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Sample records for suppressed liver injury

  1. Arctigenin protects against liver injury from acute hepatitis by suppressing immune cells in mice.

    Science.gov (United States)

    Cheng, Xixi; Wang, Huafeng; Yang, Jinlai; Cheng, Yingnan; Wang, Dan; Yang, Fengrui; Li, Yan; Zhou, Dongmei; Wang, Yanxia; Xue, Zhenyi; Zhang, Lijuan; Zhang, Qi; Yang, Luhong; Zhang, Rongxin; Da, Yurong

    2018-03-23

    As a phenylpropanoid and dibenzylbutyrolactone lignan present in medical plants, such as those used in traditional Chinese herbal medicine, including Arctium lappa (Niubang), arctigenin exhibits antimicrobial, anti-inflammatory, and anticancer activities. In this study, we investigated the protective role of arctigenin in Concanavalin A (ConA)-induced acute hepatitis in mice. Arctigenin remarkably reduced the congestion and necroinflammation of livers, and improved hepatic function (ALT and AST) in ConA-induced acute hepatitis in vivo. The infiltration of CD4 T, NKT and macrophages into the livers was found to be reduced with arctigenin treatment. Arctigenin suppressed ConA-induced T lymphocyte proliferations that might have resulted from enhanced IL-10 production by macrophages and CD4 T cells. These results suggested that arctigenin could be a powerful drug candidate for acute hepatitis through immune suppression. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. 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.

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

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    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.

  4. Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction.

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    Caroline C Duwaerts

    Full Text Available Both Kupffer cells and invariant natural killer T (iNKT cells suppress neutrophil-dependent liver injury in a mouse model of biliary obstruction. We hypothesize that these roles are interdependent and require iNKT cell-Kupffer cell cross-activation. Female, wild-type and iNKT cell-deficient C57Bl/6 mice were injected with magnetic beads 3 days prior to bile duct ligation (BDL in order to facilitate subsequent Kupffer cell isolation. On day three post-BDL, the animals were euthanized and the livers dissected. Necrosis was scored; Kupffer cells were isolated and cell surface marker expression (flow cytometry, mRNA expression (qtPCR, nitric oxide (NO (. production (Griess reaction, and protein secretion (cytometric bead-array or ELISAs were determined. To address the potential role of NO (. in suppressing neutrophil accumulation, a group of WT mice received 1400W, a specific inducible nitric oxide synthase (iNOS inhibitor, prior to BDL. To clarify the mechanisms underlying Kupffer cell-iNKT cell cross-activation, WT animals were administered anti-IFN-γ or anti-lymphocyte function-associated antigen (LFA-1 antibody prior to BDL. Compared to their WT counterparts, Kupffer cells obtained from BDL iNKT cell-deficient mice expressed lower iNOS mRNA levels, produced less NO (. , and secreted more neutrophil chemoattractants. Both iNOS inhibition and IFN-γ neutralization increased neutrophil accumulation in the livers of BDL WT mice. Anti-LFA-1 pre-treatment reduced iNKT cell accumulation in these same animals. These data indicate that the LFA-1-dependent cross-activation of iNKT cells and Kupffer cells inhibits neutrophil accumulation and cholestatic liver injury.

  5. A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production.

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    Uchio, Ryusei; Higashi, Yohei; Kohama, Yusuke; Kawasaki, Kengo; Hirao, Takashi; Muroyama, Koutarou; Murosaki, Shinji

    2017-01-01

    Turmeric ( Curcuma longa ) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 µg/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3·0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-α protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone.

  6. War liver injuries

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    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.

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

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    Fu-Chao Liu

    2016-01-01

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

  8. 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 ...

  9. Pyrroloquinoline-quinone suppresses liver fibrogenesis in mice.

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    Dongwei Jia

    Full Text Available Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injuries, and its progression toward cirrhosis is the major cause of liver-related morbidity and mortality worldwide. However, anti-fibrotic treatment remains an unconquered area for drug development. Accumulating evidence indicate that oxidative stress plays a critical role in liver fibrogenesis. In this study, we found that PQQ, a natural anti-oxidant present in a wide variety of human foods, exerted potent anti-fibrotic and ROS-scavenging activity in Balb/C mouse models of liver fibrosis. The antioxidant activity of PQQ was involved in the modulation of multiple steps during liver fibrogenesis, including chronic liver injury, hepatic inflammation, as well as activation of hepatic stellate cells and production of extracellular matrix. PQQ also suppressed the up-regulation of RACK1 in activated HSCs in vivo and in vitro. Our data suggest that PQQ suppresses oxidative stress and liver fibrogenesis in mice, and provide rationale for the clinical application of PQQ in the prevention and treatment of liver fibrosis.

  10. Antidepressant-induced liver injury.

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    DeSanty, Kevin P; Amabile, Celene M

    2007-07-01

    To review principles of drug-induced liver injury (DILI), summarize characteristics of antidepressant-mediated liver injury, and provide recommendations for monitoring and management. A search relating to antidepressant-induced liver injury was performed using MEDLINE (1966-March 2007). Search terms included antidepressant, cholestasis, hepatotoxicity, jaundice, liver injury, toxic hepatitis, and transaminases. Reference citations not identified in the initial database search were also utilized. All English-language case reports, letters, and review articles identified from the data sources were used. Case reports and letters relating to hepatotoxicity from antidepressant overdose were excluded. Antidepressant-induced liver injury described in published cases were of the idiopathic type and, by definition, cannot be predicted based on dose or specific risk factors. Paroxetine had the largest number of cases within the selective serotonin-reuptake inhibitor class. Nefazodone, a serotonin-norepinephrine reuptake inhibitor, appeared to have the most serious cases and is the only antidepressant agent that carries a Food and Drug Administration Black Box Warning regarding hepatotoxicity. The tricyclic antidepressants and monoamine oxidase inhibitors are capable of producing hepatotoxicity, but fewer cases with these agents have been reported in the past 15 years, possibly due to a decline in their use. Causality has not been well established in all reports due to the concurrent use of other drugs and/or underlying liver disease. Most antidepressant agents have the potential to produce idiopathic liver injury. There is no way to prevent idiopathic DILI, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. The clinician must be careful to provide ongoing therapy of the underlying depressive disorder and be aware of possible drug discontinuation syndromes should potential hepatotoxicity be suspected.

  11. MORPHOLOGY OF ISCHEMIC INJURY OF LIVER ALLOGRAFT

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    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. 

