (120.30 nm) at a dose of 8 mg/kg BW showed significantly better hepatoprotection than corresponding dose of free sesamol (FS; p recovery group confirmed absence of regenerative capacity of hepatic tissue, post injury. Use of lipidic nanocarrier system for sesamol improved its efficiency to control hepatic injury. Enhanced effect is probably due to: a) improved oral bioavailability, b) controlled and prolonged effect of entrapped sesamol and iii) reduction in irritation and toxicity, if any, upon oral administration. S-SLNs may be considered as a therapeutic option for hepatic ailments as effectiveness post

  16. War liver injuries

    Directory of Open Access Journals (Sweden)

    Stanković Nebojša

    2005-01-01

    Full Text Available Aim. To provide a retrospective analysis of our results and experience in primary surgical treatment of subjects with war liver injuries. Methods. From July 1991 to December 1999, 204 subjects with war liver injuries were treated. A total of 82.8% of the injured were with the liver injuries combined with the injuries of other organs. In 93.7%, the injuries were caused by fragments of explosive devices or bullets of various calibers. In 140 (68.6% of the injured there were minor lesions (grade I to II, treated with simple repair or drainage. There were complex injuries of the liver (grade III-V in 64 (31.4% of the injured. Those injuries required complex repair (hepatorrhaphy, hepatotomy, resection debridement, resection, packing alone. The technique of perihepatic packing and planned reoperation had a crucial and life-saving role when severe bleeding was present. Routine peritoneal drainage was applied in all of the injured. Primary management of 74.0% of the injured was performed in war hospitals. Results. After primary treatment, 72 (35.3% of the injured were with postoperative complications. Reoperation was done in 66 injured. Total mortality rate in 204 injured was 18.1%. All the deceased had significant combined injuries. Mortality rates due to the liver injury of the grade III, IV and V were 16.6%, 70.0% and 83.3%, respectively. Conclusion. Complex liver injuries caused very high mortality rate and the management of the injured was delicate under war circumstances (if the injured reached the hospital alive. Our experience under war circumstances and with war surgeons of limited knowledge of the liver surgery and war surgery, confirmed that it was necessary to apply compressive abdominal packing alone or in combination with other techniques for hemostasis in the treatment of liver injuries grade III-V, resuscitation and rapid transportation to specialized hospitals.

  17. Prevention of Carbon Tetrachloride-induced Hepatic Steatosis and ...

    African Journals Online (AJOL)

    Prevention of Carbon Tetrachloride-induced Hepatic Steatosis and Cellular Damage by Aqueous Extract of Dacryodes edulis Seeds in Wistar Rats. ... Group E was given only Dacryodes edulis extract (1000 mg/kg body weight) daily for two weeks, while group F received only a single dose of CCl4 on day 14. The extract ...

  18. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... Drug-induced liver injury (DILI) is a term increasingly being used by most clinicians and is synonymous with drug-induced hepatotoxicity. A succinct definition of a DILI is 'a liver injury induced by a drug or herbal medicine resulting in liver test abnormalities or liver dysfunction with a reasonable exclusion of ...

  19. Role of phosphatase and tensin homolog deleted on chromosome ten in a rat model of carbon tetrachloride-induced liver fibrosis and the effect of qi-tonifying and blood-activating prescription

    Directory of Open Access Journals (Sweden)

    NIU Xuemin

    2018-01-01

    Full Text Available Objective To investigate the role of phosphatase and tensin homology deleted on chromosome ten (PTEN in a rat model of carbon tetrachloride (CCl4-induced liver fibrosis and the molecular mechanism of action of qi-tonifying and blood-activating prescription in regulating PTEN and inhibiting liver fibrosis. Methods A total of 27 male Wistar rats were randomly divided into three groups, with 9 rats in each group. The rats in liver fibrosis group were treated with CCl4 to establish a model of liver fibrosis, and those in qi-tonifying and blood-activating prescription group were also treated with CCl4 to establish a model and then given a self-made qi-tonifying and blood-activating prescription containing Astragalus membranaceus, Salvia miltiorrhiza, and poria. The rats in the control group were given intraperitoneally injected olive oil. HE staining, Masson staining, and immunohistochemical staining of collagen type I alpha 1 (Col1A1 and collagen type Ⅳ (Col4 were performed to observe the degree of liver fibrosis and collagen deposition; qRT-PCR, immunohistochemistry, and Western blot were used to measure the expression of transforming growth factor-β1 (TGF-β1, PTEN, and downstream genes AKT, mTOR, and p70S6K. A one-way analysis of variance was used for comparison of continuous data between multiple groups and the least significant difference t-test was used for further comparison between any two groups. Results In the liver fibrosis group, liver pathology showed perisinusoidal fibrosis and fibrous tissue proliferation, collagen deposition, and formation of fibrous septum in the portal area; compared with the control group, the liver fibrosis group had significant increases in the mRNA and protein expression of TGF-β1, a significant reduction in the expression of PTEN, and significant increases in the mRNA and phosphorylated protein expression of AKT, mTOR, and p70S6K (all P<0.01. The qi-tonifying and blood-activating prescription group had a

  20. l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor.

    Science.gov (United States)

    Pérez-Vargas, J E; Zarco, N; Vergara, P; Shibayama, M; Segovia, J; Tsutsumi, V; Muriel, P

    2016-02-01

    Here we evaluated the ability of L-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachloride (CCl4) to rats (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks), and at the same time, adding L-theanine (8.0 mg/kg) to the drinking water. Rats had ad libitum access to water and food throughout the treatment period. CCl4 treatment promoted NF-κB activation and increased the expression of both TGF-β and CTGF. CCl4 increased the serum activities of alanine aminotransferase and γ-glutamyl transpeptidase and the degree of lipid peroxidation, and it also induced a decrease in the glutathione and glutathione disulfide ratio. L-Theanine prevented increased expression of NF-κB and down-regulated the pro-inflammatory (interleukin (IL)-1β and IL-6) and profibrotic (TGF-β and CTGF) cytokines. Furthermore, the levels of messenger RNA encoding these proteins decreased in agreement with the expression levels. L-Theanine promoted the expression of the anti-inflammatory cytokine IL-10 and the fibrolytic enzyme metalloproteinase-13. Liver hydroxyproline contents and histopathological analysis demonstrated the anti-fibrotic effect of l-theanine. In conclusion, L-theanine prevents CCl4-induced experimental hepatic cirrhosis in rats by blocking the main pro-inflammatory and pro-fibrogenic signals. © The Author(s) 2015.

  1. Acute Liver Injury and Failure.

    Science.gov (United States)

    Thawley, Vincent

    2017-05-01

    Acute liver injury and acute liver failure are syndromes characterized by a rapid loss of functional hepatocytes in a patient with no evidence of pre-existing liver disease. A variety of inciting causes have been identified, including toxic, infectious, neoplastic, and drug-induced causes. This article reviews the pathophysiology and clinical approach to the acute liver injury/acute liver failure patient, with a particular emphasis on the diagnostic evaluation and care in the acute setting. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Bioavailability of andrographolide and protection against carbon tetrachloride-induced oxidative damage in rats

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Haw-Wen [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Huang, Chin-Shiu [Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan (China); Li, Chien-Chun [School of Nutrition, Chung Shan Medical University, Taichung, Taiwan (China); Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan (China); Lin, Ai-Hsuan; Huang, Yu-Ju [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Wang, Tsu-Shing [Department of Biomedical Science, Chung Shan Medical University, Taichung, Taiwan (China); Yao, Hsien-Tsung, E-mail: htyao@mail.cmu.edu.tw [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Lii, Chong-Kuei, E-mail: cklii@mail.cmu.edu.tw [Department of Nutrition, China Medical University, Taichung, Taiwan (China); Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan (China)

    2014-10-01

    Andrographolide, a bioactive diterpenoid, is identified in Andrographis paniculata. In this study, we investigated the pharmacokinetics and bioavailability of andrographolide in rats and studied whether andrographolide enhances antioxidant defense in a variety of tissues and protects against carbon tetrachloride-induced oxidative damage. After a single 50-mg/kg administration, the maximum plasma concentration of andrographolide was 1 μM which peaked at 30 min. The bioavailability of andrographolide was 1.19%. In a hepatoprotection study, rats were intragastrically dosed with 30 or 50 mg/kg andrographolide for 5 consecutive days. The results showed that andrographolide up-regulated glutamate cysteine ligase (GCL) catalytic and modifier subunits, superoxide dismutase (SOD)-1, heme oxygenase (HO)-1, and glutathione (GSH) S-transferase (GST) Ya/Yb protein and mRNA expression in the liver, heart, and kidneys. The activity of SOD, GST, and GSH reductase was also increased in rats dosed with andrographolide (p < 0.05). Immunoblot analysis and EMSA revealed that andrographolide increased nuclear Nrf2 contents and Nrf2 binding to DNA, respectively. After the 5-day andrographolide treatment, one group of animals was intraperitoneally injected with carbon tetrachloride (CCl{sub 4}) at day 6. Andrographolide pretreatment suppressed CCl{sub 4}-induced plasma aminotransferase activity and hepatic lipid peroxidation (p < 0.05). These results suggest that andrographolide is quickly absorbed in the intestinal tract in rats with a bioavailability of 1.19%. Andrographolide protects against chemical-induced oxidative damage by up-regulating the gene transcription and activity of antioxidant enzymes in various tissues. - Highlights: • The bioavailability of andrographolide is 1.19% in rats. • Plasma concentration reaches 1 μM after giving 50 mg/kg andrographolide. • Andrographolide up-regulates Nrf2-dependent antioxidant genes. • Andrographolide increases antioxidant defense

  3. Haemobilia following blunt liver injury

    African Journals Online (AJOL)

    Corresponding author: G L Laing (grantandjulia@gmail.com). Blunt liver trauma is commonly managed by non-operative measures. We report a case of an American Association for the Surgery of Trauma grade III liver injury and its complications, successfully managed by a combination of minimally invasive interventions.

  4. 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...

  5. High velocity missile injuries of the liver

    African Journals Online (AJOL)

    exsanguination six hours after surgery. The second patient died of septicaemia on the fifth postoperative clay (Table 111). TABLE Ill Outcome of treatment of patients with high velocity missile injuries of the liver. Discussion. The diagnosis of penetrating abdominal injury is usually straightforward. Injury to the liver m:ly be.

  6. MORPHOLOGY OF ISCHEMIC INJURY OF LIVER ALLOGRAFT

    Directory of Open Access Journals (Sweden)

    L. V. Shkalova

    2010-01-01

    Full Text Available The literature data in modern transplantology concerning morphology of ischemic injury of liver allograft are analyzed in the article. Questions of pathogenesis of liver allograft ischemic injury, histological features that indicate the possibility of donor liver transplantation are discussed in detail, as well as the role of steatosis and its reverse is highlighted. We tried to systematize the morphological changes depending on severity of ischemic injury; also we focused on the questions of persistency of the ischemic injury in the liver allograft. 

  7. Montelukast induced acute hepatocellular liver injury

    Directory of Open Access Journals (Sweden)

    Harugeri A

    2009-01-01

    Full Text Available A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM and Naranjo′s algorithm was ′probable′. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.

  8. 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.

  9. Effect of Apitherapy Formulations against Carbon Tetrachloride-Induced Toxicity in Wistar Rats after Three Weeks of Treatment

    Directory of Open Access Journals (Sweden)

    Calin Vasile Andritoiu

    2014-08-01

    Full Text Available The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution. Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

  10. TREATMENT OF BLUNT LIVER INJURIES IN CHILDREN

    Directory of Open Access Journals (Sweden)

    Ana Kostić

    2003-04-01

    Full Text Available Liver is the largest parenchymatous organ, well vascularized, weighing approximately 1.8-3.0% of the whole body weight. Among all abdominal traumas liver injuries account for 25%. For more serious liver injuries the mortality is around 40% in children below 10 years of age. For lesions of the juxtahepatic veins (three major hepatic veins or the retrohepatic portion of v. cava or for complex, combined intraabdominal injuries, the mortality is even up to 70%.This work analyzed the period 1988-2000 during which there were 19 children admitted and treated for blunt liver injuries at the Clinic of Pediatric Surgery and Orthopedics in Nis; I, II and III scale injuries prevailed (17 cases; 89.4%. These injuries were surgically treated for the most part (17 cases; 89.4%. In 7 children (36.8% there were combined injuries. The lethality was 26.3%-5 cases, with three major complications: two intrahepatic hematomas and one biliary fistula associated with biliary peritonitis and biloma formation.

  11. 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

  12. Effects of Melatonin on Liver Injuries and Diseases.

    Science.gov (United States)

    Zhang, Jiao-Jiao; Meng, Xiao; Li, Ya; Zhou, Yue; Xu, Dong-Ping; Li, Sha; Li, Hua-Bin

    2017-03-23

    Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

  13. Aspirin-Induced Acute Liver Injury

    OpenAIRE

    Laster, Janese; 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.

  14. Liver Autophagy in Anorexia Nervosa and Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Marouane Kheloufi

    2014-01-01

    Full Text Available Autophagy, a lysosomal catabolic pathway for long-lived proteins and damaged organelles, is crucial for cell homeostasis, and survival under stressful conditions. During starvation, autophagy is induced in numerous organisms ranging from yeast to mammals, and promotes survival by supplying nutrients and energy. In the early neonatal period, when transplacental nutrients supply is interrupted, starvation-induced autophagy is crucial for neonates’ survival. In adult animals, autophagy provides amino acids and participates in glucose metabolism following starvation. In patients with anorexia nervosa, autophagy appears initially protective, allowing cells to copes with nutrient deprivation. However, when starvation is critically prolonged and when body mass index reaches 13 kg/m2 or lower, acute liver insufficiency occurs with features of autophagic cell death, which can be observed by electron microscopy analysis of liver biopsy samples. In acetaminophen overdose, a classic cause of severe liver injury, autophagy is induced as a protective mechanism. Pharmacological enhancement of autophagy protects against acetaminophen-induced necrosis. Autophagy is also activated as a rescue mechanism in response to Efavirenz-induced mitochondrial dysfunction. However, Efavirenz overdose blocks autophagy leading to liver cell death. In conclusion, in acute liver injury, autophagy appears as a protective mechanism that can be however blocked or overwhelmed.

  15. Liver injury associated with dimethyl fumarate in multiple sclerosis patients.

    Science.gov (United States)

    Muñoz, Monica A; Kulick, Corrinne G; Kortepeter, Cindy M; Levin, Robert L; Avigan, Mark I

    2017-12-01

    In pre-approval trials, there was an increased incidence of mild, transient elevations of liver aminotransferases in study subjects treated with dimethyl fumarate (DMF). To evaluate post-marketing cases of drug-induced liver injury associated with DMF. We identified 14 post-marketing cases of clinically significant liver injury. Findings included newly elevated serum liver aminotransferase and bilirubin levels that developed as early as a few days after the first dose of DMF. The pattern of liver injury was primarily hepatocellular. No cases resulted in liver failure. Health professionals should be alerted to possible serious liver injury in patients receiving DMF.

  16. Mechanisms of Alcoholic Liver Injury

    Directory of Open Access Journals (Sweden)

    Samuel W French

    2000-01-01

    Full Text Available There have been numerous recent advances in the understanding of the mechanisms of alcoholic liver disease pathogenesis. Endotoxin-induced Kupffer cell activation plays a role in cytokine-mediated inflammatory changes in the liver, and this can be blocked by a diet high in saturated fat, by a diet containing lactobacillus, which does not produce endotoxin, by neomycin antibiotic sterilization of the gut, by eliminating Kupffer cells, or by removing tumour necrosis factor-alpha with antibody or by using tumour necrosis factor-alpha knockout mice. The fatty liver component is mainly the result of the nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide redox shift to the reduced state by ethanol oxidation generation of reduced nicotinamide adenine dinucleotide, although this too can be blocked by a diet high in saturated fat. Hepatocytic enlargement occurs due to ethanol-induced inhibition of the ubiquitin-proteasome pathway of cytoplasmic protein degradation and the retention of oxidized proteins in hepatocytes. The liver is scarred by stellate cells that have been activated by inflammatory cytokines and growth factors produced by activated Kupffer cells, and by bile ductule metaplasia. Mallory bodies and balloon cell degeneration develop through the ethanol-induced oxidative stress-protein kinase activation pathway, inhibition of phosphatase activity and inhibition of the ubiquitin-proteasome pathway.

  17. Paintball-related traumatic liver injury.

    Science.gov (United States)

    Luck, Joshua; Bell, Daniel; Bashir, Gareth

    2016-04-27

    Paintball is a popular recreational sport played at both amateur and professional level. Ocular injuries are well recognised, although there is a growing body of literature documenting superficial vascular as well as deep solid organ injuries. An 18-year-old man presented with signs and symptoms consistent with acute appendicitis. Intraoperatively, a grade III liver injury was identified and packed before a relook at 48 h. No further active bleeding was identified; however, follow-up ultrasound at 3 weeks demonstrated non-resolution of a large subcapsular haematoma. The patient was readmitted for a short period of observation and discharged with repeat ultrasound scheduled for 3 months. This represents the first report of paintball-related blunt traumatic injury to the liver. Solid organ injuries of this nature have only been reported three times previously-all in the urological setting. This case also highlights issues surrounding the use of routine follow-up imaging in blunt liver trauma and provides a concise discussion of the relevant literature. 2016 BMJ Publishing Group Ltd.

  18. Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis

    Science.gov (United States)

    Lu, Yin-Ying; Wang, Chun-Ping; Zhou, Lin; Chen, Yan; Su, Shu-Hui; Feng, Yong-Yi; Yang, Yong-Ping

    2008-01-01

    AIM: To determine the platelet-activating factor (PAF) synthesis and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis. METHODS: Kupffer cells, isolated from the livers of control and CCl4-induced cirrhotic rats, were placed in serum-free medium overnight. PAF saturation binding, ET-1 saturation and competition binding were assayed. ET-1 induced PAF synthesis, mRNA expression of PAF, preproendothelin-1, endothelin A (ETA) and endothelin B (ETB) receptors were also determined. RESULTS: A two-fold increase of PAF synthesis (1.42 ± 0.14 vs 0.66 ± 0.04 pg/μg DNA) and a 1.48-fold increase of membrane-bound PAF (1.02 ± 0.06 vs 0.69 ± 0.07 pg/μg DNA) were observed in activated Kupffer cells of cirrhotic rats. The application of ET-1 to Kupffer cells induced PAF synthesis in a concentration-dependent manner in both cirrhotic and normal rats via ETB receptor, but PAF synthesis in the activated Kupffer cells was more effective than that in the normal Kupffer cells. In activated Kupffer cells, PAF receptor expression and PAF binding capacity were markedly enhanced. Activated Kupffer cells raised the [125I]-ET-1 binding capacity, but changed neither the affinity of the receptors, nor the expression of ETA receptor. CONCLUSION: Kupffer cells in the course of CCl4-induced cirrhosis are the main source of increased PAF. ET-1 is involved endogenously in stimulating the PAF synthesis in activated Kupffer cells via ETB receptor by paracrine. ETA receptor did not appear in activated Kupffer cells, which may exacerbate the hepatic and extrahepatic complications of cirrhosis. PMID:18205269

  19. Drug-induced liver injury due to antibiotics.

    Science.gov (United States)

    Björnsson, Einar S

    Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

  20. Molecular mechanisms of liver injury: apoptosis or necrosis.

    Science.gov (United States)

    Wang, Kewei

    2014-10-01

    Hepatic apoptosis is thought of as a prevalent mechanism in most forms of liver injury. However, the role of hepatic apoptosis is often intermixed with the cellular necrosis. It remains unknown how apoptosis is relevant to the progression of the liver injury. This review summarizes the characteristics of both hepatic apoptosis and necrosis in pathogenesis of liver diseases. Apoptosis and necrosis represent alternative outcomes of different etiology during liver injury. Apoptosis is a main mode of cell death in chronic viral hepatitis, but is intermingled with necrosis in cholestatic livers. Necrosis is the principal type of liver cell killing in acetaminophen-induced hepatotoxicity. Anti-apoptosis as a strategy is beneficial to liver repair response. Therapeutic options of liver disease depend on the understanding toward pathogenic mechanisms of different etiology. Copyright © 2014 Elsevier GmbH. All rights reserved.

  1. Role of Interleukin-22 in chronic liver injury.

    Science.gov (United States)

    Carmo, Rodrigo F; Cavalcanti, Maria S M; Moura, Patrícia

    2017-10-01

    Liver fibrosis is the result of an exacerbated wound-healing response associated with chronic liver injury. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and frequently requires liver transplantation. The host immune response has an important role driving fibrosis deposition by activating hepatic stellate cells (HSCs). Interleukin-22 (IL-22) is a cytokine that plays a key role in promoting antimicrobial immunity and tissue repair at barrier surfaces. Data from literature suggest that IL-22 has a protective role in the liver by reducing fibrosis in some pathological conditions, however the results are contradictory. This review highlights current knowledge of IL-22' role in chronic liver injury, as well as its therapeutic potential for the treatment of chronic liver injury. Copyright © 2016 Elsevier Ltd. All rights reserved.

  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. The Impact of Liver Graft Injury on Cancer Recurrence Posttransplantation.

    Science.gov (United States)

    Li, Chang-Xian; Man, Kwan; Lo, Chung-Mau

    2017-11-01

    Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma. However, cancer recurrence, posttransplantation, remains to be the critical issue that affects the long-term outcome of hepatocellular carcinoma recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute-phase liver graft injury is a result of hepatic ischemia reperfusion injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death, and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute-phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating the tumor cell invasion and migration but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic ischemia reperfusion injury on tumor recurrence posttransplantation, both in clinical and animal cohorts.

  5. 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. © 2011 John Wiley & Sons A/S.

  6. Nephroprotective effects of Colpomenia sinuosa (Derbes & Solier against carbon tetrachloride induced kidney injury in Wistar rats

    Directory of Open Access Journals (Sweden)

    Lekameera Ramarajan

    2012-05-01

    Full Text Available Objective: To establish the protective effect of seaweed Colpomenia sinuosa against carbon tetra chloride (CCl4 induced oxidative stress and resultant dysfunction of rat kidney. Methods: Seven to eight weeks old male Wistar rats (150-220g were exposed to CCl4 (1.5 ml/kg injection then treated with seaweed Colpomenia sinuosa (100 mg/kg body weight in 0.3% CMC solution. Blood was collected at the 5th day of experimental period to estimate the Total count (TC, Hemoglobin (HB, Total protein (TP, Glucose, Albumin, Cholesterol, TGL and Urea. Results: The results shows significantly decreased (P<0.01 level of TC, the cholesterol and urea levels shows significantly increased (P<0.05 in CCl4 treated groups when compared to control groups. These levels were found to be normalized by oral feeding of C. sinuosa. Then the rats were sacrificed and kidneys taken for enzyme analyses and histological examination. In the CCl4 treated group significantly increased activities in TBARS, SOD, CAT, GPX, GSH (P<0.05 when compared to control group. These increased activities were found to near normal in the CCl 4 + C. sinuosa treated group and Seaweed C. sinuosa treated alone group did not change any enzyme activity. Exposure to CCl4 resulted hydrobhic changes in epithelium and Hypercellulartity of glomerulus was seen in the CCl 4 + drug treated group. Conclusions: These results suggest that the nephroprotective effect of C. sinuosa can be attributed to its enhancing effects on antioxidant defense system and lead to prevent the damage by exposure of CCl4 toxicity.

  7. Liver injury from herbals and dietary supplements in the U.S. 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

    2014-10-01

    The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). 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 U.S. 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 caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by 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 LT. 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 or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408). © 2014 by the American Association for the Study of Liver Diseases.

  8. Ischemia/Reperfusion Injury in Liver Surgery and Transplantation: Pathophysiology

    Directory of Open Access Journals (Sweden)

    Kilian Weigand

    2012-01-01

    Full Text Available Liver ischemia/reperfusion (IR injury is caused by a heavily toothed network of interactions of cells of the immune system, cytokine production, and reduced microcirculatory blood flow in the liver. These complex networks are further elaborated by multiple intracellular pathways activated by cytokines, chemokines, and danger-associated molecular patterns. Furthermore, intracellular ionic disturbances and especially mitochondrial disorders play an important role leading to apoptosis and necrosis of hepatocytes in IR injury. Overall, enhanced production of reactive oxygen species, found very early in IR injury, plays an important role in liver tissue damage at several points within these complex networks. Many contributors to IR injury are only incompletely understood so far. This paper tempts to give an overview of the different mechanisms involved in the formation of IR injury. Only by further elucidation of these complex mechanisms IR injury can be understood and possible therapeutic strategies can be improved or be developed.

  9. Carbon tetrachloride-induced hepatic and renal damages in rat: inhibitory effects of cacao polyphenol.

    Science.gov (United States)

    Suzuki, Koichiro; Nakagawa, Kiyotaka; Yamamoto, Takayuki; Miyazawa, Taiki; Kimura, Fumiko; Kamei, Masanori; Miyazawa, Teruo

    2015-01-01

    Here, we investigated the protective effect of cacao polyphenol extract (CPE) on carbon tetrachloride (CCl4)-induced hepato-renal oxidative stress in rats. Rats were administered CPE for 7 days and then received intraperitoneal injection of CCl4. Two hours after injection, we found that CCl4 treatment significantly increased biochemical injury markers, lipid peroxides (phosphatidylcholine hydroperoxide (PCOOH) and malondialdehyde (MDA)) and decreased glutathione peroxidase activity in kidney rather than liver, suggesting that kidney is more vulnerable to oxidative stress under the present experimental conditions. CPE supplementation significantly reduced these changes, indicating that this compound has antioxidant properties against CCl4-induced oxidative stress. An inhibitory effect of CPE on CCl4-induced CYP2E1 mRNA degradation may provide an explanation for CPE antioxidant property. Together, these results provide quantitative evidence of the in vivo antioxidant properties of CPE, especially in terms of PCOOH and MDA levels in the kidneys of CCl4-treated rats.

  10. The protective role of pomegranate juice against carbon tetrachloride-induced oxidative stress in rats.

    Science.gov (United States)

    Pirinççioğlu, Mihdiye; Kızıl, Göksel; Kızıl, Murat; Kanay, Zeki; Ketani, Aydın

    2014-11-01

    Most pomegranate (Punica granatum Linn., Punicaceae) fruit parts are known to possess enormous antioxidant activity. The present study was carried out to determine the phenolic and flavonoid contents of Derik pomegranate juice and determine its effect against carbon tetrachloride (CCl4)-induced toxicity in rats. Animals were divided into four groups (n = 6): group I: control, group II: CCl4 (1 ml/kg), group III: CCl4 + pomegranate juice and group IV: CCl4 + ursodeoxycholic acid (UDCA). Treatment duration was 4 weeks, and the dose of CCl4 was administered once a week to groups II, III and IV during the experimental period. CCl4-treated rats caused a significant increase in serum enzyme levels, such as aspartate aminotransferase, alanine aminotransferase and total bilirubin, and decrease in albumin, when compared with control. Administration of CCl4 along with pomegranate juice or UDCA significantly reduces these changes. Analysis of lipid peroxide (LPO) levels by thiobarbutiric acid reaction showed a significant increase in liver, kidney and brain tissues of CCl4-treated rats. However, both pomegranate juice and UDCA prevented the increase in LPO level. Histopathological reports also revealed that there is a regenerative activity in the liver and kidney cells. Derik pomegranate juice showed to be hepatoprotective against CCl4-induced hepatic injury. In conclusion, present study reveals a biological evidence that supports the use of pomegranate juice in the treatment of chemical-induced hepatotoxicity. © The Author(s) 2012.

  11. Management and treatment of liver injury in children.

    Science.gov (United States)

    Arslan, Serkan; Güzel, Mahmut; Turan, Cüneyt; Doğanay, Selim; Doğan, Ahmet Burak; Aslan, Ali

    2014-01-01

    We aimed to assess the causes of trauma that result in liver injury and additional solid organ injuries, management types and results of management in children referred to our clinic for liver injuries. The records of 52 patients who were managed for liver injuries due to blunt abdominal trauma between January 2005-2010 were reviewed retrospectively. The patients were 1-17 (8.3±5.4) years old; 32 (62%) were male and 20 (38%) were female. Causes of injuries included pedestrian traffic accidents (19, 37%), falls from height (15, 29%), passenger traffic accidents (8, 15%), bicycle accidents (8, 15%), and objects falling on the body (2, 4%). Isolated liver injury was present in 32 patients (62%), while 20 patients (38%) had other organ injuries. Liver injuries were grade I in 6 patients (12%), grade II in 14 (28%), grade III in 22 (43%), grade IV in 9 (17%), and grade V in 1 (2%). Forty-five patients (87%) were managed conservatively in this series of liver injury, whereas seven patients (13%) who had unstable vital signs underwent surgery. The mortality rate, duration of stay in intensive care and hospital, and number of blood transfusions were higher in surgically managed patients, while hemoglobin level and blood pressure were significantly lower in surgically managed patients. As a result, conservative management should be preferred in patients with liver injuries who are hemodynamically stable. Conservative management has some advantages, including shorter duration of stay in hospital, less need for blood transfusion and lower morbidity and mortality rates.

  12. Systematic Review on Chinese Herbal Medicine Induced Liver Injury

    National Research Council Canada - National Science Library

    Zhang, Peng; Ye, Yongan; Yang, Xianzhao; Jiao, Yuntao

    2016-01-01

    .... However, there are still veils on causative herbs and clinical characteristics. Aim. To systematically review data on CHM induced liver injury with particular focus on causative herbs and clinical characteristics. Methods...

  13. Quercetin prevents pyrrolizidine alkaloid clivorine-induced liver injury in mice by elevating body defense capacity

    National Research Council Canada - National Science Library

    Ji, Lili; Ma, Yibo; Wang, Zaiyong; Cai, Zhunxiu; Pang, Chun; Wang, Zhengtao

    2014-01-01

    ... of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury...

  14. Sterile inflammation in acute liver injury: myth or mystery?

    OpenAIRE

    Woolbright, Benjamin L.; Jaeschke, Hartmut

    2015-01-01

    Inflammation during liver injury normally serves as a mechanism for cleaning up debris and as a stimulant for regeneration. However, aberrant levels of inflammation can provoke further liver injury and inhibit regeneration through the release of damaging reactive oxygen species. Considerable effort has gone into understanding the mechanisms that control the switch between healthy and pathological inflammation. The identification of a receptor system that detects damage-associated molecular pa...

  15. Effects of lycopene-beadlet or tomato-powder feeding on carbon tetrachloride-induced hepatotoxicty in rats.

    Science.gov (United States)

    Kim, Y; DiSilvestro, R; Clinton, S

    2004-02-01

    The carotenoid lycopene has been touted as possessing various antioxidant properties, but there are no demonstrations that lycopene inhibits tissue injury due to acute oxidant stress. Thus, the present study examined the effects of intake of lycopene or tomato extract, a rich source of lycopene, on acute liver injury caused by the oxidant carbon tetrachloride (CCl4). Feeding with tomato extract (10% tomato powder), but not with lycopene (0.25% lycopene beadlets), partially inhibited CCl4-induced hepatic injury based on the serum activities of sorbitol dehydrogenase and aspartate aminotransferase. No effect was seen for either lycopene or tomato extract on serum beta-glucuronidase activity, a marker of lysosomal injury. We concluded that tomato extract, but not lycopene, partially protected against acute liver injury due to chemically-induced oxidant stress.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. Protective Effects of Antrodia Cinnamomea Against Liver Injury

    Directory of Open Access Journals (Sweden)

    Yen-Wenn Liu

    2012-10-01

    Full Text Available Chinese herbal medicine (中草藥 attracts much attention in the treatment of liver injuries. Numerous studies have revealed various biological activities of medicinal mushrooms such as Antrodia Cinnamomea (牛樟芝. Although A. cinnamomea is rare in the wild, recent developments in fermentation and cultivation technologies make the mycelia and fruiting bodies of this valuable medicinal mushroom readily available. Liver diseases such as fatty liver, hepatitis, hepatic fibrosis, and liver cancer are complicated processes of liver injuries that have tremendous impact on human society. In this article, we reviewed studies about the hepatoprotective effects of the fruiting bodies and mycelia of A. cinnamomea performed in different experimental models. The results of those studies suggest the potential application of A. cinnamomea in preventing and treating liver diseases and its potential to be developed into health foods or new drugs.

  18. 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.

  19. Inflammatory Stress Potentiates Emodin-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Can eTu

    2015-10-01

    Full Text Available Herbal medicines containing emodin, widely used for the treatment of hepatitis in clinic, have been reported with hepatotoxicity in individuals. A modest inflammatory stress potentiating liver injury has been linked to the idiosyncratic drug-induced liver injury (IDILI. In this study, we investigated the hypothesis that lipopolysaccharide (LPS interacts with emodin could synergize to cause liver injury in rats. Emodin (ranging from 20, 40 to 80 mg/kg, which is in the range of liver protection, was administered to rats, before LPS (2.8 mg/kg or saline vehicle treatment. The biochemical tests showed that non-toxic dosage of LPS coupled with emodin caused significant increases of plasma ALT and AST activities as compared to emodin alone treated groups (P<0.05. In addition, with LPS or emodin alone could not induce any changes in ALT and AST activity, as compared with the control group (0.5% CMC-Na treatment. Meanwhile, the plasma proinflammatory cytokines, TNF-α, IL-1β, and IL-6 increased significantly in the emodin/LPS groups compared to either emodin groups or the LPS (P<0.05. Histological analysis showed that liver damage was only found in emodin/LPS cotreatmented rat livers samples. These results indicate that non-toxic dosage of LPS potentiates the hepatotoxicity of emodin. This discovery raises the possibility that emodin and herbal medicines containing it may induce liver injury in the inflammatory stress even in their therapeutic dosages.

  20. Congenital biliary atresia: liver injury begins at birth

    DEFF Research Database (Denmark)

    Makin, Erica; Quaglia, Alberto; Kvist, Nina

    2009-01-01

    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...

  1. 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.

    2016-01-01

    The surgically-demanding mouse orthotopic liver transplant model was first described in 1991. It has proved a powerful research tool for 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, since 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 has provided valuable mechanistic insights into the immuno- and pathobiology of the liver and the regulation of graft rejection and tolerance over the past 25 years. The molecular pathways identified in 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. 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 liver and other diseases. PMID:26709949

  2. [Current diagnostic and therapeutic approaches in liver injuries].

    Science.gov (United States)

    Vyhnánek, F; Denemark, L; Duchác, V

    2003-01-01

    The recent improvements in hospital care system (centralized specialized care) and the use of new imaging methods and modern technologies in surgical treatment have greatly enhanced successful outcomes of therapy in liver injury. The aim of the study was to evaluate the contribution of procedures included in the diagnostic-therapeutic algorithms to the treatment of blunt injury to the liver in our patient population. Our group consisted of 43 patients with blunt injury to the liver who were treated at the Emergency Department between 1998 and 2002. In 28 patients, blunt injury was part of polytrauma, in 7 patients it was associated with thoraco-abdominal injury and, in 8 patients, it was the only trauma sustained. The diagnosis and therapy were based on the algorithm currently used for treating liver injury at the Emergency Department. In addition to clinical examination and assessment of the actual status of hemodynamics, spinal computed tomography was carried out to establish the therapeutic procedure. Fourteen patients were treated conservatively according to the criteria of a non-surgical approach and 29 patients underwent urgent surgery. Indications for revision surgery included, apart from signs of ongoing abdominal bleeding related to liver injury, combined spleen and kidney trauma. All patients with thoraco-abdominal involvement had laparotomy; in addition, four underwent thoracotomy including repair of the lacerated lung by suturing and three patients required suturing of a rupture of the right part of the diaphragm. In the patients treated conservatively, 10 showed spontaneous regression of parenchymal hematomas and four had to be treated by suction drainage. Out of 29 patients operated on, five died with signs of an irreversible hemorrhagic shock from multiple trauma and one died of multiple organ failure. The principal criterion determining therapy in blunt liver injury is the patient's hemodynamic status; laparotomy is mandatory in intra

  3. An in vitro method of alcoholic liver injury using precision-cut liver slices from rats

    NARCIS (Netherlands)

    Klassen, Lynell W.; Thiele, Geoffrey M.; Duryee, Michael J.; Schaffert, Courtney S.; DeVeney, Amy L.; Hunter, Carlos D.; Olinga, Peter; Tuma, Dean J.

    2008-01-01

    Alcohol abuse results in liver injury, but investigations into the mechanism(s) for this injury have been hampered by the lack of appropriate in vitro culture models in which to conduct in depth and specific studies. In order to overcome these shortcomings, we have developed the use of precision-cut

  4. 3-Alkynyl selenophene protects against carbon-tetrachloride-induced and 2-nitropropane-induced hepatic damage in rats.

    Science.gov (United States)

    Wilhelm, Ethel Antunes; Jesse, Cristiano Ricardo; Prigol, Marina; Alves, Diego; Schumacher, Ricardo Frederico; Nogueira, Cristina Wayne

    2010-12-01

    The aim of this study was to investigate the protective effect of 3-alkynyl selenophene (3-ASP) on acute liver injury induced by carbon tetrachloride (CCl(4)) and 2-nitropropane (2-NP) in rats. On the first day of treatment, the animals received 3-ASP (25 mg/kg, p.o.). On the second day, the rats received CCl(4) (1 mg/kg, i.p.) or 2-NP (100 mg/kg, p.o.). Twenty-four hours after CCl(4) or 2-NP administration, the animals were euthanized, and their plasma and liver were removed for biochemical and histological analyses. The histological analysis revealed extensive injury in the liver of CCl(4)-exposed and 2-NP-exposed rats, which was attenuated by 3-ASP. 3-ASP significantly attenuated (1) the increase in plasmatic aspartate and alanine aminotransferase activities and lipid peroxidation levels induced by CCl(4) and 2-NP; (2) the inhibition of δ-aminolevulinic dehydratase activity caused by 2-NP; and (3) the decrease in ascorbic acid (AA) levels and catalase (CAT) activity caused by CCl(4). AA levels and CAT activity remained unaltered in the liver of rats exposed to 2-NP. The protective effect of 3-ASP on acute liver injury induced by CCl(4) and 2-NP in rats was demonstrated.

  5. S-ADENOSYLMETHIONINE IN LIVER HEALTH, INJURY, AND CANCER

    Science.gov (United States)

    Lu, Shelly C.; Mato, José M.

    2013-01-01

    S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well. PMID:23073625

  6. Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Jung-Chun Lin

    Full Text Available Carbon tetrachloride (CCl4 is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2, and tumor necrosis factor-α (TNF-α], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.

  7. Comparison of acute kidney injury between open and laparoscopic liver resection: Propensity score analysis

    National Research Council Canada - National Science Library

    Young-Jin Moon; In-Gu Jun; Ki-Hun Kim; Seon-Ok Kim; Jun-Gol Song; Gyu-Sam Hwang

    2017-01-01

    .... Considering that laparoscopic surgery is beneficial in reducing the inflammatory response, we compared the incidence of postoperative acute kidney injury between laparoscopic liver resection and open liver resection...

  8. [Neutrophils' contribution to ischaemia and reperfusion injury in liver].

    Science.gov (United States)

    Helewski, Krzysztof J; Kowalczyk-Ziomek, Grazyna I; Konecki, Janusz

    2007-01-01

    Neutrophils are cells which induce liver injury due to ischaemia and reperfusion. They are active especially in the later phase of reperfusion (> 6 hrs) since they gather in the liver and release mediators damaging hepatocytes directly. Inflow ofneutrophils into the liver is possible due to chemotaxia which involves, among others, chemokines CXC (interleukin-8 and its counterparts). Neutrophils' ability to induce chemotaxia is determined by their specific glycoprotein receptors in cell membranes. Neutrophils contribute to ischaemia/reperfusion liver injury because they adhere to vessel endothelium, cross the wall of hepatic microcirculation vessels and adhere to hepatocytes. Selectins play a crucial role in neutrophils' contact with endothelial cells, and ICAM-1, predominantly in their adhesion to hepatocytes. Also beta2-integrin and Mac-1 play essential role. Neutrophils damage hepatocytes by realising proteases, free radicals, TNF-alpha, TGF-beta and leucotrien. Neutrophils together with endothelial cells also disturb the hepatic microcirculation.

  9. Hepatitis B virus inhibits insulin receptor signaling and impairs liver regeneration via intracellular retention of the insulin receptor.

    Science.gov (United States)

    Barthel, Sebastian Robert; Medvedev, Regina; Heinrich, Thekla; Büchner, Sarah Manon; Kettern, Nadja; Hildt, Eberhard

    2016-11-01

    Hepatitis B virus (HBV) causes severe liver disease but the underlying mechanisms are incompletely understood. During chronic HBV infection, the liver is recurrently injured by immune cells in the quest for viral elimination. To compensate tissue injury, liver regeneration represents a vital process which requires proliferative insulin receptor signaling. This study aims to investigate the impact of HBV on liver regeneration and hepatic insulin receptor signaling. After carbon tetrachloride-induced liver injury, liver regeneration is delayed in HBV transgenic mice. These mice show diminished hepatocyte proliferation and increased expression of fibrosis markers. This is in accordance with a reduced activation of the insulin receptor although HBV induces expression of the insulin receptor via activation of NF-E2-related factor 2. This leads to increased intracellular amounts of insulin receptor in HBV expressing hepatocytes. However, intracellular retention of the receptor simultaneously reduces the amount of functional insulin receptors on the cell surface and thereby attenuates insulin binding in vitro and in vivo. Intracellular retention of the insulin receptor is caused by elevated amounts of α-taxilin, a free syntaxin binding protein, in HBV expressing hepatocytes preventing proper targeting of the insulin receptor to the cell surface. Consequently, functional analyses of insulin responsiveness revealed that HBV expressing hepatocytes are less sensitive to insulin stimulation leading to delayed liver regeneration. This study describes a novel pathomechanism that uncouples HBV expressing hepatocytes from proliferative signals and thereby impedes compensatory liver regeneration after liver injury.

  10. Protective effect of bixin on carbon tetrachloride-induced hepatotoxicity in rats

    OpenAIRE

    Moreira, Priscila R; Maioli, Marcos A; Medeiros, Hyllana CD; Guelfi, Marieli; Pereira, Flávia TV; Mingatto, Fábio E

    2014-01-01

    Background: The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats.Results: The animals were divided into four groups with six rats in each group. CCl4 ...