  12. High velocity missile injuries of the liver

    African Journals Online (AJOL)

    large exit wounds or evidence of cavitating injury to the liver or all of the above. Bomb blast fragment injury with marked tissue destruction with burns of the surrounding tissue was also considered as high velocity inissile injury. Demographic data and mechanisms of injury were noted. A policy of mandatory laparotomy was ...

  13. Autophagy and Liver Ischemia-Reperfusion Injury

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    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.

  14. [The catalase inhibitor aminotriazole alleviates acute alcoholic liver injury].

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    Ai, Qing; Ge, Pu; Dai, Jie; Liang, Tian-Cai; Yang, Qing; Lin, Ling; Zhang, Li

    2015-02-25

    In this study, the effects of catalase (CAT) inhibitor aminotriazole (ATZ) on alcohol-induced acute liver injury were investigated to explore the potential roles of CAT in alcoholic liver injury. Acute liver injury was induced by intraperitoneal injection of alcohol in Sprague Dawley (SD) rats, and various doses of ATZ (100-400 mg/kg) or vehicle were administered intraperitoneally at 30 min before alcohol exposure. After 24 h of alcohol exposure, the levels of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) in plasma were determined. The degree of hepatic histopathological abnormality was observed by HE staining. The activity of hepatic CAT, hydrogen peroxide (H₂O₂) level and malondialdehyde (MDA) content in liver tissue were measured by corresponding kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in plasma were determined by ELISA method. The results showed that treatment with ATZ dose-dependently suppressed the elevation of ALT, AST and LDH levels induced by alcohol exposure, and that ATZ alleviated alcohol-induced histopathological alterations. Furthermore, ATZ inhibited the activity of CAT, reduced hepatic levels of H₂O₂and MDA in alcohol exposed rats. ATZ also decreased the levels of plasma TNF-α and IL-6 in rats with alcohol exposure. These results indicated that ATZ attenuated alcohol-induced acute liver injury in rats, suggesting that CAT might play important pathological roles in the pathogenesis of alcoholic liver injury.

  15. Protective Effects of Guava Pulp on Cholestatic Liver Injury

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    Peng, Jian; Yue, Chunyan; Qiu, Kai; Chen, Jie; Aller, Maria-Angeles; Ko, Kwang Suk

    2013-01-01

    Background. Cholestatic liver injury is a leading cause of chronic liver diseases involved with oxidative stress changes and inflammation; thus, antioxidant and anti-inflammation compound-rich guava may play a pivotal role in protecting against the cholestatic liver damages. Our aims for this study are to determine whether guava pulp (GP) has protective effects on cholestatic liver injury-induced mouse model and on interleukin-6 (IL-6) mediated proliferation of QBC939 cholangiocarcinoma cell line. Methods. Mice were induced to cholestatic liver damage by left and median bile duct ligation (LMBDL) surgery and then treated with GP. Plasma and liver samples were collected for biochemical and pathological assays. 5-Bromo-2′-deoxyuridine (BrdU) assay and Western blots were used to detect proliferation and gene expression in QBC939 cells, respectively. Results. Compared with LMBDL only group, in GP-treated mice, the levels of alanine aminotransferase (ALT) and bilirubin decreased, biliary epithelial cell proliferation and liver fibrogenesis were suppressed, Src/MEK/ERK1/2/c-Myc pathway and expressions of transforming growth factor β1(TGF-β1), tissue inhibitor of metalloproteinases TIMP), and procollagen 1α1(COL1α1) were downregulated significantly. Moreover, the GP extract reduced IL-6-enhanced QBC939 cell proliferation, p-ERK, and c-Myc expression as well. Conclusions. GP may provide a new perspective for the treatment of cholestatic liver injury. PMID:27335829

  16. Radiation-associated liver injury.

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    Pan, Charlie C; Kavanagh, Brian D; Dawson, Laura A; Li, X Allen; Das, Shiva K; Miften, Moyed; Ten Haken, Randall K

    2010-03-01

    The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver. Published by Elsevier Inc.

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

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    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

  18. Radiation-Associated Liver Injury

    OpenAIRE

    Pan, Charlie C; Kavanagh, Brian D; Dawson, Laura A.; Li, X. Allen; Das, Shiva K; Miften, Moyed; Haken, Randall K Ten

    2010-01-01

    The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on ...

  19. Drug-induced liver injury

    DEFF Research Database (Denmark)

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

    2017-01-01

    and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent...... 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...

  20. Administration of Drug Induce Liver Injury to the Inpatients with Liver Disease

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    Sindy E. Cinthya

    2012-06-01

    Full Text Available Drug induced liver injury is a serious human health problems. Pre-existing liver diseases are risk factor of liver injury by the drugs. The study was conducted to evaluate the use of drug induced liver injury in patients hospitalized with liver disease at one hospital in Kota Tasikmalaya. Informations were collected retrospectively in the period 2010-2011 from the patient’s medical record. A total of 52 patients research subjects were discovered 50 patients (96% using drug induced liver injury and 2 patients (4% did not use it. Drug induced liver injury most widely used were ranitidine (31.3%, ceftriaxone (23.1%, and paracetamol (16.4%. Level of the DILI usage in patient with liver disease was relative high (96%. Further research is needed to determine the effect of the drug induced liver injury to liver injury.

  1. 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

  2. Liver injury in invasive aspergillus. Echographic findings

    International Nuclear Information System (INIS)

    Otero Fernandez, R.; Garcia Revillo, J.; Paez Moreno, J.; Zurera Tendero, L.J.

    1994-01-01

    Aspergillus is the second most common mycoses in immuno compromised patients. The invasive form is associated with a mortality of approximately 100%. We present a case of invasive aspergillus in a heart transplant recipient in whom ultrasound disclosed the presence of liver injury which was later confirmed by necropsy. We review the available literature. (Author) 15 refs

  3. 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.

  4. Mechanisms of viral hepatitis induced liver injury.

    Science.gov (United States)

    Nakamoto, Yasunari; Kaneko, Shuichi

    2003-09-01

    Among seven human hepatitis viruses (A to E, G and TT virus), hepatitis B (HBV) and C (HCV) viruses are able to persist in the host for years and principally contribute to the establishment of chronic hepatitis. During the course of persistent infection, continuous intrahepatic inflammation maintains a cycle of liver cell destruction and regeneration that often terminates in hepatocellular carcinoma (HCC). While the expression and retention of viral proteins in hepatocytes may influence the severity and progression of liver disease, the mechanisms of liver injury in viral hepatistis are defined to be due not to the direct cytopathic effects of viruses, but to the host immune response to viral proteins expressed by infected hepatocytes. In the process of liver injury, hepatocellular death (apoptosis) induced by the proapoptotic molecules of T cells activated following antigen recognition triggers a cascade of antigen nonspecific effector systems and causes necroinflammatory disease. Accordingly, the regulation of the immune response, e.g., via the cell death pathways, in chronically infected patients should prevent the development of HCC.

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

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    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.

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

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    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.

  7. Elemental characterization of injuries in fish liver

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-01-01

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

  8. 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.

  9. 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.

  10. Phytosterols Promote Liver Injury and Kupffer Cell Activation in Parenteral Nutrition–Associated Liver Disease

    Science.gov (United States)

    El Kasmi, Karim C.; Anderson, Aimee L.; Devereaux, Michael W.; Vue, Padade M.; Zhang, Wujuan; Setchell, Kenneth D. R.; Karpen, Saul J.; Sokol, Ronald J.

    2014-01-01

    Parenteral nutrition–associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)–based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD. PMID:24107776

  11. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers

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    Kim, Jae-Sung, E-mail: Jae.Kim@surgery.ufl.edu; Wang, Jin-Hee, E-mail: jin-hee.wang@surgery.ufl.edu; Biel, Thomas G., E-mail: Thomas.Biel@surgery.ufl.edu; Kim, Do-Sung, E-mail: do-sung.kim@surgery.med.ufl.edu; Flores-Toro, Joseph A., E-mail: Joseph.Flores-Toro@surgery.ufl.edu; Vijayvargiya, Richa, E-mail: rvijayvargiya@ufl.edu; Zendejas, Ivan, E-mail: ivan.zendejas@surgery.ufl.edu; Behrns, Kevin E., E-mail: Kevin.Behrns@surgery.ufl.edu

    2013-12-15

    Onset of the mitochondrial permeability transition (MPT) plays a causative role in ischemia/reperfusion (I/R) injury. Current therapeutic strategies for reducing reperfusion injury remain disappointing. Autophagy is a lysosome-mediated, catabolic process that timely eliminates abnormal or damaged cellular constituents and organelles such as dysfunctional mitochondria. I/R induces calcium overloading and calpain activation, leading to degradation of key autophagy-related proteins (Atg). Carbamazepine (CBZ), an FDA-approved anticonvulsant drug, has recently been reported to increase autophagy. We investigated the effects of CBZ on hepatic I/R injury. Hepatocytes and livers from male C57BL/6 mice were subjected to simulated in vitro, as well as in vivo I/R, respectively. Cell death, intracellular calcium, calpain activity, changes in autophagy-related proteins (Atg), autophagic flux, MPT and mitochondrial membrane potential after I/R were analyzed in the presence and absence of 20 μM CBZ. CBZ significantly increased hepatocyte viability after reperfusion. Confocal microscopy revealed that CBZ prevented calcium overloading, the onset of the MPT and mitochondrial depolarization. Immunoblotting and fluorometric analysis showed that CBZ blocked calpain activation, depletion of Atg7 and Beclin-1 and loss of autophagic flux after reperfusion. Intravital multiphoton imaging of anesthetized mice demonstrated that CBZ substantially reversed autophagic defects and mitochondrial dysfunction after I/R in vivo. In conclusion, CBZ prevents calcium overloading and calpain activation, which, in turn, suppresses Atg7 and Beclin-1 depletion, defective autophagy, onset of the MPT and cell death after I/R. - Highlights: • A mechanism of carbamazepine (CBZ)-induced cytoprotection in livers is proposed. • Impaired autophagy is a key event contributing to lethal reperfusion injury. • The importance of autophagy is extended and confirmed in an in vivo model. • CBZ is a potential

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

    Directory of Open Access Journals (Sweden)

    Qinlong Liu

    2012-01-01

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

  13. 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.

  14. Assessment of emerging biomarkers of liver injury in human subjects.

    Science.gov (United States)

    Schomaker, Shelli; Warner, Roscoe; Bock, Jeff; Johnson, Kent; Potter, David; Van Winkle, Joyce; Aubrecht, Jiri

    2013-04-01

    Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug-induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury.

  15. 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.

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

    Science.gov (United States)

    Karidis, Nikolaos P; Kouraklis, Gregory; Theocharis, Stamatios E

    2006-01-01

    The hepatocyte, the main cellular component of the liver, exhibits variable susceptibility to different types of injury induced by endogenous or exogenous factors. Hepatocellular dysfunction or death and regeneration are dependent upon the complicated interactions between numerous biologically active molecules. Platelet-activating factor (PAF) seems to play a pivotal role as the key mediator of liver injury in the clinical and experimental setting, as implied by the beneficial effects of its receptor antagonists. A comprehensive up-to-date overview of the specific functional and regulatory properties of PAF in conditions associated with liver injury is attempted in this review. PMID:16773686

  17. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice

    International Nuclear Information System (INIS)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl 3 ) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified.

  18. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice.

    Science.gov (United States)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-11

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl₃) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. 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...

  20. 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.

  1. 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.

  2. Computed tomographic findings of liver injury in adults

    International Nuclear Information System (INIS)

    Ha, Deok Gi; Lee, Hyeon Kyeong; Lee, Won Jae; Oh, Yeon Hee; Lee, Sung Hee; Yun, Jee Yeong; Lee, Tae Woo; Lee, Sung Woo; Park, Soo Soung

    1994-01-01

    We studied to compare computed tomographic(CT) findings of liver injury with management method in adults and, moreover, to present the CT basis for the management. We retrospectively reviewed CT scans of 43 adults diagnosed as liver injury during a 66 month period. Thirty-eight patients were hemodynamically stable. Thirty-two of them were managed conservatively, whereas six managed operatively. Five unstable patients underwent emergency operation. We classified CT findings according to the severity of liver injuries(ie, hematoma, laceration, and periportal tracking) and hemoperitoneum, ranging from grade 1 to 5 and from 0 to 3 +. respectively. Thus, we compared the CT classifications with their management(ie, operation rate), especially hemodynamically stable patients. Operation rates of all patients and hemodynamically stable patients were 26% and 16%, respectively. Operation rate at each grade of liver injury was low, especially in hemodynamically stable, despite relatively high operation rate in grade 4. Operation rate of 3+ homoperitoneum was 100%, including hemodynamically stable patients, in contrast to otherwise low operation rate of others. Most liver injury in adults, including grade 4, were managed conservatively, especially hemodynamically stable. Though large amount of hemoperitoneum(ie, 3+) required operation, most hemooperitoeum were managed conservatively. Thus, CT findings of liver injury is helpful in the decision for the management method

  3. PROTECTIVE EFFECTS OF HYPOTHALAMIC BETA-ENDORPHIN NEURONS AGAINST ALCOHOL-INDUCED LIVER INJURIES AND LIVER CANCERS IN RAT ANIMAL MODELS

    Science.gov (United States)

    Murugan, Sengottuvelan; Boyadjieva, Nadka; Sarkar, Dipak K.