  11. Cardiotrophin-1 reduces ischemia/reperfusion injury during liver transplant.

    Science.gov (United States)

    Aguilar-Melero, Patricia; Luque, Antonio; Machuca, María M; Pérez de Obanos, María P; Navarrete, Rocío; Rodríguez-García, Inés C; Briceño, Javier; Iñiguez, María; Ruiz, Juan; Prieto, Jesús; de la Mata, Manuel; Gomez-Villamandos, Rafael J; Muntane, Jordi; López-Cillero, Pedro

    2013-05-01

    Orthotopic liver transplantation (OLT) is currently the elective treatment for advanced liver cirrhosis and acute liver failure. Ischemia/reperfusion damage may jeopardize graft function during the postoperative period. Cardiotrophin-1 (CT-1) has demonstrated cytoprotective properties in different experimental models of liver injury. There is no evidence to demonstrate its potential use in the prevention of the ischemia/reperfusion injury that occurs during OLT. The present study is the first report to show that the administration of CT-1 to donors would benefit the outcome of OLT. We tested the cytoprotective effect of CT-1 administered to the donor prior to OLT in an experimental pig model. Hemodynamic changes, hepatic histology, cell death parameters, activation of cell signaling pathways, oxidative and nitrosative stress, and animal survival were analyzed. Our data showed that CT-1 administration to donors increased animal survival, improved cardiac and respiratory functions, and reduced hepatocellular injury as well as oxidative and nitrosative stress. These beneficial effects, related to the activation of AKT, ERK, and STAT3, reduced caspase-3 activity and diminished IL-1β and TNF-α expression together with IL-6 upregulation in liver tissue. The administration of CT-1 to donors reduced ischemia/reperfusion injury and improved survival in an experimental pig model of OLT. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Effect of intensive insulin treatment on the liver in hyperglycemic rats with liver injury

    Directory of Open Access Journals (Sweden)

    Jun-xun MA

    2014-01-01

    Full Text Available Objective To reproduce a liver injury model in hyperglycemic rats, and investigate the effect of intensive insulin therapy on the liver. Methods Streptozotocin (STZ and D-gal were injected to reproduce hyperglycemic liver injury model in rats. These rats were divided into intensive insulin group (with blood glucose controlled at 6-8mmol/L and conventional treatment group (with blood glucose 9-12mmol/L. Before and 1, 3, 5, 7 days after the reproduction of the model, the rats were sacrificed, and alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, total protein, alkaline phosphatase were determined. The pathological sections of the liver tissues from the model rats and normal rats were made, they were examined after HE staining. Electron microscopic examination was also performed for the liver tissue of the 7-d models. Results Liver injury model of rats with hyperglycemia was successfully reproduced. Intensive insulin therapy can reduce the death risk in model rats. The mortality of rats was lower in intensive insulin group than in conventional treatment group (P<0.01. After intensive insulin therapy, ALT, AST, T-Bil and ALP decreased, while albumin and total protein increased (P<0.01 or P<0.05. HE staining and transmission electron microscopy revealed that degeneration and necrosis of hepatocytes were ameliorated. Conclusion The liver injury model of rats with hyperglycemia has been successfully reproduced. Intensive insulin therapy can decrease the mortality of model rats and reduce the degree of rat liver injury, and the results show a prospect for clinical application. DOI: 10.11855/j.issn.0577-7402.2013.01

  13. Protective effect of bixin on carbon tetrachloride-induced hepatotoxicity in rats.

    Science.gov (United States)

    Moreira, Priscila R; Maioli, Marcos A; Medeiros, Hyllana C D; Guelfi, Marieli; Pereira, Flávia T V; Mingatto, Fábio E

    2014-09-29

    The liver is an important organ for its ability to transform xenobiotics, making the liver tissue a prime target for toxic substances. The carotenoid bixin present in annatto is an antioxidant that can protect cells and tissues against the deleterious effects of free radicals. In this study, we evaluated the protective effect of bixin on liver damage induced by carbon tetrachloride (CCl4) in rats. The animals were divided into four groups with six rats in each group. CCl4 (0.125 mL kg(-1) body wt.) was injected intraperitoneally, and bixin (5.0 mg kg(-1) body wt.) was given by gavage 7 days before the CCl4 injection. Bixin prevented the liver damage caused by CCl4, as noted by the significant decrease in serum aminotransferases release. Bixin protected the liver against the oxidizing effects of CCl4 by preventing a decrease in glutathione reductase activity and the levels of reduced glutathione and NADPH. The peroxidation of membrane lipids and histopathological damage of the liver was significantly prevented by bixin treatment. Therefore, we can conclude that the protective effect of bixin against hepatotoxicity induced by CCl4 is related to the antioxidant activity of the compound.

  14. Eighteen cases of liver injury following ingestion of Polygonum multiflorum.

    Science.gov (United States)

    Dong, Huihui; Slain, Douglas; Cheng, Junchi; Ma, Weihang; Liang, Weifeng

    2014-02-01

    Polygonum multiflorum is a popular Chinese herbal medication. In this case series, we report on 18 otherwise healthy non-viral hepatitis patients who developed liver dysfunction following consumption of P. multiflorum alone. Concurrent and retrospective analysis was used in this study. The causality of P. multiflorum in liver injury was graded by the Council for International Organizations of Medical Sciences (CIOMS) toxicity scale. From 2005 to 2012, 18 cases of hepatotoxicity potentially involving P. multiflorum. The median age was 42 years old (range from 18 to 63). Median time of onset of symptoms was 27 days (1-120). Prevailing clinical symptoms were fatigue, loss of appetite and jaundice. Sixteen patients had elevated level of total bilirubin (>21 mol/L); liver enzymes elevated markedly in all patients (ALT>40 U/L, AST>40 U/L, GGT>50 U/L), except for alkaline phosphatase which elevated only in nine patients. Based on the liver enzyme pattern, the type of liver injuries were hepatocellular according to CIOMS. In terms of causality, 14 of 18 patients were evaluated as being highly probable. All patients were responding well to P. multiflorum stoppage, and liver protective-supportive care. P. multiflorum products can be associated with hepatotoxicity in otherwise healthy non-viral hepatitis infected patients, regardless of herbal processing. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. 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.

  16. Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice.

    Science.gov (United States)

    Ince, Sinan; Keles, Hikmet; Erdogan, Metin; Hazman, Omer; Kucukkurt, Ismail

    2012-07-01

    The protective effect of boric acid against liver damage was evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male albino mice were treated intraperitoneally (i.p.) with boric acid (50, 100, and 200 mg/kg) or silymarin daily for 7 days and received 0.2% CCl(4) in olive oil (10 mL/kg, i.p.) on day 7. Results showed that administration of boric acid significantly reduced the elevation in serum levels of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and the level of malondialdehyde in the liver that were induced by CCl(4) in mice. Boric acid treatment significantly increased glutathione content, as well as the activities of superoxide dismutase and catalase in the liver. Boric acid treatment improved the catalytic activity of cytochrome P450 2E1 and maintained activation of nuclear factor kappa light-chain enhancer of activated B cell gene expression, with no effect on inducible nitric oxide synthase gene expression in the livers of mice. Histopathologically, clear decreases in the severity of CCl(4)-induced lesions were observed, particularly at high boric acid concentrations. Results suggest that boric acid exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely the result of both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  17. Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy

    Science.gov (United States)

    Lin, Chih-Wen; Chen, Yaw-Sen; Lin, Chih-Che; Chen, Yun-Ju; Lo, Gin-Ho; Lee, Po-Huang; Kuo, Po-Lin; Dai, Chia-Yen; Huang, Jee-Fu; Chung, Wang-Long; Yu, Ming-Lung

    2015-01-01

    The deregulation of autophagy is involved in liver regeneration. Here, we investigated the role of autophagy in the regulation of liver regeneration after partial hepatectomy (PHx) and the development of pharmacological interventions for improved liver regeneration after PHx. We show that autophagy was activated in the early stages of liver regeneration following 70% PHx in vivo. Moreover, amiodarone was associated with a significant enhancement of autophagy, liver growth, and hepatocyte proliferation, along with reduced liver injury and the termination of liver regeneration due to decreased transforming growth factor-β1 expression after 70% PHx. The promotion of autophagy appeared to selectively increase the removal of damaged mitochondria. We also found that Atg7 knockdown or pretreatment with chloroquine aggravated the liver injury associated with 70% PHx and reduced liver growth and hepatocyte proliferation. Finally, amiodarone improved liver regeneration, survival, and liver injury after 90% PHx. In conclusion, our results indicate that autophagy plays an important role in mouse liver regeneration and that modulating autophagy with amiodarone may be an effective method of improving liver regeneration, increasing survival, and ameliorating liver injury following PHx. PMID:26515640

  18. 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.

    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

  19. Causality assessment of liver injury after chronic oral amiodarone intake.

    Science.gov (United States)

    Llanos, Lucía; Moreu, Rocío; Peiró, Ana M; Pascual, Sonia; Francés, Rubén; Such, José; Horga, José F; Pérez-Mateo, Miguel; Zapater, Pedro

    2009-04-01

    The number of patients receiving amiodarone will increase in future years. As clinically significant hepatotoxicity associated with oral amiodarone is infrequent and difficult to predict, a new Bayesian-developed model is proposed to help in the causality assessment of amiodarone-induced liver injury. Incidence of abnormal liver enzymes in patients receiving amiodarone was obtained from placebo controlled clinical trials. Published case reports of amiodarone-induced hepatotoxicity were identified through a literature search. Maximum number of expected hepatotoxicity cases in amiodarone and placebo-treated patients was calculated using Poisson distribution. The calculated odds ratio was used as a Prior Odds (PrO) to subsequent quantification, using a Bayesian-approach, of individual amiodarone-induced hepatotoxicity likelihood. PrO of amiodarone-induced hepatotoxicity was 0.48. Thirty nine amiodarone-associated hepatotoxicity case reports were retrieved. Half of published case reports developed an irreversible damage. The amiodarone Bayesian model combining information about latency period and period of remission, together with analytical parameters properly defines the toxicity profile shown in published case reports. The analytical pattern defined by this model is different from the one expected if liver injury in published cases was caused by other etiologies. A method based on a Bayesian-approach, which links information from clinical trials with clinical hepatotoxicity profile from published case reports can be a useful tool for amiodarone-induced liver injury causality assessment. At present, this method is limited due to scarcity and quality of available data. Further efforts are needed to improve model ability in order to identify amiodarone-induced liver injury.

  20. Hepatoprotective activity of Symplocos racemosa bark on carbon tetrachloride-induced hepatic damage in rats

    Directory of Open Access Journals (Sweden)

    Dhananjay Wakchaure

    2011-01-01

    Full Text Available The present study aims to evaluate the hepatoprotective activity of ethanol extract of Symplocos racemosa (EESR bark on carbon tetrachloride (CCl4-induced hepatic damage in rats. CCl4 with olive oil (1 : 1 (0.2 ml/kg, i.p. was administered for ten days to induce hepatotoxicity. EESR (200 and 400 mg/kg, p.o. and silymarin (100 mg/kg p.o. were administered concomitantly for fourteen days. The degree of hepatoprotection was measured using serum transaminases (AST and ALT, alkaline phosphatase, bilirubin, albumin, and total protein levels. Metabolic function of the liver was evaluated by thiopentone-induced sleeping time. Antioxidant activity was assessed by measuring liver malondialdehyde, glutathione, catalase, and superoxide dismutase levels. Histopathological changes of liver sample were also observed. Significant hepatotoxicity was induced by CCl4 in experimental animals. EESR treatment showed significant dose-dependent restoration of serum enzymes, bilirubin, albumin, total proteins, and antioxidant levels. Improvements in hepatoprotection and morphological and histopathological changes were also observed in the EESR treated rats. It was therefore concluded that EESR bark is an effective hepatoprotective agent in CCl4-induced hepatic damage, and has potential clinical applications for treatment of liver diseases.

  1. Traditional Chinese Medicine Induced Liver Injury.

    Science.gov (United States)

    Teschke, Rolf

    2014-06-01

    Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some

  2. Traditional Chinese Medicine Induced Liver Injury

    Science.gov (United States)

    2014-01-01

    Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some

  3. Sesamol loaded solid lipid nanoparticles: a promising intervention for control of carbon tetrachloride induced hepatotoxicity

    OpenAIRE

    Singh, Neha; Khullar, Neeraj; Kakkar, Vandita; Kaur, Indu Pal

    2015-01-01

    Background Sesamol, a component of sesame seed oil, exhibited significant antioxidant activity in a battery of in vitro and ex vivo tests including lipid peroxidation induced in rat liver homogenates. Latter established its potential for hepatoprotection. However, limited oral bioavailability, fast elimination (as conjugates) and tendency towards gastric irritation/toxicity (especially forestomach of rodents) may limit its usefulness. Presently, we packaged sesamol into solid lipid nanopartic...

  4. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis

    Directory of Open Access Journals (Sweden)

    Gao Hong-Ying

    2012-05-01

    Full Text Available Abstract The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, hexadecenoic acid (HA, laminin (LN, hydroxyproline (Hyp, and glutathione (GSH, malondialdehyde (MDA, superoxide dismutase (SOD in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E staining and Masson Trichrome (MT examination. The expression of transforming growth factor-β1 (TGF-β1 and α-smooth muscle actin (α-SMA was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis.

  5. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction.

    Science.gov (United States)

    Wang, Wei-Wei; Zhang, Yu; Huang, Xiao-Bing; You, Nan; Zheng, Lu; Li, Jing

    2017-10-14

    To investigate whether fecal microbiota transplantation (FMT) prevents hepatic encephalopathy (HE) in rats with carbon tetrachloride (CCl4)-induced acute hepatic dysfunction. A rat model of HE was established with CCl4. Rat behaviors and spatial learning capability were observed, and hepatic necrosis, intestinal mucosal barrier, serum ammonia levels and intestinal permeability were determined in HE rats receiving FMT treatment. Furthermore, the expression of tight junction proteins (Claudin-1, Claudin-6 and Occludin), Toll-like receptor (TLR) 4/TLR9, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α was examined. FMT improved rat behaviors, HE grade and spatial learning capability. Moreover, FMT prevented hepatic necrosis and intestinal mucosal barrier damage, leading to hepatic clearance of serum ammonia levels and reduced intestinal permeability. The expression of TLR4 and TLR9, two potent mediators of inflammatory response, was significantly downregulated in the liver of rats treated with FMT. Consistently, circulating pro-inflammatory factors such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were remarkably decreased, indicating that FMT is able to limit systemic inflammation by decreasing the expression of TLR4 and TLR9. Importantly, HE-induced loss of tight junction proteins (Claudin-1, Claudin-6 and Occludin) was restored in intestinal tissues of rats receiving FMT treatment. FMT enables protective effects in HE rats, and it improves the cognitive function and reduces the liver function indexes. FMT may cure HE by altering the intestinal permeability and improving the TLR response of the liver.

  6. Calotropis procera latex affords protection against carbon tetrachloride induced hepatotoxicity in rats.

    Science.gov (United States)

    Padhy, B M; Srivastava, A; Kumar, V L

    2007-09-25

    In the present study, latex of Calotropis procera possessing potent antioxidant and anti-inflammatory properties was evaluated for its hepatoprotective effect against carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. Subcutaneous injection of CCl(4,) administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and tumor necrosis factor alpha (TNF-alpha). Histological analysis of the liver of these rats revealed marked necro-inflammatory changes that were associated with increase in the levels of TBARS, PGE(2) and catalase and decrease in the levels of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Daily oral administration of aqueous suspension of dried latex (DL) of Calotropis procera at 5, 50 and 100mg/kg doses produced a dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver. The DL treatment also normalized various biochemical parameters of oxidative stress. Our study shows that the antioxidant and anti-inflammatory effects of DL and silymarin were comparable and suggests that DL could be used as a hepatoprotective agent.

  7. 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.

  8. 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

  9. Attenuation of sepsis-induced rat liver injury by epigallocatechin ...

    African Journals Online (AJOL)

    http://dx.doi.org/10.4314/tjpr.v16i12.11. Original Research Article. Attenuation of sepsis-induced rat liver injury by epigallocatechin gallate via suppression of oxidative stress-related inflammation. Jian-xin Yang1, Yu-lin Li1*, Ning-chuan Shi2. 1Department of Emergency, The Second Affiliated Hospital, College of Medicine, ...

  10. Metronidazole Induced Liver Injury: A Rare Immune Mediated Drug Reaction

    Directory of Open Access Journals (Sweden)

    Dayakar Kancherla

    2013-01-01

    Full Text Available Drug induced liver injury (DILI can result either from dose-dependent direct hepatotoxicity or from an unpredictable dose-independent idiosyncratic reaction. Incidence of idiosyncratic DILI is estimated to be approximately 10–15 per 100,000 patient years. Here we report an extremely rare case of metronidazole induced delayed immune-allergic hepatocellular liver injury masquerading as autoimmune hepatitis. A previously healthy 54-year-old Caucasian male, who was treated with metronidazole for Clostridium difficile associated diarrhea, presented 3 months later with right upper quadrant abdominal pain. Laboratory tests revealed total bilirubin level of 12.7 mg/dL, direct bilirubin of 7.2 mg/dL, alanine aminotransferase (ALT of 973 IU/L, aspartate transaminase (AST of 867 IU/L, alkaline phosphatase (AP of 96 IU/L, and an INR of 1.9, suggestive of hepatocellular pattern of injury. A detailed workup for hepatitis revealed no other etiology. A clinical diagnosis of metronidazole induced liver injury was made. With a persistent rise in his bilirubin and transaminase levels, the patient was started on oral prednisone. At the 2-week posthospitalization follow-up visit, the patient reported a significant improvement in his overall sense of being well and liver functions tests trended down substantially (total bilirubin 7.2 mg/dL, ALT 420 IU/L, AST 276 IU/L, AP 183 IU/L, and INR 1.5.

  11. Systematic review of severe acute liver injury caused by terbinafine.

    Science.gov (United States)

    Yan, Jun; Wang, Xiaolin; Chen, Shengli

    2014-08-01

    Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is the preferred drug to treat onychomycosis. However, severe acute hepatitis from oral terbinafine administration has been recently reported. To describe a representative case, and review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine. The literature was searched for publications on severe hepatitis caused by terbinafine using MEDLINE, China Biology Medicine Disc, and the VIP Medical Information Resource System. Related references were searched manually. Seventeen English and three Chinese references of case reports were included after eliminating duplicate publications. No randomized control studies were found. Liver enzyme levels were found to have been increased significantly. Abdominal ultrasound demonstrated cholestasis. Severe acute liver injury is a known, but unusual complication of terbinafine exposure. The prognosis is often good with appropriate treatment. Liver function assessment before treatment and periodic monitoring 4-6 weeks after initiation of treatment is recommended.

  12. Hepatoprotective and curative properties of Kombucha tea against carbon tetrachloride-induced toxicity.

    Science.gov (United States)

    Murugesan, G S; Sathishkumar, M; Jayabalan, R; Binupriya, A R; Swaminathan, K; Yun, S E

    2009-04-01

    Kombucha tea (KT) is sugared black tea fermented with a symbiotic culture of acetic acid bacteria and yeasts, which is said to be tea fungus. KT is claimed to have various beneficial effects on human health, but there is very little scientific evidence available in the literature. In the present study, KT along with black tea (BT) and black tea manufactured with tea fungus enzymes (enzyme-processed tea, ET) was evaluated for hepatoprotective and curative properties against CCl4-induced toxicity, using male albino rats as an experimental model by analyzing aspartate transaminase, alanine transaminase, and alkaline phosphatase in plasma and malondialdehyde content in plasma and liver tissues. Histopathological analysis of liver tissue was also included. Results showed that BT, ET, and KT have the potential to revert the CCl4-induced hepatotoxicity. Among the three types of teas tried, KT was found to be more efficient than BT and ET. Antioxidant molecules produced during the fermentation period could be the reason for the efficient hepatoprotective and curative properties of KT against CCI4-induced hepatotoxicity.

  13. Effects of different probiotic strains of Lactobacillus and Bifidobacterium on bacterial translocation and liver injury in an acute liver injury model.

    Science.gov (United States)

    Adawi, D; Ahrné, S; Molin, G

    2001-11-08

    Septic complications represent frequent causes of morbidity in liver diseases and following hepatic operations. Most infections are caused by the individual own intestinal microflora. The intestinal microflora composition is important in physiological and pathophysiological processes in the human gastrointestinal tract, but their influence on liver in different situations is unclear. We therefore studied the effect of different Lactobacillus strains and a Bifidobacterium strain on the extent of liver injury, bacterial translocation and intestinal microflora in an acute liver injury model. Sprague-Dawley rats were divided into five groups: acute liver injury control, acute liver injury + B. animalis NM2, acute liver injury + L. acidophilus NMI, acute liver injury + L. rhamnosus ATCC 53103, and acute liver injury + L. rhamnosus DSM 6594 and L. plantarum DSM 9843. The bacteria were administered rectally daily for 8 days. Liver injury was induced on the 8th day by intraperitoneal injection of D-galactosamine (1.1 g/kg BW). Samples were collected 24 h after the liver injury. Liver enzymes and bilirubin serum levels, bacterial translocation (to arterial and portal blood, liver and mesenteric lymph nodes (MLNs)), and intestinal microflora were evaluated. L. acidophilus NM1; L. rhamnosus ATCC 53103, and L. rhamnosus DSM 6594 + L. plantarum DSM 9843 decreased bacterial translocation compared to the liver injury control group. B. animalis NM2 increased bacterial translocation to the mesenteric lymph nodes. The levels of alanine aminotransferase (ALAT) were significantly lower in the L. acidophilus, L. rhamnosus ATCC 53103, L. rhamnosus DSM 6594 + L. plantarum DSM 9843 groups compared to the liver injury group. The L. rhamnosus and L. rhamnosus + L. plantarum groups significantly reduced ALAT levels compared to the B. animalis group. All administered bacteria decreased the Enterobacteriaceae count in the cecum and colon. Administration of different lactobacilli and a

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

    African Journals Online (AJOL)

    2013-12-02

    Dec 2, 2013 ... ANTI-RETROVIRAL THERAPY RELATED LIVER INJURY (ARLI): A SERIES OF 11 CASES. A. E. O. Otedo, MBChB, MMed ... Background: HIV Anti-retroviral therapy (ART) related liver injury (ARLI) is associated with elevated liver .... and the patients were given palliative and supportive care as in-patients; ...

  15. Manipulation of nitric oxide in an animal model of acute liver injury ...

    African Journals Online (AJOL)

    Background: Nitric oxide may have a protective effect on the liver during endotoxemia and chronic inflammation. There is evidence that it maintains liver and intestinal tissue integrity during inflammatory processes. We evaluated the impact of altering nitric oxide release on acute liver injury, the associated gut injury and ...

  16. Clinical Characteristics of Patients with Drug-induced Liver Injury.

    Science.gov (United States)

    Yang, Li-Xia; Liu, Cheng-Yuan; Zhang, Lun-Li; Lai, Ling-Ling; Fang, Ming; Zhang, Chong

    2017-01-20

    Drug is an important cause of liver injury and accounts for up to 40% of instances of fulminant hepatic failure. Drug-induced liver injury (DILI) is increasing while the diagnosis becomes more difficult. Though many drugs may cause DILI, Chinese herbal medicines have recently emerged as a major cause due to their extensive use in China. We aimed to provide drug safety information to patients and health carers by analyzing the clinical and pathological characteristics of the DILI and the associated drug types. A retrospective analysis was conducted in 287 patients diagnosed with DILI enrolled in our hospital from January 2011 to December 2015. The categories of causative drugs, clinical and pathological characteristics were reviewed. Western medicines ranked as the top cause of DILI, accounting for 163 out of the 287 DILI patients (56.79%) in our study. Among the Western medicine, antituberculosis drugs were the highest cause (18.47%, 53 patients) of DILI.   Antibiotics (18 patients, 6.27%) and antithyroid (18 patients, 6.27%) drugs also ranked among the major causes of DILI. Chinese herbal medicines are another major cause of DILI, accounting for 36.59% of cases (105 patients). Most of the causative Chinese herbal medicines were those used to treat osteopathy, arthropathy, dermatosis, gastropathy, leukotrichia, alopecia, and gynecologic diseases. Hepatocellular hepatitis was prevalent in DILI, regardless of Chinese herbal medicine or Western medicine-induced DILI. Risks and the rational use of medicines should be made clear to reduce the occurrence of DILI. For patients with liver injury of unknown origin, liver tissue pathological examination is recommended for further diagnosis.

  17. Human liver chimeric mouse model based on diphtheria toxin-induced liver injury.

    Science.gov (United States)

    Ren, Xiao-Nan; Ren, Rong-Rong; Yang, Hua; Qin, Bo-Yin; Peng, Xiu-Hua; Chen, Li-Xiang; Li, Shun; Yuan, Meng-Jiao; Wang, Chao; Zhou, Xiao-Hui

    2017-07-21

    To establish an inducible liver injury mouse model and transplant human hepatocytes to obtain liver-humanized mice. We crossed three mouse strains, including albumin (Alb)-cre transgenic mice, inducible diphtheria toxin receptor (DTR) transgenic mice and severe combined immune deficient (SCID)-beige mice, to create Alb-cre/DTR/SCID-beige (ADSB) mice, which coincidentally harbor Alb-cre and DTR transgenes and are immunodeficient. As the Cre expression is driven by the liver-specific promoter Alb (encoding ALB), the DTR stop signal flanked by two loxP sites can be deleted in the ADSB mice, resulting in DTR expression in the liver. ADSB mice aged 8-10 wk were injected intraperitoneally (i.p.) with diphtheria toxin (DT) and liver damage was assessed by serum alanine aminotransferase (ALT) level. Two days later, mouse livers were sampled for histological analysis, and human hepatocytes were transplanted into the livers on the same day. A human ALB enzyme-linked immunosorbent assay was performed 7, 14, 21 and 28 d after transplantation. Human CD68 immunohistochemistry was performed 30 and 90 d after transplantation. We crossed Alb-cre with DTR and SCID-beige mice to obtain ADSB mice. These mice were found to have liver damage 4 d after i.p. injection of 2.5 ng/g bodyweight DT. Bodyweight began to decrease on day 2, increased on day 7, and was lowest on day 4 (range, 10.5%-13.4%). Serum ALT activity began to increase on day 2 and reached a peak value of 289.7 ± 16.2 IU/mL on day 4, then returned to background values on day 7. After transplantation of human liver cells, peripheral blood human ALB level was 1580 ± 454.8 ng/mL (range, 750.2-3064.9 ng/mL) after 28 d and Kupffer cells were present in the liver at 30 d in ADSB mice. Human hepatocytes were successfully repopulated in the livers of ADSB mice. The inducible mouse model of humanized liver in ADSB mice may have functional applications, such as hepatocyte transplantation, hepatic regeneration and drug metabolism.

  18. Oroxylin A accelerates liver regeneration in CCl₄-induced acute liver injury mice.

    Directory of Open Access Journals (Sweden)

    Runzhi Zhu

    Full Text Available INTRODUCTION: Based on the previous research that oroxylin A can suppress inflammation, we investigated the hepatoprotective role of oroxylin A against CCl₄-induced liver damage in mice and then studied the possible alteration of the activities of cytokine signaling participating in liver regeneration. Wild type (WT mice were orally administrated with oroxylin A (60 mg/kg for 4 days after CCl₄ injection, the anti-inflammatory effects of oroxylin A were assessed directly by hepatic histology and indirectly by measuring serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and Albumin. Proliferating cell nuclear antigen (PCNA staining was performed to evaluate the role of oroxylin A in promoting hepatocyte proliferation. Serum IL-1β, TNF-α, IL-6 and IL-1Ra levels were measured by enzyme-linked immunosorbent assay (ELISA and liver HGF, EGF, TNF-α, IL-6, IL-1Ra and IL-1β gene expression was determined by quantitative real-time PCR. The data indicated that the IL-6 and TNF-α mRNA of oroxylin A administered group significantly increased higher than the control within 12 hours after CCl4 treatment. Meanwhile, oroxylin A significantly enhanced the expression of IL-1Ra at the early phase, which indicated that oroxylin A could facilitate the initiating events in liver regeneration by increasing IL-1Ra which acts as an Acute-Phase Protein (APP. In addition, a lethal CCl₄-induced acute liver failure model offers a survival benefit in oroxylin A treated WT mice. However, oroxylin A could not significantly improve the percent survival of IL-1RI⁻/⁻ mice with a lethal CCl₄-induced acute liver failure. CONCLUSIONS: Our study confirmed that oroxylin A could strongly promote liver structural remodeling and functional recovery through IL-1Ra/IL-1RI signaling pathway. All these results support the possibility of oroxylin A being a therapeutic candidate for acute liver injury.

  19. Comparison of isolated and concomitant liver injuries: is hepatic trauma entirely responsible for the outcome?

    Science.gov (United States)

    Yazici, P; Aydin, U; Sozbilen, M

    2010-01-01

    This study was undertaken to examine both isolated and concomitant liver injuries to clarify the role of liver trauma on outcome. This retrospective study was a review of all abdominal trauma patients who presented with liver injuries, with or without concomitant injury at Ege University School of Medicine over a 3-year period. Presentation, injury grade, management, and outcomes were analyzed. Patients with isolated hepatic injury (Group A) were compared with patients who had concomitant hepatic injury (liver and spleen/small bowel) (Group B). Significance was set at 95% confidence intervals. Of 368 patients, 80 (21%) presented with liver injury. Of these, the aetiology was as follows: 53 (66.2%) blunt injury, 19 (23%) penetrating injury, and 8 (10%) gun shot trauma. There were 38 patients in Group A and 42 in Group B. Of these 42 patients, 19 were diagnosed with serious types of injury ; eight thoracic, three open long bone fracture, one intra-cardiac, one intracranial. Six additional patients were observed with injuries to large abdominal vessels. Eleven patients (28.9%) with isolated hepatic injury were managed non-operatively. Mortality, intensive care unit and hospital length of stay, and transfusion requirements were significantly higher in Group B. Only the number of transfused blood units and the grade of liver injury were found to be effective on outcome whereas stepwise regression analysis revealed that injury type (penetrating) and blood transfusion were predictive for mortality. This study highlighted that although isolated liver injury results in good outcome with non-operative management, concomitant injuries to the liver lead to a higher failure and mortality rate. However, liver injury itself is rarely responsible for death.

  20. Hepatic deletion of Smad7 in mouse leads to spontaneous liver dysfunction and aggravates alcoholic liver injury.

    Directory of Open Access Journals (Sweden)

    Lu Zhu

    Full Text Available BACKGROUND: TGF-β has been known to play an important role in various liver diseases including fibrosis and alcohol-induced fatty liver. Smad7 is an intracellular negative regulator of TGF-β signaling. It is currently unclear whether endogenous Smad7 has an effect on liver function and alcoholic liver damage. METHODOLOGY/PRINCIPAL FINDINGS: We used Cre/loxP system by crossing Alb-Cre mice with Smad7(loxP/loxP mice to generate liver-specific deletion of Smad7 with loss of the indispensable MH2 domain. Alcoholic liver injury was achieved by feeding mice with a liquid diet containing 5% ethanol for 6 weeks, followed by a single dose of ethanol gavage. Deletion of Smad7 in the liver was associated with increased Smad2/3 phosphorylation in the liver or upon TGF-β treatment in primary hepatocytes. The majority of mice with liver specific deletion of Smad7 (Smad7(liver-KO were viable and phenotypically normal, accompanied by only slight or no reduction of Smad7 expression in the liver. However, about 30% of Smad7(liver-KO mice with high efficiency of Smad7 deletion had spontaneous liver dysfunction, demonstrated as low body weight, overall deterioration, and increased serum levels of AST and ALT. Degeneration and elevated apoptosis of liver cells were observed with these mice. TGF-β-induced epithelial to mesenchymal transition (EMT was accelerated in Smad7-deleted primary hepatocytes. In addition, alcohol-induced liver injury and steatosis were profoundly aggravated in Smad7 deficient mice, associated with upregulation of critical genes involved in lipogenesis and inflammation. Furthermore, alcohol-induced ADH1 expression was significantly abrogated by Smad7 deletion in hepatocytes. CONCLUSION/SIGNIFICANCE: In this study, we provided in vivo evidence revealing that endogenous Smad7 plays an important role in liver function and alcohol-induced liver injury.

  1. Carbon tetrachloride-induced hepatotoxicity: studies in developing rats and protection by zinc.

    Science.gov (United States)

    Cagen, S Z; Klaasen, C D

    1980-11-01

    This investigation was designed to evaluate carbon tetrachlorid (CCl4)-induced hepatotoxicity in developing rats and in adult rats pretreated with zinc. Hepatotoxicity of CCl4 in rats as young as 4 days of age was similar to that in adults. However, CCl4 metabolism, measured by in vitro binding of 14CCl4 to hepatic microsomal protein and lipid, was significantly lower in 4- and 14-day old rats than in adults. The sensitivity of young animals to CCl4 toxicity may be due to metabolic ketosis since blood concentrations of acetoacetate were 3-5 times higher in young rats than in adult animals. It has previously been shown that adult rats are more sensitive to CCl4 toxicity when they are in the ketonic state. The protection from CCl4 toxicity that was afforded adult rats pretreated with zinc was determined to be independent of the effect of zinc on CCl4 metabolism. Since treatment with zinc results in a large increase in hepatic concentration of metallothionein and that some product of 14CCl4 appeared to bind to zinc-induced metallothionein, it was suggested that metallothionein may protect against CCl4-induced liver damage by sequestering reactive metabolites of CCl4. These studies represent two examples of how the toxicity of a chemical whose toxicity is mediated via a metabolite can be modified by factors independent of metabolic activation.

  2. Hepatoprotective effects of fermented Curcuma longa L. on carbon tetrachloride-induced oxidative stress in rats.

    Science.gov (United States)

    Kim, Yongjae; You, Yanghee; Yoon, Ho-Geun; Lee, Yoo-Hyun; Kim, Kyungmi; Lee, Jeongmin; Kim, Min Soo; Kim, Jong-Choon; Jun, Woojin

    2014-05-15

    The hepatoprotective effect of fermented Curcuma longa L. (FC) was investigated in rats under CCl4-induced oxidative stress. FC at a dose of 30 or 300 mg/kg body weight (b.w.) was orally administered for 14 days followed by a single dose of CCl4 (1.25 mL/kg b.w. in 20% corn oil) on day 14. Pretreatment with FC drastically prevented the elevated activities of serum AST, ALT, LDH, and ALP caused by CCl4-induced hepatotoxicity. Histopathologically evident hepatic necrosis was significantly ameliorated by FC pretreatment. When compared to the CCl4-alone treated group, rats pretreated with FC displayed the reduced level of malondialdehyde. Furthermore, FC enhanced antioxidant capacities with higher activities of catalase, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase, and level of reduced glutathione. These results suggest that FC could be a candidate used for the prevention against various liver diseases induced by oxidative stress via elevating antioxidative potentials and decreasing lipid peroxidation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Hepatoprotective effect of Rosa canina fruit extract against carbon tetrachloride induced hepatotoxicity in rat

    Directory of Open Access Journals (Sweden)

    Heibatollah Sadeghi

    2016-03-01

    Full Text Available Objective: The present study was conducted to investigate the hepatoprotective activity of hydro-ethanolic fruit extract of Rosa canina (R. canina against carbon tetrachloride (CCl4-induced hepatotoxicity in rats. Methods: Male Wistar albino rats were randomly divided into six groups of 8 animals of each, including control, toxic (CCl4, R. canina 250, 500, and 750 mg/kg + CCl4 and R. canina 750 mg/kg alone. R. canina (p.o., daily and CCl4 (1 ml/kg twice a week, 50% v/v in olive oil, i.p. were administered to animals for six weeks. Serum analysis was performed to assay the levels of aspartate aminotransferase (AST, alanine amino transaminase (ALT, alkaline phosphatase (ALP, albumin (ALB, total protein (TP and malondialdehyde (MDA. Biochemical observations were also supplemented with histopathological examination (haematoxylin and eosin staining of liver section.Results: Hepatotoxicity was evidenced by considerable increase in serum levels of AST, ALT, ALP, and lipid peroxidation (MDA and decrease in levels of ALB and TP. Injection of CCL4 also induced congestion in central vein, and lymphocyte infiltration. Treatment with hydro-alcoholic fruit extract of R. canina at doses of 500 and 750 mg/kg significantly reduced CCl4-elevated levels of ALT, AST, ALP and MDA (p

  4. Sulforaphane protects against sodium valproate-induced acute liver injury.

    Science.gov (United States)

    Nazmy, Entsar A; El-Khouly, Omar A; Atef, Hoda; Said, Eman

    2017-04-01

    Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic malondialdehyde and tumour necrosis factor α content significantly declined with concomitant increase in hepatic heme oxygenase-1 content and glutathione concentration with SFN treatment. In conclusion, SFN can significantly ameliorate VPA-induced hepatotoxicity and liver injury primarily by direct association between antioxidant and anti-inflammatory properties.

  5. Effect of Bicyclol tablets on drug induced liver injuries after kidney transplantation

    National Research Council Canada - National Science Library

    Wenjun Shang; Yonghua Feng; Jinfeng Li; Xinzhou Wang; Hongchang Xie; Guiwen Feng

    2017-01-01

    .... Bicyclol tablets possess obvious anti-inflammatory and liver-protective functions. This study aimed to explore the clinical effect of preventive application of Bicyclol on drug induced liver injuries at an early stage after kidney transplantation...

  6. 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).

  7. Campomanesia adamantium (Myrtaceae fruits protect HEPG2 cells against carbon tetrachloride-induced toxicity

    Directory of Open Access Journals (Sweden)

    Thaís de Oliveira Fernandes

    2015-01-01

    Full Text Available Campomanesia adamantium (Myrtaceae is an antioxidant compounds-rich Brazilian fruit popularly known as gabiroba. In view of this, it was evaluated the hepatoprotective effects of pulp (GPE or peel/seed (GPSE hydroalcoholic extracts of gabiroba on injured liver-derived HepG2 cells by CCl4 (4 mM. The results showed the presence of total phenolic in GPSE was (60% higher when compared to GPE, associated with interesting antioxidant activity using DPPH·− assay. Additionally, HPLC chromatograms and thin layer chromatography of GPE and GPSE showed the presence of flavonoids. Pretreatment of HepG2 cells with GPE or GPSE (both at 800–1000 μg/mL significantly (p < 0.0001 protected against cytotoxicity induced by CCl4. Additionally, the cells treated with both extracts (both at 1000 μg/mL showed normal morphology (general and nuclear contrasting with apoptotic characteristics in the cells only exposed to CCl4. In these experiments, GPSE also was more effective than GPE. In addition, CCl4 induced a marked increase in AST (p < 0.05 and ALT (p < 0.0001 levels, while GPE or GPSE significantly (p < 0.0001 reduced these levels, reaching values found in the control group. In conclusion, the results suggest that gabiroba fruits exert hepatoprotective effects on HepG2 cells against the CCl4-induced toxicity, probably, at least in part, associated with the presence of antioxidant compounds, especially flavonoids.

  8. The effects of grape seed and colchicine on carbon tetrachloride induced hepatic damage in rats.

    Science.gov (United States)

    Atasever, Ayhan; Yaman, Duygu

    2014-10-01

    This study aims to determine the effects of grape seed and colchicine on carbon tetrachloride (CCl4) induced hepatic damage and on some serum biochemical parameters. Sixty male Wistar albino rats (200-250 g) were randomly divided into six groups (ten rats/group) and included the control group the group were given isotonic sodium chloride (1 mL/kg b.w) intraperitonealy (i.p.), group 2 the group treated i.p. injection of CCl4 (1.0 mL/kg b.w) in corn oil twice in the first week, Groups 3 and 4 injected with CCl4 as described for group 2 and the rats were orally given (100 mg/kg b.w) GSE and i.p. injected (10 μg/rat) with colchicine for four weeks, respectively and groups 5 and 6 were the grape seed and colchicine control groups in which rats were orally given grape seed (100 mg/kg b.w) and i.p. injected with colchicine (10 μg/rat), respectively. Anorexia, weight loss, motionlessness and hepatic colour variation at necropsy were observed in groups 2, 3, and 4. Hyperemia, focal bleeding, fat degeneration, changes ranging from degenerative to necrotic, increase in connective tissue elements, pronounced in portal sites in particular, and infiltration of lymphoid series cell observed in the livers of the rats in group 2, treated with CCl4. Histological hepatic changes in the rats in group 3 and 4 were similar to those in group 2. The levels of serum total protein, albumin and globulin decreased in groups 2, 3, and 4, compared with groups 1, 5 and 6; aspartate transaminase (ALT) activities increased. The lowest alkaline phosphatase (ALP) activities were in groups 4 and 5. We concluded that GSE and colchicine have not sufficient ameliorative effects to CCl4 induced acute hepatic damage. Copyright © 2014 Elsevier GmbH. All rights reserved.

  9. Amelioration of carbon tetrachloride-induced hepatotoxicity by terpenoid extract from leaves of Vernonia amydgalina.

    Science.gov (United States)

    Babalola, O O; Anetor, J I; Adeniyi, F A

    2001-01-01

    Sesquiterpene lactone extract from the leaves of Vernonia amygdalina was tested for antihepatotoxic activity. Adult male rats were selected for the study. One group of rats was treated with toxic doses of carbon tetrachloride (CCl4) the second group was pretreated with known concentration of terpenoid extract from leaves of V. amygdalina. One hour prior to receiving toxic doses of CCl4, Kolaviron, a biflavonoid extract of the seeds of Garcina kola was used as a positive control. Serum enzymes, alanine amino transferase (ALT), ornithine carbamoyl transferase (OCT) that are known to be very sensitive to cytotoxic hepatic injury, and aspertate amino transferase (AST) that is particularly sensitive to carbon tetrachloride poisoning, were measured as indices of hepatotoxicity. The results obtained showed that there were reduction in the activities of serum ALT, AST and OCT from 20.57 +/- 5.59, 10.46 +/- 6.71 and 184.8 +/- 10.45 in animals treated with toxic doses of CCl4 to 3.40 +/- 0.10, 3.95 +/- 0.15 and 1293 +/- 12.10 in animal pretreated with terpenoid extract before CCl4 intoxication, representing 83.5%, 62.3%, and 30% decrease respectively. These decreases were statistically significant (P sesquiterpene lactone extract from the leaves of V. amygdalina like kolaviron, a biflavonoid extract from the seeds of G. kola has antihepatotoxic activity in CCl4-induced hepatic damage in rats.

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

    OpenAIRE

    Liu, Mei; Zheng, Su-Jun; Xu, Weihong; Zhang, Jianying; Chen, Yu; Duan, Zhongping

    2014-01-01

    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 ...

  11. In vivo protective effect of phosphatidylcholine on carbon tetrachloride induced nephrotoxicity.

    Science.gov (United States)

    Kim, Sokho; Na, Ji-Young; Song, Kibbeum; Kwon, Jungkee

    2016-11-01

    Phosphatidylcholine (PC) from egg yolk is a bioactive substance with various beneficial effects, including anti-inflammatory and anti-oxidant effects. Recently, this substance has been reported to prevent acute hepatotoxicity. In the present study, we aimed to evaluate the putative protective effect of PC on carbon tetrachloride (CCl4)-induced nephrotoxicity in ICR mice. Many previous studies demonstrated that CCl4 induces nephrotoxicity resulting in renal oxidative damage. CCl4 in corn oil (0.1ml, 1.2g/kg) was intra-peritoneally injected into 7-week-old ICR mice twice a week. PC in corn oil (0.1ml, 100mg/kg) was then orally injected daily for a week. In 7 days, blood urea nitrogen (BUN) and creatinine concentrations had significantly increased in the CCl4 group compared to the control group, whereas the PC and CCl4 co-injected group had significantly decreased BUN and creatinine concentrations compared to the CCl4 group. Comparative analysis of histopathological injuries revealed that PC abrogated the nephrotoxicity of CCl4 at 7 days. Accordingly, PC also improved renal fibrosis induced by CCl4. Various biomarkers associated with oxidative damage appeared to be up-regulated in the CCl4 group, whereas in the PC and CCl4 co-injected group, levels of oxidative damage significantly decreased. Aquaporin1 (AQP1), an important water transport protein in the kidney, was down regulated in the CCl4 group compared to the control group. PC counteracted this effect. These results strongly suggest that PC can protect against oxidative damage induced by CCl4 in the kidney and enhance recovery from renal disorders. Copyright © 2016 Elsevier GmbH. All rights reserved.

  12. Protective effects of Lactuca sativa ethanolic extract on carbon tetrachloride induced oxidative damage in rats

    Directory of Open Access Journals (Sweden)

    Hefnawy Taha M. Hefnawy

    2013-08-01

    Full Text Available Objective: To study the protective effects of the ethanolic extract of lettuce (Lactuca sativa L. var. longifolia leaves against the toxicity caused by carbon tetrachloride (CCl4 in reproductive system of rats. Methods: Lettuce leaves were dried and extracted with ethanol (plant: solvent, 1:10, w/v. The extract was filtered and evaporated to yield dried lettuce extract. Animals were divided into seven groups and treated with CCl4 and different concentrations of lettuce extract. At the end of the experimental period, the animals were sacrificed and blood was collected and centrifuged for serum separation. Body weights, testis size, histopathology of testis and liver, catalase (CAT activity, superoxide dismutase (SOD activity, peroxidase (POD activity, reduced glutathione (GSH, glutathione peroxidase activity (GSH-Px, thiobarbituric acid reactive substances (TBARS, nitrite level, and serum hormones were determined. Results: Oxidative stress induced by CCl4 (2 mL/kg body weight in rat decreases the increase in body weight and relative testis weight. It also markedly increases the level of TBARS and nitrites along with corresponding decrease in reduced glutathione and various antioxidant enzymes in testis (i.e., CAT, POD, SOD and GSH-Px. Serum level of testosterone, luteinizing hormone and follicle stimulating hormone was decreased while estradiol and prolactin were increased during CCl 4 treatment. Histopathology of CCl4-treated rats indicated the partial degeneration of germ and leydig cells along with deformities in spermatogenesis. Supplementation of lettuce extract (100, 150, 200 mg/kg body weight orally once a week for 10 weeks results in decrease of TBARS and nitrite, while increase in antioxidant enzymes; CAT, POD, SOD, GSH-Px and GSH contents. Serum level of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, prolactin, histology, body weight and relative testis weight was also concomitantly restored to near normal

  13. Protective effects of Lactuca sativa ethanolic extract on carbon tetrachloride induced oxidative damage in rats

    Science.gov (United States)

    Hefnawy, Hefnawy Taha M.; Ramadan, Mohamed Fawzy

    2013-01-01

    Objective To study the protective effects of the ethanolic extract of lettuce (Lactuca sativa L. var. longifolia) leaves against the toxicity caused by carbon tetrachloride (CCl4) in reproductive system of rats. Methods Lettuce leaves were dried and extracted with ethanol (plant: solvent, 1:10, w/v). The extract was filtered and evaporated to yield dried lettuce extract. Animals were divided into seven groups and treated with CCl4 and different concentrations of lettuce extract. At the end of the experimental period, the animals were sacrificed and blood was collected and centrifuged for serum separation. Body weights, testis size, histopathology of testis and liver, catalase (CAT) activity, superoxide dismutase (SOD) activity, peroxidase (POD) activity, reduced glutathione (GSH), glutathione peroxidase activity (GSH-Px), thiobarbituric acid reactive substances (TBARS), nitrite level, and serum hormones were determined. Results Oxidative stress induced by CCl4 (2 mL/kg body weight) in rat decreases the increase in body weight and relative testis weight. It also markedly increases the level of TBARS and nitrites along with corresponding decrease in reduced glutathione and various antioxidant enzymes in testis (i.e., CAT, POD, SOD and GSH-Px). Serum level of testosterone, luteinizing hormone and follicle stimulating hormone was decreased while estradiol and prolactin were increased during CCl4 treatment. Histopathology of CCl4-treated rats indicated the partial degeneration of germ and leydig cells along with deformities in spermatogenesis. Supplementation of lettuce extract (100, 150, 200 mg/kg body weight orally) once a week for 10 weeks results in decrease of TBARS and nitrite, while increase in antioxidant enzymes; CAT, POD, SOD, GSH-Px and GSH contents. Serum level of testosterone, luteinizing hormone, follicle stimulating hormone, estradiol, prolactin, histology, body weight and relative testis weight was also concomitantly restored to near normal level by

  14. Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury

    OpenAIRE

    Takasu, Chie; Vaziri, Nosratola D; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Farzaneh, Seyed H; Shimada, Mitsuo; Stamos, Michael J; Ichii, Hirohito

    2017-01-01

    AIM To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODS Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO ? metabolites, anti-oxid...