    2014-01-01

    Background Recently, retrograde tracing has provided evidence for an influence of hypothalamic β-endorphin (BEP) neurons on the liver, but functions of these neurons are not known. We evaluated the effect of BEP neuronal activation on alcohol-induced liver injury and hepatocellular cancer. Methods Male rats received either BEP neuron transplants or control transplants in the hypothalamus and randomly assigned to feeding alcohol-containing liquid diet or control liquid diet for 8 weeks or to treatment of a carcinogen diethylnitrosamine (DEN). Liver tissues of these animals were analyzed histochemically and biochemically for tissue injuries or cancer. Results Alcohol-feeding increased liver weight and induced several histopathological changes such as prominent microvesicular steatosis and hepatic fibrosis. Alcohol feeding also increased protein levels of triglyceride, hepatic stellate cell activation factors and catecholamines in the liver and endotoxin levels in the plasma. However, these effects of alcohol on the liver were reduced in animals with BEP neuron transplants. BEP neuron transplants also suppressed carcinogen-induced liver histopathologies such as extensive fibrosis, large focus of inflammatory infiltration, hepatocelluar carcinoma, collagen deposition, numbers of preneoplastic foci, levels of hepatic stellate cell activation factors and catecholamines, as well as inflammatory milieu and the levels of NK cell cytotoxic factors in the liver. Conclusion These findings are the first evidence for a role of hypothalamic BEP neurons in influencing liver functions. Additionally, the data identify that BEP neuron transplantation prevents hepatocellular injury and hepatocellular carcinoma formation possibly via influencing the immune function. PMID:25581653

  4. Topiramate ameliorates abdominal aorta cross-clamping induced liver injury in rats.

    Science.gov (United States)

    Cure, Erkan; Cure, Medine C; Tumkaya, Levent; Kalkan, Yildiray; Aydin, Ibrahim; Kirbas, Aynur; Yilmaz, Arif; Yuce, Suleyman; Gokce, Mehmet F

    2014-01-01

    Ischemia/reperfusion (I/R) injury in the liver occurs after a prolonged period of ischemia followed by restoration of hepatic blood perfusion. During the surgery of abdominal aorta, I/R injury causes damage to lower extremities and many organs, especially liver. The antioxidant and tumor necrosis factor-alpha (TNF-α) suppression effects of topiramate (TPM) have been reported in several studies. We evaluated the potential protective effect of TPM on cellular damage in liver tissue during I/R injury. Thirty male Wistar albino rats were divided into three groups: Control, I/R, and I/R plus TPM (I/R + TPM) groups. Laparotomy without I/R injury was performed in the control group. After laparotomy, cross-ligation of infrarenal abdominal aorta was applied for 2 h in I/R groups that was followed by 2 h of reperfusion. TPM (100 mg/kg/day) was orally administrated to the animals in the I/R + TPM group for seven consecutive days before I/R procedure. The I/R group's TNF-α and interleukin-6 (IL-6) levels were significantly higher than those of the control (P = 0.010; P = 0.002) and I/R + TPM groups (P = 0.010; P = 0.002, respectively). Asymmetric dimethyl arginine (ADMA) levels of I/R group were higher than the control (P = 0.015) and I/R + TPM groups. I/R caused serious histopathological damage to liver tissue; however, TPM led to very low histopathological changes. Our data demonstrated that TPM treatment prominently decreases the severity of liver I/R injury. TPM pretreatment may have preventive effects on liver injury via I/R during intra-abdominal surgery.

  5. Effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury

    Directory of Open Access Journals (Sweden)

    Yin-Tian Deng

    2016-11-01

    Full Text Available Objective: To study the effect of selective hepatic inflow occlusion during liver cancer resection on liver ischemia-reperfusion injury. Methods: A total of 68 patients with primary liver cancer who underwent left liver resection in our hospital between May 2012 and August 2015 were selected for study and divided into group A (selective hepatic inflow occlusion of left liver and group B (Prignle hepatic inflow occlusion according to different intraoperative blood occlusion methods, serum was collected before and after operation to determine liver enzyme content, the removed liver tissue was collected to determine energy metabolism indexes, inflammation indexes and oxidative stress indexes. Results: 1 d, 3 d and 5 d after operation, GPT, GOT, GGT, LDH and ALP content in serum of both groups were significantly higher than those before operation, and GPT, GOT, GGT, LDH and ALP content in serum of group A 1 d, 3 d and 5 d after operation were significantly lower than those of group B; ATP, ADP, AMP, PI3K, AKT, GSK3β, T-AOC, PrxI and Trx content in liver tissue of group A were significantly higher than those of group B while PTEN, IL-12p40, MDA and MPO content were significantly lower than those of group B. Conclusions: Selective hepatic inflow occlusion during liver cancer resection can reduce the liver ischemia-reperfusion injury, improve the energy metabolism of liver cells and inhibit inflammation and oxidative stress in liver tissue.

  6. Drug-induced liver injury associated with HIV medications.

    Science.gov (United States)

    Jain, Mamta K

    2007-08-01

    Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.

  7. 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

  8. 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.

  9. Prostaglandin E1 Preconditioning Attenuates Liver Ischemia Reperfusion Injury in a Rat Model of Extrahepatic Cholestasis.