  15. Genipin alleviates sepsis‐induced liver injury by restoring autophagy

    Science.gov (United States)

    Cho, Hong‐Ik; Kim, So‐Jin; Choi, Joo‐Wan

    2016-01-01

    Background and Purpose Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli including inflammation and microbial infection. Genipin, an aglycon of geniposide found in gardenia fruit, is well known to have anti‐inflammatory, antibacterial and antioxidative properties. This study examined the protective mechanisms of genipin against sepsis, with particular focus on the autophagic signalling pathway. Experimental Approach Mice were subjected to sepsis by caecal ligation and puncture (CLP). Genipin (1, 2.5 and 5 mg·kg−1) or vehicle (saline) was injected i.v. immediately (0 h) after CLP, and chloroquine (60 mg·kg−1), an autophagy inhibitor, was injected i.p. 1 h before CLP. Blood and liver tissues were isolated 6 h after CLP. Key Results Genipin improved survival rate and decreased serum levels of aminotransferases and pro‐inflammatory cytokines after CLP; effects abolished by chloroquine. The liver expression of autophagy‐related protein (Atg)12‐Atg5 conjugate increased after CLP, and this increase was enhanced by genipin. CLP decreased Atg3 protein liver expression, and genipin attenuated this decrease. CLP impaired autophagic flux, as indicated by increased liver expression of microtubule‐associated protein‐1 light chain 3‐II and sequestosome‐1/p62 protein; this impaired autophagic flux was restored by genipin, and chloroquine abolished this effect. Genipin also attenuated the decreased expression of lysosome‐associated membrane protein‐2 and Rab7 protein and increased expression of calpain 1 protein induced by CLP in the liver. Conclusions and Implications Our findings suggest that genipin protects against septic injury by restoring impaired autophagic flux. Therefore, genipin might be a potential therapeutic agent for the treatment of sepsis. PMID:26660048

  16. Genipin alleviates sepsis-induced liver injury by restoring autophagy.

    Science.gov (United States)

    Cho, Hong-Ik; Kim, So-Jin; Choi, Joo-Wan; Lee, Sun-Mee

    2016-03-01

    Autophagy is an essential cytoprotective system that is rapidly activated in response to various stimuli including inflammation and microbial infection. Genipin, an aglycon of geniposide found in gardenia fruit, is well known to have anti-inflammatory, antibacterial and antioxidative properties. This study examined the protective mechanisms of genipin against sepsis, with particular focus on the autophagic signalling pathway. Mice were subjected to sepsis by caecal ligation and puncture (CLP). Genipin (1, 2.5 and 5 mg·kg(-1) ) or vehicle (saline) was injected i.v. immediately (0 h) after CLP, and chloroquine (60 mg·kg(-1) ), an autophagy inhibitor, was injected i.p. 1 h before CLP. Blood and liver tissues were isolated 6 h after CLP. Genipin improved survival rate and decreased serum levels of aminotransferases and pro-inflammatory cytokines after CLP; effects abolished by chloroquine. The liver expression of autophagy-related protein (Atg)12-Atg5 conjugate increased after CLP, and this increase was enhanced by genipin. CLP decreased Atg3 protein liver expression, and genipin attenuated this decrease. CLP impaired autophagic flux, as indicated by increased liver expression of microtubule-associated protein-1 light chain 3-II and sequestosome-1/p62 protein; this impaired autophagic flux was restored by genipin, and chloroquine abolished this effect. Genipin also attenuated the decreased expression of lysosome-associated membrane protein-2 and Rab7 protein and increased expression of calpain 1 protein induced by CLP in the liver. Our findings suggest that genipin protects against septic injury by restoring impaired autophagic flux. Therefore, genipin might be a potential therapeutic agent for the treatment of sepsis. © 2015 The British Pharmacological Society.

  17. Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.

    Science.gov (United States)

    Yoshikawa, Kenichi; Kawashima, Reimi; Hirose, Yuki; Shibata, Keiko; Akasu, Takafumi; Hagiwara, Noriko; Yokota, Takeharu; Imai, Nami; Iwaku, Akira; Kobayashi, Go; Kobayashi, Hirohiko; Kinoshita, Akiyoshi; Fushiya, Nao; Kijima, Hiroyuki; Koike, Kazuhiko; Saruta, Masayuki

    2017-07-21

    We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.

  18. NF-κB induced the donor liver cold preservation related acute lung injury in rat liver transplantation model.

    Directory of Open Access Journals (Sweden)

    An Jiang

    Full Text Available We have observed at our clinical work that acute lung injury (ALI often occurs in patients transplanted with donor livers persevered for long time. So, we conducted this study to investigate the influence of cold preservation time (CPT of donor liver on ALI induced by liver transplantation (LT, and further study the role of nuclear factor-κB (NF-κB in the process.Wistar rats were used as donors and recipients to establish orthotopic rat liver transplantation models. Donor livers were preserved at 4°C for different lengths of time. The effect of NF-κB inhibitor, ammonium pyrrolidinedithiocarbamate (PDTC, on ALI was detected. All samples were harvested after 3 h reperfusion. The severity of liver injury was evaluated first. The expressions of tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β in liver tissue and liver outflow serum were measured respectively. The severity indexes of ALI, the activity of NF-κB and inhibitor-κBα (I-κBα in lung/liver were measured accordingly.With the prolonged liver CPT, the liver damage associated indexes and ALI-related indexes all increased significantly. TNF-α and IL-1β in liver outflow serum increased accordingly, and the activity of NF-κB in liver/lung increased correspondingly. All these ALI-associated indexes could be partially reversed by the use of PDTC.Extended CPT aggravates the damage of donor liver and induces the expressions of TNF-α and IL-1β in liver. These inflammatory factors migrate to lung via liver outflow blood and activate NF-κB in lung, inducing ALI finally. NF-κB may play a critical role in LT-related ALI. Patients with or at risk of ALI may benefit from acute anti-inflammatory treatment with PDTC.

  19. Oral contraceptives worsen endotoxin-induced liver injury in rats.

    Science.gov (United States)

    Konno, Akira; Enomoto, Nobuyuki; Takei, Yoshiyuki; Hirose, Miyoko; Ikejima, Kenichi; Sato, Nobuhiro

    2002-08-01

    Oral contraceptives are widely used; however, these drugs occasionally cause liver injury. Recently, it was reported that estriol worsens alcoholic liver injury by the mechanism involving activation of Kupffer cells as a result of gut-derived endotoxin. However, the relationship between oral contraceptives and endotoxin-induced liver injury has not been elucidated. Here we show that oral contraceptives sensitize Kupffer cells via a mechanism dependent on increased gut permeability to endotoxin. Female Wistar rats (200-250 g) were given intraperitoneally a combination of estradiol (35 ng/kg of 17 alpha-Ethynylestradiol) and progesterone (2 microg/kg of Norethindrone), each dose being similar to that contained in oral contraceptives (EP treatment). After 24 hr, a sublethal dose of lipopolysaccharide (LPS; 5 mg/kg) was injected via the tail vein. In some experiments, antibiotics (150 mg/kg/day of polymyxin B and 450 mg/kg/day of neomycin) were administered orally for 4 days before EP treatment. Gut permeability was measured in isolated segments of ileum by translocation of horseradish peroxidase. Kupffer cells were isolated and cultured in RPMI 1640 + 10% fetal bovine serum for 24 hr. After addition of LPS (100 ng/ml) to the culture medium, intracellular calcium concentration ([Ca2+](i) ) was measured with fura-2. Liver histology in rats given EP treatment intraperitoneally followed by an injection of LPS (5 mg/kg) 24 hr later revealed pronounced liver damage with massive necrosis. Whereas mean values of alanine aminotransferase (ALT) in the control, nontreated rats were 30 +/- 6 IU/liter, ALT increased to 75 +/- 21 IU/liter 24 hr after LPS injection. This increase was aggravated 6-fold (483 +/- 118 IU/liter; p< 0.05) by EP treatment. The EP treatment-induced increase in ALT was completely blocked by antibiotics (82 +/- 26 IU/liter; p< 0.05). Gut permeability was increased approximately 10-fold with EP treatment. This increase in gut permeability was not altered by

  20. Reversal of carbon tetrachloride-induced hepatic injury by aqueous extract of Artemisia absinthium in Sprague-Dawley rats.

    Science.gov (United States)

    Saxena, Monika; Shukla, Sangeeta

    2012-01-01

    In the present study, we evaluated the protective activity of an aqueous extract of Artemisia absinthium against CCl4-induced hepatic damage in rats. The protective activity of this extract at three doses (2.5, 5, and 10 ml/ kg, once orally) against CCl4-induced oxidative damage (1.5 ml/kg, once intraperitoneally) in rats was analyzed. Various blood and tissue biochemical studies were performed, and the administration of the toxicant significantly altered blood biochemical variables. Hepatic lipid peroxidation (LPO) was significantly elevated, whereas glutathione (GSH) level was considerable depleted after intoxication. Remarkable decreases in the activities of adenosine triphosphatase (ATPase) and glucose-6-phosphatase (G-6-Pase) after intoxication were observed. Treatment with all three doses reversed altered tissue biochemical values, but the greatest protection was observed at the lowest dose (2.5 ml/kg). The results of this study show that A. absinthium induces strong hepatoprotective activity. It decreased the hexobarbitone-induced sleep time and improved cholerectic activity (bile flow and bile solids) and excretory capacity, and it also stimulated bile secretion. The potent antioxidant activity of A. absinthium was indicated by scavenging effects on 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and hydrogen peroxide (H2O2). Thus, be considered for use in reducing hepatic damage and may serve as an alternative medicine in hepatic etiologies.

  1. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure

    NARCIS (Netherlands)

    Lisman, T.; Bakhtiari, K.; Adelmeijer, J.; Meijers, J. C. M.; Porte, R. J.; Stravitz, R. T.

    . Background: It has been well established that hemostatic potential in patients with chronic liver disease is in a rebalanced status due to a concomitant decrease in pro- and antihemostatic drivers. The hemostatic changes in patients with acute liver injury/failure (ALI/ALF) are similar but not

  2. Biliverdin protects against liver ischemia reperfusion injury in swine.

    Directory of Open Access Journals (Sweden)

    Barbara Andria

    Full Text Available Ischemia reperfusion injury (IRI in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs.

  3. Biliverdin protects against liver ischemia reperfusion injury in swine.

    Science.gov (United States)

    Andria, Barbara; Bracco, Adele; Attanasio, Chiara; Castaldo, Sigismondo; Cerrito, Maria Grazia; Cozzolino, Santolo; Di Napoli, Daniele; Giovannoni, Roberto; Mancini, Antonio; Musumeci, Antonino; Mezza, Ernesto; Nasti, Mario; Scuderi, Vincenzo; Staibano, Stefania; Lavitrano, Marialuisa; Otterbein, Leo E; Calise, Fulvio

    2013-01-01

    Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs.

  4. 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.

  5. 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.

  6. [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.

  7. Alcoholic liver injury: defenestration in noncirrhotic livers--a scanning electron microscopic study

    DEFF Research Database (Denmark)

    Horn, T; Christoffersen, P; Henriksen, Jens Henrik Sahl

    1987-01-01

    (fractional area of fenestrae) was observed in acinar Zone 3, both in biopsies with and without Zone 3 fibrosis as judged by light microscopy. A significant reduction of porosity as shown in this study may influence the blood hepatocytic exchange and contribute to the alcohol-induced liver injury.......The fenestration of hepatic sinusoidal endothelial cells in 15 needle biopsies obtained from chronic alcoholics without cirrhosis was studied by scanning electron microscopy. As compared to nonalcoholics, a significant reduction in the number of fenestrae and porosity of the sinusoidal lining wall...

  8. 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 ...

  9. Protective Effect of Urtica dioica on Liver Injury Induced By Hepatic Ischemia Reperfusion Injury in Rats

    Directory of Open Access Journals (Sweden)

    Alpaslan TERZİ

    2010-05-01

    Full Text Available Background: This study was designed to investigate the effects of Urtica dioica on liverischemia reperfusion injury in rats. Methods: Thirty male Wistar-albino rats were used in this experimental study. Animals weredivided into three groups as sham operated (group 1, control (group 2, and Urtica dioicatreatment group (group 3. Urtica dioica 2ml/kg were administered intraperitoneally beforeischemia and immediately after the reperfusion. The levels of total antioxidant capacity, totalfree sulfidril group, Total oxidant status, Oxidative stress index, and myeloperoxidase in livertissues were measured. The serum levels of ALT, AST and LDH were also measuredResults: Total antioxidant capacity and total free sulfidril group in liver tissue were significantlyhigher in group 3 than in group 2. Oxidative stress index and myeloperoxidase in liver tissuewere significantly lower in group 3 than the group 2. The levels of liver enzymes in treatmentgroup were significantly lower than those in the control group. Histological tissue damage wasmilder in the treatment group than that in the control group.Conclusion: It is concluded that Urtica dioica increase the antioxidant capacity and decreaseoxidative stress and liver enzymes in the hepatic ischemi reperfusion injury of rats.

  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. 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

  12. Acute Renal Injury Evaluation After Liver Transplantation: With RIFLE Criteria.

    Science.gov (United States)

    Aksu Erdost, H; Ozkardesler, S; Ocmen, E; Avkan-Oguz, V; Akan, M; Iyilikci, L; Unek, T; Ozbilgin, M; Meseri Dalak, R; Astarcioglu, I

    2015-06-01

    The aim of this study was to identify acute renal injury (ARI) through the use of RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria and to investigate perioperative risk factors for ARI in liver transplantation (LT). We reviewed medical records of adult LT patients retrospectively. Postoperative ARI was staged with RIFLE criteria by the 1st and 7th days of the surgery. We analyzed 440 adult LT patients, categorized as risk (R), injury (I), or failure (F) according to the RIFLE criteria. In this study, in the first postoperative day, incidence of ARI was 7.95%; all of them were R-class, and, on the 7th day, the incidence of ARI was 7.27%, as R-class 6.59% and I-class 0.68%. Significant risk factors were detected within the first postoperative day including pre-operative hemoglobin levels 20) (P = .002). This study showed that RBC and FFP transfusion, perioperative blood loss, and MELD score >20 are risk factors for LT-related ARI. Also normalization of hemoglobin levels with non-blood products in patients with preoperative low hemoglobin levels can diminish the need for RBC and that can prevent ARI. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Commensal Lactobacillus Controls Immune Tolerance during Acute Liver Injury in Mice

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    Nobuhiro Nakamoto

    2017-10-01

    Full Text Available Summary: Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-β through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance. : Nakamoto et.al. find that Lactobacillus accumulates in the gut and activates IL-22 production by innate lymphoid cells during acute liver injury. Gut-derived IL-22 contributes to liver tolerance via induction of regulatory DCs. Keywords: immune tolerance, dendritic cell, innate lymphoid cell, acute liver injury, interleukin-10, interleukin-22, microbiota, dysbiosis

  14. Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury

    Directory of Open Access Journals (Sweden)

    Ravirajsinh N. Jadeja

    2016-01-01

    Full Text Available Oxidative stress plays a major role in acute and chronic liver injury. In hepatocytes, oxidative stress frequently triggers antioxidant response by activating nuclear erythroid 2-related factor 2 (Nrf2, a transcription factor, which upregulates various cytoprotective genes. Thus, Nrf2 is considered a potential therapeutic target to halt liver injury. Several studies indicate that activation of Nrf2 signaling pathway ameliorates liver injury. The hepatoprotective potential of naturally occurring compounds has been investigated in various models of liver injuries. In this review, we comprehensively appraise various phytochemicals that have been assessed for their potential to halt acute and chronic liver injury by enhancing the activation of Nrf2 and have the potential for use in humans.

  15. Anti-Retroviral Therapy Related Liver Injury (ARLI): A Series of 11 ...

    African Journals Online (AJOL)

    Objective: To describe anti-retroviral-related liver injury (ARLI) in HIV positive patients, their CD4+ cell counts, biochemical and viral markers and liver ultrasound. Design: Prospective, descriptive, consecutive entry study. Setting: Kisumu District Hospital liver clinic/medical outpatient clinic, Nairobi Rheumatology Clinic and ...

  16. A metabolomic perspective of griseofulvin-induced liver injury in mice

    OpenAIRE

    Liu, Ke; Yan, Jiong; Sachar, Madhav; Zhang, Xinju; Guan, Ming; Xie, Wen; Ma, Xiaochao

    2015-01-01

    Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contribute...

  17. Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2016-01-01

    Full Text Available Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p, effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury.

  18. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response.

    Science.gov (United States)

    Cai, Shi-Ying; Ouyang, Xinshou; Chen, Yonglin; Soroka, Carol J; Wang, Juxian; Mennone, Albert; Wang, Yucheng; Mehal, Wajahat Z; Jain, Dhanpat; Boyer, James L

    2017-03-09

    Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2(-/-) mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes from Tlr9(-/-) mice, while liver injury was diminished both in conventional and hepatocyte-specific Tlr9(-/-) mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.

  19. 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.

  20. 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.

  1. Acetaminophen-induced acute liver injury in mice.

    Science.gov (United States)

    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. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  2. Cellular imaging predictions of clinical drug-induced liver injury.

    Science.gov (United States)

    Xu, Jinghai J; Henstock, Peter V; Dunn, Margaret C; Smith, Arthur R; Chabot, Jeffrey R; de Graaf, David

    2008-09-01

    Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50-60% and an exceptionally low false-positive rate of 0-5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals.

  3. Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury.

    Science.gov (United States)

    Chen, Yuan-Li; Xu, Guo; Liang, Xiao; Wei, Juan; Luo, Jing; Chen, Guan-Nan; Yan, Xiao-Di; Wen, Xue-Ping; Zhong, Ming; Lv, Xin

    2016-01-01

    Pyroptosis is a programmed cell death associated with caspase-1 and accompanied by the secretion of a large number of pro-inflammatory cytokines. In the acute stage of sepsis, the release of several pro-inflammatory cytokines aggravates hepatic cell death, and acute liver injury is aggravated with the progress of the disease, resulting in acute liver failure with a very high mortality rate. The present study investigated the effect of inhibiting hepatic cell pyroptosis on the septic acute liver injury. Septic acute liver injury mice model was established by cecal ligation and puncture (CLP model). The liver tissues were assessed for inflammatory infiltration by HE, serum concentrations of ALT, AST, IL-1β, and IL-18 were examined by ELISA, hepatic cell pyroptosis was determined by flow cytometry, and expressions of caspase-1 and NLRP3 were assessed by Western blot. CLP-induced acute liver injury was distinct at 24 h post-operation, with the highest hepatic cell pyroptosis rate. The pyroptosis rate and liver injury indexes were positively correlated. Western blot showed that the expressions of pyroptosis-related proteins, caspase-1, and NLRP3, were increased. Normal mouse hepatic cells were cultured in vitro and LPS+ATP introduced to establish the cell model of septic acute liver injury. The expressions of caspase-1, NLRP3, IL-1β, and IL-18 in LPS+ATP group were significantly higher than the control group by Western blot and ELISA. The inhibitors of NLRP3 (Glyburide) and caspase-1 (AC-YVAD-CMK) alone or in combination were used to pre-treat the hepatic cells, which revealed that the pyroptosis rate was decreased and the cell damage alleviated. The in vivo assay in rats showed that post inhibitor treatment, the 10-days survival was significantly improved and the liver damage reduced. Therefore, inhibiting the hepatic cell pyroptosis could alleviate CLP-induced acute liver injury, providing a novel treatment target for septic acute liver injury.

  4. False positive acetaminophen concentrations in patients with liver injury

    Science.gov (United States)

    Polson, Julie; Wians, Frank H.; Orsulak, Paul; Fuller, Dwain; Murray, Natalie G.; Koff, Jonathan M.; Khan, Adil I.; Balko, Jody A.; Hynan, Linda S.; Lee, William M.

    2013-01-01

    Background Acetaminophen toxicity is the most common form of acute liver failure in the U.S. After acetaminophen overdoses, quantitation of plasma acetaminophen can aid in predicting severity of injury. However, recent case reports have suggested that acetaminophen concentrations may be falsely increased in the presence of hyperbilirubinemia. Methods We tested sera obtained from 43 patients with acute liver failure, mostly unrelated to acetaminophen, utilizing 6 different acetaminophen quantitation systems to determine the significance of this effect. In 36 of the 43 samples with bilirubin concentrations ranging from 1.0-61.5 mg/dl no acetaminophen was detectable by gas chromatography-mass spectroscopy. These 36 samples were then utilized to test the performance characteristics of 2 immunoassay and 4 enzymatic-colorimetric methods. Results Three of four colorimetric methods demonstrated ‘detectable’ values for acetaminophen in from 4 to 27 of the 36 negative samples, low concentration positive values being observed when serum bilirubin concentrations exceeded 10 mg/dl. By contrast, the 2 immunoassay methods (EMIT, FPIA) were virtually unaffected. The false positive values obtained were, in general, proportional to the quantity of bilirubin in the sample. However, prepared samples of normal human serum with added bilirubin showed a dose-response curve for only one of the 4 colorimetric assays. Conclusions False positive acetaminophen tests may result when enzymatic-colorimetric assays are used, most commonly with bilirubin concentrations >10 mg/dl, leading to potential clinical errors in this setting. Bilirubin (or possibly other substances in acute liver failure sera) appears to affect the reliable measurement of acetaminophen, particularly with enzymatic-colorimetric assays. PMID:18279672

  5. Comparison of acute kidney injury between open and laparoscopic liver resection: Propensity score analysis.

    Directory of Open Access Journals (Sweden)

    Young-Jin Moon

    Full Text Available The inflammatory response has been shown to be a major contributor to acute kidney injury. Considering that laparoscopic surgery is beneficial in reducing the inflammatory response, we compared the incidence of postoperative acute kidney injury between laparoscopic liver resection and open liver resection. Among 1173 patients who underwent liver resection surgery, 222 of 926 patients who underwent open liver resection were matched with 222 of 247 patients who underwent laparoscopic liver resection, by using propensity score analysis. The incidence of postoperative acute kidney injury assessed according to the creatinine criteria of the Kidney Disease: Improving Global Outcomes definition was compared between those 1:1 matched groups. A total 77 (6.6% cases of postoperative acute kidney injury occurred. Before matching, the incidence of acute kidney injury after laparoscopic liver resection was significantly lower than that after open liver resection [1.6% (4/247 vs. 7.9% (73/926, P < 0.001]. After 1:1 matching, the incidence of postoperative acute kidney injury was still significantly lower after laparoscopic liver resection than after open liver resection [1.8% (4/222 vs. 6.3% (14/222, P = 0.008; odds ratio 0.273, 95% confidence interval 0.088-0.842, P = 0.024]. The postoperative inflammatory marker was also lower in laparoscopic liver resection than in open liver resection in matched set data (white blood cell count 12.7 ± 4.0 × 103/μL vs. 14.9 ± 3.9 × 103/μL, P < 0.001. Our findings suggest that the laparoscopic technique, by decreasing the inflammatory response, may reduce the occurrence of postoperative acute kidney injury during liver resection surgery.

  6. Comparison of acute kidney injury between open and laparoscopic liver resection: Propensity score analysis.

    Science.gov (United States)

    Moon, Young-Jin; Jun, In-Gu; Kim, Ki-Hun; Kim, Seon-Ok; Song, Jun-Gol; Hwang, Gyu-Sam

    2017-01-01

    The inflammatory response has been shown to be a major contributor to acute kidney injury. Considering that laparoscopic surgery is beneficial in reducing the inflammatory response, we compared the incidence of postoperative acute kidney injury between laparoscopic liver resection and open liver resection. Among 1173 patients who underwent liver resection surgery, 222 of 926 patients who underwent open liver resection were matched with 222 of 247 patients who underwent laparoscopic liver resection, by using propensity score analysis. The incidence of postoperative acute kidney injury assessed according to the creatinine criteria of the Kidney Disease: Improving Global Outcomes definition was compared between those 1:1 matched groups. A total 77 (6.6%) cases of postoperative acute kidney injury occurred. Before matching, the incidence of acute kidney injury after laparoscopic liver resection was significantly lower than that after open liver resection [1.6% (4/247) vs. 7.9% (73/926), P kidney injury was still significantly lower after laparoscopic liver resection than after open liver resection [1.8% (4/222) vs. 6.3% (14/222), P = 0.008; odds ratio 0.273, 95% confidence interval 0.088-0.842, P = 0.024]. The postoperative inflammatory marker was also lower in laparoscopic liver resection than in open liver resection in matched set data (white blood cell count 12.7 ± 4.0 × 103/μL vs. 14.9 ± 3.9 × 103/μL, P kidney injury during liver resection surgery.

  7. Risk factors for central bile duct injury complicating partial liver resection

    NARCIS (Netherlands)

    Boonstra, E. A.; de Boer, M. T.; Sieders, E.; Peeters, P. M. J. G.; de Jong, K. P.; Slooff, M. J. H.; Porte, R. J.

    Background: Bile duct injury is a serious complication following liver resection. Few studies have differentiated between leakage from small peripheral bile ducts and central bile duct injury (CBDI), defined as an injury leading to leakage or stenosis of the common bile duct, common hepatic duct,

  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...... of this study was to investigate the occurrence of HPA post liver trauma. METHODS: A retrospective study from 2000-2010 of conservatively treated patients with blunt liver trauma was performed to investigate the incidence and nature of HPA. After the initial CT scan patients were admitted to the department...... 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. LiMAx Test Improves Diagnosis of Chemotherapy-Associated Liver Injury Before Resection of Colorectal Liver Metastases.

    Science.gov (United States)

    Lock, Johan F; Westphal, Tilman; Rubin, Tom; Malinowski, Maciej; Schulz, Antje; Jara, Maximilian; Bednarsch, Jan; Stockmann, Martin

    2017-09-01

    Chemotherapy of colorectal liver metastases (CLMs) prior to liver resection implies the risk of chemotherapy-associated liver injury, leading to increased postoperative morbidity and mortality OBJECTIVE: The aim of this study was to evaluate the LiMAx (liver maximum capacity) test for diagnosis of chemotherapy-associated liver injury. This was a retrospective analysis of patients with CLMs, prior to liver resection. We performed preoperative assessment of liver function using biochemical parameters and the LiMAx test. The individual history of chemotherapy within 12 months, including regimen, number of cycles, and therapy-free interval were collected, and histopathological evaluation of tumor-free liver tissue was performed in resected patients. A total of 204 patients were included, of whom 127 (62%) had received previous chemotherapy. The LiMAx test was worse after chemotherapy (340 ± 95 vs. 391 ± 82 µg/kg/h; p < 0.001). Impaired LiMAx results (<315 µg/kg/h) were determined in 49% of patients after chemotherapy, and no effects of chemotherapy, liver steatosis or fibrosis on biochemical parameters were observed. LiMAx impairment was dependent on the number of oxaliplatin cycles, the therapy-free interval, and obesity in multivariate analysis. In addition, the LiMAx test was worse in patients with relevant steatosis, fibrosis and steatohepatitis. Patients with an impaired LiMAx showed sufficient regeneration during chemotherapy cessation when surgery was postponed (272 ± 57 - 348 ± 72 µg/kg/h; p = 0.003). The LiMAx test enables non-invasive preoperative diagnosis of chemotherapy-associated liver injury. Preoperative performance of the LiMAx test can augment surgical strategy and timing of surgery after previous chemotherapy, thus avoiding increased postoperative morbidity.

  11. Increased liver-specific proteins in circulating extracellular vesicles as potential biomarkers for drug- and alcohol-induced liver injury.

    Directory of Open Access Journals (Sweden)

    Young-Eun Cho

    Full Text Available Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury. The circulating EVs, isolated from plasma of APAP-exposed, ethanol-fed mice, or alcoholic hepatitis patients versus normal control counterparts, were characterized by proteomics and biochemical methods. Liver specific EV proteins were analyzed by immunoblots and ELISA. The amounts of total and liver-specific proteins in circulating EVs from APAP-treated mice significantly increased in a dose- and time-dependent manner. Proteomic analysis of EVs from APAP-exposed mice revealed that the amounts of liver-specific and/or hepatotoxic proteins were increased compared to those of controls. Additionally, the increased protein amounts in EVs following APAP exposure returned to basal levels when mice were treated with N-acetylcysteine or glutathione. Similar results of increased amounts and liver-specific proteins in circulating EVs were also observed in mice exposed to hepatotoxic doses of thioacetamide or d-galactosamine but not by non-hepatotoxic penicillin or myotoxic bupivacaine. Additionally, binge ethanol exposure significantly elevated liver-specific proteins in circulating EVs from mice and alcoholics with alcoholic hepatitis, compared to control counterparts. These results indicate that circulating EVs in drug- and alcohol-mediated hepatic injury contain liver-specific proteins that could serve as specific biomarkers for hepatotoxicity.

  12. 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.

  13. Efficacy and safety of sitagliptin for the treatment of diabetes mellitus complicated by chronic liver injury

    OpenAIRE

    Asakawa, Masahiro; Mitsui, Hiroshi; Akihisa, Momoko; Sekine, Tetsuo; Niitsu, Yoshihiro; Kobayashi, Arisa; Miyake, Atsuko; Hashimoto, Naoaki; Kawamura, Mitsunobu; Ogawa, Yoshihiro

    2015-01-01

    Aim To investigate the efficacy and safety of a dipeptidyl peptidase-4 inhibitor, sitagliptin, for treating diabetes mellitus complicated by chronic liver injury. Methods Sitagliptin was administered for 13.7???10.1?months to 122 patients with DM complicated by chronic liver injury (including 19 patients with liver cirrhosis), and changes in hemoglobin A1c (HbA1c) and liver enzymes (transaminases, etc.) were evaluated. Results HbA1c was reduced from 8.48???1.43% to 7.87???1.35% (P?

  14. Ischemic preconditioning attenuates ischemia/reperfusion injury in rat steatotic liver: role of heme oxygenase-1-mediated autophagy

    OpenAIRE

    Liu, Anding; Guo, Enshuang; Yang, Jiankun; Li, Renlong; Yang, Yan; Liu, Shenpei; Hu, Jifa; Jiang, Xiaojing; Dirsch, Olaf; Dahmen, Uta; Sun, Jian; Ouyang, Mingwen

    2016-01-01

    Steatotic livers are more susceptible to ischemia/reperfusion (I/R) injury, which is ameliorated by ischemic preconditioning (IPC). Autophagy possesses protective action on liver I/R injury and declines in steatotic livers. The aim of this study was to test the hypothesis that the increased susceptibility of steatotic livers to I/R injury was associated with defective hepatic autophagy, which could be restored by IPC via heme oxygenase-1 (HO-1) signaling. Obesity and hepatic steatosis was ind...

  15. Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury.

    Science.gov (United States)

    Takasu, Chie; Vaziri, Nosratola D; Li, Shiri; Robles, Lourdes; Vo, Kelly; Takasu, Mizuki; Pham, Christine; Farzaneh, Seyed H; Shimada, Mitsuo; Stamos, Michael J; Ichii, Hirohito

    2017-07-07

    To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

  16. 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

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

    African Journals Online (AJOL)

    Nickel treatment also produced oxidative liver injury characterized by increasing serum glucose concentration, glutamate-pyruvate transaminase (GPT), alanine aminotransferase (GOT) and alkaline phosphatase (ALP) activities. Meanwhile nickel supplementation decreased serum total protein and albumin in animals.

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

    Science.gov (United States)

    Zheng, Elizabeth X.; Navarro, Victor J.

    2015-01-01

    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. PMID:26357638

  19. Major bowel and diaphragmatic injuries associated with blunt spleen or liver rupture.

    Science.gov (United States)

    Buckman, R F; Piano, G; Dunham, C M; Soutter, I; Ramzy, A; Militello, P R

    1988-09-01

    The incidence of major bowel and diaphragm injuries occurring in association with blunt spleen and liver ruptures in adults was studied. Of 142 patients with splenic injuries, five had major bowel injuries and 12 had diaphragmatic ruptures. Of 102 patients with blunt hepatic injury, 13 had either bowel or diaphragm ruptures or both. Six bowel and diaphragm injuries occurred in 42 patients with blunt ruptures of both the liver and spleen. Anatomically minor spleen injuries were associated with a 4.8% risk of bowel or diaphragm rupture. Anatomically major splenic lacerations had associated bowel or diaphragm wounds in 16.4% of cases (p = 0.024). A 20% incidence of partial-thickness bowel wounds was found in patients with hepatic or splenic injury, but the natural history of these wounds is unknown.

  20. Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions.

    Science.gov (United States)

    Teckman, Jeffrey H; Mangalat, Nisha

    2015-02-01

    α-1-Antitrypsin (α1AT) is a serum glycoprotein synthesized in the liver. The majority of patients with α1AT deficiency liver disease are homozygous for the Z mutant of α1AT (called ZZ or 'PIZZ'). This mutant gene directs the synthesis of an abnormal protein which folds improperly during biogenesis. Most of these mutant Z protein molecules undergo proteolysis; however, some of the mutant protein accumulates in hepatocytes. Hepatocytes with the largest mutant protein burdens undergo apoptosis, causing compensatory hepatic proliferation. Cycles of hepatocyte injury, cell death and compensatory proliferation results in liver disease ranging from mild asymptomatic enzyme elevations to hepatic fibrosis, cirrhosis and hepatocellular carcinoma. There is a high variability in clinical disease presentation suggesting that environmental and genetic modifiers are important. Management of α1AT liver disease is based on standard supportive care and liver transplant. However, increased understanding of the cellular mechanisms of liver injury has led to new clinical trials.

  1. Do contrast media (iomeprol, gadopentetate dimeglumine) deteriorate ischemia/reperfusion injury of the liver?

    Science.gov (United States)

    Demir, R; Banafsche, R; Melling, N; Gebhard, M-M; Klar, E

    2007-05-01

    Hepatic microcirculation is a main determinant of reperfusion injury and graft quality in liver transplantation. One of the important diagnostic procedures to recognize reperfusion failure is contrast-enhanced computed tomography or magnetic resonance imaging. To examine the additional effect of contrast media (iomeprol and gadopentetate dimeglumine) on hepatic microcirculation and hepatic cellular damage in the phase of early ischemia/reperfusion injury of the rat liver. The partial warm ischemia-reperfusion injury model of rat liver was used. Microcirculation and leukocyte-endothelium interaction were measured by intravital microscopy. Hepatic cellular damage was indicated by liver enzyme activity in the sera. The evaluation parameters were measured at baseline and at 30, 60, and 90 min after reperfusion. The contrast media (iomeprol group, n = 6; gadopentetate dimeglumine group, n = 6) or Ringer's solution (control group, n = 8) were applied after 30 min of reperfusion. No additional injury to the ischemia/reperfusion injury of the liver after intravenous application of radiographic contrast media was found. Some protective effect was even recorded after application of iodinated contrast media. The use of contrast media during diagnostic procedure of the liver seems to be relatively safe, even in the stage of early reperfusion after liver transplantation.

  2. Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts.

    Science.gov (United States)

    Kukan, M; Haddad, P S

    2001-05-01

    In liver transplantation, it is currently hypothesized that nonparenchymal cell damage and/or activation is the major cause of preservation-related graft injury. Because parenchymal cells (hepatocytes) appear morphologically well preserved even after extended cold preservation, their injury after warm reperfusion is ascribed to the consequences of nonparenchymal cell damage and/or activation. However, accumulating evidence over the past decade indicated that the current hypothesis cannot fully explain preservation-related liver graft injury. We review data obtained in animal and human liver transplantation and isolated perfused animal livers, as well as isolated cell models to highlight growing evidence of the importance of hepatocyte disturbances in the pathogenesis of normal and fatty graft injury. Particular attention is given to preservation time-dependent decreases in high-energy adenine nucleotide levels in liver cells, a circumstance that (1) sensitizes hepatocytes to various stimuli and insults, (2) correlates well with graft function after liver transplantation, and (3) may also underlie the preservation time-dependent increase in endothelial cell damage. We also review damage to bile duct cells, which is increasingly being recognized as important in the long-lasting phase of reperfusion injury. The role of hydrophobic bile salts in that context is particularly assessed. Finally, a number of avenues aimed at preserving hepatocyte and bile duct cell integrity are discussed in the context of liver transplantation therapy as a complement to reducing nonparenchymal cell damage and/or activation.

  3. A metabolomic perspective of griseofulvin-induced liver injury in mice.

    Science.gov (United States)

    Liu, Ke; Yan, Jiong; Sachar, Madhav; Zhang, Xinju; Guan, Ming; Xie, Wen; Ma, Xiaochao

    2015-12-01

    Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Role of Stem Cells Transplantation in Tissue Regeneration After Acute or Chronic Acetaminophen Induced Liver Injury.

    Science.gov (United States)

    Katselis, Charalampos; Apostolou, Konstantinos; Feretis, Themistoklis; Papanikolaou, Ioannis G; Zografos, George C; Toutouzas, Konstantinos; Papalois, Apostolos

    2016-01-01

    Acetaminophen-induced liver injury (APAP) is recognized as a frequent etiologic factor responsible for hepatic damage in the developed world. Management remains still elusive as treatment options are limited and their results are inconclusive. Consequently new strategies are explored at the experimental level. Mesenchymal stem cells (MSCs) present a promising modality as they can promote liver regeneration (LG) and compensate acute liver injury (ALI). Our research was focused on articles related to drug-induced liver injury, mechanisms of liver regeneration (LG) after Acute Liver Injury (ALI) and recent experimental protocols of Mesenchymal Stem Cells (MSCs) transplantation after chemical insult. All these studies are cited on Pubmed and MedLine. This review has three distinct sections. First recent developments in ALI pathogenesis are presented. The second section covers cellular pathways and histological findings relevant to liver regeneration. The final chapter analyzes MSCs transplantation protocols after ALI and interrelation between liver regeneration and hepatic differentiation of MSCs. Adipose tissue stem cells (ADSCs) and (MSCs) transplantation represents a promising modality in severe ALI management although many aspects remain to be clarified.

  5. High velocity missile injuries of the liver | Ogwang | East and Central ...

    African Journals Online (AJOL)

    A prospective study of 15 consecutive patients admitted with high velocity missile liver injuries of the liver was done at Lacor hospital between November 1996 and May 1997. Operative findings, treatment offered and factors influencing morbidity and mortality were noted. All patients were followed up for two months ...

  6. Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

    Science.gov (United States)

    Maiwall, Rakhi; Sarin, Shiv Kumar; Kumar, Suman; Jain, Priyanka; Kumar, Guresh; Bhadoria, Ajeet Singh; Moreau, Richard; Kedarisetty, Chandan Kumar; Abbas, Zaigham; Amarapurkar, Deepak; Bhardwaj, Ankit; Bihari, Chhagan; Butt, Amna Subhan; Chan, Albert; Chawla, Yogesh Kumar; Chowdhury, Ashok; Dhiman, RadhaKrishan; Dokmeci, Abdul Kadir; Ghazinyan, Hasmik; Hamid, Saeed Sadiq; Kim, Dong Joon; Komolmit, Piyawat; Lau, George K; Lee, Guan Huei; Lesmana, Laurentius A; Jamwal, Kapil; Mamun-Al-Mahtab; Mathur, Rajendra Prasad; Nayak, Suman Lata; Ning, Qin; Pamecha, Viniyendra; Alcantara-Payawal, Diana; Rastogi, Archana; Rahman, Salimur; Rela, Mohamed; Saraswat, Vivek A; Shah, Samir; Shiha, Gamal; Sharma, Barjesh Chander; Sharma, Manoj Kumar; Sharma, Kapil; Tan, Soek Siam; Chandel, Shivendra Singh; Vashishtha, Chitranshu; Wani, Zeeshan A; Yuen, Man-Fung; Yokosuka, Osamu; Duseja, Ajay; Jafri, Wasim; Devarbhavi, Harshad; Eapen, C E; Goel, Ashish; Sood, Ajit; Ji, Jia; Duan, Z; Chen, Y

    2017-10-01

    There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (Pfailure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. 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

  8. 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.

  9. 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.

  10. Acute liver injury induced by levetiracetam and temozolomide co-treatment.

    Science.gov (United States)

    Khoury, Tawfik; Chen, Shmuel; Abu Rmeileh, Ayman; Daher, Saleh; Yaari, Shaul; Benson, Ariel A; Cohen, Jonah; Mizrahi, Meir

    2017-03-01

    Temozolomide (TMZ) is an alkylating agent used for treatment of brain neoplasms and levetiracetam (LEV) is a commonly used antiepileptic. When administered separately each medication has few negative side effects impacting the liver. We sought to determine the risk of liver injury associated with the co-administration of TMZ and LEV. A case-control study was performed comparing patients who received combination therapy of TMZ and LEV (group A) with matched controls (group B) who received monotherapy with one of either TMZ or LEV. We assessed patient demographics, laboratory results including presence of liver injury, and mortality. Twenty-six patients were included in group A and 68 patients were included in group B. Both groups were similar with respect to demographics and baseline liver function tests (P>0.05). There was a significant elevation in liver enzymes in 73%, 46%, 19%, 31% and 27% of ALT, AST, ALK-P, GGT and bilirubin, respectively, in group A, as compared to elevations of 10.3%, 19%, 1.5%, 7% and 1.5%, respectively in group B (P<0.05). One patient in group A died as a result of acute liver failure while no deaths from acute liver failure occurred in group B (P=0.05). Univariate analysis identified combination therapy as a risk factor for liver injury. Multivariate regression showed that only co-treatment with TMZ and LEV was an independent risk factor for liver injury with an odds ratio of 19.1 (95 CI, 2.16-160). Combination therapy with TMZ and LEV may precipitate acute liver injury and even death. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  11. 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.

  12. 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...

  13. A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage

    Science.gov (United States)

    Kim, Ju Seung; Jang, Young Rock; Lee, Ji Won; Kim, Jin Yong; Chung, Dong Hae; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2011-01-01

    Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range. PMID:22102391

  14. Drug Induced Liver Injury: Review with a Focus on Genetic Factors, Tissue Diagnosis, and Treatment Options

    Science.gov (United States)

    Khoury, Tawfik; Rmeileh, Ayman Abu; Yosha, Liron; Benson, Ariel A.; Daher, Saleh; Mizrahi, Meir

    2015-01-01

    Drug-induced liver injury (DILI) is a rare but potentially life threatening adverse drug reaction. DILI may mimic any morphologic characteristic of acute or chronic liver disease, and the histopathologic features of DILI may be indistinguishable from those of other causes of liver injury, such as acute viral hepatitis. In this review article, we provide an update on causative agents, clinical features, pathogenesis, diagnosis modalities, and outcomes of DILI. In addition, we review results of recently reported genetic studies and updates on pharmacological and invasive treatments. PMID:26356634

  15. CD18 deficiency improves liver injury in the MCD model of steatohepatitis.

    Science.gov (United States)

    Pierce, Andrew A; Duwaerts, Caroline C; Siao, Kevin; Mattis, Aras N; Goodsell, Amanda; Baron, Jody L; Maher, Jacquelyn J

    2017-01-01

    Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.