    Science.gov (United States)

    Xu, Feng; Liu, Xiaolin; Wang, Chao; Dai, Chaoliu

    2018-01-01

    The aim of this study is to explore the hepatoprotective effect of intraportal prostaglandin E1 (PGE1) on liver ischemia reperfusion (IR) injury using an extrahepatic cholestatic model, observing oxidative stress markers, proinflammatory factors, apoptotic marker proteins, and an adhesion molecule. The extrahepatic cholestatic model was induced by common bile duct ligation. After seven days, rats were subjected to ischemia by Pringle maneuver for 15 min, followed by 1, 6, or 24 h of reperfusion. Prostaglandin E1 (PGE group) or normal saline (NS group) was continuously infused from 15 min before liver ischemia to 1 h after reperfusion. After reperfusion, histopathological evaluation of the liver was performed, as were measurements of bilirubin, biochemical enzymes, oxidative stress markers (GSH and MDA), proinflammatory factors (MPO, TNF- α , and IL-1 β ), apoptotic marker proteins (Bcl-2 and Bax), and the adhesion molecule (ICAM-1). PGE1 pretreatment attenuated IR injury in extrahepatic cholestatic liver probably by suppressing MDA, MPO, TNF- α , IL-1 β , ICAM-1, and Bax levels and improving GSH and Bcl-2 levels. In conclusion, PGE1 protects extrahepatic cholestatic liver from IR injury by improving hepatic microcirculation and reducing oxidative stress damage, intrahepatic neutrophil infiltration, and hepatocyte apoptosis.

  10. Prostaglandin E1 Preconditioning Attenuates Liver Ischemia Reperfusion Injury in a Rat Model of Extrahepatic Cholestasis

    Directory of Open Access Journals (Sweden)

    Feng Xu

    2018-01-01

    Full Text Available The aim of this study is to explore the hepatoprotective effect of intraportal prostaglandin E1 (PGE1 on liver ischemia reperfusion (IR injury using an extrahepatic cholestatic model, observing oxidative stress markers, proinflammatory factors, apoptotic marker proteins, and an adhesion molecule. The extrahepatic cholestatic model was induced by common bile duct ligation. After seven days, rats were subjected to ischemia by Pringle maneuver for 15 min, followed by 1, 6, or 24 h of reperfusion. Prostaglandin E1 (PGE group or normal saline (NS group was continuously infused from 15 min before liver ischemia to 1 h after reperfusion. After reperfusion, histopathological evaluation of the liver was performed, as were measurements of bilirubin, biochemical enzymes, oxidative stress markers (GSH and MDA, proinflammatory factors (MPO, TNF-α, and IL-1β, apoptotic marker proteins (Bcl-2 and Bax, and the adhesion molecule (ICAM-1. PGE1 pretreatment attenuated IR injury in extrahepatic cholestatic liver probably by suppressing MDA, MPO, TNF-α, IL-1β, ICAM-1, and Bax levels and improving GSH and Bcl-2 levels. In conclusion, PGE1 protects extrahepatic cholestatic liver from IR injury by improving hepatic microcirculation and reducing oxidative stress damage, intrahepatic neutrophil infiltration, and hepatocyte apoptosis.

  11. 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

  12. Diphenhydramine as a Cause of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yunseok Namn

    2017-01-01

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

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

    Directory of Open Access Journals (Sweden)

    Akiko Kojima-Yuasa

    2016-12-01

    Full Text Available Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme’s activity and reduced intracellular thiobarbituric acid reactive substances (TBARS levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

  14. Polyol Pathway Exacerbated Ischemia/Reperfusion-Induced Injury in Steatotic Liver

    Science.gov (United States)

    Zhang, Changhe; Huang, Changjun; Tian, Yuan

    2014-01-01

    Background. The polyol pathway, a bypass pathway of glucose metabolism initiated by aldose reductase (AR), has been shown to play an important role in mediating tissue ischemia/reperfusion (I/R) impairment recently. Here, we investigated how and why this pathway might affect the fatty liver following I/R. Methods. Two opposite models were created: mice with high-fat-diet-induced liver steatosis were treated with aldose reductase inhibition (ARI) and subsequent I/R; and AR-overexpressing L02 hepatocytes were sequentially subjected to steatosis and hypoxia/reoxygenation. We next investigated (a) the hepatic injuries, including liver function, histology, and hepatocytes apoptosis/necrosis; (b) the NAD(P)(H) contents, redox status, and mitochondrial function; and (c) the flux through the caspase-dependent apoptosis pathway. Results. AR-inhibition in vivo markedly attenuated the I/R-induced liver injuries, maintained the homeostasis of NAD(P)(H) contents and redox status, and suppressed the caspase-dependent apoptosis pathway. Correspondingly, AR overexpression in vitro presented the opposite effects. Conclusion. The flux through the polyol pathway may render steatotic liver greater vulnerability to I/R. Interventions targeting this pathway might provide a novel adjunctive approach to protect fatty liver from ischemia. PMID:24967007

  15. 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.

  16. Identification and Characterization of Cefazolin-Induced Liver Injury.

    Science.gov (United States)

    Alqahtani, Saleh A; Kleiner, David E; Ghabril, Marwan; Gu, Jiezhun; Hoofnagle, Jay H; Rockey, Don C

    2015-07-01

    Cephalosporin antibiotics are popular because they have a broad spectrum of activity and are generally well tolerated; however, cephalosporin-induced liver injury is considered rare. We describe a new syndrome associated with a single intravenous dose of cefazolin and the clinical features of cephalosporin-induced liver injury. The Drug-Induced Liver Injury (DILI) Network collected detailed clinical data on 1212 patients with DILI between 2004 and 2012. We analyzed data from 41 patients in whom cephalosporins were implicated as primary agents of liver disease; 33 formally were adjudicated as having cephalosporin-induced DILI. Nineteen patients developed clinically apparent DILI after a single intravenous dose of cefazolin. All patients developed self-limited liver injury 3 to 23 days after receiving cefazolin during surgery-often during a minor outpatient procedure. The latency period was 20 days. Clinical features included itching, jaundice, nausea, fever, and rash. Laboratory abnormalities included a mixed or cholestatic pattern of serum enzyme increases. We identified 14 more patients with DILI attributed to other cephalosporins (5 first-generation, 2 second-generation, 6 third-generation, and 1 fourth-generation agent). Although latency and injury patterns were similar for cefazolin and other cephalosporins, the other cephalosporins were associated with more severe courses of injury, including 2 deaths from liver failure. DILI can develop after a single dose of cefazolin. It is characterized by a latency period of 1 to 3 weeks after exposure, a cholestatic biochemical pattern, and a self-limited moderate to severe clinical course. Other cephalosporins can cause a similar but more severe injury. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    SIZENANDO VIEIRA STARLING

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

  18. Histologic Characterization of Kratom Use-Associated Liver Injury.

    Science.gov (United States)

    Riverso, Michael; Chang, Michael; Soldevila-Pico, Consuelo; Lai, Jinping; Liu, Xiuli

    2018-02-01

    Kratom is an herbal product derived from the leaves of Southeast Asian Mitragyna speciosa trees. It has traditionally been used by indigenous people to relieve fatigue and manage pain, diarrhea, or opioid withdrawal. The use of kratom has become more commonplace in the United States for similar purposes. Only rare reports of kratom liver toxicity exist in the literature but without histologic characterization. Herein, we report one case of kratom use-associated liver toxicity in a 38-year-old patient. The patient complained of dark colored urine and light colored stools after using kratom. He had unremarkable physical examination. Laboratory testing at presentation revealed elevated alanine aminotransferase (389 U/L), aspartate aminotransferase (220 U/L), total bilirubin (5.1 mg/dL), and alkaline phosphatase (304 U/L). There was no serology evidence of viral hepatitis A, B, and C. The acetaminophen level at presentation was below detectable limits. Ultrasound examination of the right upper quadrant revealed normal echogenicity and contour of the liver without bile ductal dilatation or disease of the gallbladder. The patient underwent liver biopsy 4 days after the initial presentation which revealed a pattern of acute cholestatic liver injury including zone 3 hepatocellular and canalicular cholestasis, focal hepatocyte dropout, mild portal inflammation, and bile duct injury. Kratom was stopped, the patient improved clinically and biochemically and was discharged 8 days after the initial presentation. To our best knowledge, this is the first case report detailing the histology of kratom use-associated liver injury.

  19. Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats

    International Nuclear Information System (INIS)

    Balaha, Mohamed; Kandeel, Samah; Barakat, Waleed

    2016-01-01

    Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1 ml/kg 10% CCL 4 in olive oil three times/week (every other day) for 12 weeks to induce hepatic cirrhosis. Carvedilol (10 mg/kg/day suspended in 0.5% CMC orally), silymarin (50 mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL 4 induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries. - Highlights: • Chronic liver damage ends into hepatocellular carcinoma in 5% of patients. • Persistent elevation of IL-6 induces hepatocarcinogenesis in chronic

  20. Global Consequences of Liver Ischemia/Reperfusion Injury

    Science.gov (United States)

    Kalimeris, Konstantinos; Tasoulis, Marios-Konstantinos; Lykoudis, Panagis M.; Smyrniotis, Vassilios; Arkadopoulos, Nikolaos

    2014-01-01

    Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ's post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion. PMID:24799983

  1. Injuries of the retrohepatic inferior vena cava and the liver

    Directory of Open Access Journals (Sweden)

    Koprivica Radenko

    2008-01-01

    Full Text Available Beckground. Injuries of the retrohepatic inferior vena cava, and the liver have mortality rate up to 71-78%. We presented a patient with combined injury of the retrohepatic inferior vena cava, liver, craniocerebral and thoracic traumas, inflicted in a traffic accident. Case report. Man, 20 years old has been injured in a traffic accident. At admission, 20 minutes after the injury, the patient was comatose and hypotensive. Bloody content was obtained by abdominal tracer. The patient underwent emergent laparotomy, utilizing trifurcated incision and cell saver device. Abdominal exploration revealed two liters of free blood and massive retroperitoneal hematoma. Manual compression of the liver was done, as well as perihepatic packing, complete hepatic vascular exclusion and mobilization of the right liver lobe. Due to impressive chemodynamic instability supraceliac aortic clamping was performed. Upon exposure of the retrohepatic inferior vena cava and right liver lobe, multiple lacerations of retrohepatic inferior vena cava and right hepatic vein, and right hepatic vein avulsion were found. We also identified an injury of VII and VIII segments of the liver (grade V according to the Moore's classification. Nonexpansive hepatoduodenal ligament hematoma and the injury of II and III segments of the liver group II/III according to Moore were found. Venorrhaphy of the inferior vena cava was done in the area of circumference of the right hepatic vein, a portion of which served as autologous vein patch. Continuous prolene 3/0 venorrhaphy of the distal caval laceration was done. Total caval and aorta clamping time of the inferior vena cava was 41 minutes. Atypical resection, debridment, of hepatic segments was done by using a harmonic scalpel. Hepatoduodenal ligament was declamped after 65 minutes. Fibrin glue was applied on the resectioned area of liver. The patient received 3.2 l of autologuos blood transfusion with 5 units of packed red blood cells, 6

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

    African Journals Online (AJOL)

    Green tea contains four major polyphenols, of which EGCG is the most active antioxidant component [10]. In the present study, the protective role of EGCG against oxidative stress and liver injury in rats subjected to CLP-induced sepsis was investigated. EXPERIMENTAL. Animals and reagents. Adult male Wistar rats (mean ...

  3. 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...

  4. Hepatic injury after whole-liver irradiation in the rat

    International Nuclear Information System (INIS)

    Geraci, J.P.; Jackson, K.L.; Mariano, M.S.; Leitch, J.M.

    1985-01-01

    Radiation-induced hepatic injury in rats, which is characterized by marked ascites accompanied by liver necrosis, fibrosis, and vein lesions, is described in this study. These adverse sequelae are produced within 30 days after irradiation if there is surgical removal of two-thirds of the liver immediately after whole-liver irradiation. The LD/sub 50/30/ day and median survival time after liver irradiation and two-thirds partial hepatectomy is 24 Gy and 17 days, respectively. Death is preceded by reduction in liver function as measured by [ 131 I]-labeled rose bengal clearance. Prior to death, liver sepsis and endotoxemia were detected in most irradiated, partially hepatectomized animals. Pretreatment of the animals with endotoxin and/or antibiotic decontamination of the GI tract resulted in increased survival time, but no irradiated, partially hepatectomized animal survived beyond 63 days. This suggests that sepsis and endotoxemia resulting from the bacteria in the intestine are the immediate cause of death after 30-Gy liver irradiation and partial hepatectomy. It is concluded that the hepatectomized rat model is an economical and scientifically manageable experimental system to study a form of radiation hepatitis that occurs in compromised human livers

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

    African Journals Online (AJOL)

    We evaluated the impact of altering nitric oxide release on acute liver injury, the associated gut injury and bacterial translocation, at different time intervals. Methods: An acute rat liver injury model induced by D-galactosamine was used. Sprague Dawley rats were divided into four main groups: normal control, acute liver ...

  6. 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.