  16. Several issues regarding evaluation of renal injury and renal insufficiency in patients with liver disease

    Directory of Open Access Journals (Sweden)

    HAO Kunyan

    2016-07-01

    Full Text Available In patients with liver disease such as viral hepatitis and liver cirrhosis, renal injury and renal insufficiency can be generally classified as acute kidney injury (AKI, chronic kidney disease, and acute-on-chronic nephropathy. AKI can be classified as stage 1 (risk stage, stage 2 (injury stage, and stage 3 (failure stage. Traditionally hepatorenal syndrome is classified as types Ⅰ and Ⅱ, and in recent years, type Ⅲ hepatorenal syndrome with organic renal injury has been proposed. Hepatorenal disorder(HRD is used to describe any renal disease which occurs in patients with liver cirrhosis. At present, sensitive and accurate biochemical parameters used to evaluate renal function in patients with liver disease in clinical practice include estimated glomerular filtration rate, increase in serum creatinine within unit time, and serum cystatin C level, and urinary microalbumin level also plays an important role in the early diagnosis of nephropathy. Causes of liver disease, severity, complications including infection, nutritional status, therapeutic drugs, and underlying nephropathy may be associated with renal injury and renal insufficiency in patients with liver disease and should be differentiated.

  17. 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.

  18. [Identification and early diagnosis for traditional Chinese medicine-induced liver injury based on translational toxicology].

    Science.gov (United States)

    Wang, Jia-Bo; Xiao, Xiao-He; Du, Xiao-Xi; Zou, Zheng-Sheng; Song, Hai-Bo; Guo, Xiao-Xin

    2014-01-01

    Recently traditional Chinese medicine (TCM)-induced liver injury has been an unresolved critical issue which impacts TCM clinical safety. The premise and key step to reduce or avoid drug-induced liver injury (DILI) is to identify the drug source of liver injury in early stage. Then the timely withdrawal of drug and treatment can be done. However, the current diagnosis of DILI is primarily governed by exclusive method relying on administering history supplied by patients and experience judgment from doctors, which lacks objective and reliable diagnostic indices. It is obvious that diagnosis of TCM-induced liver injury is especially difficult due to the complicated composition of TCM medication, as well the frequent combination of Chinese and Western drugs in clinic. In this paper, we proposed construction of research pattern and method for objective identification of TCM-related DILI based on translational toxicology, which utilizes clinical specimen to find specific biomarkers and characteristic blood-entering constituents, as well the clinical biochemistry and liver biopsy. With integration of diagnosis marker database, bibliographic database, medical record database and clinical specimen database, an integrative diagnosis database for TCM-related DILI can be established, which would make a transformation of clinical identification pattern for TCM-induced liver injury from subjective and exclusive to objective and index-supporting mode. This would be helpful to improve rational uses of TCM and promote sustainable development of TCM industry.

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

    Science.gov (United States)

    2012-01-01

    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. PMID:23217091

  20. 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.

  1. Severe Starvation-Induced Hepatocyte Autophagy as a Cause of Acute Liver Injury in Anorexia Nervosa: A Case Report

    Directory of Open Access Journals (Sweden)

    S. Restellini

    2013-01-01

    Full Text Available Introduction. Mild elevation of transaminase may be observed in anorexia nervosa, but acute liver injury is uncommon. A complex programmed cell death in response to starvation, called autophagy, has been described in experimental and human studies. Case Presentation. A 24-year-old woman suffering from anorexia nervosa was hospitalized for severe malnutrition. At admission, there were biological signs of acute liver injury but no electrolytic imbalance. After having ruled out the most common causes of liver injury, the patient was carefully refed. As liver tests remained abnormal, liver biopsy was performed. At histology and electron microscopy, numerous signs suggestive of starvation-induced hepatocyte autophagy were found. Discussion. Severe starvation can be associated with acute liver injury that is slowly reversible with careful enteral nutrition. In this clinical situation, profound hepatic glycogen depletion in association with autophagy appears as the leading cause of liver injury.

  2. CYP1A2 polymorphism in Chinese patients with acute liver injury induced by Polygonum multiflorum.

    Science.gov (United States)

    Ma, K F; Zhang, X G; Jia, H Y

    2014-07-25

    The objective of this study was to evaluate the genotype and allelic frequencies of CYP1A2 in Chinese patients with acute liver injury induced by Polygonum multiflorum. We examined the clinical mechanism of acute liver injury induced by P. multiflorum. According to the diagnostic criteria for drug-induced liver injury (DILI), 43 cases of P. multiflorum-induced liver injury admitted to the First Affiliated Hospital, Zhejiang University were identified between January 2008 and December 2012. An additional 43 control subjects were also chosen. Several alleles, including 1C, 1F, 2, 7, 9, and 11 of CYP1A2 were amplified from genomic DNA and sequenced. We used the chi-square test to determine whether CYP1A2 allele polymorphisms are associated with acute liver injury induced by P. multiflorum. The frequency of the CYP1A2 1C allele was 46.5% in P. multiflorum-induced DILI patients, which was significantly different from the frequency of 27.9% observed in healthy subjects. The frequency of the CYP1A2 1F allele was 63.9% in P. multiflorum-induced DILI patients, compared to 57.0% in healthy controls; the difference was not significant. The allelic frequencies of CYP1A2 2, CYP1A2 7, CYP1A2 9, and CYP1A2 11 were too low to be detected. The frequency of the CYP1A2 1C mutation in Chinese patients with P. multiflorum-induced acute liver injury differed from that in healthy Chinese people, indicating that CYP1A2 1C is probably related to metabolism of P. multiflorum, which is followed by acute liver injury.

  3. Heat stroke leading to acute liver injury & failure: A case series from the Acute Liver Failure Study Group.

    Science.gov (United States)

    Davis, Brian C; Tillman, Holly; Chung, Raymond T; Stravitz, Richard T; Reddy, Rajender; Fontana, Robert J; McGuire, Brendan; Davern, Timothy; Lee, William M

    2017-04-01

    In the United States, nearly 1000 annual cases of heat stroke are reported but the frequency and outcome of severe liver injury in such patients is not well described. The aim of this study was to describe cases of acute liver injury (ALI) or failure (ALF) caused by heat stroke in a large ALF registry. Amongst 2675 consecutive subjects enrolled in a prospective observational cohort of patients with ALI or ALF between January 1998 and April 2015, there were eight subjects with heat stroke. Five patients had ALF and three had ALI. Seven patients developed acute kidney injury, all eight had lactic acidosis and rhabdomyolysis. Six patients underwent cooling treatments, three received N-acetyl cysteine (NAC), three required mechanical ventilation, three required renal replacement therapy, two received vasopressors, one underwent liver transplantation, and two patients died-both within 48 hours of presentation. All cases occurred between May and August, mainly in healthy young men because of excessive exertion. Management of ALI and ALF secondary to heat stroke should focus on cooling protocols and supportive care, with consideration of liver transplantation in refractory patients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. 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.

  5. 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

  6. 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.

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

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    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

  8. 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. Copyright 2001 National Science Council, ROC and S. Karger AG, Basel

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

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    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.

  10. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

    Science.gov (United States)

    Amersi, Farin; Buelow, Roland; Kato, Hirohisa; Ke, Bibo; Coito, Ana J.; Shen, Xiu-Da; Zhao, Delai; Zaky, Joseph; Melinek, Judy; Lassman, Charles R.; Kolls, Jay K.; Alam, J.; Ritter, Thomas; Volk, Hans-Dieter; Farmer, Douglas G.; Ghobrial, Rafik M.; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.

    1999-01-01

    We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibitor zinc protoporphyrin (ZnPP), upregulation of HO-1 by Western blots correlated with amelioration of histologic features of I/R injury. Adjunctive infusion of ZnPP abrogated the beneficial effects of Ad-HO-1 gene transfer, documenting the direct involvement of HO-1 in protection against I/R injury. Following cold ischemia/isotransplantation, HO-1 overexpression extended animal survival from 40% in untreated controls to about 80% after CoPP or Ad-HO-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by T cells and macrophages. Hence, CoPP- or gene therapy–induced HO-1 prevented I/R injury in steatotic rat livers. These findings provide the rationale for refined new treatments that should increase the supply of usable donor livers and ultimately improve the overall success of liver transplantation. J. Clin. Invest. 104:1631–1639 (1999). PMID:10587527

  11. Investigation of Liver Injury of Polygonum multiflorum Thunb. in Rats by Metabolomics and Traditional Approaches

    Science.gov (United States)

    Li, Yun-Xia; Gong, Xiao-Hong; Liu, Mei-Chen; Peng, Cheng; Li, Peng; Wang, Yi-Tao

    2017-01-01

    Liver injury induced by Polygonum multiflorum Thunb. (PM) have been reported since 2006, which aroused widespread concern. However, the toxicity mechanism of PM liver injury remained unclear. In this study, the mechanism of liver injury induced by different doses of PM after long-term administration was investigated in rats by metabolomics and traditional approaches. Rats were randomly divided into control group and PM groups. PM groups were oral administered PM of low (10 g/kg), medium (20 g/kg), high (40 g/kg) dose, while control group was administered distilled water. After 28 days of continuous administration, the serum biochemical indexes in the control and three PM groups were measured and the liver histopathology were analyzed. Also, UPLC-Q-TOF-MS with untargeted metabolomics was performed to identify the possible metabolites and pathway of liver injury caused by PM. Compared with the control group, the serum levels of ALT, AST, ALP, TG, and TBA in middle and high dose PM groups were significantly increased. And the serum contents of T-Bil, D-Bil, TC, TP were significantly decreased. However, there was no significant difference between the low dose group of PM and the control group except serum AST, TG, T-Bil, and D-Bil. Nine biomarkers were identified based on biomarkers analysis. And the pathway analysis indicated that fat metabolism, amino acid metabolism and bile acid metabolism were involved in PM liver injury. Based on the biomarker pathway analysis, PM changed the lipid metabolism, amino acid metabolism and bile acid metabolism and excretion in a dose-dependent manner which was related to the mechanism of liver injury. PMID:29163173

  12. Investigation of Liver Injury of Polygonum multiflorum Thunb. in Rats by Metabolomics and Traditional Approaches

    Directory of Open Access Journals (Sweden)

    Yun-Xia Li

    2017-11-01

    Full Text Available Liver injury induced by Polygonum multiflorum Thunb. (PM have been reported since 2006, which aroused widespread concern. However, the toxicity mechanism of PM liver injury remained unclear. In this study, the mechanism of liver injury induced by different doses of PM after long-term administration was investigated in rats by metabolomics and traditional approaches. Rats were randomly divided into control group and PM groups. PM groups were oral administered PM of low (10 g/kg, medium (20 g/kg, high (40 g/kg dose, while control group was administered distilled water. After 28 days of continuous administration, the serum biochemical indexes in the control and three PM groups were measured and the liver histopathology were analyzed. Also, UPLC-Q-TOF-MS with untargeted metabolomics was performed to identify the possible metabolites and pathway of liver injury caused by PM. Compared with the control group, the serum levels of ALT, AST, ALP, TG, and TBA in middle and high dose PM groups were significantly increased. And the serum contents of T-Bil, D-Bil, TC, TP were significantly decreased. However, there was no significant difference between the low dose group of PM and the control group except serum AST, TG, T-Bil, and D-Bil. Nine biomarkers were identified based on biomarkers analysis. And the pathway analysis indicated that fat metabolism, amino acid metabolism and bile acid metabolism were involved in PM liver injury. Based on the biomarker pathway analysis, PM changed the lipid metabolism, amino acid metabolism and bile acid metabolism and excretion in a dose-dependent manner which was related to the mechanism of liver injury.

  13. 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.

  14. Antifibrotic effects of Artemisia capillaris and Artemisia iwayomogi in a carbon tetrachloride-induced chronic hepatic fibrosis animal model.

    Science.gov (United States)

    Wang, Jing-Hua; Choi, Min-Kyung; Shin, Jang-Woo; Hwang, Seock-Yeon; Son, Chang-Gue

    2012-03-06

    Artemisia capillaris and Artemisia iwayomogi, both members of the Compositae family, have been indiscriminately used for various liver disorders as traditional hepatotherapeutic medicines in Korea for many years. In this study, the anti-hepatofibrotic effects of Artemisia capillaris and Artemisia iwayomogi were comparatively analyzed using a carbon tetrachloride (CCl(4))-induced liver fibrosis rat model. Hepatic fibrosis was induced via a 10-week course of intraperitoneal CCl(4) injections (50% dissolved in olive oil, 2mL/kg, twice per week). Water extract of Artemisia capillaris (AC) or Artemisia iwayomogi (AI) was orally administered six times per week from the 5th to the 10th week. AI (50mg/kg) significantly attenuated the CCl(4)-induced excessive release of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) in serum (p<0.05), and hydroxyproline and malondialdehyde (MDA) contents in liver tissue (p<0.05). Further, AI markedly ameliorated the depletion of total antioxidant capacity (TAC), glutathione (GSH), and superoxide dismutase (SOD) in liver tissue (p<0.01). Unexpectedly, AC did not exert any effects on the above parameters. Histopathological and immunohistochemical analyses revealed that AI drastically reduced inflammation, necrosis, fatty infiltration, collagen accumulation, and activation of hepatic satellite cells in liver tissue. These changes were not observed with AC treatment. Several critical genes of fibrosis-related cytokines including transforming growth factor beta (TGF-β), platelet-derived growth factor beta (PDGF-β), and alpha smooth muscle actin (α-SMA) were more prominently downregulated by AI compared to AC treatment. Our results show that AI exerts greater hepatoprotective and anti-fibrotic effects as compared with AC via enhancing antioxidant capacity and downregulating fibrogentic cytokines. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  15. 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.

  16. Herbal Traditional Chinese Medicine and suspected liver injury: A prospective study.

    Science.gov (United States)

    Melchart, Dieter; Hager, Stefan; Albrecht, Sabine; Dai, Jingzhang; Weidenhammer, Wolfgang; Teschke, Rolf

    2017-10-18

    To analyze liver tests before and following treatment with herbal Traditional Chinese Medicine (TCM) in order to evaluate the frequency of newly detected liver injury. Patients with normal values of alanine aminotransferase (ALT) as a diagnostic marker for ruling out pre-existing liver disease were enrolled in a prospective study of a safety program carried out at the First German Hospital of TCM from 1994 to 2015. All patients received herbal products, and their ALT values were reassessed 1-3 d prior to discharge. To verify or exclude causality for suspected TCM herbs, the Roussel Uclaf Causality Assessment Method (RUCAM) was used. This report presents for the first time liver injury data derived from a prospective, hospital-based and large-scale study of 21470 patients who had no liver disease prior to treatment with herbal TCM. Among these, ALT ranged from 1 × to liver adaptive abnormalities. However, 26 patients (0.12%) experienced higher ALT values of ≥ 5 × ULN (300.0 ± 172.9 U/L, mean ± SD). Causality for TCM herbs was RUCAM-based probable in 8/26 patients, possible in 16/26, and excluded in 2/26 cases. Bupleuri radix and Scutellariae radix were the two TCM herbs most commonly implicated. In 26 (0.12%) of 21470 patients treated with herbal TCM, liver injury with ALT values of ≥ 5 × ULN was found, which normalized shortly following treatment cessation, also substantiating causality.

  17. Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation.

    Science.gov (United States)

    Cai, Xiaxia; Bao, Lei; Wang, Nan; Xu, Meihong; Mao, Ruixue; Li, Yong

    2016-03-31

    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. 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. 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. These data indicate potential biomarkers and confirm the benefit of dietary nucleotides on alcoholic liver injury.

  18. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.

    Science.gov (United States)

    Donati, Monia; Conforti, Anita; Lenti, Maria Carmela; Capuano, Annalisa; Bortolami, Oscar; Motola, Domenico; Moretti, Ugo; Vannacci, Alfredo; Rafaniello, Concetta; Vaccheri, Alberto; Arzenton, Elena; Bonaiuti, Roberto; Sportiello, Liberata; Leone, Roberto

    2016-07-01

    Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%. This is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis. We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00). Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity. © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  19. 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

  20. Donor graft interferon regulatory factor-1 gene transfer worsens liver transplant ischemia/reperfusion injury.

    Science.gov (United States)

    Kim, Kee-Hwan; Dhupar, Rajeev; Ueki, Shinya; Cardinal, Jon; Pan, Pinhua; Cao, Zongxian; Cho, Sung W; Murase, Noriko; Tsung, Allan; Geller, David A

    2009-08-01

    Liver ischemia and reperfusion (IR) injury is a phenomenon that leads to graft dysfunction after liver transplantation. Understanding the molecular mechanisms behind this process is crucial to developing strategies to prevent short- and long-term graft dysfunction. The purpose of this study was to explore the role of the transcription factor interferon regulatory factor-1 (IRF-1) in a model of orthotopic rat liver transplantation. Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 3 hours preservation in cold University of Wisconsin solution. Adenovirus-expressing IRF-1 (AdIRF-1) or control gene vector (Adnull) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as controls. Recipients were humanely killed 1-24 hours post-transplantation. Rats that underwent OLT with long-term preserved grafts (18 hours) displayed increased hepatic nuclear expression of IRF-1 protein at 1 and 3 hours. Rats pretreated with AdIRF-1 before transplantation had elevated alanine aminotransferase levels and increased expression of interferon (IFN)-beta, IFN-gamma, interleukin-12, and inducible nitric oxide synthase in the short-term period (3 hours) when compared with donor livers pretreated with Adnull. AdIRF-1 pretreated donor livers also exhibited increased susceptibility to early apoptosis in the transplanted grafts as shown by increased terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining and expression of cleaved caspase-3. Additionally, AdIRF-1 pretreated donor livers had increased activation of the MAP kinase Jun N-terminal kinase as compared with Adnull pretreated donor livers. IRF-1 is an important regulator of IR injury after OLT in rats. Targeting of IRF-1 may be a potential strategy to ameliorate ischemic liver injury after transplantation to minimize organ dysfunction.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  2. Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models.

    Science.gov (United States)

    Verma, Neeraj; Singh, Anil P; Amresh, G; Sahu, P K; Rao, Ch V

    2011-05-01

    To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl(4))-induced liver damage in preventive and curative models. Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl(4)-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl(4) treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl(4)-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl(4)-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl(4)-induced hepatic damage in rats.

  3. Protective effect of ethyl acetate fraction of Rhododendron arboreum flowers against carbon tetrachloride-induced hepatotoxicity in experimental models

    Science.gov (United States)

    Verma, Neeraj; Singh, Anil P.; Amresh, G.; Sahu, P. K.; Rao, Ch. V.

    2011-01-01

    Objective: To evaluate the hepatoprotective potential of ethyl acetate fraction of Rhododendron arboreum (Family: Ericaceae) in Wistar rats against carbon tetrachloride (CCl4)-induced liver damage in preventive and curative models. Materials and Methods: Fraction at a dose of 100, 200, and 400 mg/kg was administered orally once daily for 14 days in CCl4-treated groups (II, III, IV, V and VI). The serum levels of glutamic oxaloacetic transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase (SALP), γ-glutamyltransferase (γ -GT), and bilirubin were estimated along with activities of glutathione S-transferase (GST), glutathione reductase, hepatic malondialdehyde formation, and glutathione content. Result and Discussion: The substantially elevated serum enzymatic activities of SGOT, SGPT, SALP, γ-GT, and bilirubin due to CCl4 treatment were restored toward normal in a dose-dependent manner. Meanwhile, the decreased activities of GST and glutathione reductase were also restored toward normal. In addition, ethyl acetate fraction also significantly prevented the elevation of hepatic malondialdehyde formation and depletion of reduced glutathione content in the liver of CCl4-intoxicated rats in a dose-dependent manner. Silymarin used as standard reference also exhibited significant hepatoprotective activity on post-treatment against CCl4-induced hepatotoxicity in rats. The biochemical observations were supplemented with histopathological examination of rat liver sections. The results of this study strongly indicate that ethyl acetate fraction has a potent hepatoprotective action against CCl4-induced hepatic damage in rats. PMID:21713093

  4. Dynamics of Proliferative and Quiescent Stem Cells in Liver Homeostasis and Injury.

    Science.gov (United States)

    Cao, Wanlu; Chen, Kan; Bolkestein, Michiel; Yin, Yuebang; Verstegen, Monique M A; Bijvelds, Marcel J C; Wang, Wenshi; Tuysuz, Nesrin; Ten Berge, Derk; Sprengers, Dave; Metselaar, Herold J; van der Laan, Luc J W; Kwekkeboom, Jaap; Smits, Ron; Peppelenbosch, Maikel P; Pan, Qiuwei

    2017-10-01

    Adult liver stem cells are usually maintained in a quiescent/slow-cycling state. However, a proliferative population, marked by leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), was recently identified as an important liver stem cell population. We aimed to investigate the dynamics and functions of proliferative and quiescent stem cells in healthy and injured livers. We studied LGR5-positive stem cells using diphtheria toxin receptor and green fluorescent protein (GFP) knock-in mice. In these mice, LGR5-positive cells specifically coexpress diphtheria toxin receptor and the GFP reporter. Lineage-tracing experiments were performed in mice in which LGR5-positive stem cells and their daughter cells expressed a yellow fluorescent protein/mTmG reporter. Slow-cycling stem cells were investigated using GFP-based, Tet-on controlled transgenic mice. We studied the dynamics of both stem cell populations during liver homeostasis and injury induced by carbon tetrachloride. Stem cells were isolated from mouse liver and organoid formation assays were performed. We analyzed hepatocyte and cholangiocyte lineage differentiation in cultured organoids. We did not detect LGR5-expressing stem cells in livers of mice at any stage of a lifespan, but only following liver injury induced by carbon tetrachloride. In the liver stem cell niche, where the proliferating LGR5 + cells are located, we identified a quiescent/slow-cycling cell population, called label-retaining cells (LRCs). These cells were present in the homeostatic liver, capable of retaining the GFP label over 1 year, and expressed a panel of progenitor/stem cell markers. Isolated single LRCs were capable of forming organoids that could be carried in culture, expanded for months, and differentiated into hepatocyte and cholangiocyte lineages in vitro, demonstrating their bona fide stem cell properties. More interestingly, LRCs responded to liver injury and gave rise to LGR5-expressing stem cells, as well as

  5. Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study

    OpenAIRE

    Gerth, Hans U.; Pohlen, Michele; Th?lking, Gerold; Pavenst?dt, Hermann; Brand, Marcus; Wilms, Christian; H?sing-Kabar, Anna; G?rlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H.?J.

    2017-01-01

    Background The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. Aim We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver in...

  6. [Advances in clinical differentiation between immunological and drug-induced liver injury].

    Science.gov (United States)

    Wang, Y; Li, Y N; Zhang, J; Wang, B M; Zhou, L

    2017-09-20

    The differentiation between autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) is a difficult task in clinical practice. Some AIH patients had a medication history before disease onset, and some DILI patients may have positive serum antibody. In addition, these two groups of patients have similar clinical symptoms, serological examination results, and liver histopathology, which lead to the difficulties in differentiation. However, correct differential diagnosis is of great significance in making clinical treatment decisions and preventing liver cirrhosis. Therefore, it is necessary to investigate the association between immunological and drug-induced liver injury from the perspectives of pathogenesis, similarities and differences in clinical features, serological examination results, and histological changes, prospects of new biomarkers in differentiation, and the significance of hormone therapy and clinical follow-up in differential diagnosis and treatment, in order to provide a reference for clinical decision-making and research in future.

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

    Directory of Open Access Journals (Sweden)

    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.  Early initiation of MARS® dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation.

    Science.gov (United States)

    Pillukat, Mike Hendrik; Schomacher, Tina; Baier, Peter; Gabriëls, Gert; Pavenstädt, Hermann; Schmidt, Hartmut H J

    2016-01-01

     Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation.

  9. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

    Directory of Open Access Journals (Sweden)

    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.

  10. Mitochondrial Roles and Cytoprotection in Chronic Liver Injury

    Directory of Open Access Journals (Sweden)

    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.

  11. Clinical Features and Outcomes of Complementary and Alternative Medicine Induced Acute Liver Failure and Injury.

    Science.gov (United States)

    Hillman, Luke; Gottfried, Michelle; Whitsett, Maureen; Rakela, Jorge; Schilsky, Michael; Lee, William M; Ganger, Daniel

    2016-07-01

    The increasing use of complementary and alternative medicines (CAMs) has been associated with a rising incidence of CAM-induced drug-induced liver injury (DILI). The aim of this study was to examine the clinical features and outcomes among patients with acute liver failure (ALF) and acute liver injury (ALI) enrolled in the Acute Liver Failure Study Group database, comparing CAM-induced with prescription medicine (PM)-induced DILI. A total of 2,626 hospitalized patients with ALF/ALI of any etiology were prospectively enrolled between 1998 and 2015 from 32 academic transplant centers. Only those with CAM or PM-induced ALI/ALF were selected for analysis. A total of 253 (9.6%) subjects were found to have idiosyncratic DILI, of which 41 (16.3%) were from CAM and 210 (83.7%) were due to PM. The fraction of DILI-ALF/ALI cases due to CAM increased from 1998-2007 to 2007-2015 (12.4 vs. 21.1%, P=0.047). There was no difference in the type of liver injury-hepatocellular, cholestatic, or mixed-between groups as determined by R score (P=0.26). PM-induced DILI showed higher serum alkaline phosphatase levels compared with the CAM group (median IU/L, 171 vs. 125, P=0.003). The CAM population had fewer comorbid conditions (1.0 vs. 2.0, Pliver injury and emphasizes the importance of early referral and evaluation for liver transplantation when CAM-induced liver injury is suspected.

  12. Contrast based real time assessment of microcirculatory changes in a fatty liver after ischemia reperfusion injury

    OpenAIRE

    Kolachala, Vasantha L.; Jiang, Rong; Abramowsky, Carlos R.; Gupta, Nitika A.

    2016-01-01

    A fatty liver is known to have impairment of microcirculation, which is worsened after ischemia reperfusion injury (IRI). This makes most fatty grafts unsuitable for transplantation, and in the absence of real time assessment of microcirculation this selection has been at best, random. The goal of this study was to demonstrate the utility of a contrast enhanced ultrasound model in quantitative assessment of the microcirculation of a fatty liver. We subjected fatty mice to IRI and blood flow d...

  13. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats

    OpenAIRE

    Shaqura, Mohammed; Mohamed, Doaa M.; Aboryag, Noureddin B.; Bedewi, Lama; Dehe, Lukas; Treskatsch, Sascha; Shakibaei, Mehdi; Schaefer, Michael; Mousa, Shaaban A

    2017-01-01

    Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. Sham operated and ACF rats were compared for th...

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

    OpenAIRE

    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 Centell...

  15. 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.

  16. Ecklonia cava polyphenol protects the liver against ethanol-induced injury in rats.

    Science.gov (United States)

    Takahashi, Mai; Satake, Naoko; Yamashita, Haruka; Tamura, Akiko; Sasaki, Mio; Matsui-Yuasa, Isao; Tabuchi, Masaki; Akahoshi, Yasumitsu; Terada, Masaki; Kojima-Yuasa, Akiko

    2012-07-01

    The development of alcoholic liver disease is a complex process that involves both the parenchymal and non-parenchymal cells of the liver. We examined the effect of an Ecklonia cava extract on ethanol-induced liver injury. Isolated hepatocytes and hepatic stellate cells (HSCs) were incubated with ethanol. Ecklonia cava polyphenol (ECP) was added to the cultures that had been incubated with ethanol. Male Wistar rats were fed a diet that included 0.02% or 0.2% ECP or no ECP. For a period of 3 weeks, the animals were given drinking water containing 5% ethanol and were also treated with carbon tetrachloride (CCl4) (0.1 ml/kg of body weight). In the cultured hepatocytes, the ECP treatment suppressed the ethanol-induced increase in cell death by maintaining intracellular glutathione (GSH) levels. In HSCs, ECP treatment suppressed the ethanol-induced increases in type I collagen and α-smooth muscle actin expression by maintaining intracellular levels of reactive oxygen species and GSH. We examined the effects of ECP on serum AST and ALT activity, as well as the progression of liver fibrosis in rats treated with ethanol and CCl4. ECP treatment suppressed plasma AST and ALT activities in the ethanol- and CCl4-treated rats. ECP treatment fully protected the rats against ethanol- and CCl4-induced liver injury. ECP may be a candidate for preventing ethanol-induced liver injury. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Experience with OxyELITE pro and acute liver injury in active duty service members.

    Science.gov (United States)

    Foley, Sean; Butlin, Evan; Shields, Wade; Lacey, Brent

    2014-12-01

    1,3-dimethylamylamine (DMAA) is a common additive in sport supplements that was banned by the FDA in 2013. Specifically, this additive received much publication for its role in causing adverse cardiovascular events, particularly sudden cardiac death. However, it has been our experience that products containing this additive may also lead to acute liver injury and liver failure. We present a series of seven cases encountered by a military treatment facility in Southern California which involved the use of OxyELITE Pro, a sport supplement containing DMAA, that all resulted in acute liver injury with two cases requiring transplant for acute liver failure. To our knowledge, this is the first case series reported involving OxyELITE Pro or other DMAA-containing supplements with a specific focus on acute liver injury. This review is limited by the paucity of clinical studies and trials based on OxyElite Pro and its effect on the liver. The presented cases are notably observation, and no standardized diagnostic or treatment protocol was utilized. This series is important to the general population as a whole due to the prevalence of sport supplement use, and is particularly important for practitioners who work with the military or athletic populations due to the high use in these demographics. These cases are followed by a brief discussion regarding DMAA.

  18. Pistacia Terebinthus Coffee Protects against Thioacetamide-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    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.

  19. 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

  20. 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.

  1. Calcium-deficient diet attenuates carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation and inflammatory response

    Directory of Open Access Journals (Sweden)

    Hiroki Yoshioka

    2016-06-01

    Full Text Available The aim of this study is to investigate whether a Ca-deficient diet has an attenuating effect on carbon tetrachloride (CCl4-induced hepatotoxicity. Four-week-old male ddY mice were fed a Ca-deficient diet for 4 weeks as a part of the experimental protocol. While hypocalcemia was observed, there was no significant change in body weight. The CCl4-exposed hypocalcemic mice exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase activities at both 6 h and 24 h even though markers of renal function remained unchanged. Moreover, lipid peroxidation was impaired and total antioxidant power was partially recovered in the liver. Studies conducted in parallel with the biochemical analysis revealed that hepatic histopathological damage was attenuated 24 h post CCl4 injection in hypocalcemic mice fed the Ca-deficient diet. Finally, this diet impaired CCl4-induced inflammatory responses. Although upregulation of Ca concentration is a known indicator of terminal progression to cell death in the liver, these results suggest that Ca is also involved in other phases of CCl4-induced hepatotoxicity, via regulation of oxidative stress and inflammatory responses.

  2. ANTIHEPATOTOXIC EFFECT OF MARRUBIUM VULGARE AND WITHANIA SOMNIFERA EXTRACTS ON CARBON TETRACHLORIDE-INDUCED HEPATOTOXICITY IN RATS

    Science.gov (United States)

    Elberry, Ahmed A.; Harraz, Fathalla M.; Ghareib, Salah A.; Nagy, Ayman A.; Gabr, Salah A.; Suliaman, Mansour I.; Abdel-Sattar, Essam

    2010-01-01

    Marrubium vulgare and Withania somnifera are used in folk medicine of several countries. Many researches showed that they are used for the treatment of variety of diseases due to their antioxidant effects. The present aim of this study was to evaluate the antihepatotoxic and antioxidant activities of the both extracts against carbon tetrachloride (CCl4)-induced hepatic damage in rats. Both extracts were given orally in a dose of 500 mg/kg/day for 4 weeks along with CCl4 started at the 7th week of induction of hepatotoxicity. The antihepatotoxic activity was assessed by measuring aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), tissue content and malondialdehyde (MDA) as well as histopathological examination. Both extracts showed a significant antihepatotoxic effect by reducing significantly the levels of AST, ALT and LDH. However, ALP levels were decreased non-significantly. Regarding the antioxidant activity, they exhibited significant effects by increasing the GPx, GR and GST activities with increased GSH tissue contents and decreased production of MDA level. Furthermore, both extracts alleviated histopathological changes in rats’ liver treated with CCl4. M. vulgare and W. somnifera protect the rats’ liver against CCl4-induced hepatotoxicity. This effect may be attributed, at least in part, to the antioxidant activities of these extracts. PMID:24825994

  3. Hepatoprotective and antioxidant effects of Hibiscus sabdariffa extract against carbon tetrachloride-induced hepatocyte damage in Cyprinus carpio.

    Science.gov (United States)

    Yin, Guojun; Cao, Liping; Xu, Pao; Jeney, Galina; Nakao, Miki

    2011-01-01

    The present study aims to evaluate the hepatoprotective and antioxidant effects of Hibiscus sabdariffa extract on the carbon tetrachloride (CCl(4))-induced hepatocyte damage in fish and provide evidence as to whether it can be potentially used as a medicine for liver diseases in aquaculture. H. sabdariffa extract (100, 200, and 400 μg/mL) was added to the carp primary hepatocyte culture before (pre-treatment), after (post-treatment), and both before and after (pre- and post-treatment) the incubation of the hepatocytes with CCl(4). CCl(4) at 8 mM in the culture medium produced significantly elevated levels of lactate dehydrogenase (LDH), glutamate oxalate transaminase (GOT), glutamate pyruvate transaminase (GPT), and malondialdehyde (MDA) and significantly reduced levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Pre-treatment and pre- and post-treatment of the hepatocytes with H. sabdariffa extract significantly reduced the elevated levels of LDH, GOT, GPT, and MDA and increased the reduced activities of SOD and GSH-Px in a dose-dependent manner; post-treatment did not show any protective effect. The results suggest that H. sabdariffa extract can be potentially used for preventing rather than curing liver diseases in fish.

  4. 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.

  5. Quantitative histological assessment of hepatic ischamia-reperfusion injuries following ischemic pre- and post-conditioning in the rat liver

    DEFF Research Database (Denmark)

    Knudsen, Anders Riegels; Kannerup, Anne-Sofie; Grønbæk, Henning

    2013-01-01

    Quantitative histological assessment of hepatic ischamia-reperfusion injuries following ischemic pre- and post-conditioning in the rat liver......Quantitative histological assessment of hepatic ischamia-reperfusion injuries following ischemic pre- and post-conditioning in the rat liver...

  6. Neutral sphingomyelinase inhibition alleviates apoptosis, but not ER stress, in liver ischemia-reperfusion injury.

    Science.gov (United States)

    Tuzcu, Hazal; Unal, Betul; Kırac, Ebru; Konuk, Esma; Ozcan, Filiz; Elpek, Gulsum O; Demir, Necdet; Aslan, Mutay

    2017-03-01

    Previous studies have revealed the activation of neutral sphingomyelinase (N-SMase)/ceramide pathway in hepatic tissue following warm liver ischemia reperfusion (IR) injury. Excessive ceramide accumulation is known to potentiate apoptotic stimuli and a link between apoptosis and endoplasmic reticulum (ER) stress has been established in hepatic IR injury. Thus, this study determined the role of selective N-SMase inhibition on ER stress and apoptotic markers in a rat model of liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reactions monitoring (MRM) method using ultrafast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared with controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. A significant increase was observed in ER stress markers C/EBP-homologous protein (CHOP) and 78 kDa glucose-regulated protein (GRP78) in IR injury, which was not significantly altered by N-SMase inhibition. Inhibition of N-SMase caused a significant reduction in phospho-NF-kB levels, hepatic TUNEL staining, cytosolic cytochrome c, and caspase-3, -8, and -9 activities which were significantly increased in IR injury. Data herein confirm the role of ceramide in increased apoptotic cell death and highlight the protective effect of N-SMase inhibition in down-regulation of apoptotic stimuli responses occurring in hepatic IR injury.

  7. Lipid peroxidation may not be important in an early stage of alcohol-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Inomata, T.; Rao, G.A.; Tsukamoto, H.

    1986-03-01

    Role of lipid peroxidation (LP) in alcoholic liver injury (ALI) is still controversial. The authors have previously described a rat model which produced the sequential injury from alcoholic fatty liver to liver necrosis and fibrosis. In the present study, the authors have examined the degree of LP and GSH/GSSG ratio in the liver to investigate whether the LP can be identified in an early stage of progressive ALI. Six pairs of male Wistar rats were continuously infused intragastrically for 30 days with a high fat diet (25% total calories) plus either ethanol or isocaloric amount of dextrose. Following intoxication, the content of diene conjugates in mitochondrial and microsomal lipids as well as the liver GSH/GSSG ratio were determined by the diene difference spectrum and fluorometry, respectively. The UV absorption at 234nm by mitochondrial lipid from alcoholic rats (0.668 +/- 0.023 OD/mg) was significantly (p<0.05) lower than that of controls (0.977 +/- 0.102 OD/mg). The microsomal lipid, however, exhibited a similar absorbance in the two groups (0.986 +/- 0.086 vs 1.149 +/- 0.091 OD/mg0. Similarly, no difference in the ratio of GSH/GSSG was found (6.05 +/- 0.27 vs 5.35 +/- 0.44). These results do not support a concept that LP is an important pathogenetic factor for the progression of alcoholic fatty liver to liver necrosis.

  8. Nitrite enhances liver graft protection against cold ischemia reperfusion injury through a NOS independent pathway.

    Science.gov (United States)

    Cherif-Sayadi, Amani; Hadj Ayed-Tka, Kaouther; Zaouali, Mohamed Amine; Bejaoui, Mohamed; Hadj-Abdallah, Najet; Bouhlel, Ahlem; Ben Abdennebi, Hassen

    2017-12-01

    Nitrite has been found to protect liver graft from cold preservation injury. However, the cell signaling pathway involved in this protection remains unclear. Here, we attempt to clarify if the NOS pathway by using the NOS inhibitor, L-NAME (L-N(G)-Nitroarginine methyl ester). Rat livers were conserved for 24 h at 4°C in (IGL-1) solution enriched or not with nitrite at 50 nM. In a third group, rats were pretreated with 50 mg/kg of L-NAME before their liver procurement and preservation in IGL-1 supplemented with nitrite (50 nM) and L-NAME (1 mM). After 24 h of cold storage, rat livers were ex-vivo perfused at 37°C during 2 h. Control livers were perfused without cold storage. Nitrite effectively protected the rat liver grafts from the onset of cold I/R injury. L-NAME treatment did not abolish the beneficial effects of nitrite. Liver damage, protein oxidation and lipid peroxidation remained at low levels in both nitrite-treated groups when compared to IGL-1 group. Antioxidant enzyme activities and functional parameters were unchanged after NOS inhibition. Despite NOS inhibition by L-NAME, nitrite can still provide hepatic protection during cold I/R preservation. This suggests that nitrite acts through a NOS-independent pathway.

  9. 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.

  10. Incidence of liver injury among cancer patients receiving chemotherapy in an integrated health system.

    Science.gov (United States)

    Ulcickas Yood, Marianne; Bortolini, Michele; Casso, Deborah; Beck, Jean G; Oliveria, Susan A; Wells, Karen E; Woodcroft, Kimberley J; Wang, Lisa I

    2015-04-01

    Using liver laboratory tests (LLTs), Hy's law is a method used to identify drug-induced liver injury (DILI), after excluding other causes. Elevated LLTs in chemotherapy-exposed patients may result from tumor effects or comorbidities. This study evaluated incidence of Hy's law in chemotherapy-treated cancer patients. We identified breast, colorectal, and lung cancer patients diagnosed in 1 January 2000 to 31 December 2007 at a Midwestern health system. Using automated data, potential Hy's law (PHL) cases were defined by patterns of elevated LLTs suggestive of DILI. Among those treated with chemotherapy, we excluded PHL patients with pre-existing conditions that could cause liver injury, producing a cohort meeting Hy's law criteria, according to automated data. Medical record review, conducted among these automated data-derived Hy's law patients, further excluded those with causes of liver injury other than chemotherapy. Using automated data, among chemotherapy-exposed patients (N = 2788), 91 (3.3%) met PHL criteria using LLTs and 64 (2.3%) met Hy's law after excluding underlying liver injury using the International Classification of Diseases, 9th Revision codes. After a medical record review, 62 of 64 patients qualifying as Hy's law through automated data had other potential causes, leaving two patients (0.07%; 95%CI: 0.01-0.24%) with chemotherapy as a likely alternative cause of liver injury. Abnormal LLTs are common in chemotherapy-treated patients. Medical record review showed that the incidence of Hy's law events is rare. These data provide context for evaluating DILI in clinical trials and postmarketing surveillance of anticancer therapies, understanding that automated data alone may substantially overestimate the number of Hy's law cases. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Low-Dose N,N-Dimethylformamide Exposure and Liver Injuries in a Cohort of Chinese Leather Industry Workers.

    Science.gov (United States)

    Qi, Cong; Gu, Yiyang; Sun, Qing; Gu, Hongliang; Xu, Bo; Gu, Qing; Xiao, Jing; Lian, Yulong

    2017-05-01

    We assessed the risk of liver injuries following low doses of N,N-dimethylformamide (DMF) below threshold limit values (20 mg/m) among leather industry workers and comparison groups. A cohort of 429 workers from a leather factory and 466 non-exposed subjects in China were followed for 4 years. Poisson regression and piece-wise linear regression were used to examine the relationship between DMF and liver injury. Workers exposed to a cumulative dose of DMF were significantly more likely than non-exposed workers to develop liver injury. A nonlinear relationship between DMF and liver injury was observed, and a threshold of the cumulative DMF dose for liver injury was 7.30 (mg/m) year. The findings indicate the importance of taking action to reduce DMF occupational exposure limits for promoting worker health.

  12. Ischemic preconditioning protects against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy.

    Science.gov (United States)

    Liu, Anding; Fang, Haoshu; Wei, Weiwei; Dirsch, Olaf; Dahmen, Uta

    2014-12-01

    Ischemic preconditioning exerts a protective effect in hepatic ischemia/reperfusion injury. The exact mechanism of ischemic preconditioning action remains largely unknown. Recent studies suggest that autophagy plays an important role in protecting against ischemia/reperfusion injury. However, the role of autophagy in ischemic preconditioning-afforded protection and its regulatory mechanisms in liver ischemia/reperfusion injury remain poorly understood. This study was designed to determine whether ischemic preconditioning could protect against liver ischemia/reperfusion injury via heme oxygenase-1-mediated autophagy. Laboratory investigation. University animal research laboratory. Male inbred Lewis rats and C57BL/6 mice. Ischemic preconditioning was produced by 10 minutes of ischemia followed by 10 minutes of reperfusion prior to 60 minutes of ischemia. In a rat model of hepatic ischemia/reperfusion injury, rats were pretreated with wortmannin or rapamycin to evaluate the contribution of autophagy to the protective effects of ischemic preconditioning. Heme oxygenase-1 was inhibited with tin protoporphyrin IX. In a mouse model of hepatic ischemia/reperfusion injury, autophagy or heme oxygenase-1 was inhibited with vacuolar protein sorting 34 small interfering RNA or heme oxygenase-1 small interfering RNA, respectively. Ischemic preconditioning ameliorated liver ischemia/reperfusion injury, as indicated by lower serum aminotransferase levels, lower hepatic inflammatory cytokines, and less severe ischemia/reperfusion-associated histopathologic changes. Ischemic preconditioning treatment induced autophagy activation, as indicated by an increase of LC3-II, degradation of p62, and accumulation of autophagic vacuoles in response to ischemia/reperfusion injury. When ischemic preconditioning-induced autophagy was inhibited with wortmannin in rats or vacuolar protein sorting 34-specific small interfering RNA in mice, liver ischemia/reperfusion injury was worsened, whereas

  13. Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis.

    Science.gov (United States)

    Baader, Manuel; Bretschneider, Tom; Broermann, Andre; Rippmann, Joerg F; Stierstorfer, Birgit; Kuttruff, Christian A; Mark, Michael

    2018-02-01

    Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injury in rats. Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg -1 twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals. Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis. © 2017 The British Pharmacological Society.

  14. Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury

    Science.gov (United States)

    Issan, Y.; Katz, Y.; Sultan, M.; Safran, M.; Michal, Laniado-Schwartzman; Nader, G. Abraham; Kornowski, R.; Grief, F.; Pappo, O.; Hochhauser, E.

    2017-01-01

    Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)–dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB’s regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation. PMID:23435964

  15. Modulation of gamma-irradiation and carbon tetrachloride induced oxidative stress in the brain of female rats by flaxseed oil.

    Science.gov (United States)

    Ismail, Amel F M; Salem, Asmaa A M; Eassawy, Mamdouh M T

    2016-08-01

    The activity of flaxseed oil (FSO) on gamma-irradiation (7Gy) and/or carbon tetrachloride (CCl4) induced acute neurotoxicity in rats' brain was investigated. The results revealed a significant decrease (pbrain tissues of γ-irradiated and CCl4 intoxicated animals. Those effects were augmented due to the effect of CCl4-induced toxicity in γ-irradiated rats. The treatment of FSO displayed significant amendment of the studied parameters in the brain tissues of γ-irradiated and CCl4 intoxicated animals. FSO has a neuroprotective effect against CCl4-induced brain injury in gamma-irradiated rats. This effect is interrelated to the ability of FSO to scavenges the free radicals, enhances the antioxidant enzymes activity, increases GSH contents, down-regulates the inflammatory responses, ameliorates the iron, calcium, copper, magnesium, manganese levels and inhibiting the gene expression level of XO and iNOS in the brain tissues of intoxicated animals. In conclusion, this study demonstrated that the potent antioxidant and anti-inflammatory activities of FSO have the ability to improve the antioxidant status, suppress the inflammatory responses, and regulate the trace elements in the brain tissues of γ-irradiated, CCl4, and their combined effect in intoxicated animals. Consequently, FSO exhibited neuroprotective activity on γ-irradiated, CCl4, and their combined effect induced brain injury in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Influence of zinc sulfate intake on acute ethanol-induced liver injury in rats

    Science.gov (United States)

    Bolkent, Sema; Arda-Pirincci, Pelin; Bolkent, Sehnaz; Yanardag, Refiye; Tunali, Sevim; Yildirim, Sukriye

    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. PMID:16865776

  17. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats

    Directory of Open Access Journals (Sweden)

    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.

  18. Liver injury from ampicillin-induced intestinal microbiota distresses ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of ampicillin on rat intestinal microflora and liver in the presence of high carbohydrate and protein diets. Methods: Male Wistar albino rats were divided into four groups. The first group served as the control, the second group was treated with ampicillin (50 mg/kg for 3 weeks) and fed with a ...

  19. Liver injury from ampicillin-induced intestinal microbiota distresses ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of ampicillin on rat intestinal microflora and liver in the presence of high carbohydrate and protein ... Gut microbial flora has spatial and temporal complexity that varies from person to person, body niche, age, geographic location, health status, diet and type of host [3]. Even within the same ...

  20. The Protective Properties of the Strawberry (Fragaria ananassa) against Carbon Tetrachloride-Induced Hepatotoxicity in Rats Mediated by Anti-Apoptotic and Upregulation of Antioxidant Genes Expression Effects.

    Science.gov (United States)

    Hamed, Sherifa S; Al-Yhya, Nouf A; El-Khadragy, Manal F; Al-Olayan, Ebtesam M; Alajmi, Reem A; Hassan, Zeinab K; Hassan, Salwa B; Abdel Moneim, Ahmed E

    2016-01-01

    The strawberry (Fragaria ananassa) has been extensively used to treat a wide range of ailments in many cultures. The present study was aimed at evaluating the hepatoprotective effect of strawberry juice on experimentally induced liver injury in rats. To this end, rats were introperitoneally injected with carbon tetrachloride (CCl4) with or without strawberry juice supplementation for 12 weeks and the hepatoprotective effect of strawberry was assessed by measuring serum liver enzyme markers, hepatic tissue redox status and apoptotic markers with various techniques including biochemistry, ELISA, quantitative PCR assays and histochemistry. The hepatoprotective effect of the strawberry was evident by preventing CCl4-induced increase in liver enzymes levels. Determination of oxidative balance showed that strawberry treatment significantly blunted CCl4-induced increase in oxidative stress markers and decrease in enzymatic and non-enzymatic molecules in hepatic tissue. Furthermore, strawberry supplementation enhanced the anti-apoptotic protein, Bcl-2, and restrained the pro-apoptotic proteins Bax and caspase-3 with a marked reduction in collagen areas in hepatic tissue. These findings demonstrated that strawberry (F. ananassa) juice possessed antioxidant, anti-apoptotic and anti-fibrotic properties, probably mediated by the presence of polyphenols and flavonoids compounds.

  1. The protective properties of the strawberry (Fragaria ananassa against carbon tetrachloride-induced hepatotoxicity in rats mediated by anti-apoptotic and upregulation of antioxidant genes expression effects

    Directory of Open Access Journals (Sweden)

    Sherifa shaker hamed

    2016-08-01

    Full Text Available The strawberry (Fragaria ananassa has been extensively used to treat a wide range of ailments in many cultures. The present study was aimed at evaluating the hepatoprotective effect of strawberry juice on experimentally induced liver injury in rats. To this end, rats were introperitoneally injected with carbon tetrachloride (CCl4 with or without strawberry juice supplementation for 12 weeks and the hepatoprotective effect of strawberry was assessed by measuring serum liver enzyme markers, hepatic tissue redox status and apoptotic markers with various techniques including biochemistry, ELISA, quantitative PCR assays and histochemistry. The hepatoprotective effect of the strawberry was evident by preventing CCl4-induced increase in liver enzymes levels. Determination of oxidative balance showed that strawberry treatment significantly blunted CCl4-induced increase in oxidative stress markers and decrease in enzymatic and non-enzymatic molecules in hepatic tissue. Furthermore, strawberry supplementation enhanced the anti-apoptotic protein, Bcl-2, and restrained the pro-apoptotic proteins Bax and caspase-3 with a marked reduction in collagen areas in hepatic tissue. These findings demonstrated that strawberry (Fragaria ananassa juice possessed antioxidant, anti-apoptotic and anti-fibrotic properties, probably mediated by the presence of polyphenols and flavonoids compounds.

  2. 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. © Georg Thieme Verlag KG Stuttgart · New York.

  3. An Innovative Hyperbaric Hypothermic Machine Perfusion Protects the Liver from Experimental Preservation Injury

    Directory of Open Access Journals (Sweden)

    Ferdinando A. Giannone

    2012-01-01

    Full Text Available Purpose. Hypothermic machine perfusion systems seem more effective than the current static storage to prevent cold ischemic liver injury. Thus, we test an innovative hyperbaric hypothermic machine perfusion (HHMP, which combines hyperbaric oxygenation of the preservation solution and continuous perfusion of the graft. Methods. Rat livers were preserved with Celsior solution according to 4 different modalities: normobaric static preservation; hyperbaric static preservation at 2 atmosphere absolute (ATA; normobaric dynamic preservation, with continuous perfusion; hyperbaric dynamic preservation, with continuous perfusion at 2 ATA. After 24 h cold preservation, we assessed different parameters. Results. Compared to baseline, livers preserved with the current static storage showed severe ultrastructural damage, glycogen depletion and an increased oxidative stress. Normobaric perfused livers showed improved hepatocyte ultrastructure and ameliorated glycogen stores, but they still suffered a significant oxidative damage. The addition of hyperbaric oxygen produces an extra benefit by improving oxidative injury and by inducing endothelial NO synthase (eNOS gene expression. Conclusions. Preservation by means of the present innovative HHMP reduced the liver injury occurring after the current static cold storage by lowering glycogen depletion and oxidative damage. Interestingly, only the use of hyperbaric oxygen was associated to a blunted oxidative stress and an increased eNOS gene expression.

  4. Possible gasoline-induced chronic liver injury due to occupational malpractice in a motor mechanic: a case report.

    Science.gov (United States)

    Gunathilaka, Mahesh Lakmal; Niriella, Madunil Anuk; Luke, Nathasha Vihangi; Piyarathna, Chathura Lakmal; Siriwardena, Rohan Chaminda; De Silva, Arjuna Priyadarshin; de Silva, Hithanadura Janaka

    2017-07-03

    Hydrocarbon-induced occupational liver injury is a well-known clinical entity among petroleum industry workers. There are many types of hydrocarbon exposure, with inhalation being the most common. Hydrocarbon-induced occupational liver injury is a rarely suspected and commonly missed etiological agent for liver injury. We report a case of a non-petroleum industry worker with chronic liver disease secondary to hydrocarbon-induced occupational liver injury caused by chronic low-grade hydrocarbon ingestion due to occupational malpractice. A 23-year-old Sri Lankan man who was a motor mechanic presented to our hospital with decompensated cirrhosis. He had been chronically exposed to gasoline via inadvertent ingestion due to occupational malpractice. He used to remove gasoline from carburetors by sucking and failed to practice mouth washing thereafter. On evaluation, he had histologically proven established cirrhosis. A comprehensive history and workup ruled out other nonoccupational etiologies for cirrhosis. The patient's long-term occupational gasoline exposure and clinical course led us to a diagnosis of hydrocarbon-induced occupational liver injury leading to decompensated cirrhosis. Hydrocarbon-induced occupational liver injury should be considered as a cause when evaluating a patient with liver injury with possible exposure in relevant occupations.

  5. Hypothermic machine perfusion of the liver and the critical balance between perfusion pressures and endothelial injury

    NARCIS (Netherlands)

    't Hart, NA; van der Plaats, A; Leuvenink, HGD; van Goor, H; Wiersema-Buist, J; Verkerke, GJ; Rakhorst, G; Ploeg, RJ

    2005-01-01

    Hypothermic machine perfusion (HMP) provides better protection against cold ischemic injury than cold storage in marginal donor kidneys. Also, in liver transplantation a switch from static cold storage to HMP could be beneficial as it would allow longer preservation times and the use of marginal

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

    African Journals Online (AJOL)

    2013-12-02

    Dec 2, 2013 ... and protease inhibitors, low body mass index, low platelet count and deranged renal functions prior ART initiation are associated with ... Risk factors for liver injury should be evaluated before initiating anti-retroviral therapy .... Event. Number. Haepatomegaly and ascites. 6. Haepatomegaly and gall stones.

  7. 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

  8. Application of urine proteomics for biomarker discovery in drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Kramers, Cornelis; Masereeuw, R.|info:eu-repo/dai/nl/155644033; 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

  9. Changes in cholangiocyte bile salt transporter expression and bile duct injury after orthotopic liver transplantation

    NARCIS (Netherlands)

    Hoekstra, H.; Op Den Dries, S.; Buis, C.I.; Khan, A.A.; Gouw, A.S.H.; Groothuis, G.M.M.; Lisman, T.; Porte, R.J.

    2010-01-01

    Background: Bile salts have been shown to contribute to bile duct injury after orthotopic liver transplantation (OLT). Cholangiocytes modify bile composition by reabsorption of bile salts (cholehepatic shunt) and contribute to bile flow by active secretion of sodium and water via cystic fibrosis

  10. Liver X receptor α is essential for the capillarization of liver sinusoidal endothelial cells in liver injury.

    Science.gov (United States)

    Xing, Yan; Zhao, Tingting; Gao, Xiaoyan; Wu, Yuzhang

    2016-02-18

    Liver X receptors (LXRs) play essential roles in lipogenesis, anti-inflammatory action and hepatic stellate cells (HSCs) activation in the liver. However, the effects of LXRs on the capillarization of liver sinusoidal endothelial cells (LSECs) in liver fibrosis remain undetermined. Here, we demonstrated that LXRα plays an important role in LSECs capillarization in a manner that involved Hedgehog (Hh) signaling. We found that LXRα expression in LSECs was increased in the carbon tetrachloride (CCl4)-induced fibrosis model. LXRα deletion markedly exacerbated CCl4-induced lesions assessed by histopathology, as well as inflammation and collagen deposition. Furthermore, capillarization of the sinusoids was aggravated in CCl4 -treated LXRα-deficient mice, as evidenced by increased CD34 expression, the formation of continuous basement membranes and aggravation of the loss of fenestrae. In vitro, LXR agonist could maintain freshly isolated LSECs differentiation on day 3. Furthermore, LXRα deletion led to increased expression of Hedgehog (Hh)-regulated gene in LSECs in the injured liver. Conversely, the LXR agonist could inhibit the Hh pathway in cultured LSECs. These responses indicated that LXRα suppressed the process of LSECs capillarization by repressing Hh signaling. Overall, our findings suggest that LXRα, by restoring the differentiation of LSECs, may be critical for the regression of liver fibrosis.

  11. 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

  12. Protective Effect of Akkermansia muciniphila against Immune-Mediated Liver Injury in a Mouse Model

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    Wenrui Wu

    2017-09-01

    Full Text Available Accumulating evidence indicates that gut microbiota participates in the pathogenesis and progression of liver diseases. The severity of immune-mediated liver injury is associated with different microbial communities. Akkermansia muciniphila can regulate immunologic and metabolic functions. However, little is known about its effects on gut microbiota structure and function. This study investigated the effect of A. muciniphila on immune-mediated liver injury and potential underlying mechanisms. Twenty-two C57BL/6 mice were assigned to three groups (N = 7–8 per group and continuously administrated A. muciniphila MucT or PBS by oral gavage for 14 days. Mouse feces were collected for gut microbiota analysis on the 15th day, and acute liver injury was induced by Concanavalin A (Con A, 15 mg/kg injection through the tail vein. Samples (blood, liver, ileum, colon were assessed for liver injury, systemic inflammation, and intestinal barrier function. We found that oral administration of A. muciniphila decreased serum ALT and AST and alleviated liver histopathological damage induced by Con A. Serum levels of pro-inflammatory cytokines and chemokines (IL-2, IFN-γ, IL-12p40, MCP-1, MIP-1a, MIP-1b were substantially attenuated. A. muciniphila significantly decreased hepatocellular apoptosis; Bcl-2 expression increased, but Fas and DR5 decreased. Further investigation showed that A. muciniphila enhanced expression of Occludin and Tjp-1 and inhibited CB1 receptor, which strengthened intestinal barriers and reduced systemic LPS level. Fecal 16S rRNA sequence analysis indicated that A. muciniphila increased microbial richness and diversity. The community structure of the Akk group clustered distinctly from that of mice pretreated with PBS. Relative abundance of Firmicutes increased, and Bacteroidetes abundance decreased. Correlation analysis showed that injury-related factors (IL-12p40, IFN-γ, DR5 were negatively associated with specific genera

  13. Acute kidney injury and post-reperfusion syndrome in liver transplantation.

    Science.gov (United States)

    Umbro, Ilaria; Tinti, Francesca; Scalera, Irene; Evison, Felicity; Gunson, Bridget; Sharif, Adnan; Ferguson, James; Muiesan, Paolo; Mitterhofer, Anna Paola

    2016-11-14

    In the past decades liver transplantation (LT) has become the treatment of choice for patients with end stage liver disease (ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death (DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease (CKD). Acute kidney injury (AKI) post-LT has been recently recognized as an important risk factor for the occurrence of de novo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome (PRS) that can influence recipient's morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since pre-LT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A PubMed search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on PubMed search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors

  14. Hepatic NK cell-mediated hypersensitivity to ConA-induced liver injury in mouse liver expressing hepatitis C virus polyprotein.

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    Fu, Qiuxia; Yan, Shaoduo; Wang, Licui; Duan, Xiangguo; Wang, Lei; Wang, Yue; Wu, Tao; Wang, Xiaohui; An, Jie; Zhang, Yulong; Zhou, Qianqian; Zhan, Linsheng

    2017-08-08

    The role of hepatic NK cells in the pathogenesis of HCV-associated hepatic failure is incompletely understood. In this study, we investigated the effect of HCV on ConA-induced immunological hepatic injury and the influence of HCV on hepatic NK cell activation in the liver after ConA administration. An immunocompetent HCV mouse model that encodes the entire viral polyprotein in a liver-specific manner based on hydrodynamic injection and φC31o integrase was used to study the role of hepatic NK cells. Interestingly, the frequency of hepatic NK cells was reduced in HCV mice, whereas the levels of other intrahepatic lymphocytes remained unaltered. Next, we investigated whether the reduction in NK cells within HCV mouse livers might elicit an effect on immune-mediated liver injury. HCV mice were subjected to acute liver injury models upon ConA administration. We observed that HCV mice developed more severe ConA-induced immune-mediated hepatitis, which was dependent on the accumulated intrahepatic NK cells. Our results indicated that after the administration of ConA, NK cells not only mediated liver injury through the production of immunoregulatory cytokines (IFN-γ, TNF-α and perforin) with direct antiviral activity, but they also killed target cells directly through the TRAIL/DR5 and NKG2D/NKG2D ligand signaling pathway in HCV mice. Our findings suggest a critical role for NK cells in oversensitive liver injury during chronic HCV infection.

  15. Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver

    Science.gov (United States)

    Yildiz, Fahrettin; Coban, Sacit; Terzi, Alpaslan; Ates, Mustafa; Aksoy, Nurten; Cakir, Hale; Ocak, Ali Riza; Bitiren, Muharrem

    2008-01-01

    AIM: To determine whether Nigella sativa prevents hepatic ischemia-reperfusion injury to the liver. METHODS: Thirty rats were divided into three groups as sham (Group 1), control (Group 2), and Nigella sativa (NS) treatment group (Group 3). All rats underwent hepatic ischemia for 45 min followed by 60 min period of reperfusion. Rats were intraperitoneally infused with only 0.9% saline solution in group 2. Rats in group 3 received NS (0.2 mL/kg) intraperitoneally, before ischemia and before reperfusion. Blood samples and liver tissues were harvested from the rats, and then the rats were sacrificed. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were determined. Total antioxidant capacity (TAC), catalase (CAT), total oxidative status (TOS), oxidative stress index (OSI) and myeloperoxidase (MPO) in hepatic tissue were measured. Also liver tissue histopathology was evaluated by light microscopy. RESULTS: The levels of liver enzymes in group 3 were significantly lower than those in the group 2. TAC in liver tissue was significantly higher in group 3 than in group 2. TOS, OSI and MPO in hepatic tissue were significantly lower in group 3 than the group 2. Histological tissue damage was milder in the NS treatment group than that in the control group. CONCLUSION: Our results suggest that Nigella sativa treatment protects the rat liver against to hepatic ischemia-reperfusion injury. PMID:18777598

  16. Cod liver oil in sodium nitrite induced hepatic injury: does it have a potential protective effect?

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    Sherif, I O; Al-Gayyar, M M

    2015-01-01

    Exposure to sodium nitrites, a food additive, at high levels has been reported to produce reactive nitrogen and oxygen species that cause dysregulation of inflammatory responses and tissue injury. In this work, we examined the impact of dietary cod liver oil on sodium nitrite-induced inflammation in rats. Thirty-two adult male Sprague-Dawely rats were treated with 80 mg/kg sodium nitrite in presence/absence of 5 ml/kg cod liver oil. Liver sections were stained with hematoxylin/eosin. We measured hepatic tumor necrosis factor (TNF)-α, interleukin-1 beta (IL)-1β, C-reactive protein (CRP), transforming growth factor (TGF)-β1, and caspase-3. Cod liver oil reduced sodium nitrite-induced hepatocyte damage. In addition, cod liver oil results in reduction of hepatic TNF-α, IL-1β, CRP, TGF-β1, and caspase-3 when compared with the sodium nitrite group. Cod liver oil ameliorates sodium nitrite-induced hepatic injury via multiple mechanisms including blocking sodium nitrite-induced elevation of inflammatory cytokines, fibrosis mediators, and apoptosis markers.

  17. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

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    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.

  18. Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury.

    Science.gov (United States)

    Yang, Mu-Qing; Du, Qiang; Goswami, Julie; Varley, Patrick R; Chen, Bin; Wang, Rong-Hua; Morelli, Adrian E; Stolz, Donna B; Billiar, Timothy R; Li, Jiyu; Geller, David A

    2017-10-23

    The role and regulators of extracellular vesicles (EV) secretion in hepatic ischemia/reperfusion (IR) injury have not been defined. Rab27a is a GTPase known to control EVs release. Interferon regulatory factor 1 (IRF-1) is a transcription factor that plays an important role in liver IR and regulates certain GTPases. However, the relationships among IRF-1, Rab27a, and EVs secretion are largely unknown. Here, we show induction of IRF-1 and Rab27a both in vitro in hypoxic hepatocytes and in vivo in warm IR and orthotopic liver transplantation livers. Interferon γ stimulation, IRF-1 transduction, or IR promoted Rab27a expression and EVs secretion. Meanwhile, silencing of IRF-1 decreased Rab27a expression and EVs secretion. Rab27a silencing decreased EVs secretion and liver IR injury. Ten putative IRF-1 binding motifs in the 1,692 base pairs Rab27a promoter region were identified. Chromatin immunoprecipitation and electrophoretic mobility shift assay verified five functional IRF-1 binding motifs, which were confirmed by Rab27a promoter luciferase assay. IR-induced EVs contained higher oxidized phospholipids (OxPL). OxPLs on EVs surface activated neutrophil through toll like receptor 4 (TLR-4) pathway. OxPL-neutralizing E06 antibody blocked the effect of EVs and decreased liver IR injury. These findings provide a novel mechanism by which IRF-1 regulates Rab27a transcription and EVs secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  19. Nebivolol Ameliorates Hepatic Ischemia/Reperfusion Injury on Liver But Not on Distant Organs.

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    Ulger, Burak Veli; Erbis, Halil; Turkcu, Gul; Ekinci, Aysun; Turkoglu, Mehmet Akif; Ekinci, Cenap; Yilmaz, Vural Taner; Bac, Bilsel

    2015-01-01

    Hepatic ischemia/reperfusion injury may occur after large tumor resection and liver transplantation procedures. Nitric oxide was shown to have protective effects on ischemia/reperfusion injury. Nebivolol is a compound that has been reported to improve nitric oxide release. We evaluated the effects of nebivolol in a rat liver ischemia/reperfusion model. A total of 40 rats were randomly divided into four groups (n = 10 each). Group I underwent only laparotomy, Group II was administered nebivolol and then underwent laparotomy, Group III underwent laparotomy and hepatic ischemia/reperfusion, and Group IV was administered nebivolol and then underwent laparotomy and hepatic ischemia/reperfusion. Serum AST, ALT, urea, and creatinine levels, and TAS and TOS levels of liver, lung, and kidney tissues were determined. Histopathological determination was also performed. Nebivolol significantly reduced liver function tests in group IV, but it did not improve renal functions. Oxidative stress and abnormal histopathological findings were found to be reduced in liver tissue in group IV. Although the oxidative stress was increased after hepatic ischemia/reperfusion, nebivolol could not reduce the oxidative stress in kidney tissue. There were no significant differences between group III and group IV in terms of the histopathological changes in kidney tissue. There were no significant differences in lung tissue between the groups. The results of this study suggest that nebivolol has protective effects on liver but not on distant organs in a hepatic ischemia/reperfusion injury model. These experimental findings indicate that nebivolol may be useful in the treatment of hepatic ischemia/reperfusion injury.

  20. Protective effects of nicotinamide against acetaminophen-induced acute liver injury.

    Science.gov (United States)

    Shi, Youdan; Zhang, Li; Jiang, Rong; Chen, Weiying; Zheng, Weiping; Chen, Li; Tang, Li; Li, Longhui; Li, Longjiang; Tang, Weixue; Wang, Yaping; Yu, Yu

    2012-12-01

    Nicotinamide (NAM), the amide form of vitamin B3, is involved in a wide range of biological processes. Recent evidence revealed the anti-inflammatory and anti-oxidant properties of NAM and suggests it may be used as a novel strategy in the prevention of acute liver injury. In the present study, we investigated the potential protective effects of NAM on acetaminophen (APAP)-induced acute liver injury in mice. Mice were treated with NAM at 400mg/kg 30 min before or after administration of APAP at a hepatotoxic dose of 400mg/kg body weight via intraperitoneal injection. Liver injury and the expression of inflammation-related molecules were determined by histological examination and biochemical analysis, respectively. In addition, the survival rate of mice was assessed after APAP administration. Pretreatment with NAM for 30 min significantly decreased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and malondialdehyde (MDA), and diminished histopathologic evidence of hepatic toxicity in mice following APAP administration. Similarly, posttreatment with NAM also decreased plasma ALT and AST levels in APAP-administrated mice. Furthermore, both pretreatment and posttreatment with NAM prolonged the survival rate of acute liver injury mice, accompanied by a significant reduction in the plasma levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and interleukin-6 (IL-6). Together, these findings suggest that NAM possesses protective effects on APAP-induced liver injury, which may involve the anti-inflammatory action. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Cocktail of chemical compounds robustly promoting cell reprogramming protects liver against acute injury

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    Yuewen Tang

    2017-02-01

    Full Text Available Abstract Tissue damage induces cells into reprogramming-like cellular state, which contributes to tissue regeneration. However, whether factors promoting the cell reprogramming favor tissue regeneration remains elusive. Here we identified combination of small chemical compounds including drug cocktails robustly promoting in vitro cell reprogramming. We then administrated the drug cocktails to mice with acute liver injuries induced by partial hepatectomy or toxic treatment. Our results demonstrated that the drug cocktails which promoted cell reprogramming in vitro improved liver regeneration and hepatic function in vivo after acute injuries. The underlying mechanism could be that expression of pluripotent genes activated after injury is further upregulated by drug cocktails. Thus our study offers proof-of-concept evidence that cocktail of clinical compounds improving cell reprogramming favors tissue recovery after acute damages, which is an attractive strategy for regenerative purpose.

  2. 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.

  3. Levosimendan: a cardiovascular drug to prevent liver ischemia-reperfusion injury?

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    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.

  4. Dietary Nucleotides Supplementation and Liver Injury in Alcohol-Treated Rats: A Metabolomics Investigation

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    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.

  5. Protective mechanism of grape seed oil on carbon tetrachloride-induced brain damage in γ-irradiated rats.

    Science.gov (United States)

    Ismail, Amel F M; Moawed, Fatma S M; Mohamed, Marwa Abdelhameed

    2015-12-01

    This study investigated the possible beneficial effects of grape seed oil (GSO) on carbon tetrachloride (CCl4)-induced acute neurotoxicity in γ-irradiated rats. A statistical significant decrease in superoxide-dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GPx) activities and reduced glutathione (GSH) content were exhibited. Further, a significant elevation in malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor-beta-1 (TGF-β1) levels was observed. Furthermore, xanthine oxidase (XO) and inducible nitric oxide synthase (iNOS) gene expression were elevated in the γ-irradiated animals treated with an acute dose of CCl4. The pretreatment of GSO exerts significant amelioration of the studied parameters. In conclusion, this study demonstrated that GSO has a neuroprotective effect against CCl4-induced brain injury in γ-irradiated rats, which is likely attributed to its ability to scavenge the free radicals, suppress the inflammatory responses, improve the activity of the antioxidant enzymes and inhibit the XO and iNOS gene expression levels. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury.

    Science.gov (United States)

    Wang, Yuhua; Liu, Yanlong; Sidhu, Anju; Ma, Zhenhua; McClain, Craig; Feng, Wenke

    2012-07-01

    Endotoxemia is a contributing cofactor to alcoholic liver disease (ALD), and alcohol-induced increased intestinal permeability is one of the mechanisms of endotoxin absorption. Probiotic bacteria have been shown to promote intestinal epithelial integrity and protect barrier function in inflammatory bowel disease (IBD) and in ALD. Although it is highly possible that some common molecules secreted by probiotics contribute to this action in IBD, the effect of probiotic culture supernatant has not yet been studied in ALD. We examined the effects of Lactobacillus rhamnosus GG culture supernatant (LGG-s) on the acute alcohol-induced intestinal integrity and liver injury in a mouse model. Mice on standard chow diet were supplemented with supernatant from LGG culture (10(9) colony-forming unit/mouse) for 5 days, and one dose of alcohol at 6 g/kg body wt was administered via gavage. Intestinal permeability was measured by FITC-FD-4 ex vivo. Alcohol-induced liver injury was examined by measuring the activity of alanine aminotransferase (ALT) in plasma, and liver steatosis was evaluated by triglyceride content and Oil Red O staining of the liver sections. LGG-s pretreatment restored alcohol-induced reduction in ileum mRNA levels of claudin-1, intestine trefoil factor (ITF), P-glycoprotein (P-gp), and cathelin-related antimicrobial peptide (CRAMP), which play important roles on intestinal barrier integrity. As a result, LGG-s pretreatment significantly inhibited the alcohol-induced intestinal permeability, endotoxemia and subsequently liver injury. Interestingly, LGG-s pretreatment increased ileum mRNA expression of hypoxia-inducible factor (HIF)-2α, an important transcription factor of ITF, P-gp, and CRAMP. These results suggest that LGG-s ameliorates the acute alcohol-induced liver injury by promoting HIF signaling, leading to the suppression of alcohol-induced increased intestinal permeability and endotoxemia. The use of bacteria-free LGG culture supernatant provides a

  7. Bioactivation of nevirapine to a reactive quinone methide: implications for liver injury.

    Science.gov (United States)

    Sharma, Amy M; Li, Yan; Novalen, Maria; Hayes, M Anthony; Uetrecht, Jack

    2012-08-20

    Nevirapine (NVP) treatment is associated with a significant incidence of liver injury. We developed an anti-NVP antiserum to determine the presence and pattern of covalent binding of NVP to mouse, rat, and human hepatic tissues. Covalent binding to hepatic microsomes from male C57BL/6 mice and male Brown Norway rats was detected on Western blots; the major protein had a mass of ~55 kDa. Incubation of NVP with rat CYP3A1 and 2C11 or human CYP3A4 also led to covalent binding. Treatment of female Brown Norway rats or C57BL/6 mice with NVP led to extensive covalent binding to a wide range of proteins. Co-treatment with 1-aminobenzotriazole dramatically changed the pattern of binding. The covalent binding of 12-hydroxy-NVP, the pathway that leads to a skin rash, was much less than that of NVP, both in vitro and in vivo. An analogue of NVP in which the methyl hydrogens were replaced by deuterium also produced less covalent binding than NVP. These data provide strong evidence that covalent binding of NVP in the liver is due to a quinone methide formed by oxidation of the methyl group. Attempts were made to develop an animal model of NVP-induced liver injury in mice. There was a small increase in ALT in some NVP-treated male C57BL/6 mice at 3 weeks that resolved despite continued treatment. Male Cbl-b(-/-) mice dosed with NVP had an increase in ALT of >200 U/L, which also resolved despite continued treatment. Liver histology in these animals showed focal areas of complete necrosis, while most of the liver appeared normal. This is a different pattern from the histology of NVP-induced liver injury in humans. This is the first study to report hepatic covalent binding of NVP and also liver injury in mice. It is likely that the quinone methide metabolite is responsible for NVP-induced liver injury.

  8. IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production

    Science.gov (United States)

    Yokota, Shinichiro; Yoshida, Osamu; Dou, Lei; Spadaro, Anthony V.; Isse, Kumiko; Ross, Mark A.; Stolz, Donna B.; Kimura, Shoko; Du, Qiang; Demetris, Anthony J.; Thomson, Angus W.; Geller, David A.

    2015-01-01

    Ischemia and reperfusion (I/R) injury following liver transplantation (LTx) is an important problem that significantly impacts clinical outcomes. Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays a critical role in liver injury. Our objective was to determine the immunomodulatory role of IRF-1 during I/R injury following allogeneic LTx. IRF-1 was induced in liver grafts immediately after reperfusion in both human and mouse LTx. IRF-1 contributed significantly to I/R injury as IRF-1 KO grafts displayed much less damage assessed by serum alanine aminotransferase (ALT) and histology. In vitro, IRF-1 regulated both constitutive and induced expression of IL-15, as well as IL-15Rα mRNA expression in murine hepatocytes and liver dendritic cells (DC). Specific knockdown of IRF-1 in human primary hepatocytes gave similar results. In addition, we identified hepatocytes as the major producer of soluble IL-15/IL-15Rα complexes in the liver. IRF-1 KO livers had significantly reduced NK, NKT and CD8+T cell numbers, while rIL-15/IL-15Rα restored these immune cells, augmented cytotoxic effector molecules, promoted systemic inflammatory responses, and exacerbated liver injury in IRF-1 KO graft recipients. These results indicate that IRF-1 promotes LTx I/R injury via hepatocyte IL-15/IL-15Rα production and suggest that targeting IRF-1 and IL-15/IL-15Rα may be effective in reducing I/R injury associated with LTx. PMID:25964490

  9. Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice.

    Science.gov (United States)

    Delima, Roheeth D; Chua, Anita C G; Tirnitz-Parker, Janina E E; Gan, Eng K; Croft, Kevin D; Graham, Ross M; Olynyk, John K; Trinder, Debbie

    2012-08-01

    Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice. Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model

  10. 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. Copyright © 2016. Published by Elsevier Ireland Ltd.

  11. Barley Sprouts Extract Attenuates Alcoholic Fatty Liver Injury in Mice by Reducing Inflammatory Response

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    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.

  12. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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    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.

  13. 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.

  14. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

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    Qin eDong

    2015-10-01

    Full Text Available Heshouwu (HSW, the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions,particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA and chenodeoxycholic acid (CDCA, taurocholic acid (TCA, glycocholic acid (GCA, glycochenodeoxycholic acid (GCDCA, deoxycholic acid (DCA, glycodeoxycholic acid (GDCA, ursodeoxycholic acid (UDCA and hyodeoxycholic acid (HDCA in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW .

  15. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

    Science.gov (United States)

    Dong, Qin; Li, Na; Li, Qi; Zhang, Cong-En; Feng, Wu-Wen; Li, Guang-Quan; Li, Rui-Yu; Tu, Can; Han, Xue; Bai, Zhao-Fang; Zhang, Ya-Ming; Niu, Ming; Ma, Zhi-Jie; Xiao, Xiao-He; Wang, Jia-Bo

    2015-01-01

    Heshouwu (HSW), the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions, particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs) were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA) and chenodeoxycholic acid (CDCA), taurocholic acid (TCA), glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), ursodeoxycholic acid (UDCA), and hyodeoxycholic acid (HDCA) in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA) was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW. PMID:26483689

  16. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model

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    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.

  17. Liver regeneration - The best kept secret: A model of tissue injury response

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    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.

  18. Inhibition of Histone Deacetylase by Butyrate Protects Rat Liver from Ischemic Reperfusion Injury

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    Jie Sun

    2014-11-01

    Full Text Available We showed previously that pretreatment of butyrate, which is an endogenous histone deacetylase (HDAC inhibitor normally fermented from undigested fiber by intestinal microflora, seriously alleviated ischemia reperfusion (I/R-induced liver injury by inhibiting the nuclear factor κB (NF-κB pathway. The goal of this study was to investigate the effect of butyrate administrated at the onset of ischemia for HDAC inhibition in hepatic I/R injury. Sprague Dawley rats were subjected to warm ischemia for 60 min followed by 6 and 24 h of reperfusion. Butyrate was administrated at the onset of ischemia. Liver injury was evaluated by serum levels of aminotransferase, inflammatory factors, and histopathology. The levels of acetylated histone H3 and expression of heat shock protein (Hsp 70 were measured by Western blot. After reperfusion, the levels of acetylated histone H3 significantly decreased. Butyrate treatment markedly prevented the reduction of acetylated histone H3 and upregulated the expression of Hsp70, thereby reducing liver injury. Our study demonstrated that I/R resulted in marked reduction of histone acetylation; butyrate exerted a great hepatoprotective effect through HDAC inhibition and Hsp70 induction.

  19. Renoprotective effect of crocin following liver ischemia/ reperfusion injury in Wistar rats.

    Science.gov (United States)

    Mard, Seyyed Ali; Akbari, Ghaidafeh; Mansouri, Esrafil; Parsanahad, Mahdi

    2017-10-01

    The objectives of the current study were to evaluate the effects of hepatic ischemia/reperfusion (IR) injury on the activity of antioxidant enzymes, biochemical factors, and histopathological changes in rat kidney, and to investigate the effect of crocin on IR-related changes. Thirty-two male Wistar rats were randomly allocated into four groups (n=8). They were sham-operated, IR, crocin pre-treatment, and crocin pretreatment+IR groups. Sham-operated and Crocin pre-treatment groups received normal saline (N/S, 2 ml/day) and crocin (200 mg/kg) for seven consecutive days intraperitoneally (IP), respectively, then rats underwent laparotomy, only. IR and crocin pretreatment+IR groups received N/S and crocin with the same dose, time, and route, respectively, then rats underwent partial (70%) ischemia for 45 min that was followed by reperfusion for 60 min. At the end of the experiment, kidney specimens were taken for histopathological and antioxidant evaluations and also blood samples were obtained for biochemical analysis. The results of the present study showed that crocin pre-treatment significantly increased the activity of antioxidants, decreased the serum levels of liver enzymes and blood urea nitrogen following IR-induced hepatic injury. Crocin also ameliorated kidney's histopathological disturbance beyond IR-induced hepatic injury. Crocin as an antioxidant agent protected renal insult following liver IR injury by increasing the activity of antioxidant enzymes, reducing serum levels of liver enzymes, and improving histopathological changes.

  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. Macrophage migration inhibitory factor contributes to ethanol-induced liver injury by mediating cell injury, steatohepatitis and steatosis

    Science.gov (United States)

    Barnes, Mark A.; McMullen, Megan R.; Roychowdhury, Sanjoy; Pisano, Sorana G.; Liu, Xiuli; Stavitsky, Abram B.; Bucala, Richard; Nagy, Laura E.

    2012-01-01

    MIF, a multi-potent protein that exhibits both cytokine and chemotactic properties, is expressed by many cell types, including hepatocytes and non-parenchymal cells. We hypothesized that MIF is a key contributor to liver injury after ethanol exposure. Female C57BL/6 or MIF−/− mice were fed an ethanol-containing liquid diet or pair-fed control diet for 4 (11% total kcal; early response) or 25 (32% kcal; chronic response) days. Expression of MIF mRNA was induced at both 4d and 25d of ethanol feeding. After chronic ethanol, hepatic triglycerides and plasma ALT and AST were increased in wild-type, but not MIF−/−, mice. In order to understand the role of MIF in chronic ethanol-induced liver injury, we investigated the early response of wild-type and MIF−/− to ethanol. Ethanol feeding for 4d increased apoptosis of hepatic macrophages and activated complement in both wild-type and MIF−/− mice. However, TNFα expression was increased only in wild-type mice. This attenuation of TNF-α expression was associated with fewer F4/80+ macrophages in liver of MIF−/− mice. After 25d of ethanol feeding, chemokine expression was increased in wild-type mice, but not MIF−/− mice. Again, this protection was associated with decreased F4/80+ cells in MIF−/− mice after ethanol feeding. Chronic ethanol feeding also sensitized wild-type, but not MIF−/−, mice to lipopolysaccharide, increasing chemokine expression and monocyte recruitment into the liver. Conclusion Taken together, these data indicate that MIF is an important mediator in the regulation of chemokine production and immune cell infiltration in the liver during ethanol feeding and promotes ethanol-induced steatosis and hepatocyte damage. PMID:23174952

  2. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats

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    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.

  3. Alleviation of Ischemia-Reperfusion Injury in Liver Steatosis by Augmenter of Liver Regeneration Is Attributed to Antioxidation and Preservation of Mitochondria.

    Science.gov (United States)

    Weng, Junhua; Li, Wen; Jia, Xiaowei; An, Wei

    2017-10-01

    Fatty liver is one of the major impediments to liver surgery and liver transplantation because steatotic hepatocytes are more susceptible to ischemia-reperfusion injury (IRI). In this study, the effects of augmenter of liver regeneration (ALR) on hepatic IRI in steatotic mice were investigated. In vivo, liver steatosis of mice was induced by feeding a methionine-choline-deficient diet for 2 weeks. Three days before hepatic partial warm IRI, mice were transfected with the ALR-containing adenovirus. In an in vitro study, the protective effect of ALR on steatotic HepG2 cells was analyzed after hypoxia/reoxygenation (HR) treatment. The transfection of the ALR gene into steatotic mice attenuated liver injury, inhibiting hepatic oxidative stress, increasing antioxidation capacities, promoting liver regeneration, and consequently suppressing cell apoptosis/death. Furthermore, resistance to HR injury was notably increased in ALR-transfected cells compared with the vector-transfected cells. The HR-induced rise in the mitochondrial reactive oxygen species was reduced, and cellular antioxidant activities were enhanced. The ALR transfection prevented cells from apoptosis, which can be attributed to the preservation of the mitochondrial membrane potential, enhancement of oxygen consumption rate and production of adenosine triphosphate. ALR protects steatotic hepatocytes from IRI by attenuating oxidative stress and mitochondrial dysfunction, as well as improving antioxidant effect. ALR may be used as a potential therapeutic agent when performing surgery and transplantation of steatotic liver.

  4. Vismodegib suppresses TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis.

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    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.

  5. Abrogation of carbon tetrachloride-induced hepatotoxicity in Sprague-Dawley rats by Ajwa date fruit extract through ameliorating oxidative stress and apoptosis.

    Science.gov (United States)

    Elsadek, Bakheet; El-Sayed, El-Sayed; Mansour, Ahmed; Elazab, Ayman

    2017-11-01

    Ajwa, a variety of date palme Phoenix dactylifera L., has long been used and considered as one of the most popular fruits in the North Africa and Middle East region. For Muslims this fruit is of religious importance and is mentioned several times in Quran. Besides being a part of the Arabian essential diet, dates have been used traditionally for number of complications. This study aimed to evaluate the possible potential of Ajwa date extract to guard against carbon tetrachloride (CCL4)-induced liver damage in rats. Adult male Sprague-Dawley rats were given Ajwa date extract and silymarin (a standard reference drug) at doses of 300 & 50mg/kg, p.o., respectively for 2 weeks before CCl4 (2 ml/kg, s. c., twice weekly for 8 consecutive weeks), and concomitantly administered with CCl4 for 8 consecutive weeks. Like silymarin, Ajwa date extract produced significant decrease in serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total cholesterol, triglycerides (TG) and LDL-cholesterol as well as lipid peroxides measured as malondialdehyde (MDA), hydroxyproline and caspase-3 contents of liver tissue with marked increase in serum albumin, HDL-cholesterol and reduced glutathione (GSH) content as well as enzyme activities of super oxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST). In conclusion, Ajwa date extract afforded significant protection against CCl4-induced hepatocellular injury; an effect that could be attributed to its antioxidant, antiapoptotic and antifibrotic activities.

  6. Evaluation of the liver injury unit scoring system to predict survival in a multinational study of pediatric acute liver failure.

    Science.gov (United States)

    Lu, Brandy R; Zhang, Song; Narkewicz, Michael R; Belle, Steven H; Squires, Robert H; Sokol, Ronald J

    2013-05-01

    To examine the predictive value of the Liver Injury Units (LIU) and admission values (aLIU) of bilirubin and prothrombin time and international normalized ratio scores in a large cohort from the Pediatric Acute Liver Failure (PALF) Study Group, a multinational prospective study. LIU and aLIU scores were calculated for 461 and 579 individuals, respectively, enrolled in the PALF study from 1999 to 2008. Receiver operator characteristic curves were used to evaluate the scores with respect to survival without liver transplantation (LT), death, or LT by 21 days after enrollment. At 21 days, 50.3% of participants were alive without LT, 36.2% underwent LT, and 13.4% died. The c-indices for transplant-free survival were 0.81 based on the LIU score with the international normalized ratio (95% CI, 0.78-0.85) and 0.76 based on the aLIU score (95% CI, 0.72-0.79). The LIU score predicted LT better than it predicted death (c-index for LT 0.84, c-index for death 0.76). Based on data from a large, multicenter cohort of patients with PALF, the LIU score was a better predictor of transplant-free survival than was the aLIU score. The LIU score might be a helpful, dynamic tool to predict clinical outcomes in patients with PALF. Copyright © 2013 Mosby, Inc. All rights reserved.

  7. Roles of the Hemostatic System and Neutrophils in Liver Injury From Co-exposure to Amiodarone and Lipopolysaccharide

    Science.gov (United States)

    Ganey, Patricia E.