  7. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

    Science.gov (United States)

    Puglisi, Maria Ausiliatrice; Tesori, Valentina; Lattanzi, Wanda; Piscaglia, Anna Chiara; Gasbarrini, Giovanni Battista; D'Ugo, Domenico M.; Gasbarrini, Antonio

    2011-01-01

    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. PMID:22228987

  8. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of withaferin A on tumor growth and metastasis in liver in a nude mouse model. Methods: Withaferin A was injected through a portal vein to the orthotopic liver tumor in a nude mice model. Xenogen in vivo imaging system was used to monitor tumor growth and metastasis. The effect of ...

  9. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  11. Melatonin Protective Effects against Liver Ischemia/Reperfusion Injury

    Directory of Open Access Journals (Sweden)

    Abbas Khonakdar-Tarsi

    2016-02-01

    Full Text Available Hepatic ischemia-reperfusion (I/R is a common phenomenon during liver surgery, transplantation, infection and trauma which results in damage and necrosis of the hepatic tissue through different pathways. Mechanisms involved in I/R damage are very intricate and cover several aspects. Several factors are involved in I/R-induced damages; briefly, decrease in sinusoidal perfusion and ATP generation because of low or no O2 supply, increase in production of reactive oxygen species (ROS and inflammatory factors and destruction of parenchymal cells resulted by these molecules are of the main causes of liver tissue injury during reperfusion. Melatonin’s antioxidant effect, and regulatory roles in the expression of different genes in the I/R insulted liver have been investigated by several studies. Melatonin and its metabolites are of the powerful direct scavengers of free radicals and ROS, so it can directly protect liver cell impairment from oxidative stress following I/R. In addition, this bioactive molecule up-regulates anti-oxidant enzyme genes like superoxide dismutase (SOD, glutathione peroxidase (GSH-Px and catalase (CAT. Tumor necrosis factors (TNF-α and interleukin-1 (IL-1, as potent pro-inflammatory factors, are generated in huge amounts during reperfusion. Melatonin is able to alleviate TNF-α generation and has hepatoprotective effect during I/R. It reduces the production of pro-inflammatory cytokines and chemokines via reducing the binding of NF-κB to DNA. Imbalance between vasodilators (nitric oxide, NO and vasoconstrictors (endothelin, ET during I/R was shown to be the primary cause of liver microcirculation disturbance. Melatonin helps maintaining the stability of liver circulation and reduces hepatic injury during I/R through preventing alteration of the normal balance between ET and NO. The aim of this review was to explore the mechanisms of liver I/R injuries and the protective effects of melatonin against them.

  12. Judge of surgical indication for blunt injuries of liver and spleen by CT imaging

    International Nuclear Information System (INIS)

    Nakagawa, Takao; Yokoyama, Toshimitsu; Suga, Hiroyasu; Deguchi, Yoshizumi; Hasegawa, Yasuhiro; Muraoka, Ryusuke; Ishikawa, Masatake; Suzuki, Tadashi.

    1997-01-01

    Recent studies have elucidated that the findings of injuries of parenchimatous organs such as liver and spleen by computed tomography (CT) are consistent with those by surgical operation. But it is still unclear whether CT findings can determine operative indication for blunt injuries of liver and spleen. We performed a retrospective study on 35 lesions of blunt injuries of liver and spleen in 33 cases for blunt injuries of liver and spleen at our hospitals to examine whether CT findings can determine the severity of damage and surgical indication for the injuries, and the following results were obtained. Based on CT findings, the presence of injury was confirmed in all cases except for one lesion. Comparison of CT findings and operative or laparoscopic findings in 12 cases undergoing operation or laparoscopy for liver/spleen injury revealed that the findings of each method were almost the same with few exceptions. When liver/spleen injuries were classified according to the Japanese Association for the Surgery of Trauma (JAST) Classification of injury of liver and spleen, cases with emergency operation had severe injury of Type IIIb for the liver and Type IIIb or higher for the spleen, while conservative treatment was possible for injury cases of Type IIIa or lower of the liver and spleen. From these results, the JAST Classification of these injuries based upon CT imaging was found to be a suitable method for selecting an appropriate treatment for blund injury of liver and spleen. (author)

  13. Judge of surgical indication for blunt injuries of liver and spleen by CT imaging

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, Takao; Yokoyama, Toshimitsu; Suga, Hiroyasu; Deguchi, Yoshizumi; Hasegawa, Yasuhiro; Muraoka, Ryusuke [Fukui Medical School (Japan); Ishikawa, Masatake; Suzuki, Tadashi

    1997-10-01

    Recent studies have elucidated that the findings of injuries of parenchimatous organs such as liver and spleen by computed tomography (CT) are consistent with those by surgical operation. But it is still unclear whether CT findings can determine operative indication for blunt injuries of liver and spleen. We performed a retrospective study on 35 lesions of blunt injuries of liver and spleen in 33 cases for blunt injuries of liver and spleen at our hospitals to examine whether CT findings can determine the severity of damage and surgical indication for the injuries, and the following results were obtained. Based on CT findings, the presence of injury was confirmed in all cases except for one lesion. Comparison of CT findings and operative or laparoscopic findings in 12 cases undergoing operation or laparoscopy for liver/spleen injury revealed that the findings of each method were almost the same with few exceptions. When liver/spleen injuries were classified according to the Japanese Association for the Surgery of Trauma (JAST) Classification of injury of liver and spleen, cases with emergency operation had severe injury of Type IIIb for the liver and Type IIIb or higher for the spleen, while conservative treatment was possible for injury cases of Type IIIa or lower of the liver and spleen. From these results, the JAST Classification of these injuries based upon CT imaging was found to be a suitable method for selecting an appropriate treatment for blund injury of liver and spleen. (author)

  14. 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.

  15. 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

  16. SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jiyung Shin

    2013-11-01

    Full Text Available Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD+-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

  17. Mouse Precision-Cut Liver Slices as an ex Vivo Model To Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Groothuis, Geny M. M.; Merema, M.T.

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in

  18. Withaferin A Suppresses Liver Tumor Growth in a Nude Mouse ...

    African Journals Online (AJOL)

    The effect of withaferin A on tumor volume, invasive growth pattern, expression of Pyk2, upregulation of BAX/P53, apoptotic signaling and ... the direct effect of withaferin A on liver cancer cells and endothelial cells was further investigated. Results: A significant ... tumor cell invasiveness in colon cancer [7] and is related to ...