    2013-01-01

    It has been demonstrated that co-treatment of rats with amiodarone (AMD) and bacterial lipopolysaccharide (LPS) produces idiosyncrasy-like liver injury. In this study, the hypothesis that the hemostatic system and neutrophils contribute to AMD/LPS-induced liver injury was explored. Rats were treated with AMD (400mg/kg, ip) or vehicle and 16h later with LPS (1.6×106 endotoxin units/kg, iv) or saline (Sal). AMD did not affect the hemostatic system by itself but significantly potentiated LPS-induced coagulation activation and fibrinolysis impairment. Increased hepatic fibrin deposition and subsequent hypoxia were observed only in AMD/LPS-treated animals, starting before the onset of liver injury. Administration of anticoagulant heparin abolished AMD/LPS-induced hepatic fibrin deposition and reduced AMD/LPS-induced liver damage. Polymorphonuclear neutrophils (PMNs) accumulated in liver after treatment with LPS or AMD/LPS, but PMN activation was only observed in AMD/LPS-treated rats. Rabbit anti-rat PMN serum, which reduced accumulation of PMNs in liver, prevented PMN activation and attenuated AMD/LPS-induced liver injury in rats. PMN depletion did not affect hepatic fibrin deposition. Anticoagulation prevented PMN activation without affecting PMN accumulation. In summary, both the hemostatic system alteration and PMN activation contributed to AMD/LPS-induced liver injury in rats, in which fibrin deposition was critical for the activation of PMNs. PMID:23912913

  8. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury

    OpenAIRE

    Amersi, Farin; Buelow, Roland; Kato, Hirohisa; Ke, Bibo; Coito, Ana J.; Shen, Xiu-Da; Zhao, Delai; Zaky, Joseph; Melinek, Judy; Lassman, Charles R.; Kolls, Jay K.; Alam, J.; Ritter, Thomas; Volk, Hans-Dieter; Farmer, Douglas G.

    1999-01-01

    We examined the effects of upregulation of heme oxygenase-1 (HO-1) in steatotic rat liver models of ex vivo cold ischemia/reperfusion (I/R) injury. In the model of ischemia/isolated perfusion, treatment of genetically obese Zucker rats with the HO-1 inducer cobalt protoporphyrin (CoPP) or with adenoviral HO-1 (Ad-HO-1) significantly improved portal venous blood flow, increased bile production, and decreased hepatocyte injury. Unlike in untreated rats or those pretreated with the HO-1 inhibito...

  9. GRPR antagonist protects from drug-induced liver injury by impairing neutrophil chemotaxis and motility.

    Science.gov (United States)

    Czepielewski, Rafael S; Jaeger, Natália; Marques, Pedro E; Antunes, Maísa M; Rigo, Maurício M; Alvarenga, Débora M; Pereira, Rafaela V; da Silva, Rodrigo D; Lopes, Tiago G; da Silva, Vinícius D; Porto, Bárbara N; Menezes, Gustavo B; Bonorino, Cristina

    2017-04-01

    Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Papadimas, George K.; Kondyli, Vasiliki G.; Kourentzi, Kalliopi T.; Hereti, Rosa I.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi 151 27, Attiki (Greece)

    2004-06-01

    The hepatoprotective effect of putrescine against cadmium liver injury was investigated. Male Wistar rats were injected with a dose of cadmium (6.5 mg CdCl{sub 2}/kg bodyweight, intraperitoneally). Normal saline (group I) or putrescine (300 {mu}mol/kg bodyweight; group II) were injected 2, 5 and 8 h later. A number of animals of both groups were killed 0, 12, 16, 24, 48 or 60 h after cadmium intoxication. Liver tissue was histologically assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay for hepatocytes and nonparenchymal liver cells. The discrimination between hepatic cell subpopulations was achieved histochemically. The mitotic index in hematoxylin-eosin-stained sections and by the immunochemical detection of Ki67 nuclear antigen, {sup 3}H-thymidine incorporation into hepatic DNA, and hepatic thymidine kinase activity were all used as indices of liver regeneration. Both hepatocyte apoptosis and liver necrosis evolved in a biphasic temporal pattern. Nonparenchymal cell apoptosis and peliosis hepatis evolved in a monophasic pattern and were correlated closely. Putrescine administration totally reversed liver necrosis and hepatocyte apoptosis. The time profile of nonparenchymal apoptosis was altered and peliosis hepatis was also totally attenuated. In conclusion, putrescine protected hepatocytes and modulated the mechanism of cadmium-induced acute hepatotoxicity. (orig.)

  11. Curcumin Attenuates N-Nitrosodiethylamine-Induced Liver Injury in Mice by Utilizing the Method of Metabonomics.

    Science.gov (United States)

    Qiu, Peiyu; Sun, Jiachen; Man, Shuli; Yang, He; Ma, Long; Yu, Peng; Gao, Wenyuan

    2017-03-08

    N-Nitrosodiethylamine (DEN) exists as a food additive in cheddar cheese, processed meats, beer, water, and so forth. It is a potent hepatocarcinogen in animals and humans. Curcumin as a natural dietary compound decreased DEN-induced hepatocarcinogenesis in this research. According to the histopathological examination of liver tissues and biomarker detection in serum and livers, it was demonstrated that curcumin attenuated DEN-induced hepatocarcinogenesis through parts of regulating the oxidant stress enzymes (T-SOD and CAT), liver function (ALT and AST) and LDHA, AFP level, and COX-2/PGE2 pathway. Furthermore, curcumin attenuated metabolic disorders via increasing concentration of glucose and fructose, and decreasing levels of glycine and proline, and mRNA expression of GLUT1, PKM and FASN. Docking study indicated that curcumin presented strong affinity with key metabolism enzymes such as GLUT1, PKM, FASN and LDHA. There were a number of amino acid residues involved in curcumin-targeting enzymes of hydrogen bonds and hydrophobic interactions. All in all, curcumin exhibited a potent liver protective agent inhibiting chemically induced liver injury through suppressing liver cellular metabolism in the prospective application.

  12. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

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

    DEFF Research Database (Denmark)

    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 conclusion, an increase in AFP was strongly associated with a favorable outcome in patients with acetaminophen-induced liver injury. AFP may be useful as a supplement to existing prognostic criteria. We suggest that the introduction of highly sensitive EIAs for the detection of AFP will require...

  14. Adderall Induced Acute Liver Injury: A Rare Case and Review of the Literature

    OpenAIRE

    Vanga, Rohini R.; Bal, Bikram; Olden, Kevin W.

    2013-01-01

    Adderall (dextroamphetamine/amphetamine) is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD) and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the...

  15. Perioperative risk factors for acute kidney injury after liver resection surgery: an historical cohort study.

    Science.gov (United States)

    Tomozawa, Arisa; Ishikawa, Seiji; Shiota, Nobuhiro; Cholvisudhi, Phantila; Makita, Koshi

    2015-07-01

    This study aimed to identify the incidence and risk factors for acute kidney injury (AKI) after liver resection surgery and to clarify the relationship between postoperative AKI and outcome. We conducted a historical cohort study of patients who underwent liver resection surgery with sevoflurane anesthesia from January 2004 to October 2011. Acute kidney injury was diagnosed based on the Acute Kidney Injury Network classification within 72 hr after the surgery. Patient data, surgical and anesthetic data, and laboratory data were extracted manually from the patients' electronic charts. Multivariable logistic regression analysis was used to identify perioperative risk factors for postoperative AKI. Acute kidney injury was diagnosed in 78 of 642 patients (12.1%; 95% confidence interval [CI]: 9.7 to 14.9). Multivariable analysis showed an independent association between postoperative AKI and preoperative estimated glomerular filtration rate (adjusted odds ratio [aOR] 0.74; 95% CI: 0.64 to 0.85), preoperative hypertension (aOR 2.10; 95% CI: 1.11 to 3.97), and intraoperative red blood cell transfusion (aOR 1.04; 95% CI: 1.01 to 1.07). Development of AKI within 72 hr after liver resection surgery was associated with increased hospital mortality, prolonged length of stay, and increased rates of mechanical ventilation, reintubation, and renal replacement therapy. Perioperative risk factors for AKI after liver resection surgery are similar to those established for other surgical procedures. Further studies are needed to establish causality and to determine whether interventions on modifiable risk factors can reduce the incidence of postoperative AKI and improve patient outcome. This study was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN 000008089).

  16. Protective Effect of Ghrelin on Sodium Valproate-induced Liver Injury in Rat

    OpenAIRE

    Sadeghi Niaraki, Mandana; Nabavizadeh, Fatemeh; Vaezi, Gholam H.; Alizadeh, Ali M.; Nahrevanian, Hossein; Moslehi, Azam; Azizian, Saleh

    2013-01-01

    Ghrelin is a peptide that has protective effects on many tissues injury. It has anti-inflammatory and anti-oxidant effects. Sodium valproate is widely used anticonvuisant and anti-depression drug with hepatotoxic side effects. The aim of this study was to evaluated the protective role of ghrelin in liver toxicity due to sodium valproate overdose. Eighteen rats were used in this study and divided in to three groups, containing: control, sodium valproate, and sodium valproate and ghrelin groups...

  17. Protective effect of ghrelin on sodium Valproate-induced liver injury in rat

    OpenAIRE

    Sadeghi, Niaraki; Nabavizadeh, Fatemeh; Vaezi, Gholam; Alizadeh, Ali; Nahrevanian, Hossein; Moslehi, Azam; Azizian, Saleh

    2013-01-01

    Ghrelin is a peptide that has protective effects on many tissues injury. It has anti-inflammatory and anti-oxidant effects. Sodium valproate is widely used anticonvuisant and anti-depression drug with hepatotoxic side effects. The aim of this study was to evaluated the protective role of ghrelin in liver toxicity due to sodium valproate overdose. Eighteen rats were used in this study and divided in to three groups, containing: control, sodium valproate, and sodium valproate and ghrelin groups...

  18. IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury

    Directory of Open Access Journals (Sweden)

    Sang Jun Han

    2018-04-01

    Full Text Available Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2 is a major producer of mitochondrial NADPH, required for glutathione (GSH-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx and glutathione reductase (GR. Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR-associated mitochondrial injury using Idh2-knockout (Idh2-/- mice and wild-type (Idh2+/+ littermates. Mice were subjected to either 60 min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino-2-oxoethyl triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant. HIR induced severe histological and functional damages of liver in both Idh2+/+ mice and Idh2-/- mice and those damages were more severe in Idh2-/- mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2-/- mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2-/- mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Keywords: Liver ischemia, Mitochondria, Oxidative stress, Apoptosis, IDH2

  19. Adderall induced acute liver injury: a rare case and review of the literature.

    Science.gov (United States)

    Vanga, Rohini R; Bal, Bikram; Olden, Kevin W

    2013-01-01

    Adderall (dextroamphetamine/amphetamine) is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD) and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the case of a 55-year-old woman who developed acute liver failure during the treatment of ADHD with Adderall. She presented to the emergency room with worsening abdominal pain, malaise, and jaundice requiring hospitalization. She had a past history of partial hepatic resection secondary to metastasis from colon cancer which was under remission at the time of presentation. She recovered after intensive monitoring and conservative management. Adderall should be used carefully in individuals with underlying liver conditions.

  20. Adderall Induced Acute Liver Injury: A Rare Case and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Rohini R. Vanga

    2013-01-01

    Full Text Available Adderall (dextroamphetamine/amphetamine is a widely prescribed medicine for the treatment of attention-deficit/hyperactivity disorder (ADHD and is considered safe with due precautions. Use of prescribed Adderall without intention to overdose as a cause of acute liver injury is extremely rare, and to our knowledge no cases have been reported in the English literature. Amphetamine is an ingredient of recreational drugs such as Ecstacy and is known to cause hepatotoxicity. We describe here the case of a 55-year-old woman who developed acute liver failure during the treatment of ADHD with Adderall. She presented to the emergency room with worsening abdominal pain, malaise, and jaundice requiring hospitalization. She had a past history of partial hepatic resection secondary to metastasis from colon cancer which was under remission at the time of presentation. She recovered after intensive monitoring and conservative management. Adderall should be used carefully in individuals with underlying liver conditions.

  1. Drugs of abuse and addiction: A slippery slope toward liver injury.

    Science.gov (United States)

    Roy, Dijendra Nath; Goswami, Ritobrata

    2016-08-05

    Substances of abuse induce alteration in neurobehavioral symptoms, which can lead to simultaneous exacerbation of liver injury. The biochemical changes of liver are significantly observed in the abused group of people using illicit drugs or drugs that are abused. A huge amount of work has been carried out by scientists for validation experiments using animal models to assess hepatotoxicity in cases of drugs of abuse. The risk of hepatotoxicity from these psychostimulants has been determined by different research groups. Hepatotoxicity of these drugs has been recently highlighted and isolated case reports always have been documented in relation to misuse of the drugs. These drugs induce liver toxicity on acute or chronic dose dependent process, which ultimately lead to liver damage, acute fatty infiltration, cholestatic jaundice, liver granulomas, hepatitis, liver cirrhosis etc. Considering the importance of drug-induced hepatotoxicity as a major cause of liver damage, this review emphasizes on various drugs of abuse and addiction which induce hepatotoxicity along with their mechanism of liver damage in clinical aspect as well as in vitro and in vivo approach. However, the mechanisms of drug-induced hepatotoxicity is dependent on reactive metabolite formation via metabolism, modification of covalent bonding between cellular components with drug and its metabolites, reactive oxygen species generation inside and outside of hepatocytes, activation of signal transduction pathways that alter cell death or survival mechanism, and cellular mitochondrial damage, which leads to alteration in ATP generation have been notified here. Moreover, how the cytokines are modulated by these drugs has been mentioned here. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Beneficial effects of apple peel polyphenols on vascular endothelial dysfunction and liver injury in high choline-fed mice.

    Science.gov (United States)

    Jia, Mengfan; Ren, Daoyuan; Nie, Yan; Yang, Xingbin

    2017-03-22

    This study was designed to investigate the preventive effects of Red Fuji apple peel polyphenolic extract (APP) on vascular endothelial dysfunction and liver injury in mice fed a high choline diet. The mice were fed 3% dietary choline in drinking water for 8 weeks and displayed vascular dysfunction and liver damage (p polyphenolic extract from apple peel might be regarded as a preventive and therapeutic product for the amelioration of HC diet-induced vascular dysfunction and hepatic injury.

  3. Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Xin Liu

    2017-04-01

    Full Text Available The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

  4. Collagen, fibrinogen and thrombin biological addesive is effective in treating experimental liver injuries

    Directory of Open Access Journals (Sweden)

    FREDERICO MICHELINO DE OLIVEIRA

    Full Text Available ABSTRACT Objective : to evaluate the effectiveness of a collagen-based adhesive associated with fibrinogen and thrombin in experimental liver injury in rats. Methods : the study included 30 Wistar rats randomly divided into three groups: A, B and C. All underwent standard liver traumatic injury. In group A the lesion was treated with the adhesive; in group B, with conventional absorbable suture; and in group C, there was no treatment. We analyzed the time of hemostasis, mortality, occurrence of adhesions and any histological changes. Results : there was no statistical difference in relation to mortality (p = 0.5820. The group treated with the adhesive showed the lowest hemostasis times (p = 0.0573, odds ratio 13.5 and lower incidence of adhesions (p = 0.0119. Microscopic histological alterations of Groups A and B were similar, with foreign body granuloma formation separating the adhesive material or the suture from the hepatic stroma. Conclusion : the adhesive of collagen associated with fibrinogen and thrombin was effective in the treatment of experimental hepatic injury, providing a lower incidence of adhesions between the liver and surrounding structures.

  5. The collagen, fibrinogen and thrombin biological adhesive is effective in treating experimental liver injuries

    Directory of Open Access Journals (Sweden)

    Frederico Michelino de Oliveira

    Full Text Available ABSTRACT Objective: to evaluate the effectiveness of an collagen-based adhesive associated with fibrinogen and thrombin in experimental liver injuries in rats. Methods: we randomly divided 30 Wistar rats into three groups: A, B and C. All underwent a standard liver traumatic injury. In group A, the lesion was treated with the adhesive; in group B, with conventional, absorbable suture; group C received no treatment. We analyzed the time of hemostasis, mortality, occurrence of adhesions and any histological changes. Results: there was no statistical difference in relation to mortality (p=0.5820. The adhesive treated group showed the lowest hemostasis times (p=0.0573, odds ratio 13.5 and lower incidence of adhesions (p=0.0119. The histological alterations of the Groups A and B were similar, with foreign body granuloma formation separating the adhesive material and the hepatic stroma suture. Conclusion: the collagen adhesive associated with fibrinogen and thrombin was effective in treating experimental hepatic injury, providing a lower incidence of adhesions between the liver and surrounding structures.

  6. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Tong Zhou

    2017-01-01

    Full Text Available Chronic excessive alcohol consumption (more than 40–80 g/day for males and more than 20–40 g/day for females could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT, aspartate transaminase (AST, hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

  7. Avermectin induced liver injury in pigeon: mechanisms of apoptosis and oxidative stress.

    Science.gov (United States)

    Zhu, Wen-Jun; Li, Ming; Liu, Ci; Qu, Jian-Ping; Min, Ya-Hong; Xu, Shi-Wen; Li, Shu

    2013-12-01

    Extensive use of avermectin (AVM) can result in environment pollution, and it is important to evaluate the potential impact this antibiotic has on ecological systems. Few published literatures have discussed the liver injury mechanisms induced by AVM on birds. In this study, pigeons were exposed to feed containing AVM (0, 20, 40 and 60 mg/kg diet) for 30, 60, 90 days respectively. The results showed that AVM increased the number of apoptosis and the expression level of caspase-3, 8, fas mRNA in the liver of pigeons. Ultrastructural alterations, including mitochondrial damage and chromatin aggregation, become severe with increase exposure dose. Exposure to AVM induced significant changes in antioxidant enzyme {superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px)} activities and malondialdehyde (MDA) content, augmented protein carbonyl (PCO) content and DNA-protein crosslink (DPC) coefficient, in a concentration-dependent manner in the liver of pigeons. Our results show that AVM has toxic effect in pigeon liver, and the mechanism of injury caused by AVM is closely related to apoptosis and oxidative stress. © 2013 Elsevier Inc. All rights reserved.

  8. Metabolomic approaches in the discovery of potential urinary biomarkers of drug-induced liver injury (DILI).

    Science.gov (United States)

    Araújo, Ana Margarida; Carvalho, Márcia; Carvalho, Félix; Bastos, Maria de Lourdes; Guedes de Pinho, Paula

    2017-09-01

    Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs. In this sense, metabolomics has been increasingly playing an important role in the discovery of biomarkers of liver damage, although the characterization of the mechanisms of toxicity induced by xenobiotics remains a huge challenge. These new-generation biomarkers will offer obvious benefits for the pharmaceutical industry, regulatory agencies, as well as a personalized clinical follow-up of patients, upon validation and translation into clinical practice or approval for routine use. This review describes the current status of the metabolomics applied to the early diagnosis and prognosis of DILI and in the discovery of new potential urinary biomarkers of liver injury.

  9. Grape seed proanthocyanidin protects liver against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress.

    Science.gov (United States)

    Xu, Zhen-Chao; Yin, Jie; Zhou, Bo; Liu, Yu-Ting; Yu, Yue; Li, Guo-Qiang

    2015-06-28

    To explore the effect of grape seed proanthocyanidin (GSP) in liver ischemia/reperfusion (IR) injury and alleviation of endoplasmic reticulum stress. Male Sprague-Dawley rats (220-250 g) were divided into three groups, namely, sham, IR, and GSP groups (n = 8 each). A liver IR (70%) model was established and reperfused for 6 h. Prior to reperfusion, the GSP group was administered with GSP (100 mg/kg) for 15 d, and liver histology was then investigated. Serum aminotransferase and inflammatory mediators coupled with superoxide dismutase and methane dicarboxylic aldehyde were detected. Western blot was conducted to analyze the expression of glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, activating transcription factor-4, inositol-requiring enzyme-1, procaspase-12, and nuclear factor-κb. Apoptotic cells were detected by TUNEL staining. The serum aminotransferase, apoptotic cells, and Suzuki scores decreased in the GSP group compared with the IR group (Ps endoplasmic reticulum stress through regulation of related signaling pathways to protect the liver against IR injury.

  10. Dendrobium huoshanense polysaccharide prevents ethanol-induced liver injury in mice by metabolomic analysis.

    Science.gov (United States)

    Wang, Xiao-Yu; Luo, Jian-Ping; Chen, Rui; Zha, Xue-Qiang; Pan, Li-Hua

    2015-01-01

    The prevalence of alcohol consumption has increased in modern dietary life and alcoholic liver injury can follow. Dendrobium huoshanense polysaccharide (DHP) is a homogeneous polysaccharide isolated from Dendrobium huoshanense, which possesses hepatoprotection function. In this study, we investigated the metabolic profiles of serum and liver tissues extracts from control, ethanol-treated and DHP\\ethanol-treated mice using a UHPLC/LTQ Orbitrap XL MS-based metabolomics approach. Our results indicated that DHP alleviated early steatosis and inflammation in liver histology and the metabolomic analysis of serum and hepatic tissue revealed that first, ethanol treatment mainly altered phosphatidylcholines (PCs) including PC (13:0) and phosphocholine, arachidonic acid metabolites including 20-ethyl PGF2α and amino acids including L-Proline; Second, DHP supplementation ameliorated the altered metabolic levels particularly involved in phosphocholine and L-Proline. These data suggested that DHP might restore the perturbed metabolism pathways by ethanol exposure to prevent the progression of alcoholic liver injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Hepatoprotective Effects of Panus giganteus (Berk. Corner against Thioacetamide- (TAA- Induced Liver Injury in Rats

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    Wei-Lun Wong

    2012-01-01

    Full Text Available Panus giganteus, a culinary and medicinal mushroom consumed by selected indigenous communities in Malaysia, is currently being considered for large scale cultivation. This study was undertaken to investigate the hepatoprotective effects of P. giganteus against thioacetamide- (TAA- induced liver injury in Sprague-Dawley rats. The rats were injected intraperitoneally with TAA thrice weekly and were orally administered freeze-dried fruiting bodies of P. giganteus (0.5 or 1 g/kg daily for two months, while control rats were given vehicle or P. giganteus only. After 60 days, rats administered with P. giganteus showed lower liver body weight ratio, restored levels of serum liver biomarkers and oxidative stress parameters comparable to treatment with the standard drug silymarin. Gross necropsy and histopathological examination further confirmed the hepatoprotective effects of P. giganteus. This is the first report on hepatoprotective effects of P. giganteus. The present study showed that P. giganteus was able to prevent or reduce the severity of TAA-induced liver injury.

  12. Protective Effect of Ghrelin on Sodium Valproate-induced Liver Injury in Rat

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    Sadeghi Niaraki, Mandana

    2013-02-01

    Full Text Available Ghrelin is a peptide that has protective effects on many tissues injury. It has anti-inflammatory and anti-oxidant effects. Sodium valproate is widely used anticonvuisant and anti-depression drug with hepatotoxic side effects. The aim of this study was to evaluated the protective role of ghrelin in liver toxicity due to sodium valproate overdose. Eighteen rats were used in this study and divided in to three groups, containing: control, sodium valproate, and sodium valproate and ghrelin groups. Nitric oxide (NO, prostaglandin E2 (PGE2 and hepatic enzymes AST (aspartate aminotransferase and ALT (alanine aminotransferase, were assessed and histologic study of liver were performed as indicators of liver damage following sodium valproate toxicity. This study showed the ghrelin decreased ALT and AST to the normal level. Our results show that ghrelin significantly increased NO metabolites and decreased PGE2 level comparison with sodium valproate group, but had no significant change compared to the control group. we showed that ghrelin administration inhibited liver injury in rats due to sodium valproate toxicity.

  13. Dietary Supplementation with Lactobacillus casei Alleviates Lipopolysaccharide-Induced Liver Injury in a Porcine Model

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    Di Zhao

    2017-11-01

    Full Text Available This study aims to determine whether Lactobacillus casei (L. casei could relieve liver injury in piglets challenged with lipopolysaccharide (LPS. Piglets were randomly allocated into one of the three groups: control, LPS, and L. casei. The control and LPS groups were fed a corn- and soybean meal-based diet, whereas the L. casei group was fed the basal diet supplemented with 6 × 106 cfu/g L. casei. On Day 31 of the trial, piglets in the LPS and L. casei groups received intraperitoneal administration of LPS (100 µg/kg body weight, while the control group received the same volume of saline. Blood and liver samples were collected for analysis. Results showed that L. casei supplementation decreased the feed/gain ratio (p = 0.027 and diarrhea incidence (p < 0.001, and attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, LPS challenge dramatically increased glutamyl transpeptidase activity (p = 0.001 in plasma as well as the concentrations of Interleukin 6 (IL-6 (p = 0.048, Tumor necrosis factor-alpha (TNF-α (p = 0.041, and Malondialdehyde (MDA (p = 0.001 in the liver, while decreasing the hepatic SOD activity. LPS also increased (p < 0.05 the mRNA levels for IL-6, IL-8, TNF-α, Toll-like receptors 4 (TLR4, Nuclear factor κB (NF-κB and Heat shock protein 70 (HSP70 in the liver. The adverse effects of LPS challenge were ameliorated by L. casei supplementation. In conclusion, dietary L. casei alleviates LPS-induced liver injury via reducing pro-inflammatory cytokines and increasing anti-oxidative capacity.

  14. 1-methylmalate from camu-camu (Myrciaria dubia) suppressed D-galactosamine-induced liver injury in rats.

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    Akachi, Toshiyuki; Shiina, Yasuyuki; Kawaguchi, Takumi; Kawagishi, Hirokazu; Morita, Tatsuya; Sugiyama, Kimio

    2010-01-01

    To evaluate the protective effects of fruit juices against D-galactosamine (GalN)-induced liver injury, lyophilized fruit juices (total 12 kinds) were fed to rats for 7 d, and then we evoked liver injury by injecting GalN. The juice of camu-camu (Myrciaria dubia) significantly suppressed GalN-induced liver injury when the magnitude of liver injury was assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, although some other juices (acerola, dragon fruit, shekwasha, and star fruit) also tended to have suppressive effects. An active compound was isolated from camu-camu juice by solvent fractionation and silica gel column chromatography. The structure was determined to be 1-methylmalate. On the other hand, malate, 1,4-dimethylmalate, citrate, and tartrate had no significant effect on GalN-induced liver injury. It is suggested that 1-methylmalate might be a rather specific compound among organic acids and their derivatives in fruit juices in suppressing GalN-induced liver injury.

  15. Protective effect of Trillium tschonoskii saponin on CCl4-induced acute liver injury of rats through apoptosis inhibition.

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    Wu, Hao; Qiu, Yong; Shu, Ziyang; Zhang, Xu; Li, Renpeng; Liu, Su; Chen, Longquan; Liu, Hong; Chen, Ning

    2016-12-01

    To explore hepatoprotective role and underlying mechanisms of Trillium tschonoskii Maxim (TTM), 36 rats were randomly divided into control, CCl4-induced liver injury model, and biphenyl dimethyl dicarboxylate (DDB) and low-, moderate-, and high-dose TTM treatment groups. After CCl4-induced model establishment, the rats from DDB and TTM groups were administrated with DDB at 0.2 g/kg per day and TTM at 0.1, 0.5, and 1.0 g/kg per day, while the rats from control and model groups were administrated with saline. After 5 days of treatments, all rats were sacrificed for determining serum ALT and AST levels and liver index, examining histopathological changes in liver through HE and TUNEL staining, and evaluating TNF-α and IL-6 mRNA expression by real-time PCR, and caspase-3, Bcl-2, and Bax expression by Western blot. Results indicated that CCl4 could induce acute liver injury and abnormal liver function in rats with obvious hepatomegaly, increased liver index, high ALT and AST levels, up-regulated TNF-α and IL-6, and overexpressed Bax and caspase-3. However, DDB and TTM could execute protective role in CCl4-induced liver injury in rats through reducing ALT and AST levels, rescuing hepatomegaly, down-regulating inflammatory factors and inhibiting hepatocyte apoptosis in a dose-dependent manner. Therefore, TTM has obvious protective role in CCl4-induced liver injury of rats through inhibiting hepatocyte apoptosis.

  16. Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study.

    Science.gov (United States)

    Gerth, Hans U; Pohlen, Michele; Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H J

    2017-01-01

    The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3-5 sessions). Independent of the underlying etiology, MARS improved the patients' bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0-15.3); SMT 3.3% (95% CI: 0-9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0-44.7), SMT 11.1% (95% CI: 0-31.7), p = 0.478). Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of

  17. Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study

    Science.gov (United States)

    Thölking, Gerold; Pavenstädt, Hermann; Brand, Marcus; Wilms, Christian; Hüsing-Kabar, Anna; Görlich, Dennis; Kabar, Iyad; Schmidt, Hartmut H. J.

    2017-01-01

    Background The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated. Aim We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD). Methods We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10). Results The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3–5 sessions). Independent of the underlying etiology, MARS improved the patients’ bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0–15.3); SMT 3.3% (95% CI: 0–9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0–44.7), SMT 11.1% (95% CI: 0–31.7), p = 0.478). Conclusions Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those

  18. Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver.

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    Shimada, Shingo; Wakayama, Kenji; Fukai, Moto; Shimamura, Tsuyoshi; Ishikawa, Takahisa; Fukumori, Daisuke; Shibata, Maki; Yamashita, Kenichiro; Kimura, Taichi; Todo, Satoru; Ohsawa, Ikuroh; Taketomi, Akinobu

    2016-12-01

    Hydrogen gas reduces ischemia and reperfusion injury (IRI) in the liver and other organs. However, the precise mechanism remains elusive. We investigated whether hydrogen gas ameliorated hepatic I/R injury after cold preservation. Rat liver was subjected to 48-h cold storage in University of Wisconsin solution. The graft was reperfused with oxygenated buffer with or without hydrogen at 37° for 90 min on an isolated perfusion apparatus, comprising the H2 (+) and H2 (-) groups, respectively. In the control group (CT), grafts were reperfused immediately without preservation. Graft function, injury, and circulatory status were assessed throughout the perfusion. Tissue samples at the end of perfusion were collected to determine histopathology, oxidative stress, and apoptosis. In the H2 (-) group, IRI was indicated by a higher aspartate aminotransferase (AST), alanine aminotransferase (ALT) leakage, portal resistance, 8-hydroxy-2-deoxyguanosine-positive cell rate, apoptotic index, and endothelial endothelin-1 expression, together with reduced bile production, oxygen consumption, and GSH/GSSG ratio (vs. CT). In the H2 (+) group, these harmful changes were significantly suppressed [vs. H2 (-)]. Hydrogen gas reduced hepatic reperfusion injury after prolonged cold preservation via the maintenance of portal flow, by protecting mitochondrial function during the early phase of reperfusion, and via the suppression of oxidative stress and inflammatory cascades thereafter. Copyright © 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

  19. Stem cell injury and restitution after ionizing irradiation in intestine, liver, salivary gland, mesenteric lymph node

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    Lee, Jae Hyun; Cho, Kyung Ja; Lee, Sun Joo; Jang, Won Suk [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1998-01-01

    There is little information about radiation injury on stem cell resident in other organs. In addition there is little experimental model in which radiation plays a role on proliferation stem cell in adult organ. This study was carried out to evaluate the early response of tissue injury and restitution in intestine, liver, salivary gland and lymph node, and to develop in vivo model to investigate stem cell biology by irradiation. The study is to assay the early response to radiation and setup an animal model for radiation effect on cellular response. Duodenal intestine, liver, submandibular salivary gland and mesenteric lymph node were selected to compare apoptosis and proliferating cell nuclear antigen (PCNA) expression to radiosensitivity. For the effect of radiation on cellular responses, rats were irradiated during starvation. Conclusionly, this study showed the value of apoptosis in detection system for evaluating cellular damage against radiation injury. Because apoptosis was regularly inducted depending on tissue-specific pattern, dose and time sequence as well as cellular activity. Furthermore in vivo model in the study will be helped in the further study to elucidate the relationship between radiation injury and starvation or malnutrition. (author). 22 refs., 6 figs

  20. Pretreatment with helium does not attenuate liver injury after warm ischemia-reperfusion.

    Science.gov (United States)

    Braun, Sebastian; Plitzko, Gabriel; Bicknell, Leonie; van Caster, Patrick; Schulz, Jan; Barthuber, Carmen; Preckel, Benedikt; Pannen, Benedikt H; Bauer, Inge

    2014-05-01

    Preconditioning with noble gases serves as an effective strategy to diminish tissue injury in different organs. The aim of this study was to investigate the influence of pretreatment with the nonanesthetic noble gas helium on hepatic injury after warm ischemia and reperfusion (IR) in comparison to ischemic preconditioning (IPC). Anesthetized and ventilated rats were randomized into six groups (n = 8/group): sham: after laparotomy, the portal triad was exposed without clamping; IPC was performed with 10 min of partial liver ischemia and 10 min of reperfusion; HePC: three cycles of 5 min with inhalation of helium 70 vol% and intermittent washout; IR: 45 min of ischemia followed by 240 min of reperfusion; IPC-IR: IPC followed by hepatic IR; HePC-IR: pretreatment with helium 70 vol% followed by hepatic IR. Hepatic injury was evaluated by measurement of serum enzymes aspartate aminotransferase and alanine aminotransferase. Hepatic mRNA expression and serum levels of tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were measured with real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Myeloperoxidase in liver tissue was assessed spectrophotometrically as a marker of neutrophil accumulation. mRNA levels of heme oxygenase 1 in liver tissue were assessed to investigate a protein of the most abundant protective system in the liver. Aspartate aminotransferase and alanine aminotransferase serum activities increased after hepatic IR (sham vs. IR; P helium pretreatment had no effect. mRNA expression of TNF-α increased in all groups except IPC-IR compared with sham, whereas mRNA expression of IL-10 increased only after helium pretreatment. Serum levels of IL-10 were not affected by any intervention, whereas serum levels of TNF-α and liver myeloperoxidase were increased after IR, but not after HePC-IR. In conclusion, pretreatment with inhaled helium does not attenuate hepatic injury after warm IR of the liver

  1. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation.

    Science.gov (United States)

    Henry, S D; Nachber, E; Tulipan, J; Stone, J; Bae, C; Reznik, L; Kato, T; Samstein, B; Emond, J C; Guarrera, J V

    2012-09-01

    Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function. Molecular data to date has been limited to extrapolation of animal studies. We analyzed liver tissue and serum collected during our Phase 1 trial of liver HMP. Grafts preserved with HMP were compared to static cold stored (SCS) transplant controls. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and transmission electron microscopy (TEM) were performed on liver biopsies. Expression of inflammatory cytokines, adhesion molecules and chemokines, oxidation markers, apoptosis and acute phase proteins and the levels of CD68 positive macrophages in tissue sections were evaluated. RT-PCR of reperfusion biopsy samples in the SCS group showed high expression of inflammatory cytokines, adhesion molecules and chemokines, oxidative markers and acute phase proteins. This upregulation was significantly attenuated in livers that were preserved by HMP. Immunofluorescence showed larger numbers of CD68 positive macrophages in the SCS group when compared to the HMP group. TEM samples also revealed ultrastructural damage in the SCS group that was not seen in the HMP group. HMP significantly reduced proinflammatory cytokine expression, relieving the downstream activation of adhesion molecules and migration of leukocytes, including neutrophils and macrophages when compared to SCS controls. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. Liver sinusoidal endothelial cells and acute non-oxidative hepatic injury induced by Pseudomonas aeruginosa pyocyanin.

    Science.gov (United States)

    Cheluvappa, Rajkumar; Cogger, Victoria C; Kwun, Sun Young; O'Reilly, Jennifer N; Le Couteur, David G; Hilmer, Sarah N

    2008-12-01

    The liver sinusoidal endothelial cell (LSEC) is damaged by many toxins, including oxidants and bacterial toxins. Any effect on LSECs of the Pseudomonas aeruginosa virulence factor, pyocyanin, may be relevant for systemic pseudomonal infections and liver transplantation. In this study, the effects of pyocyanin on in vivo rat livers and isolated LSECs were assessed using electron microscopy, immunohistochemistry and biochemistry. In particular, the effect on fenestrations, a crucial morphological aspect of LSECs was assessed. Pyocyanin treatment induced a dose-dependent reduction in fenestrations in isolated LSECs. In the intact liver, intraportal injection of pyocyanin (11.9 microM in blood) was associated with a reduction in endothelial porosity from 3.4 +/- 0.2% (n = 5) to 1.3 +/- 0.1% (n = 7) within 30 min. There were decreases in both diameter and frequency of fenestrations in the intact endothelium. There was also a decrease in endothelial thickness from 175.8 +/- 5.8 to 156.5 +/- 4.0 nm, an endothelial pathology finding previously unreported. Hepatocyte ultrastructure, liver function tests and immunohistochemical markers of oxidative stress (3-nitrotyrosine and malondialdehyde) were not affected. Pyocyanin induces significant ultrastructural changes in the LSEC in the absence of immunohistochemical evidence of oxidative stress or hepatocyte injury pointing to a novel mechanism for pyocyanin pathogenesis.

  4. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

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    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  5. Remote Ischemic Preconditioning Protects against Liver Ischemia-Reperfusion Injury via Heme Oxygenase-1-Induced Autophagy

    Science.gov (United States)

    Xiong, Xuanxuan; Xu, Yonghua; Zhang, Hai; Huang, Changjun; Tian, Yuan; Jiao, Chengyu; Wang, Xuehao; Li, Xiangcheng

    2014-01-01

    Background Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. Methods RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro. Results In liver IR, the expression of LC3-II peaked 12–24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. Conclusions RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy. PMID:24914543

  6. The effects of 10 triterpenoid compounds on experimental liver injury in mice.

    Science.gov (United States)

    Liu, J; Liu, Y; Mao, Q; Klaassen, C D

    1994-01-01

    The purpose of this study was to compare the hepatoprotective effects of 10 oleanane-type triterpenoid compounds on three known hepatotoxicants in mice. These compounds include oleanolic acid, ursolic acid, uvaol, alpha-hederin (alpha-H), hederagenin, glycyrrhizin, 18 alpha-glycyrrhetinic acid (alpha-GA), 18 beta-glycyrrhetinic acid (beta-GA), 19 alpha-hydroxyl asiatic acid 28-O-beta-D-glucoside (HAG), and 19 alpha-hydroxyl asiatic acid (HA). They were administrated sc for 3 days at 200 mumol/kg, except for alpha-H, which was given at 100 mumol/kg for 2 days. Acute liver injury was produced in male CF-1 mice by CCl4 (15 microliters/kg, ip), acetaminophen (500 mg/kg, ip), and cadmium chloride (3.7 mg/kg, iv). Liver damage was assessed by serum activities of alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological examination. alpha-Hederin, ursolic acid, and oleanolic acid markedly decreased the toxicity produced by all three hepatotoxicants. Uvaol significantly decreased CCl4- and Cd-induced hepatotoxicity, but had no effect on acetaminophen toxicity. Glycyrrhizin, alpha-GA, and beta-GA decreased acetaminophen-induced liver injury, whereas hederagenin, HAG, and HA did not protect against any of the hepatotoxicants. In addition, alpha-hederin, ursolic acid, oleanolic acid, and uvaol increased hepatic metallothionein levels by 87-, 48-, 28-, and 10-fold, respectively, as determined by the Cd/hemoglobin assay. In conclusion, among the 10 triterpenoid compounds examined, alpha-hederin, ursolic acid, and oleanolic acid appear to be the most effective in protecting against CCl4-, acetaminophen-, and Cd-induced liver injury.

  7. Hyperoxygenated hydrogen-rich solution suppresses shock- and resuscitation-induced liver injury.

    Science.gov (United States)

    Dang, Yangjie; Liu, Ting; Mei, Xiaopeng; Meng, Xiangzhong; Gou, Xingchun; Deng, Bin; Xu, Hao; Xu, Lixian

    2017-12-01

    It is not known whether simultaneous delivery of hydrogen and oxygen can reduce injury caused by hemorrhagic shock and resuscitation (HSR). This study investigated the therapeutic potential of hyperoxygenated hydrogen-rich solution (HHOS), a combined hydrogen/oxygen carrier, in a rat model of HSR-induced liver injury. Rats (n = 60) were randomly divided into 5 groups (n = 6 per group at each time point). One group underwent sham operation, and the others were subjected to severe hemorrhagic shock and then treated with lactated Ringer's solution (LRS), hydrogen-rich solution, hyperoxygenated solution, or HHOS. At 2 and 6 h after resuscitation, blood samples (n = 6) were collected from the femoral artery and serum concentrations of alanine aminotransferase and aspartate aminotransferase (AST) were measured. Rats were then sacrificed, and histopathological changes in the liver were evaluated by quantifying the percentage of apoptotic cells by caspase-3 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick-end labeling. Inflammation was assessed by assessing malondialdehyde content and tumor necrosis factor-α, and interleukin (IL)-6 expression. Compared to lactated Ringer's solution, hydrogen-rich solution, or hyperoxygenated solution groups, serum AST and alanine aminotransferase levels and IL-6, tumor necrosis factor-α, and malondialdehyde expression in liver tissue were decreased by HHOS treatment. The number of caspase-3- and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells was decreased (P < 0.05) by HHOS treatment, 2 and 6 h after resuscitation. HHOS has protective effects against liver injury in a rat model of HSR. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures

    NARCIS (Netherlands)

    Op den Dries, Sanna; Westerkamp, Andrie C.; Karimian, Negin; Gouw, Annette S. H.; Bruinsma, Bote G.; Markmann, James F.; Lisman, Ton; Yeh, Heidi; Uygun, Korkut; Martins, Paulo N.; Porte, Robert J.

    Background & Aims: The peribiliary glands of large bile ducts have been identified as a niche of progenitor cells that contribute to regeneration of biliary epithelium after injury. We aimed to determine whether injury to the peribiliary glands of donor livers is a risk factor for development of

  9. Warm ischemia time-dependent variation in liver damage, inflammation, and function in hepatic ischemia/reperfusion injury

    NARCIS (Netherlands)

    Olthof, Pim B.; Golen, van Rowan F.; Meijer, Ben; Beek, van Adriaan A.; Bennink, Roelof J.; Verheij, Joanne; Gulik, van Thomas M.; Heger, Michal

    2017-01-01

    Background Hepatic ischemia/reperfusion (I/R) injury is characterized by hepatocellular damage, sterile inflammation, and compromised postoperative liver function. Generally used mouse I/R models are too severe and poorly reflect the clinical injury profile. The aim was to establish a mouse I/R

  10. A case of traumatic rupture of a giant omphalocele and liver injury associated with transverse lie and preterm labor

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    Maria E. Linnaus

    2016-11-01

    Full Text Available Perinatal omphalocele rupture is a rare occurrence. We present a case of a baby delivered at 35 weeks with a known giant omphalocele, transverse lie, and the omphalocele downward in the birth canal who suffered rupture of the omphalocele and liver injury around the time of delivery. The pregnancy was complicated by one day of preterm labor, preterm premature rupture of the membranes, and the omphalocele was the presenting part. Despite pulmonary hypertension, rupture of the omphalocele, and a significant liver injury, individualized management with decompression of the liver hematoma allowed successful early closure with mesh followed by delayed reconstruction.

  11. Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome.

    Science.gov (United States)

    Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Tan, Dunxian; Du, Changhong; Li, Yuming; Ma, Qinlong; Yu, Junmei; Chen, Mengyan; Zhou, Chao; Pei, Liping; Zhang, Lei; Ran, Haiying; He, Mindi; Yu, Zhengping; Zhou, Zhou

    2017-04-01

    Cadmium (Cd) is a persistent environmental and occupational contaminant that accumulates in the liver and induces oxidative stress and inflammation. Melatonin possesses potent hepatoprotective properties against the development and progression of acute and chronic liver injury. Nevertheless, the molecular mechanism underlying the protective effects of melatonin against Cd-induced hepatotoxicity remains obscure. In this study, we aimed to investigate the effects of melatonin on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were intraperitoneally injected with melatonin (10 mg/kg) once a day for 3 days before exposure to CdCl2 (2.0 mg/kg). We found that Cd induced hepatocellular damage and inflammatory infiltration as well as increased serum ALT/AST enzymes. In addition, we showed that Cd triggered an inflammatory cell death, which is mediated by the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Moreover, melatonin treatment significantly alleviated Cd-induced liver injury by decreasing serum ALT/AST levels, suppressing pro-inflammatory cytokine production, inhibiting NLRP3 inflammasome activation, ameliorating oxidative stress, and attenuating hepatocyte death. Most importantly, melatonin markedly abrogated Cd-induced TXNIP overexpression and decreased the interaction between TXNIP and NLRP3 in vivo and in vitro. However, treatment with siRNA targeting TXNIP blocked the protective effects of melatonin in Cd-treated primary hepatocytes. Collectively, our results suggest that melatonin confers protection against Cd-induced liver inflammation and hepatocyte death via inhibition of the TXNIP-NLRP3 inflammasome pathway. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation.

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    J Kirk Harris

    Full Text Available Parenteral nutrition (PN has been a life-saving treatment in infants intolerant of enteral feedings. However, PN is associated with liver injury (PN Associated Liver Injury: PNALI in a significant number of PN-dependent infants. We have previously reported a novel PNALI mouse model in which PN infusion combined with intestinal injury results in liver injury. In this model, lipopolysaccharide activation of toll-like receptor 4 signaling, soy oil-derived plant sterols, and pro-inflammatory activation of Kupffer cells (KCs played key roles. The objective of this study was to explore changes in the intestinal microbiome associated with PNALI.Microbiome analysis in the PNALI mouse identified specific alterations within colonic microbiota associated with PNALI and further association of these communities with the lipid composition of the PN solution. Intestinal inflammation or soy oil-based PN infusion alone (in the absence of enteral feeds caused shifts within the gut microbiota. However, the combination resulted in accumulation of a specific taxon, Erysipelotrichaceae (23.8% vs. 1.7% in saline infused controls, in PNALI mice. Moreover, PNALI was markedly attenuated by enteral antibiotic treatment, which also was associated with significant reduction of Erysipelotrichaceae (0.6% and a Gram-negative constituent, the S24-7 lineage of Bacteroidetes (53.5% in PNALI vs. 0.8%. Importantly, removal of soy oil based-lipid emulsion from the PN solution resulted in significant reduction of Erysipelotrichaceae as well as attenuation of PNALI. Finally, addition of soy-derived plant sterol (stigmasterol to fish oil-based PN restored Erysipelotrichaceae abundance and PNALI.Soy oil-derived plant sterols and the associated specific bacterial groups in the colonic microbiota are associated with PNALI. Products from these bacteria may directly trigger activation of KCs and promote PNALI. Furthermore, the results indicate that lipid modification of PN solutions may

  13. Allicin enhances chemotherapeutic response and ameliorates tamoxifen-induced liver injury in experimental animals.

    Science.gov (United States)

    Suddek, Ghada M

    2014-08-01

    Tamoxifen (TAM) is widely used for treatment of hormone-dependent breast cancer; however, it may be accompanied with hepatic injury. Allicin is the most abundant thiosulfinate molecule from garlic with the potential to provide beneficial effects on various diseases. To elucidate the effect of commercially available allicin on both antitumor activity and liver injury of TAM. The cytotoxicity of TAM and/or allicin was evaluated in vitro using cultured Ehrlich ascites carcinoma (EAC) cells and in vivo against murine tumor (solid) model of EAC. TAM induced liver injury in rats by intraperitoneally (i.p.) injection at a dose of 45 mg/kg, for 7 successive days. TAM at a dose of 3 µM (IC50) significantly decreased percent survival of EAC to 52%. TAM combination with allicin (5 or 10 µM) showed a significant cytotoxic effect compared with the TAM-treated group as manifested by a decrease in percent survival of EAC to 35% and 29%, respectively. Allicin (10 mg/kg, orally) enhanced the efficacy of TAM (1 mg/kg, i.p.) in mice as manifested by a significant increase in solid tumor growth inhibition by 82% compared with 70% in the TAM group. In rats, TAM intoxication resulted in a significant decline in SOD, GSH, and total protein with significant elevation in TBARS, ALT and AST, ALP, LDH, total bilirubin, γGT, and TNF-α levels. These changes are abrogated by allicin treatment. The results suggest the beneficial role of allicin as an adjuvant to TAM in cancer treatment by alleviating liver injury.

  14. Renoprotective effect of crocin following liver ischemia/ reperfusion injury in Wistar rats

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    Seyyed Ali Mard

    2017-10-01

    Full Text Available Objective(s: The objectives of the current study were to evaluate the effects of hepatic ‎ischemia/reperfusion (IR injury on the activity of antioxidant enzymes, biochemical factors, and ‎histopathological changes in rat kidney, and to investigate the effect of crocin on IR-‎related changes. Materials and Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n=8. They were ‎sham-operated, IR, crocin pre-treatment, and crocin pretreatment+IR groups. Sham-operated ‎and Crocin pre-treatment groups received normal saline (N/S, 2 ml/day and crocin (200 mg/kg ‎for seven consecutive days intraperitoneally (IP, respectively, then rats underwent laparotomy, only. ‎IR and crocin pretreatment+IR groups received N/S and crocin with the same dose, time, and route, ‎respectively, then rats underwent partial (70% ischemia for 45 min that was followed by reperfusion ‎for 60 min. At the end of the experiment, kidney specimens were taken for histopathological and ‎antioxidant evaluations and also blood samples were obtained for biochemical analysis. Results: The results of the present study showed that crocin pre-treatment significantly increased ‎the activity of antioxidants, decreased the serum levels of liver enzymes and blood urea nitrogen ‎following IR-induced hepatic injury. Crocin also ameliorated kidney´s histopathological ‎disturbance beyond IR-induced hepatic injury. Conclusion: Crocin as an antioxidant agent protected renal insult following liver IR injury by ‎increasing the activity of antioxidant enzymes, reducing serum levels of liver enzymes, and ‎improving histopathological changes.‎

  15. IDH2 deficiency increases the liver susceptibility to ischemia-reperfusion injury via increased mitochondrial oxidative injury.

    Science.gov (United States)

    Han, Sang Jun; Choi, Hong Seok; Kim, Jee In; Park, Jeen-Woo; Park, Kwon Moo

    2017-09-08

    Mitochondrial NADP(+)-dependent isocitrate dehydrogenase 2 (IDH2) is a major producer of mitochondrial NADPH, required for glutathione (GSH)-associated mitochondrial antioxidant systems including glutathione peroxidase (GPx) and glutathione reductase (GR). Here, we investigated the role of IDH2 in hepatic ischemia-reperfusion (HIR)-associated mitochondrial injury using Idh2-knockout (Idh2(-/-)) mice and wild-type (Idh2(+/+)) littermates. Mice were subjected to either 60min of partial liver ischemia or sham-operation. Some mice were administered with 2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mito-TEMPO, a mitochondria-targeting antioxidant). HIR induced severe histological and functional damages of liver in both Idh2(+/+) mice and Idh2(-/-) mice and those damages were more severe in Idh2(-/-) mice than in wild-type littermates. HIR induces dysfunction of IDH2, leading to the decreases of NADPH level and mitochondrial GR and GPx functions, consequently resulting in mitochondrial and cellular oxidative injury as reflected by mitochondrial cristae loss, mitochondrial fragmentation, shift in mitochondrial fission, cytochrome c release, and cell death. These HIR-induced changes were greater in Idh2(-/-) mice than wild-type mice. The mito-TEMPO supplement significantly attenuated the aforementioned changes, and these attenuations were much greater in Idh2(-/-) mice when compared with wild-type littermates. Taken together, results have demonstrated that HIR impairs in the IDH2-NADPH-GSH mitochondrial antioxidant system, resulting in increased mitochondrial oxidative damage and dysfunction, suggesting that IDH2 plays a critical role in mitochondrial redox balance and HIR-induced impairment of IDH2 function is associated with the pathogenesis of ischemia-reperfusion-induced liver failure. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  16. The Role of Alpha-1 and Alpha-2 Adrenoceptors in Restraint Stress-Induced Liver Injury in Mice

    Science.gov (United States)

    Wang, Yimei; Jia, Li; Zhao, Zengming; Peng, Shuangqing; Lei, Linsheng

    2014-01-01

    Acute stress affects cellular integrity in many tissues including the liver, but its underlying mechanism is still unclear. The aim of the present study was to investigate the potential involvement of catecholamines and adrenoceptors in the regulation of acute restraint stress-induced liver injury. Restraint was achieved by placing mice in restraint tubes. Mice were treated with either an α-l antagonist, prazosin, an α-2 antagonist, yohimbine, a β-l antagonist, betaxolol, a β-2 antagonist, ICI 118551, or a central and peripheral catecholamine depleting agent, reserpine, and followed by restraint stress. Assessment of liver injury (serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) , hepatic total GSH, GSSG and GSH/GSSG ratio) , histopathology and of apoptosis, by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay and western blotting, was performed. Three hours of restraint stress resulted in liver injury, as indexed by elevated serum transaminase levels, decreased hepatic total GSH levels and GSH/GSSG ratio, increased hepatic GSSG levels as well as enhanced hepatocytes apoptosis. Either reserpine or prazosin or yohimbine was found to attenuate liver injury. Furthermore, prazosin and yohimbine protected against restraint-induced hepatocytes apoptosis through attenuating the activation of caspases-9 and -3 and reducing the Bax/Bcl-2 ratio. These results suggest that α-1 and α-2 adrenoceptors mediate restraint-induced liver oxidative injury through caspase-9 and Bcl-2 family of apoptotic regulatory proteins. PMID:24682087

  17. Isovolemic hemodilution with glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb) attenuated rat liver ischemia/reperfusion injury.

    Science.gov (United States)

    You, Zhen; Li, Qian; Li, Bei; Yang, Chengmin; Liu, Jin; Li, Tao

    2014-04-01

    This study was to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb) could attenuate ischemia/reperfusion (I/R)-induced liver injury. Isovolemic hemodilution of SD rats was performed by exchanging 15% total blood volume with PolyPHb. I/R was induced by left liver lobes pedicle cross-clamping for 60 min and reperfusion for 2 h. Blood pressure moderately elevated after PolyPHb infusion and returned to basal level within 10 min. The hepatic histopathological damage and the activities of liver injury markers were reduced by PolyPHb. The TUNEL staining and caspase assay indicated hepatic apoptosis was also inhibited. Therefore, our findings suggest PolyPHb can reduce liver I/R injury.

  18. Delayed rearterialization unlikely leads to nonanastomotic stricture but causes temporary injury on bile duct after liver transplantation

    OpenAIRE

    Liu, Yang; Wang, Jiazhong; Yang, Peng; Lu, Hongwei; Lu, Le; Wang, Jinlong; Li, Hua; Duan, Yanxia; Wang, Jun; Li, Yiming

    2014-01-01

    Nonanastomotic?strictures (NAS) are common biliary complications after liver transplantation (LT). Delayed rearterialization induces biliary injury in several hours. However, whether this injury can be prolonged remains unknown. The correlation of this injury with NAS occurrence remains obscure. Different delayed rearterialization times were compared using a porcine LT model. Morphological and functional changes in bile canaliculus were evaluated by transmission electron microscopy and real-t...

  19. The clinical features of drug-induced liver injury observed through liver biopsy: focus on relevancy to autoimmune hepatitis

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    Hye Young Ju

    2012-06-01

    Full Text Available Background/AimsAccurate diagnosis of drug-induced liver injury (DILI is difficult without considering the possibility of underlying diseases, especially autoimmune hepatitis (AIH. We investigated the clinical patterns in patients with a history of medication, liver-function abnormalities, and in whom liver biopsy was conducted, focusing on accompaniment by AIH.MethodsThe clinical, serologic, and histologic findings of 29 patients were compared and analyzed. The patients were aged 46.2±12.8 years (mean±SD, and 72.4% of patient were female. The most common symptom and causal drug were jaundice (58.6% and herbal medications (55.2%, respectively.ResultsAspartate aminotransferase (AST, alanine aminotransferase, total bilirubin, alkaline phosphatase, and γ-glutamyl transpeptidase levels were 662.2±574.8 U/L, 905.4±794.9 U/L, 12.9±10.8 mg/dL, 195.8±123.3 U/L, and 255.3±280.8 U/L, respectively. According to serologic and histologic findings, 21 cases were diagnosed with DILI and 8 with AIH. The AIH group exhibited significantly higher AST levels (537.1±519.1 vs. 1043.3±600.5 U/L, globulin levels (2.7±0.4 vs. 3.3±0.5 g/dL, and prothrombin time (12.9±2.4 vs. 15.2±3.9 s; P<0.05. Antinuclear antibody was positive in 7 of 21 cases of DILI and all 8 cases of AIH (P=0.002. The simplified AIH score was 3.7±0.9 in the DILI group and 6.5±0.9 in the AIH group (P<0.001.ConclusionsAccurate diagnosis is necessary for patients with a history of medication and visits for liver-function abnormalities; in particular, the possibility of AIH should be considered.

  20. Intraductal Cooling via a Nasobiliary Tube During Radiofrequency Ablation of Central Liver Tumors Reduces Biliary Injuries.

    Science.gov (United States)

    Felker, Ely R; Lee-Felker, Stephanie A; Ajwichai, Khobkhoon; Tan, Nelly; Lu, David S; Durazo, Francisco A; Raman, Steven S

    2015-06-01

    The objective of our study was to determine the safety and efficacy of intraductal perfusion of chilled 5% dextrose in water (D5W) via an endoscopic nasobiliary tube (NBT) for the prevention of thermal bile duct injury in patients undergoing percutaneous radiofrequency ablation (RFA) of central liver tumors. We performed a retrospective study comparing outcomes of 32 consecutive patients who underwent percutaneous RFA of central liver tumors without intraductal perfusion of chilled D5W (control cohort) and 14 consecutive patients who underwent temporary intraductal perfusion of chilled D5W at 2 mL/s via endoscopic NBT placement before RFA (endoscopic NBT cohort). The primary and secondary outcomes were the rate of biliary complications and local tumor progression, respectively. All patients tolerated the procedures well. There was a significantly lower rate of biliary complications in the endoscopic NBT cohort (0/14 patients, 0%) than in the control cohort (10/32 patients, 31%) (p NBT cohort (12/14 patients, 86%) compared with the control cohort (20/32 patients, 62%) (p = 0.05). There was no difference in the rate of local tumor progression between the endoscopic NBT cohort (4/19 tumors, 21%) and the control cohort (9/39 tumors, 23%) (p = 1.0). Perfusion of chilled water through an endoscopic NBT helps prevent thermal biliary injury during RFA of central liver tumors without increasing rates of local tumor progression.

  1. Erdosteine ameliorates the harmful effects of ischemia-reperfusion injury on the liver of rats.

    Science.gov (United States)

    Barlas, Aziz Mutlu; Kismet, Kemal; Erel, Serap; Kuru, Serdar; Cavusoglu, Turgut; Senes, Mehmet; Adiyaman, Zeynep; Celepli, Pinar; Hucumenoglu, Sema; Pekcici, Recep

    2017-10-01

    To investigate the potential protective effects of erdosteine against the harmful effects of ischemia-reperfusion injury on the liver in an experimental rat model. Forty rats were divided into 4 groups. In the sham group, only the hepatic pedicle was mobilized. No other manipulation or treatment was performed. In the other groups, ischemia was achieved by clamping the hepatic pedicle for 60 min. After that, 90 min reperfusion was provided. In the control group, no treatment was given. In the perioperative treatment group, 100 mg/kg erdosteine was administered 2 hours before ischemia induction. In the preoperative treatment group, 100 mg/kg/day erdosteine was administered daily for ten days before the operation. At the end of the procedures, blood and liver samples were obtained for biochemical and histopathological assessment. Treatment with erdosteine ameliorated the histopathological abnormalities when compared with the control group. Furthermore, this treatment significantly decreased the serum liver function test values. It was also found that erdosteine ameliorated the oxidative stress parameters in both the perioperative and preoperative treatment groups. The current study is the first to have shown the favorable effects of erdosteine on the harmful effects of experimental hepatic ischemia-reperfusion injury.

  2. [Clinical Analysis of Drug-induced Liver Injury Caused by Polygonum multiflorum and its Preparations].

    Science.gov (United States)

    Zhu, Yun; Liu, Shu-hong; Wang, Jia-bo; Song, Hai-bo; Li, Yong-gang; He, Ting-ting; Ma, Xiao; Wang, Zhong-xia; Wang-Li-ping; Zhou, Kun; Bai, Yun-feng; Zou, Zheng-sheng; Xiao, Xiao-he

    2015-12-01

    To analyze hepatotoxicity of Polygonum multiflorum and clinical character- istics of drug-induced liver injury (DILI) caused by Polygonum multiflorum and its preparations. A retrospective study was performed in 158 patients treated at 302 Military Hospital between January 2009 and January 2014. All of them had used Polygonum multiflorum and its preparations before the onset of DILI, and their clinical characteristics and prognoses were analyzed. Of the 158 DILI patients who used Polygonum multiflorum or its preparations, 92 (58.2%) combined with Western medicine or Chinese herbal preparations without Polygonum multiflorum; 66 patients (41.8%) used Polygonum mult florum and its preparations alone. In 66 DILI patients induced by Polygonum multiflorum or its preparations alone, 51 cases (77.3%) were induced by Polygonum multiflorum compounds and 22.7% by single Po- lygonum multiflorum; 4 cases (6.1%) were caused by crude Polygonum multiflorum and 62 (93.9%) by processed Polygonum multiflorum and its preparations. Clinical injury patterns were hepatocellular 92.4% (61 cases), cholestatic 1.5% (1 case), and mixed 6.1% (4 cases). Pathological examination was per- formed by liver biopsy in 32 cases (48.15%), manifested as hepatocellular degeneration and necrosis, fibroplasia, Kupffer cells with pigment granule, and a large number of eosinophil infiltration, were ob- served. Four patients were developed into liver failure, 4 into cirrhosis, and 1 died. Polygo- num multiflorum and its preparations could induce DILI, but clinical diagnosis of Polygonum multiflorum induced hepatotoxicity should be cautious.

  3. Exercises in hot and humid environment caused liver injury in a rat model.

    Directory of Open Access Journals (Sweden)

    DongLiang Li

    Full Text Available To investigate injury pattern during intense exercises in hot and humid environment particularly on liver in a rat exertional heat stroke model.We randomly divided 30 rats into a control group (CG, a normal temperature (25±2°C, 60%±5% humidity exercise group (NTEG and a high temperature and high humidity (35±2°C, 80%±10% humidity exercising group (HTEG, each comprising 10 animals. The NTEG and HTEG rats were forced to run in a treadmill for 1 hour maximum at 20 rpm. We analyzed liver cells of all three groups with JC-1 dye and flow cytometry for apoptosis rates in addition to liver tissue 8 - hydroxy deoxyguanosine (8 - OhdG and blood serum IL-6, tumor necrosis factor alpha (TNF-α, alanine aminotransferase ALT, aspartate amino transferase (AST, serum creatinine (CREA, blood urea nitrogen (BUN, lactate dehydrogenase (LDH, creatine phosphate kinase (CK concentrations.Compared with NTEG rats, beside reduced exercise tolerance (60±5 vs. 15±3 minutes (p = 0.002 the 8-OhdG liver tissue concentrations were significantly higher (p = 0.040 in the HTEG rats. The HTEG developed more organ tissue damage and cellular fragmentations of liver cells. In both exercise groups TNF-α and IL-6 serum concentrations were enhanced significantly (p<0.001 being highest in the HTEG animals. Serum ALT, AST, LDH, CREA, BUN and CK concentrations were significantly enhance in both exercise groups.In our exertional heat stroke rat model, we found tissue damage particularly in livers during exercises in hot and humid environment that was related to inflammation, oxidative stress and apoptosis.

  4. Immunohistochemical Analysis of Platelet Extract Effects on Liver Injury Induced by CCl4 in Male Rats

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    Zahra Hesami

    2016-01-01

    Full Text Available Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4, we used immunohistochemical analysis in male rats. Methods: In this project the 28 male Wistar rats (250-300 g were randomly divided into 4 groups, each consisting of 7 animals. The rats were divided into four experimental groups as follows: the first group (sham intraperitoneally received only olive oil as the solvent of carbon tetrachloride; second group (CCl4 intraperitoneally received carbon tetrachloride dissolved in olive oil (ratio of about 1: 1 at a concentration of 1 ml/kg and a twice a week for eight weeks; third group subcutaneously received only platelet extract at a concentration of 0.5 ml/kg twice a week for three weeks; and fourth group received both CCl4 intraperitoneally for eight weeks and platelet extract subcutaneously for last three weeks. After 8 weeks of trial blood and liver sampling were done. Blood samples sent for enzymatic (AST, ALT tests and liver samples tested for histological and immunohistochemical studies. The data were analyzed using  one-way ANOVA followed by Tukey test by Graph pad Prism 5 software and data were considered significant at p≤ 0.05. Results: The results show that platelet extract causes a significant (p≤ 0.001 decrease in liver enzymes and albumin improves the function of liver. The level of alfa smooth muscle actin (α-SMA as an index of hepatic stellate cell activation was decreased by platelet extract administration which eventually reduced the necrosis and fibrosis induced by carbon tetrachloride in studied rats

  5. 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.

  6. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice

    Science.gov (United States)

    Williams, Jessica A.; Ni, Hong-Min; Ding, Yifeng

    2015-01-01

    Alcoholic liver disease claims two million lives per year. We previously reported that autophagy protected against alcohol-induced liver injury and steatosis by removing damaged mitochondria. However, the mechanisms for removal of these mitochondria are unknown. Parkin is an evolutionarily conserved E3 ligase that is recruited to damaged mitochondria to initiate ubiquitination of mitochondrial outer membrane proteins and subsequent mitochondrial degradation by mitophagy. In addition to its role in mitophagy, Parkin has been shown to have other roles in maintaining mitochondrial function. We investigated whether Parkin protected against alcohol-induced liver injury and steatosis using wild-type (WT) and Parkin knockout (KO) mice treated with alcohol by the acute-binge and Gao-binge (chronic plus acute-binge) models. We found that Parkin protected against liver injury in both alcohol models, likely because of Parkin's role in maintaining a population of healthy mitochondria. Alcohol caused greater mitochondrial damage and oxidative stress in Parkin KO livers compared with WT livers. After alcohol treatment, Parkin KO mice had severely swollen and damaged mitochondria that lacked cristae, which were not seen in WT mice. Furthermore, Parkin KO mice had decreased mitophagy, β-oxidation, mitochondrial respiration, and cytochrome c oxidase activity after acute alcohol treatment compared with WT mice. Interestingly, liver mitochondria seemed able to adapt to alcohol treatment, but Parkin KO mouse liver mitochondria had less capacity to adapt to Gao-binge treatment compared with WT mouse liver mitochondria. Overall, our findings indicate that Parkin is an important mediator of protection against alcohol-induced mitochondrial damage, steatosis, and liver injury. PMID:26159696

  7. A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis

    Directory of Open Access Journals (Sweden)

    Thomas B

    2016-12-01

    Full Text Available Binny Thomas,1-3 Mahmoud Mohamed,1,3,4 Moza Al Hail,1-3 Fatma Alzahra Y Awwad,1 Ramy M Wahba,1 Sabir B Hassan,1 Khalid Omar,1 Wessam El Kassem,1 Palivalappila Abdul Rouf1 1Hamad Medical Corporation, Doha, Qatar; 2Robert Gordon University, Aberdeen, Scotland, UK; 3Qatar University, Doha, 4Weill Cornell Medical College, Ar-Rayyan, Qatar Abstract: We report a case of 22-year-old primigravida presented to Women’s Hospital – Hamad Medical Corporation emergency with severe epigastric pain, nausea, and vomiting. On admission, she was dehydrated with remarkably worsening symptoms. Laboratory findings revealed significantly elevated liver enzymes with unknown etiology. Her past medical history showed an admission for nausea and vomiting 3 weeks previously and she was discharged on antiemetics, and esomeprazole for the first time. Due to the predominantly elevated liver enzymes, the clinical pharmacist discussed the possibility of esomeprazole-induced adverse effects and suggested to suspend esomeprazole based on the evidence from literature review. The liver enzymes showed a substantial improvement within days after the discontinuation of the drug; however, a rechallenge was not done since it could have adversely affected the mother or the fetus. Using the Naranjo Adverse Drug Reaction Probability scales, the adverse reaction due to esomeprazole was classified as “probably”. Keywords: hyperemesis, drug-induced liver injury, esomeprazole, adverse drug reaction, ADR, proton pump inhibitor

  8. Development of novel tools for the in vitro investigation of drug-induced liver injury.

    Science.gov (United States)

    Jiang, Jian; Wolters, Jarno E J; van Breda, Simone G; Kleinjans, Jos C; de Kok, Theo M

    2015-01-01

    Due to its complex mechanisms and unpredictable occurrence, drug-induced liver injury (DILI) complicates drug identification and classification. Since species-specific differences in metabolism and pharmacokinetics exist, data obtained from animal studies may not be sufficient to predict DILI in humans. Over the last few decades, numerous in vitro models have been developed to replace animal testing. The advantages and disadvantages of commonly used liver-derived in vitro models (e.g., cell lines, hepatocyte models, liver slices, three-dimensional (3D) hepatospheres, etc.) are discussed. Toxicogenomics-based methodologies (genomics, epigenomics, transcriptomics, proteomics and metabolomics) and next-generation sequencing have also been used to enhance the reliability of DILI prediction. This review presents an overview of the currently used alternative toxicological models and of the most advanced approaches in the field of DILI research. It seems unlikely that a single in vitro system will be able to mimic the complex interactions in the human liver. Three-dimensional multicellular systems may bridge the gap between conventional 2D models and in vivo clinical studies in humans and provide a reliable basis for hepatic toxicity assay development. Next-generation sequencing technologies, in comparison to microarray-based technologies, may overcome the current limitations and are promising for the development of predictive models in the near future.

  9. Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

    Science.gov (United States)

    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

  10. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury.

    Science.gov (United States)

    Tsutsui, Akemi; Nakanuma, Yasuni; Takaguchi, Kouichi; Nakamura, Satoko; Shibata, Hiroshi; Baba, Nobuyuki; Senoh, Tomonori; Nagano, Takuya; Ikeda, Hiroko

    2015-01-01

    The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated (κ = 0.60). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  11. Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Akemi Tsutsui

    2015-01-01

    Full Text Available The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI. The Digestive Disease Week Japan 2004 (DDW-J scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected, B (DILI was suspected, and C (DILI should be considered in the differential diagnosis. Histological groups and DDW-J scale were moderately correlated (κ=0.60. The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p<0.05. While hepatocellular type was coincided in a majority of cases by histological and DDW-J scale evaluation, cholestatic type was not well coincided. In conclusion, biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

  12. Protective Effect of Urtica dioica on Liver Injury Induced By Hepatic Ischemia Reperfusion Injury in Rats

    OpenAIRE

    TERZİ, Alpaslan; YILDIZ, Fahrettin; Sacit ÇOBAN et al.

    2010-01-01

    Background: This study was designed to investigate the effects of Urtica dioica on liverischemia reperfusion injury in rats. Methods: Thirty male Wistar-albino rats were used in this experimental study. Animals weredivided into three groups as sham operated (group 1), control (group 2), and Urtica dioicatreatment group (group 3). Urtica dioica 2ml/kg were administered intraperitoneally beforeischemia and immediately after the reperfusion. The levels of total antioxidant capacity, totalfree su...

  13. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  14. 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.

  15. Pathological alterations in liver injury following congestive heart failure induced by volume overload in rats.

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    Mohammed Shaqura

    Full Text Available Heart failure has emerged as a disease with significant public health implications. Following progression of heart failure, heart and liver dysfunction are frequently combined in hospitalized patients leading to increased morbidity and mortality. Here, we investigated the underlying pathological alterations in liver injury following heart failure. Heart failure was induced using a modified infrarenal aortocaval fistula (ACF in male Wistar rats. Sham operated and ACF rats were compared for their morphometric and hemodynamic data, for histopathological and ultrastructural changes in the liver as well as differences in the expression of apoptotic factors. ACF-induced heart failure is associated with light microscopic signs of apparent congestion of blood vessels, increased apoptosis and breakdown of hepatocytes and inflammatory cell inifltration were observed. The glycogen content depletion associated with the increased hepatic fibrosis, lipid globule formation was observed in ACF rats. Moreover, cytoplasmic organelles are no longer distinguishable in many ACF hepatocytes with degenerated fragmented rough endoplasmic reticulum, shrunken mitochondria and heavy cytoplasm vacuolization. ACF is associated with the upregulation of the hepatic TUNEL-positive cells and proapoptotic factor Bax protein concomitant with the mitochondrial leakage of cytochrome C into the cell cytoplasm and the transfer of activated caspase 3 from the cytoplasm into the nucleus indicating intrinsic apoptotic events. Taken together, the results demonstrate that ACF-induced congestive heart failure causes liver injury which results in hepatocellular apoptotic cell death mediated by the intrinsic pathway of mitochondrial cytochrome C leakage and subsequent transfer of activated caspase 3 into to the nucleus to initiate overt DNA fragmentation and cell death.

  16. Effects of acute kidney injury after liver resection on long-term outcomes.

    Science.gov (United States)

    Ishikawa, Seiji; Tanaka, Manami; Maruyama, Fumi; Fukagawa, Arisa; Shiota, Nobuhiro; Matsumura, Satoshi; Makita, Koshi

    2017-10-01

    To investigate the effects of acute kidney injury (AKI) after liver resection on the long-term outcome, including mortality and renal dysfunction after hospital discharge. We conducted a historical cohort study of patients who underwent liver resection for hepatocellular carcinoma with sevoflurane anesthesia between January 2004 and October 2011, survived the hospital stay, and were followed for at least 3 years or died within 3 years after hospital discharge. AKI was diagnosed based on the Acute Kidney Injury Network classification within 72 hours postoperatively. In addition to the data obtained during hospitalization, serum creatinine concentration data were collected and the glomerular filtration rate (GFR) was estimated after hospital discharge. AKI patients (63%, P = 0.002) were more likely to reach the threshold of an estimated GFR (eGFR) of 45 ml/min/1.73 m(2) within 3 years than non-AKI patients (31%) although there was no significant difference in mortality (33% vs. 29%). Cox proportional hazard regression analysis showed that postoperative AKI was significantly associated with the composite outcome of mortality or an eGFR of 45 ml/min/1.73 m(2) (95% CI of hazard ratio, 1.05-2.96, P = 0.033), but not with mortality (P = 0.699), the composite outcome of mortality or an eGFR of 60 ml/min/1.73 m(2) (P =0.347). After liver resection, AKI patients may be at higher risk of mortality or moderate renal dysfunction within 3 years. These findings suggest that even after discharge from the hospital, patients who suffered AKI after liver resection may need to be followed-up regarding renal function in the long term.

  17. Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury.

    Science.gov (United States)

    Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Zhai, Yuan

    2017-05-01

    Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. Copyright © 2017 by The American Association of Immunologists, Inc.

  18. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.

    Science.gov (United States)

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schwarzenboeck, Alexander; Schulze, Johannes; Eickhoff, Axel

    2014-01-27

    Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.

  19. EARLY ALLOGRAFT DYSFUNCTION AND ACUTE KIDNEY INJURY AFTER LIVER TRANSPLANTATION: DEFINITIONS, RISK FACTORS AND CLINICAL SIGNIFICANCE

    Directory of Open Access Journals (Sweden)

    L. Y. Moysyuk

    2012-01-01

    Full Text Available This review discusses issues related to intensive care in recipients of transplanted liver in the early postoperative period, with an emphasis on contemporary conditions and attitudes that are specific for this group of patients. Early allograft dysfunction (EAD requires immediate diagnosis and appropriate treatment in case. The causes of the EAD and therapeutic tactics are discussed. Acute kidney injury (AKI and renal failure are common in patients after transplantation. We consider etiology, risk factors, diagnosis and treatment guidelines for AKI. The negative impact of EAD and AKI on the grafts survival and recipients is demonstrated. 

  20. The BH3-only protein bid does not mediate death-receptor-induced liver injury in obstructive cholestasis.

    Science.gov (United States)

    Nalapareddy, Padmavathi devi; Schüngel, Sven; Hong, Ji-Young; Manns, Michael P; Jaeschke, Hartmut; Vogel, Arndt

    2009-09-01

    The accumulation of bile acids during obstructive cholestasis causes liver injury and fibrosis, which is at least partly mediated by the death receptors Tumor necrosis factor-related apoptosis-inducing ligand, Tumor necrosis factor-alpha, and Fas. The BH3-interacting domain death agonist Bid is a critical mediator of death receptor-induced apoptosis in hepatocytes. Our aim for this study was, therefore, to elucidate whether Bid also mediates death receptor-induced liver injury in obstructive cholestasis. Overall, survival and various aspects of liver injury were analyzed in wild-type and Bid(-/-) mice after bile duct ligation (BDL), a commonly used model to study obstructive cholestasis in mice. Liver injury was examined at 3, 7, and 14 days after BDL. Loss of Bid did not affect the number of bile infarcts, serum aspartate aminotransferase values, or animal survival. Processing of procaspase-3 and procaspase-9, and caspase-3 enzyme activities, were not detectable in either group, and Bid(-/-) mice displayed the same pattern of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive hepatocytes as wild-type controls following BDL. In contrast to Fas-receptor deficient lpr mice, hepatic fibrosis and the inflammatory response was not affected by loss of Bid. Together, these data suggest that Bid is not a downstream target of death receptors in obstructive cholestasis and does not significantly contribute to bile acid induced liver injury and fibrosis.

  1. Prediction Model of Drug-Induced Liver Injury in Patients with Pulmonary Tuberculosis: Evaluation of the Incidence and Risk Factors

    Directory of Open Access Journals (Sweden)

    Farzaneh Dastan

    2017-03-01

    Full Text Available Introduction and objectives:Tuberculosis (TB still remains a major health concern both in developing and developed countries. The rate of the liver injury due to anti-TB drugs in developed countries has been reported up to 4%. The goal of this study is to assess the rate and risk factors for anti-tuberculosis drug-induced liver injury (DILI. Also, a model has been designed to predict DILI in patients with pulmonary tuberculosis.Methods:We conducted an observational study. The investigation was carried out in the National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran. Anti-tuberculosis drug treatment course and patients’ demographic data, medical and drug history, and social habits were extracted from their medical records. DILI was defined as an increase in serum alanine aminotransfrase (ALT or aspartate aminotransfrase (AST greater than three times of the upper limit of normal (ULN, with symptoms of liver injury, or five times of the ULN without symptoms.Results:In this study, 87 patients (33 male, 54 female, mean age 54.29±21.79 years with tuberculosis diagnosis were followed. Anti-tuberculosis induced liver injury was detected in 14 (16.1% patients. Concomitant use of hepatotoxic drugs (Isoniazid, Rifampin and Pyrazinamide and the abnormal baseline serum liver enzyme levels before the initiation of therapy were found as risk factors for anti-tuberculosis induced liver injury.Conclusion:Anti-tuberculosis induced liver injury is a major problem in tuberculosis patients which lead to treatment interruption in 14 (16.1% patients. Due to the lack of evidence regarding the mechanism of this side effect, we recommend to monitor anti-tuberculosis drug levels in order to study their probable correlations with DILI.   

  2. The use of an absorbable mesh wrap in the management of major liver injuries.

    Science.gov (United States)

    Jacobson, L E; Kirton, O C; Gomez, G A

    1992-04-01

    Uncontrollable hemorrhage remains the predominant cause of death in patients with complex liver injuries. In view of the recently reported success in control of hemorrhage from and salvage of the injured spleen and kidney with an absorbable mesh wrap, we have begun to use a similar technique in the management of major hepatic parenchymal injuries, as an alternative to suture hepatorrhaphy, lobar resection, and perihepatic packing. The technique of mesh-wrap hepatorrhaphy is described in detail. Our initial experience with four cases is reported, demonstrating the unique features of the mesh and the technical ease with which it can be applied. Advantages over conventional techniques are discussed. These include avoidance of reoperation for removal of perihepatic packing, avoidance of hepatic necrosis after wide suture hepatorrhaphy, and avoidance of the morbidity associated with lobar resections.

  3. Serum plant sterols, cholestanol, and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure.

    Science.gov (United States)

    Mutanen, Annika; Nissinen, Markku J; Lohi, Jouko; Heikkilä, Päivi; Gylling, Helena; Pakarinen, Mikko P

    2014-10-01

    Increased serum concentrations of plant sterols, including stigmasterol, during parenteral nutrition (PN) have been linked with serum biochemical signs of intestinal failure-associated liver disease (IFALD), whereas clinical data on their correlation to histologic liver injury have been limited. We studied interrelations between serum noncholesterol sterols and histologic liver injury in pediatric-onset intestinal failure (IF). Serum plant sterols (stigmasterol, avenasterol, sitosterol, and campesterol), cholestanol, and cholesterol precursors (cholestenol, lathosterol, and desmosterol) were measured in 50 IF patients at a median age 7.3 y and in 86 matched controls. Forty patients underwent liver biopsies. Sixteen patients had been receiving PN for 45 mo, and 34 patients had received PN for 9.1 mo but had not received PN for 5.4 y. Serum plant sterols were higher in patients who were currently receiving PN than in controls and were related to conjugated bilirubin (r = 0.799-0.541, P 2-fold higher in patients with persistent liver steatosis than in those without steatosis or controls (P liver steatosis after weaning off PN. Serum cholestanol reflects liver injury in IF patients. © 2014 American Society for Nutrition.

  4. Metallothionein (MT -I and MT-II expression are induced and cause zinc sequestration in the liver after brain injury.

    Directory of Open Access Journals (Sweden)

    Michael W Pankhurst

    Full Text Available UNLABELLED: Experiments with transgenic over-expressing, and null mutant mice have determined that metallothionein-I and -II (MT-I/II are protective after brain injury. MT-I/II is primarily a zinc-binding protein and it is not known how it provides neuroprotection to the injured brain or where MT-I/II acts to have its effects. MT-I/II is often expressed in the liver under stressful conditions but to date, measurement of MT-I/II expression after brain injury has focused primarily on the injured brain itself. In the present study we measured MT-I/II expression in the liver of mice after cryolesion brain injury by quantitative reverse-transcriptase PCR (RT-PCR and enzyme-linked immunosorbent assay (ELISA with the UC1MT antibody. Displacement curves constructed using MT-I/II knockout (MT-I/II(-/- mouse tissues were used to validate the ELISA. Hepatic MT-I and MT-II mRNA levels were significantly increased within 24 hours of brain injury but hepatic MT-I/II protein levels were not significantly increased until 3 days post injury (DPI and were maximal at the end of the experimental period, 7 DPI. Hepatic zinc content was measured by atomic absorption spectroscopy and was found to decrease at 1 and 3 DPI but returned to normal by 7DPI. Zinc in the livers of MT-I/II(-/- mice did not show a return to normal at 7 DPI which suggests that after brain injury, MT-I/II is responsible for sequestering elevated levels of zinc to the liver. CONCLUSION: MT-I/II is up-regulated in the liver after brain injury and modulates the amount of zinc that is sequestered to the liver.

  5. 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

    2016-11-01

    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

  6. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

    Energy Technology Data Exchange (ETDEWEB)

    Mosedale, Merrie [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Wu, Hong [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Kurtz, C. Lisa [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); Schmidt, Stephen P. [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Adkins, Karissa, E-mail: Karissa.Adkins@pfizer.com [Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340 (United States); Harrill, Alison H. [Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709 (United States); University of Arkansas for Medical Sciences, Little Rock, AR72205 (United States)

    2014-10-01

    A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug. - Highlights: • Identified susceptible and resistant mouse strains to liver injury induced by a CAD • Liver injury characterized by single cell necrosis, and phospholipidosis

  7. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

    Science.gov (United States)

    Chen, Xiong; Cai, Xueding; Le, Rongrong; Zhang, Man; Gu, Xuemei; Shen, Feixia; Hong, Guangliang; Chen, Zimiao

    2018-02-05

    Sepsis, one of the most fatal diseases worldwide, often leads to multiple organ failure, mainly due to uncontrolled inflammatory responses. Despite accumulating knowledge obtained in recent years, effective drugs to treat sepsis in the clinic are still urgently needed. Isoliquiritigenin (ISL), a chalcone compound, has been reported to exert anti-inflammatory properties. However, little is known about the effects of ISL on sepsis and its related complications. In this study, we investigated the potential protective effects of ISL on lipopolysaccharide (LPS)-induced injuries and identified the mechanisms underlying these effects. ISL inhibited inflammatory cytokine expression in mouse primary peritoneal macrophages (MPMs) exposed to LPS. In an acute lung injury (ALI) mouse model, ISL prevented LPS-induced structural damage and inflammatory cell infiltration. Additionally, pretreatment with ISL attenuated sepsis-induced lung and liver injury, accompanied by a reduction in inflammatory responses. Moreover, these protective effects were mediated by the nuclear factor kappa B (NF-κB) pathway-mediated inhibition of inflammatory responses in vitro and in vivo. Our study suggests that ISL may be a potential therapeutic agent for sepsis-induced injuries. Copyright © 2017. Published by Elsevier Inc.

  9. Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury.

    Science.gov (United States)

    Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi; Ke, Bibo; Fujii, Takehiro; Sosa, Rebecca A; Reed, Elaine F; Datta, Nakul; Zarrinpar, Ali; Busuttil, Ronald W; Araujo, Jesus A; Kupiec-Weglinski, Jerzy W

    2017-12-01

    Hepatic ischemia-reperfusion injury (IRI), characterized by exogenous antigen-independent local inflammation and hepatocellular death, represents a risk factor for acute and chronic rejection in liver transplantation. We aimed to investigate the molecular communication involved in the mechanism of liver IRI. We analyzed human liver transplants, primary murine macrophage cell cultures and IR-stressed livers in myeloid-specific heme oxygenase-1 (HO-1) gene mutant mice, for anti-inflammatory and cytoprotective functions of macrophage-specific HO-1/SIRT1 (sirtuin 1)/p53 (tumor suppressor protein) signaling. Decreased HO-1 expression in human post-reperfusion liver transplant biopsies correlated with a deterioration in hepatocellular function (serum ALT; pp53/MDM2 (murine double minute 2) expression levels decreased (pp53, which in turn attenuated macrophage activation. In a murine model of hepatic warm IRI, myeloid-specific HO-1 deletion lacked SIRT1/p53, exacerbated liver inflammation and IR-hepatocellular death, whereas adjunctive SIRT1 activation restored p53 signaling and rescued livers from IR-damage. This bench-to-bedside study identifies a new class of macrophages activated via the HO-1-SIRT1-p53 signaling axis in the mechanism of hepatic sterile inflammation. This mechanism could be a target for novel therapeutic strategies in liver transplant recipients. Post-transplant low macrophage HO-1 expression in human liver transplants correlates with reduced hepatocellular function and survival. HO-1 regulates macrophage activation via the SIRT1-p53 signaling network and regulates hepatocellular death in liver ischemia-reperfusion injury. Thus targeting this pathway in liver transplant recipients could be of therapeutic benefit. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Caffeine demethylation measured by breath analysis in experimental liver injury in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Schaad, H.J.; Renner, E.L.; Wietholtz, H.; Preisig, R. [University of Berne, Department of Clinical Pharmaceology, Berne (Switzerland); Arnaud, M.J. [Nestle Research Center, Nestec Ltd., Vevey (Switzerland)

    1995-01-01

    To assess the effect of experimental liver injury on caffeine metabolism, 1 {mu}{sup C}i/kg b.w. of [3-methyl{sup 14}C]-caffeine (together with 5 mg/kg b.w. of the cold compound) was injected i.p. to four different experimental groups and respective controls of unanesthetized male Sprague-Dawley rats. Exhaled {sup 14}CO{sub 2} was completely collected during 4 h and peak exhalation rate and fraction of dose recovered were calculated. 1/3 hepatectomy affected {sup 14}CO{sub 2} exhalation to a limited extent, decreasing solely peak exhalation rate (p<0.05 compared to sham-operated control). 2/3 hepatectomy, on the other hand, resulted in significant reduction (p<0.01) in both peak exhalation rate (by 59%) and fraction of dose recovered (by 47%), that were proportionate to the loss of liver mass (50%). End-to-side portocaval shunt led to the well-documented hepatic `atrophy`, liver weight being diminished on average to 50% within 2 weeks of surgery; however, reductions in peak exhalation rate (by 75%) and fraction of dose recovered (by 64%) were even more pronounced. Finally, 48 h bile duct ligation was equivalent to `functional 2/3 hepatectomy`, peak exhalation rate (by 65%) and fraction of dose recovered (by 56%) being markedly diminished despite increased liver weight. These results indicate that {sup 14}CO{sub 2} exhalation curves following administration of specifically labelled caffeine are quantitative indicators of acute or chronic loss of functioning liver mass. In addition, the 3-demethylation pathway appears to be particularly sensitive to the inhibitory effects of cholestasis on microsomal function. (au) (30 refs.).

  11. DONOR GRAFT INTERFERON REGULATORY FACTOR-1 (IRF-1) GENE TRANSFER WORSENS LIVER TRANSPLANT ISCHEMIA/REPERFUSION INJURY

    Science.gov (United States)

    Kim, Kee-Hwan; Dhupar, Rajeev; Ueki, Shinya; Cardinal, Jon; Pan, Pinhua; Cao, Zongxian; Cho, Sung W; Murase, Noriko; Tsung, Allan; Geller, David A

    2009-01-01

    Background Liver ischemia and reperfusion (IR) injury is a phenomenon that leads to graft dysfunction following liver transplantation. Understanding the molecular mechanisms behind this process is crucial to developing strategies to prevent short and long term graft dysfunction. The purpose of this study is to explore the role of the transcription factor, IRF-1, in a model of orthotopic rat liver transplantation. Methods Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 3 hours preservation in cold UW solution. AdIRF-1 or control gene vector (Adnull) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as controls. Recipients were sacrificed 1 to 24 hours post-transplantation. Results Rats that underwent OLT with long-term preserved graft (18 hours) displayed increased hepatic nuclear expression of IRF-1 protein at 1 and 3 hours. Rats pre-treated with AdIRF-1 prior to transplantation had increased ALT levels and increased expression of IFN-β, IFN-γ, IL-12, and iNOS in short-term period graft(3 hours) when compared with donor livers pre-treated with Adnull. AdIRF-1 pre-treated donor livers also exhibited increased susceptibility to early apoptosis in the transplanted grafts with increased TUNEL staining expression of cleaved caspase-3. Additionally, AdIRF-1 pre-treated donor livers had increased activation of the MAP kinase JNK as compared with Adnull pre-treated donor livers. Conclusions IRF-1 is an important regulator of IR injury after OLT in rats. Targeting of IRF-1 may be a potential strategy to ameliorate ischemic liver injury after transplantation in order to minimize organ dysfunction. PMID:19628072

  12. [Protective effect of intraperitoneal transplantation of human liver-derived stem cells at different times against concanavalin A-induced acute liver injury in mice].

    Science.gov (United States)

    Bi, Y Z; Fan, Z; Chen, D F; Li, S S; Wang, Q Y; Gao, P F; Wang, Q Q; Duan, Z P; Chen, Y; Kong, L B; Wang, Y B; Hong, F

    2017-03-20

    Objective: To investigate the protective effect of intraperitoneal transplantation of human liver-derived stem cells at different times against concanavalin A (ConA)-induced acute liver injury in mice. Methods: A total of 88 male C57BL/6 mice were randomly divided into normal control group (group C), ConA model group (group M), and human liver-derived stem cells (HYX1)+ConA group (group E); according to the interval between phosphate buffer/HYX1 injection and ConA injection, Groups M and E were further divided into 3-hour groups (M1 and E1 groups), 6-hour groups (M2 and E2 groups), 12-hour groups (M3 and E3 groups), 24-hour groups (M4 and E4 groups), and 48-hour groups (M5 and E5 groups). The levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and total bilirubin (TBil) in peripheral blood were measured, liver tissue sections were used to observe pathological changes, and the Ishak score for liver inflammation was determined. The independent samples t-test was used for comparison between groups, and P 0.05). The pathological sections of liver tissue showed that compared with group M, group E had significant reductions in the degree of necrosis and Ishak score (both P transplantation of human liver-derived stem cells has a protective effect against ConA-induced acute liver injury in mice, and the injection at 6 and 12 hours in advance has the best protective effect.

  13. Beneficial effects of adenosine triphosphate-sensitive K+ channel opener on liver ischemia/reperfusion injury

    Science.gov (United States)

    Nogueira, Mateus Antunes; Coelho, Ana Maria Mendonça; Sampietre, Sandra Nassa; Patzina, Rosely Antunes; Pinheiro da Silva, Fabiano; D'Albuquerque, Luiz Augusto Carneiro; Machado, Marcel Cerqueira Cesar

    2014-01-01

    AIM: To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury. METHODS: Wistar male rats underwent partial liver ischemia performed by clamping the pedicle from the medium and left anterior lateral segments for 1 h under mechanical ventilation. They were divided into 3 groups: Control Group, rats submitted to liver manipulation, Saline Group, rats received saline, and Diazoxide Group, rats received intravenous injection diazoxide (3.5 mg/kg) 15 min before liver reperfusion. 4 h and 24 h after reperfusion, blood was collected for determination of aspartate transaminase (AST), alanine transaminase (ALT), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), nitrite/nitrate, creatinine and tumor growth factor-β1 (TGF-β1). Liver tissues were assembled for mitochondrial oxidation and phosphorylation, malondialdehyde (MDA) content, and histologic analysis. Pulmonary vascular permeability and myeloperoxidase (MPO) were also determined. RESULTS: Four hours after reperfusion the diazoxide group presented with significant reduction of AST (2009 ± 257 U/L vs 3523 ± 424 U/L, P = 0.005); ALT (1794 ± 295 U/L vs 3316 ± 413 U/L, P = 0.005); TNF-α (17 ± 9 pg/mL vs 152 ± 43 pg/mL, P = 0.013; IL-6 (62 ± 18 pg/mL vs 281 ± 92 pg/mL); IL-10 (40 ± 9 pg/mL vs 78 ± 10 pg/mL P = 0.03), and nitrite/nitrate (3.8 ± 0.9 μmol/L vs 10.2 ± 2.4 μmol/L, P = 0.025) when compared to the saline group. A significant reduction in liver mitochondrial dysfunction was observed in the diazoxide group compared to the saline group (P < 0.05). No differences in liver MDA content, serum creatinine, pulmonary vascular permeability and MPO activity were observed between groups. Twenty four hours after reperfusion the diazoxide group showed a reduction of AST (495 ± 78 U/L vs 978 ± 192 U/L, P = 0.032); ALT (335 ± 59 U/L vs 742 ± 182 U/L, P = 0.048), and TGF-β1 (11 ± 1 ng/mL vs 17 ± 0.5 ng/mL, P = 0.004) serum levels when compared to

  14. Hemostatic Therapy Using Tranexamic Acid and Coagulation Factor Concentrates in a Model of Traumatic Liver Injury.

    Science.gov (United States)

    Zentai, Christian; van der Meijden, Paola E J; Braunschweig, Till; Hueck, Nicolai; Honickel, Markus; Spronk, Henri M H; Rossaint, Rolf; Grottke, Oliver

    2016-07-01

    The potential clinical benefits of targeted therapy with coagulation factor concentrates (e.g., fibrinogen) and antifibrinolytic agents (e.g., tranexamic acid [TXA]) for the treatment of trauma-induced coagulopathy are increasingly recognized. We hypothesized that human fibrinogen concentrate (FC) and prothrombin complex concentrate (PCC), administered as combined therapy with TXA, would provide additive effects for reducing blood loss in an animal trauma model. Thirty-six pigs were subjected to 2 consecutive blunt liver injuries, resulting in severe hemorrhagic shock and coagulopathy. Intervention comprised saline (control group); TXA (15 mg kg, TXA group); TXA and FC (90 mg kg, TXA-FC); or TXA, FC, and PCC (20 U kg, TXA-FC-PCC). Blood loss, thromboelastometry (ROTEM), measures of thrombin generation, platelet activation, and global coagulation variables were monitored for 4 hours. Tissue sections were examined to determine the occurrence of thromboembolic events. Total blood loss was similar in the TXA-FC and TXA-FC-PCC groups (mean ± SD: 1012 ± 86 mL and 1037 ± 118 mL, respectively; P = 1.000). These values were both lower (P coagulation measurements in a porcine model of blunt liver injury and hemorrhagic shock. FC, administered in addition to TXA, was highly effective in reducing blood loss. The lack of statistically significant reduction in blood loss when PCC was added to TXA and FC may be attributable to the absence of thrombin generation impairment in this model.

  15. Antioxidant and protective effect of inulin and catechin grafted inulin against CCl4-induced liver injury.

    Science.gov (United States)

    Liu, Jun; Lu, Jian-feng; Wen, Xiao-yuan; Kan, Juan; Jin, Chang-hai

    2015-01-01

    In this study, the antioxidant activity and hepatoprotective effect of inulin and catechin grafted inulin (catechin-g-inulin) against carbon tetrachloride (CCl4)-induced acute liver injury were investigated. Results showed that both inulin and catechin-g-inulin had moderate scavenging activity on superoxide radical, hydroxyl radical and H2O2, as well as lipid peroxidation inhibition effect. The antioxidant activity decreased in the order of Vc > catechin >catechin-g-inulin > inulin. Administration of inulin and catechin-g-inulin could significantly reduce the elevated levels of serum aspartate transaminase, alanine transaminase and alkaline phosphatase as compared to CCl4 treatment group. Moreover, inulin and catechin-g-inulin significantly increased the levels of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione and total antioxidant capacity, whereas markedly decreased the malondialdehyde level when compared with CCl4 treatment group. Notably, catechin-g-inulin showed higher hepatoprotective effect than inulin. In addition, the hepatoprotective effect of catechin-g-inulin was comparable to positive standard of silymarin. Our results suggested that catechin-g-inulin had potent antioxidant activity and potential protective effect against CCl4-induced acute liver injury. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Risk factors for acute renal injury in living donor liver transplantation: evaluation of the RIFLE criteria.

    Science.gov (United States)

    Utsumi, Masashi; Umeda, Yuzo; Sadamori, Hiroshi; Nagasaka, Takeshi; Takaki, Akinobu; Matsuda, Hiroaki; Shinoura, Susumu; Yoshida, Ryuichi; Nobuoka, Daisuke; Satoh, Daisuke; Fuji, Tomokazu; Yagi, Takahito; Fujiwara, Toshiyoshi

    2013-08-01

    Acute renal injury (ARI) is a serious complication after liver transplantation. This study investigated the usefulness of the RIFLE criteria in living donor liver transplantation (LDLT) and the prognostic impact of ARI after LDLT. We analyzed 200 consecutive adult LDLT patients, categorized as risk (R), injury (I), or failure (F), according to the RIFLE criteria. ARI occurred in 60.5% of patients: R-class, 23.5%; I-class, 21%; and F-class, 16%. Four patients in Group-A (normal renal function and R-class) and 26 patients in Group-B (severe ARI: I- and F-class) required renal replacement therapy (P 55 ml/kg (OR 3.7), overexposure to calcineurin inhibitor (OR 2.5), and preoperative diabetes mellitus (OR 3.2). The RIFLE criteria offer a useful predictive tool after LDLT. Severe ARI, defined beyond class-I, could have negative prognostic impact in the acute and late postoperative phases. Perioperative treatment strategies should be designed and balanced based on the risk factors for the further improvement of transplant prognosis. © 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  18. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles

    OpenAIRE

    Lucena, M. Isabel; Molokhia, Mariam; Shen, Yufeng; Thomas J Urban; Aithad, Guruprasad P.; Raúl J Andrade; Day, Christopher P.; Ruiz-Cabello, Francisco; Donaldson, Peter T.; Stephens, Camilla; Pirmohamed, Munir; Romero-Gómez, Manuel; Navarro, José María; Fontana, Roberto J.; Miller, Michael

    2011-01-01

    Producción Científica Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 popula...

  19. Hyperglycemia and liver ischemia reperfusion injury: A role for the advanced glycation endproduct and its receptor pathway

    OpenAIRE

    Yue, S; Zhou, HM; Zhu, JJ; Rao, JH; Busuttil, RW; Kupiec-Weglinski, JW; Lu, L; Zhai, Y

    2015-01-01

    © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons. Although pretransplant diabetes is a risk factor for mortality post-liver transplant, the underlying mechanism has not been fully defined. In a murine liver partial warm ischemia model, we addressed the question of how diabetes/hyperglycemia impacted tissue inflammatory injuries against ischemia reperfusion (IR), focusing on the advanced glycation endproduct (AGE) and its receptor (RAGE) ...

  20. Clotrimazole protects the liver against normothermic ischemia-reperfusion injury in rats.

    Science.gov (United States)

    Iannelli, A; de Sousa, G; Zucchini, N; Peyre, L; Gugenheim, J; Rahmani, R

    2009-12-01

    To investigate the possible antiapoptotic prosurvival role of the pregnane X receptor (PXR) in hepatic ischemia-reperfusion injury in rats using clotrimazole (CTZ), a strong PXR transactivator. Male Sprague-Dawley rats were divided into 3 groups of 6 each: sham-treated, control, and CTZ-treated animals. Control and CTZ-treated animals were subjected to 30 minutes of normothermic ischemia of the whole liver followed by 6 hours of reperfusion. The animals were then killed, and the liver was excised and blood samples collected. Clotrimazole induced a significant increase in expression of the CYP3A gene, indicating PXR transactivation, whereas expression of the antiapoptotic Bcl-xL gene was not increased. Serum concentrations of aspartate aminotransaminase and alanine aminotransaminase were lower in CTZ-treated animals than in control animals (difference not significant). Levels of poly(adenosine diphosphate-ribose) polymerase, a caspase-3 substrate, remained significantly higher in the CTZ-treated group compared with controls (P CTZ-treated animals than in controls (P < .05). Clotrimazole-mediated PXR transactivation protects the liver against ischemia-reperfusion apoptosis in rats. Phospho-p 44/42 extracellular signal-regulated kinase 1,2 is activated, whereas gene expression of heat shock proteins 27, 70, and 90 is downregulated by induction of PXR.

  1. Deficiency in Galectin-3 Promotes Hepatic Injury in CDAA Diet-Induced Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Kazuhiro Nomoto

    2012-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is increasingly recognized as a condition in which excess fat accumulates in hepatocytes. Nonalcoholic steatohepatitis (NASH, a severe form of NAFLD in which inflammation and fibrosis in the liver are noted, may eventually progress to end-stage liver disease. Galectin-3, a β-galactoside-binding animal lectin, is a multifunctional protein. This protein is involved in inflammatory responses and carcinogenesis. We investigated whether galectin-3 is involved in the development of NASH by comparing galectin-3 knockout (gal3−/− mice and wild-type (gal3+/+ mice with choline-deficient L-amino-acid-defined (CDAA diet-induced NAFLD/NASH. Hepatic injury was significantly more severe in the gal3−/− male mice, as compared to the gal3+/+ mice. Data generated by microarray analysis of gene expression suggested that galectin-3 deficiency causes alterations in the expression of various genes associated with carcinogenesis and lipid metabolism. Through canonical pathway analysis, involvement of PDGF and IL-6 signaling pathways was suggested in galectin-3 deficiency. Significant increase of CD14, Fos, and Jun, those that were related to lipopolysaccharide-mediated signaling, was candidate to promote hepatocellular damages in galectin-3 deficiency. In conclusion, galectin-3 deficiency in CDAA diet promotes NAFLD features. It may be caused by alterations in the expression profiles of various hepatic genes including lipopolysaccharide-mediated inflammation.

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

    Science.gov (United States)

    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

  3. Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

    Science.gov (United States)

    Pyzik, Michal; Rath, Timo; Kuo, Timothy T; Win, Sanda; Baker, Kristi; Hubbard, Jonathan J; Grenha, Rosa; Gandhi, Amit; Krämer, Thomas D; Mezo, Adam R; Taylor, Zachary S; McDonnell, Kevin; Nienaber, Vicki; Andersen, Jan Terje; Mizoguchi, Atsushi; Blumberg, Laurence; Purohit, Shalaka; Jones, Susan D; Christianson, Greg; Lencer, Wayne I; Sandlie, Inger; Kaplowitz, Neil; Roopenian, Derry C; Blumberg, Richard S

    2017-04-04

    The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.

  4. Hepatoprotective Evaluation of Ganoderma lucidum Pharmacopuncture: In vivo Studies of Ethanol-induced Acute Liver Injury

    Directory of Open Access Journals (Sweden)

    Sun-Hee Jang

    2014-09-01

    Full Text Available Objectives: Alcohol abuse is a public issue and one of the major causes of liver disease worldwide. This study was aimed at investigating the protective effect of Ganoderma lucidum pharmacopuncture (GLP against hepatotoxicity induced by acute ethanol (EtOH intoxication in rats. Methods: Sprague-Dawley (SD rats were divided into 4 groups of 8 animals each: normal, control, normal saline pharmacopuncture (NP and GLP groups. The control, NP and GLP groups received ethanol orally. The NP and the GLP groups were treated daily with injections of normal saline and Ganoderma lucidum extract, respectively. The control group received no treatment. The rats in all groups, except the normal group, were intoxicated for 6 hours by oral administration of EtOH (6 g/kg BW. The same volume of distilled water was administered to the rats in the normal group. Two local acupoints were used: Qimen (LR14 and Taechung (LR3. A histopathological analysis was performed, and the liver function and the activities of antioxidant enzymes were assessed. Results: GLP treatment reduced the histological changes due to acute liver injury induced by EtOH and significantly reduced the increase in the alanine aminotransferase (ALT enzyme; however, it had an insignificant effect in reducing the increase in aspartate aminotransferase (AST enzyme. It also significantly ameliorated the superoxide dismutase (SOD and the catalase (CAT activities. Conclusion: The present study suggests that GLP treatment is effective in protecting against ethanol-induced acute hepatic injury in SD rats by modulating the activities of ethanol metabolizing enzymes and by attenuating oxidative stress.

  5. Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.

    Directory of Open Access Journals (Sweden)

    Nury M Steuerwald

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset. Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17 immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%, NPV = 97% (95% CI, 93%-100%, accuracy = 96% (95% CI, 92%-100%].Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

  6. [Study on new extraction technology and protective effect of hugan buzure granule on liver injury in mice].

    Science.gov (United States)

    Wu, Tao; Jiang, Lan; Hajiakber, Aisa; Sun, Yuhua

    2011-02-01

    To study on the new preparation technology of Hugan Buzure granule and to compare protective effect on liver injury in rats by different extraction processes. Volatile oil extraction technology, inclusion condition and ethanol extraction condition were selected by orthogonal experiments. The experiment models of liver injury were induced by carbon tetrachloride, bacillus calmette-guerin (BCG) and plus lipolysaccharides (LPS) in rats, respectively. ALT, AST in serum, and MDA, SOD in liver were measured and the rats were killed to calculate the liver coefficient to evaluate the protective effect of Hugan Buzure granule on experimental injury in rats. The optimum conditions of volatile oil extraction were 1:12 of solid-liquid ratio, 2 h of soaking time, and 8 h of extracting time. The optimal beta-cyclodextrin inclusion complex condition was as follows: the volatile oils formed complex with the beta-CD in a ratio of 1: 6 and stirring for 1 h at 40 degrees C. The optimum ethanol extraction was as follows: refluxing and extracting 3 times with 10-fold 50% ethanol, 2 h for each time. Compared with the model group, the new technology extraction of Hugan Buzure granule could obviously inhibite the elevation of serum ALT (P new preparation technology was feasible. The new extraction could protect the liver injury in rats, which was better than extraction of current preparation technology.

  7. Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Provides Protection against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Intestinal Barrier Dysfunction, and Liver Inflammation.

    Science.gov (United States)

    Xiao, Juan; Zhang, Ruifen; Zhou, Qiuyun; Liu, Lei; Huang, Fei; Deng, Yuanyuan; Ma, Yongxuan; Wei, Zhencheng; Tang, Xiaojun; Zhang, Mingwei

    2017-11-08

    Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.

  8. Genipin protects the liver from ischemia/reperfusion injury by modulating mitochondrial quality control.

    Science.gov (United States)

    Shin, Jun-Kyu; Lee, Sun-Mee

    2017-08-01

    Hepatic ischemia and reperfusion (IR) injury is closely linked to oxidative mitochondrial damage. Since mitochondrial quality control (QC) plays a pivotal role in the recovery of impaired mitochondrial function, mitochondrial QC has emerged as a potential therapeutic target. Genipin, an iridoid compound from Gardenia jasminoides, has been showed antioxidant and anti-inflammatory properties. In this study, we investigated the hepatoprotective mechanism of genipin against IR-induced hepatic injury, particularly focusing on mitochondrial QC. Male C57BL/6 mice underwent liver ischemia for 60min, followed by reperfusion for 6h. Genipin (100mg/kg, i.p.) or vehicle (10% Tween 80 in saline) was administrated to mice 1h before ischemia. Liver and blood samples were collected 6h after reperfusion. Hepatic IR increased hepatocellular oxidative damage and induced mitochondrial dysfunction. These phenomena were ameliorated by genipin. Hepatic IR also increased the level of mitochondrial fission, such as dynamin-related protein 1 and the level of PINK1 protein expression. In contrast, hepatic IR decreased the levels of mitochondrial biogenesis related proteins (e.g., peroxisome proliferator-activated receptor gamma coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A), mitophagy related proteins (e.g., Parkin), and fusion related protein (e.g., mitofusin 2). Furthermore, hepatic IR decreased the levels of sirtuin1 protein and phosphorylation of AMP-activated protein kinase. Genipin alleviated these IR-induced changes. These data indicate that genipin protects against IR-induced hepatic injury via regulating mitochondrial QC. (225/250). Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Minocycline and Doxycycline, but not Tetracycline, Mitigate Liver and Kidney Injury after Hemorrhagic Shock/Resuscitation*

    Science.gov (United States)

    Kholmukhamedov, Andaleb; Czerny, Christoph; Hu, Jiangting; Schwartz, Justin; Zhong, Zhi; Lemasters, John J.

    2014-01-01

    have clinical efficacy to mitigate liver and kidney injury after resuscitated hemorrhage. PMID:24978888

  10. Systems Toxicology of Chemically Induced Liver and Kidney Injuries: Histopathology-Associated Gene Co-Expression Modules

    Science.gov (United States)

    2016-01-04

    2016 (wileyonlinelibrary.com) DOI 10.1002/jat.3278Systems toxicology of chemically induced liver and kidney injuries: histopathology -associated gene...Mapping chemical injuries to organ-specific histopathology outcomes via biomarkers will provide a foundation for designing precise and robust diagnostic...exposures and adverse histopathology assessments in Sprague–Dawley rats. We proposed a protocol for selecting gene modules associated with chemical-induced

  11. Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

    Science.gov (United States)

    Tautenhahn, Hans-Michael; Brückner, Sandra; Uder, Christiane; Erler, Silvio; Hempel, Madlen; von Bergen, Martin; Brach, Janine; Winkler, Sandra; Pankow, Franziska; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Dollinger, Matthias; Bartels, Michael; Pietsch, Uta; Amann, Kerstin; Christ, Bruno

    2017-06-01

    In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

  12. Chemotherapy-induced Sinusoidal Injury (CSI) score: a novel histologic assessment of chemotherapy-related hepatic sinusoidal injury in patients with colorectal liver metastasis.

    Science.gov (United States)

    Stevenson, Heather L; Prats, Mariana M; Sasatomi, Eizaburo

    2017-01-07

    Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI). The expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores. Abnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P CSI score was significantly higher in the SOS+ cases when compared to controls (P CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

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

    NARCIS (Netherlands)

    Bruinsma, Bote G.; Wu, Wilson; Ozer, Sinan; Farmer, Adam; Markmann, James F.; Yeh, Heidi; Uygun, Korkut

    2015-01-01

    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

  14. IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

    Directory of Open Access Journals (Sweden)

    A. E. Shcherba

    2013-01-01

    Full Text Available Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury

  15. Hemoglobin-glutamer 200 reduces reperfusion injury of the cold preserved rat liver by induction of heme oxygenase-1.

    Science.gov (United States)

    Topp, Stefan A; Krieg, Andreas; Koch, Alexander; Tidden, Carina M; Ramp, Uwe; Hohlfeld, Thomas; Macher, Arne; Schulte am Esch, Jan; Eisenberger, Claus F; Stoecklein, Nikolas H; Knoefel, Wolfram T

    2008-12-01

    Microcirculatory failure after cold liver preservation and reperfusion impairs tissue oxygenation and causes additional organ damage. Hemoglobin-glutamer (HbG) 200 is a hemoglobin-based oxygen carrying solution capable to improve organ oxygenation. The aim of this study was to evaluate its potential to decrease reperfusion injury after cold liver preservation. Therefore, Wistar rat livers were stored at 4 degrees C for 24 h and reperfused in the isolated perfused rat liver model with a sanguineous perfusate for 180 min. The perfusate consisted of rat blood and Krebs-Henseleit solution (Group A), supplemented by either HES 6% (Group B), or HbG (Groups C and D). In Group D heme oxygenase (HO) activity was blocked by intraperitoneal tin protoporphyrin-IX application before organ harvest. HbG supplementation increased the perfusate hemoglobin by 3,3 g/dL. After 180 min reperfusion perfusate alanine aminotransferase levels (72 +/- 27 micro/L) were significantly reduced in Group C, compared with Groups A and B (140 +/- 28 micro/L and 203 +/- 62 micro/L, respectively). These results correlated with a significant increase of HO-1 expression and activity during reperfusion. These effects could be abolished by tin protoporphyrin-IX application. HbG has been proven to be effective to reduce cold liver preservation-reperfusion injury. The positive effect on reperfusion injury depends on the induction of HO-1, which increases the bilirubin production, an important antioxidant acting as intracellular radical scavenger.

  16. Ethanol-induced liver injury and changes in sulfur amino acid metabolomics in glutathione peroxidase and catalase double knockout mice.

    Science.gov (United States)

    Kim, Sun J; Lee, Joo W; Jung, Young S; Kwon, Do Y; Park, Hee K; Ryu, Chang S; Kim, Sang K; Oh, Goo T; Kim, Young C

    2009-06-01

    Oxidative stress via generation of reactive oxygen species is suggested to be the major mechanism of alcohol-induced liver injury. We investigated the effects of glutathione peroxidase-1 and catalase double deficiency (Gpx-1(-/-)/Cat(-/-)) on liver injury and changes in the sulfur amino acid metabolism induced by binge ethanol administration. Ethanol (5 g/kg) was administered orally to the wild-type and the Gpx-1(-/-)/Cat(-/-) mice every 12 h for a total of three doses. Mice were sacrificed 6 h after the final dose. The Gpx-1/Cat deficiency alone increased malondialdehyde levels in liver significantly. Hepatic methionine adenosyltransferase (MAT) activity and S-adenosylmethionine levels were decreased, however, glutathione contents were not changed. Ethanol administration to the Gpx-1(-/-)/Cat(-/-) mice increased the elevation of serum alanine aminotransferase activity, plasma homocysteine levels, hepatic fat accumulation and lipid peroxidation compared with the wild-type animals challenged with ethanol. Also the reduction of MAT activity and S-adenosylmethionine levels was enhanced, but MATI/III expression was increased significantly. The results indicate that Gpx-1 and Cat have critical roles in the protection of liver against binge ethanol exposure. Augmentation of ethanol-induced oxidative stress may be responsible for the impairment of the transsulfuration reactions and the aggravation of acute liver injury in the Gpx-1(-/-)/Cat(-/-) mice.

  17. Circulating soluble CD36 is a novel marker of liver injury in subjects with altered glucose tolerance

    DEFF Research Database (Denmark)

    Fernández-Real, Jose-Manuel; Handberg, Aase; Ortega, Francisco

    2008-01-01

    Liver injury linked to insulin resistance is characterized by mild to moderate increases in aminotransferase activity. A soluble form of CD36 (sCD36) was recently identified in human plasma. The aim of this study was to evaluate the relationships among plasma sCD36, insulin sensitivity (SI) and i...

  18. [Pharmacotherapeutical efficiency of the dry extract "Ce-god-5" in liver injury induced by CCl4 in white rats].

    Science.gov (United States)

    Dashinamzhilov, Zh B; Turtuev, C D

    2014-01-01

    It has been established that the complex plant remedy "Ce-god-5" possesses the marked hepatoprotective effect in liver injury induced by CCl4 in white rats. The ability to inhibit the processes of lipid peroxidation and stimulate antioxidant system of the body is a basic mechanism of hepatoprotective activity of "Ce-god-5".

  19. Zn(II)-curcumin protects against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism.

    Science.gov (United States)

    Yu, Chuan; Mei, Xue-Ting; Zheng, Yan-Ping; Xu, Dong-Hui

    2014-03-01

    Curcumin can chelate metal ions, forming metallocomplexes. We compared the effects of Zn(II)-curcumin with curcumin against hemorheological alterations, oxidative stress and liver injury in a rat model of acute alcoholism. Oral administration of Zn(II)-curcumin dose-dependently prevented the ethanol-induced elevation of serum malondialdehyde (MDA) content and reductions in glutathione level and superoxide dismutase (SOD) activity. Zn(II)-curcumin also inhibited ethanol-induced liver injury. Additionally, Zn(II)-curcumin dose-dependently inhibited hemorheological abnormalities, including the ethanol-induced elevation of whole blood viscosity, plasma viscosity, blood viscosity at corrected hematocrit (45%), erythrocyte aggregation index, erythrocyte rigidity index and hematocrit. Compared to curcumin at the same dose, Zn(II)-curcumin more effectively elevated SOD activity, ameliorated liver injury and improved hemorheological variables. These results suggest that Zn(II)-curcumin protected the rats from ethanol-induced liver injury and hemorheological abnormalities via the synergistic effect of curcumin and zinc. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. The risk of acute liver injury among users of antibiotic medications : a comparison of case-only studies

    NARCIS (Netherlands)

    Brauer, Ruth; Ruigómez, Ana; Klungel, Olaf|info:eu-repo/dai/nl/181447649; Reynolds, Robert; Feudjo Tepie, Maurille; Smeeth, Liam; Douglas, Ian

    2016-01-01

    PURPOSE: The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self-controlled case series and case-crossover study and (ii) to compare the results between the case-only studies. METHODS: For the self-controlled

  1. Analysis of gene expression changes to elucidate the mechanism of chilling injury in precision-cut liver slices

    NARCIS (Netherlands)

    Guan, Na; Fahy, Gregory M.; Groothuis, Geny M. M.; de Graaf, Inge A. M.; Blomsma, Sylvia

    The exact mechanism of chilling injury (by a decrease of temperature to sub-physiological values), especially in the intact organ, is yet unknown. Precision-cut liver slices (PCLS), which closely resemble the organ from which they are derived, are an ideal in vitro model to study the mechanism of

  2. Effects of polysaccharide from fruiting bodies of Agaricus bisporus, Agaricus brasiliensis, and Phenllinus linteus on alcoholic liver injury

    NARCIS (Netherlands)

    Uyanoglu, M.; Canbek, M.; Griensven, van L.J.L.D.; Yamac, M.; Senturk, H.; Kartkaya, K.; Oglakci, A.; Turgak, O.; Kanbak, G.

    2014-01-01

    In the present study, the curative effects of crude polysaccharides (PSs) from mushrooms on the symptoms of alcoholic liver injury were investigated. PSs from Agaricus bisporus, Agaricus brasiliensis, and Phellinus linteus fruiting bodies were administered by gavage at levels of 100¿mg per kg body

  3. 76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

    Science.gov (United States)

    2011-01-27

    ... Research Manufacturers of America to discuss and debate issues regarding drug-induced liver injury (DILI... to http://www.regulations.gov . Submit written comments to the Division of Dockets Management (HFA... of both basic science and clinical experts, and selecting for specific debate and discussion issues...

  4. [Non-surgical management after blunt traumatic liver injuries: A review article].

    Science.gov (United States)

    Noyola-Villalobos, Héctor Faustino; Loera-Torres, Marco Antonio; Jiménez-Chavarría, Enrique; Núñez-Cantú, Olliver; García-Núñez, Luis Manuel; Arcaute-Velázquez, Fernando Federico

    2016-01-01

    Hepatic trauma is a common cause for admissions in the Emergency Room. Currently, non-surgical management is the standard treatment in haemodynamically stable patients with a success rate of around 85 to 98%. This haemodynamic stability is the most important factor in selecting the appropriate patient. Adjuncts in non-surgical management are angioembolisation, image-guided drainage and endoscopic retrograde cholangiopancreatography. Failure in non-surgical management is relatively rare but potentially fatal, and needs to be recognised and aggressively treated as early as possible. The main cause of failure in non-surgical management is persistent haemorrhage. The aim of this paper is to describe current evidence and guidelines that support non-surgical management of liver injuries in blunt trauma. Copyright © 2016 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  5. Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice

    Directory of Open Access Journals (Sweden)

    Bei Yang

    2014-01-01

    Full Text Available Perfluorooctanoic acid (PFOA is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day. Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice.

  6. Computational discovery and experimental verification of farnesoid X receptor agonist auraptene to protect against cholestatic liver injury.

    Science.gov (United States)

    Gao, Xiaoguang; Fu, Ting; Wang, Changyuan; Ning, Chenqing; Kong, Yulong; Liu, Zhihao; Sun, Huijun; Ma, Xiaodong; Liu, Kexin; Meng, Qiang

    2017-12-15

    Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis. Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro. Importantly, AUR was found to significantly decrease the mortality of cholestatic mice. Dynamic change analysis of bile acids and gene analysis revealed that AUR promoted bile acid efflux from liver into intestine via an induction in FXR-target genes Bsep and Mrp2 expression, and reduced hepatic uptake through an inhibition in Ntcp. Furthermore, AUR reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in Sult2a1. In addition, AUR promoted liver repair through an induction in liver regeneration-related gene, and suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α, IL-1β and IL-6. However, the changes in these genes and protein, as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. These findings suggest that AUR may be an effective approach for the prevention against cholestatic liver diseases. Copyright © 2017. Published by Elsevier Inc.

  7. Global MicroRNA Expression Profiling of Mouse Livers following Ischemia-Reperfusion Injury at Different Stages.

    Directory of Open Access Journals (Sweden)

    Weisheng Zheng

    Full Text Available Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.

  8. Analysis of gene expression changes to elucidate the mechanism of chilling injury in precision-cut liver slices.

    Science.gov (United States)

    Guan, Na; Blomsma, Sylvia A; Fahy, Gregory M; Groothuis, Geny M M; de Graaf, Inge A M

    2013-03-01

    The exact mechanism of chilling injury (by a decrease of temperature to sub-physiological values), especially in the intact organ, is yet unknown. Precision-cut liver slices (PCLS), which closely resemble the organ from which they are derived, are an ideal in vitro model to study the mechanism of chilling injury in the intact organ. In the present study we were able to separate chilling injury from other damaging events such as cryoprotectant toxicity and ice-crystal injury and performed micro-array analysis of regulated genes. Pathway analysis revealed that different stress responses, lipid/fatty acid and cholesterol biosynthesis and metabolism were affected by chilling. This indicates that the cell-membrane might be the primary site and sensor for chilling, which may initiate and amplify downstream intracellular signaling events. Most importantly, we were able to identify gene expression responses from stellate cells and Kupffer cells suggesting the involvement of all liver cell types in the injury. In conclusion, a broad spectrum of previously unknown gene expression changes induced by chilling was identified in the tissue. This is the first report of a systematic investigation on the mechanism of chilling injury in integrated tissue by micro-array analysis under conditions in which other sources of injury are minimal. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Dietary glycine blunts liver injury after bile duct ligation in rats

    Science.gov (United States)

    Froh, Matthias; Zhong, Zhi; Walbrun, Peter; Lehnert, Mark; Netter, Susanne; Wiest, Reiner; Conzelmann, Lars; Gäbele, Erwin; Hellerbrand, Claus; Schölmerich, Jürgen; Thurman, Ronald G

    2008-01-01

    AIM: To investigate the effects of (dietary) glycine against oxidant-induced injury caused by bile duct ligation (BDL). METHODS: Either a diet containing 5% glycine or a standard diet was fed to male Sprague-Dawley (SD) rats. Three days later, BDL or sham-operation was performed. Rats were sacrificed 1 to 3 d after BDL. The influence of deoxycholic acid (DCA) in the presence or absence of glycine on liver cells was determined by measurement of calcium and chloride influx in cultivated Kupffer cells and lactate dehydrogenase (LDH) activity was determined in the supernatant of cultivated hepatocytes. RESULTS: Serum alanine transaminase levels increased to about 600 U/L 1 d after BDL. However, enzyme release was blunted by about two third in rats receiving glycine. Release of the alkaline phosphatase and aspartate aminotransferase was also blocked significantly in the group fed glycine. Focal necrosis was observed 2 d after BDL. Glycine partially blocked the histopathological changes. Incubation of Kupffer cells with DCA led to increased intracellular calcium that could be blocked by incubation with glycine. However, systemic blockage of Kupffer cells with gadolinium chloride had no effects on transaminase release. Incubation of isolated hepatocytes with DCA led to a significant release of LDH after 4 h. This release was largely blocked when incubation with glycine was performed. CONCLUSION: These data indicate that glycine significantly decreased liver injury, most likely by a direct effect on hepatocytes. Kupffer cells do not appear to play an important role in the pathological changes caused by cholestasis. PMID:18932277

  10. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

    Science.gov (United States)

    Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

    2015-03-01

    Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.

  11. Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Tolosa, Laia; Jiménez, Nuria; Pérez, Gabriela; Castell, José V; Gómez-Lechón, M José; Donato, M Teresa

    2017-07-31

    Drug-induced liver injury (DILI) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI. To this end, HepG2 cells with different expression levels of specific drug-metabolism enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, GSTM1 and UGT2B7) were exposed to nine drugs with reported hepatotoxicity. A panel of pre-lethal mechanistic parameters (mitochondrial superoxide production, mitochondrial membrane potential, ROS production, intracellular calcium concentration, apoptotic nuclei) was used. Significant differences were observed according to the level of expression and/or the combination of several drug-metabolism enzymes in the cells created ad hoc according to the enzymes implicated in drug toxicity. Additionally, the main mechanisms implicated in the toxicity of the compounds were also determined showing also differences between the different types of cells employed. This screening tool allowed to mimic the variability in drug metabolism in the population and showed a highly efficient system for predicting human DILI, identifying the metabolic phenotypes associated with increased DILI risk, and indicating the mechanisms implicated in their toxicity.

  12. Effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats.

    Science.gov (United States)

    Li, Bin; Zhu, Lijie; Wu, Ting; Zhang, Jiachen; Jiao, Xinyao; Liu, Xiuying; Wang, Yanqun; Meng, Xianjun

    2015-03-01

    Alcohol-induced oxidative stress plays a crucial role in the pathological development of alcoholic liver disease. The aim of this study was to investigate the effects of triterpenoid from Schisandra chinensis on oxidative stress in alcohol-induced liver injury in rats. We found that the administration of triterpenoid attenuated alcohol-induced oxidative stress in multiple organs including liver. Moreover, the impaired liver function and histological changes resulted from alcohol consumption was improved by triterpenoid treatment. Finally, we found that pretreatment with triterpenoid from Schisandra chinensis to alcohol-fed rats increased the expression level of haem oxygenase-1 (HO-1) while inhibited the induction of cytochrome P-450 2E1 (CYP2E1) in liver microsomes. Further assays revealed that the microsomal activity of HO-1 was accordingly induced whereas CYP2E1 was suppressed in rats received triterpenoid intervention. Our findings suggest that triterpenoid from Schisandra chinensis may protect against alcohol-induced liver injury through ameliorating oxidative stress in rats.

  13. Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress.

    Science.gov (United States)

    Lv, Peng; Fan, Li-Juan; Li, Hong-Yun; Meng, Qing-Shun; Liu, Jie

    2015-01-01

    This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-κB p65 (NF-κBp65), tumor necrosis factor α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-κBp65, TNF-α, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats. © 2015 by the Association of Clinical Scientists, Inc.

  14. Hepatoprotective effect of Cymbopogon citratus aqueous extract against hydrogen peroxide-induced liver injury in male rats.

    Science.gov (United States)

    Rahim, Saleh Muhammad; Taha, Ekhlass Muhi; Al-janabi, Muneef Saeb; Al-douri, Bushra Ismael; Simon, Kumar Das; Mazlan, Abd Gaffar

    2014-01-01

    Cymbopogon citratus (Poaceae) a tropical perennial herb plant that is widely cultivated to be eaten either fresh with food or dried in tea or soft drink has been reported to possess a number of medicinal and aromatic properties. This study aimed at evaluating the protective effects of C. citratus aqueous extract against liver injury induced by hydrogen peroxide (H2O2), in male rats. Twenty-five rats were randomly divided into five different groups of five animals in each group; (1) Control. (2) Received H2O2 (0.5%) with drinking water. (3), and (4) received H2O2 and C. citratus (100 mg·kg(-1) b wt), vitamin C (250 mg·kg(-1) b wt) respectively. (5), was given C. citratus alone. The treatments were administered for 30 days. Blood samples were collected and serum was used for biochemical assay including liver enzymes activities, total protein, total bilirubin and malonaldehyde, glutathione in serum and liver homogenates. Liver was excised and routinely processed for histological examinations. C. citratus attenuated liver damage due to H2O2 administration as indicated by the significant reduction (pcitratus could effectively ameliorate H2O2-induced oxidative stress and prevent liver injury in male rats.

  15. Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

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    Kamran Qureshi

    2014-01-01

    Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

  16. Does Citrulline Have Protective Effects on Liver Injury in Septic Rats?

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    Bin Cai

    2016-01-01

    Full Text Available Citrulline (Cit supplementation was proposed to serve as a therapeutic intervention to restore arginine (Arg concentrations and improve related functions in sepsis. This study explored whether citrulline had positive effects on liver injury and cytokine release in the early stages of sepsis. The cecal ligation and puncture (CLP model was utilized in our study. Rats were divided into four groups: normal, Cit, CLP, and CLP+Cit. The CLP group and CLP+Cit group were separated into 6-, 12-, and 24-hour groups, according to the time points of sacrifice after surgery. Intragastric administration of L-citrulline was applied to rats in Cit and CLP+Cit groups before surgery. Serum AST and ALT levels and levels of MDA, SOD, NO, and iNOS in the liver tissues were evaluated. Plasma concentrations of Cit and Arg were assessed using HPLC-MS/MS. Serum concentrations of cytokines and chemokines were calculated by Luminex. Results showed SOD activities of CLP+Cit groups were significantly higher than that of CLP groups, contrasting with the MDA and NO levels which were significantly lower in CLP+Cit groups than in CLP groups. In addition, plasma concentrations of TNF-α, IL-6, and IL-1β were significantly lower in the CLP+Cit 6-hour group than in the CLP 6-hour group.

  17. Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

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    Sarah M. DeNucci

    2010-01-01

    Full Text Available The finding of more severe steatohepatitis in alcohol fed Long Evans (LE compared with Sprague Dawley (SD and Fisher 344 (FS rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.

  18. Coronin 1 is dispensable for leukocyte recruitment and liver injury in concanavalin A-induced hepatitis.

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    Siegmund, Kerstin; Lee, Woo-Yong; Tchang, Vincent S; Stiess, Michael; Terracciano, Luigi; Kubes, Paul; Pieters, Jean

    2013-06-01

    Coronin 1, a member of the evolutionary conserved coronin protein family, is highly expressed in all leukocytes. In mice and human, genetic inactivation of coronin 1 results in immuno-deficiencies that are linked to a strong reduction of naïve T cell numbers in peripheral organs, while memory/effector T cells, B cells, monocytes and neutrophils are less or not at all affected. Whether or not coronin 1 is important for leukocyte functions such as migration and phagocytosis has been a matter of debate. The current work addresses coronin 1-dependent leukocyte function by analyzing the response of coronin 1-deficient mice in a model of concanavalin A (Con A)-induced liver injury. Histological evaluation and determination of serum liver enzyme levels showed that coronin 1-deficient mice develop signs of acute hepatitis similar to Con A-treated wild type mice despite a reduced activation of T cells in the absence of coronin 1. Furthermore, analysis by intravital microscopy following Con A stimulation revealed that Gr-1+ neutrophils and CD4+ T cell adhesion in the post-sinusoidal venules increased in wild type as well as in coronin 1-deficient mice. These results suggest that coronin 1, while important for naïve T cell survival, is dispensable for other leukocyte function under inflammatory conditions in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Drug-Induced Liver Injury: Twenty Five Cases of Acute Hepatitis Following Ingestion of Polygonum multiflorum Thunb

    Science.gov (United States)

    Jung, Kyoung Ah; Yoo, Seung Suk; Kim, Hong Jun; Choi, Su Nyoung; Ha, Chang Yoon; Kim, Hyun Jin; Kim, Tae Hyo; Jung, Woon Tae; Lee, Ok Jae; Lee, Jong Sil; Shim, Sang Goon

    2011-01-01

    Background/Aims Complementary medicines, including herbal preparations and nutritional supplements, are widely used without prescriptions. As a result, there has been growing interest in the risk of hepatotoxicity with these agents. It is difficult to determine causal relationships between these herbal preparations and hepatotoxicity. We report on 25 patients diagnosed with toxic hepatitis following ingestion of Polygonum multiflorum Thunb. Methods Twenty-five patients (median age, 48 years [24 to 65 years]; M:F=18:7) with suspected P. multiflorum Thunb-induced liver injury were admitted to our hospital between 2007 and 2009. We analyzed clinical and histological data, including the types and the duration of P. multiflorum Thunb intake and the duration of hospital care. We also determined the type of liver injury using the R ratio (serum activity of ALT/serum activity of ALP). Results The types of complementary medicine used included tea (n=16), liquor (n=5), tea and liquor (n=2), powder (n=1), and honeyed pudding (n=1). The most common presenting sign was jaundice (76%), and 18 patients (72%) had evidence of hepatocellular liver injury. Histo