  19. 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

  20. 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

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

    International Nuclear Information System (INIS)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    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

  2. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

    Science.gov (United States)

    Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

  3. Carvacrol attenuates N-nitrosodiethylamine induced liver injury in experimental Wistar rats

    Directory of Open Access Journals (Sweden)

    Balan Rajan

    2015-06-01

    Full Text Available Carvacrol is a main constituent in the essential oils of countless aromatic plants including Origanum Vulgare and Thymus vulgari, which has been assessed for substantial pharmacological properties. In recent years, notable research has been embarked on to establish the biological actions of Carvacrol for its promising use in clinical applications. The present study is an attempt to reveal the protective role of Carvacrol against N-Nitrosodiethylamine (DEN induced hepatic injury in male Wistar albino rats. DEN is an egregious toxin, present in numerous environmental factors, which enhances chemical driven liver damage by inducing oxidative stress and cellular injury. Administration of DEN (200 mg/kg bodyweight, I.P to rats results in elevated marker enzymes (in both serum and tissue. Carvacrol (15 mg/kg body weight suppressed the elevation of marker enzymes (in both serum and tissue and augmented the antioxidants levels. The hoisted activities of Phase I enzymes and inferior activities of Phase II enzymes were observed in DEN-administered animals, whereas Carvacrol treated animals showed improved near normal activity. Histological observations also support the protective role of Carvacrol against DEN induced liver damage. Final outcome from our findings intimate that Carvacrol might be beneficial in attenuating toxin induced liver damage.

  4. Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia-Reperfusion Injury

    Science.gov (United States)

    Theodoraki, Kassiani; Karmaniolou, Iosifina; Tympa, Aliki; Tasoulis, Marios-Konstantinos; Nastos, Constantinos; Vassiliou, Ioannis; Arkadopoulos, Nikolaos; Smyrniotis, Vassilios

    2016-01-01

    Liver ischemia/reperfusion injury may significantly compromise hepatic postoperative function. Various hepatoprotective methods have been improvised, aiming at attenuating IR injury. With ischemic preconditioning (IPC), the liver is conditioned with a brief ischemic period followed by reperfusion, prior to sustained ischemia. Ischemic postconditioning (IPostC), consisting of intermittent sequential interruptions of blood flow in the early phase of reperfusion, seems to be a more feasible alternative than IPC, since the onset of reperfusion is more predictable. Regarding the potential mechanisms involved, it has been postulated that the slow intermittent oxygenation through controlled reperfusion decreases the burst production of oxygen free radicals, increases antioxidant activity, suppresses neutrophil accumulation, and modulates the apoptotic cascade. Additionally, favorable effects on mitochondrial ultrastructure and function, and upregulation of the cytoprotective properties of nitric oxide, leading to preservation of sinusoidal structure and maintenance of blood flow through the hepatic circulation could also underlie the protection afforded by postconditioning. Clinical studies are required to show whether biochemical and histological improvements afforded by the reperfusion/reocclusion cycles of postconditioning during early reperfusion can be translated to a substantial clinical benefit in liver resection and transplantation settings or to highlight more aspects of its molecular mechanisms. PMID:27340509

  5. Burst-suppression is reactive to photic stimulation in comatose children with acquired brain injury

    DEFF Research Database (Denmark)

    Nita, Dragos A.; Moldovan, Mihai; Sharma, Roy

    2016-01-01

    -suppression in children with acquired brain injury. Methods: Intensive care unit electroencephalographic monitoring recordings containing burst-suppression were obtained from 5 comatose children with acquired brain injury of various etiologies. Intermittent photic stimulation was performed at 1 Hz for 1 min to assess...

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

    African Journals Online (AJOL)

    Fourteen patients sustained gun shot wounds while one was injured by a bomb blast fragment. Ages ranged from 2 to 33 years (mean 24.4 years). Two patients sustained liver injury alone while the rest had other associated visceral injuries as well. Grade I, II and III liver injuries were seen in 7, 5 and 2 patients respectively.

  7. Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.

    Directory of Open Access Journals (Sweden)

    Sathidpak Nantasanti

    Full Text Available The tumor suppressors Retinoblastoma (Rb and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC. DDC is metabolized mainly by cytochrome P450 (Cyp3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.

  8. Outcome of children with blunt liver or spleen injuries: Experience from a single institution in Korea.

    Science.gov (United States)

    Kim, Ki Hoon; Kim, Jin Soo; Kim, Woon-Won

    2017-02-01

    The aim of this study is to evaluate the demographics, injury pattern, and treatment outcomes among children hospitalized for the management of blunt liver and spleen injury at a single institution in Korea, and to document trends in treatment strategies of children with blunt torso trauma. Children (injuries, hospitalized at our center between May 2010 and February 2016, were included in the present study. Data were retrospectively analyzed for demographic and injury-related information were obtained. During the study period, 34 patients with blunt liver injury and 21 patients with blunt spleen injury presented at the center. The most common cause of liver and spleen injury was motor vehicle collision, followed by fall. Thirty patients (88.2%) with liver injuries and 18 patients (85.7%) with spleen injuries were managed conservatively. No cases of mortality occurred in patients with spleen injury group; one patient (2.9%) died in patients with liver injury due to uncontrolled bleeding. Our data demonstrated that 85.7% of patients with spleen injuries and 88.2% of patients with liver injuries were managed nonoperatively. Operative management was chosen more selectively, being applied in patients with high grade organ injury scores or abrupt changes in vital status. Our findings will contribute to the available data concerning children with traumatic injuries in Korea. Copyright © 2016 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

  9. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Directory of Open Access Journals (Sweden)

    Zheng G

    2017-12-01

    Full Text Available Guoyin Zheng,1,* Fengfeng Mo,2,* Chen Ling,3,* Hao Peng,1 Wei Gu,1 Min Li,2 Zhe Chen1 1Department of Traditional Chinese Medicine, Changhai Hospital, 2Department of Military Hygiene, Second Military Medical University, 3Department of Biology, School of Life Science, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine ­aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. Keywords: Portulaca oleracea L., diabetes, liver injury, Rho–NFκB

  10. 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.

  11. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-08-15

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

  12. 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.

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

    Science.gov (United States)

    Guzman, Grace; Kallwitz, Eric R; Wojewoda, Christina; Chennuri, Rohini; Berkes, Jamie; Layden, Thomas J; Cotler, Scott J

    2009-01-01

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

  14. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Science.gov (United States)

    Peng, Hao; Gu, Wei; Li, Min; Chen, Zhe

    2018-01-01

    Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane) on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. PMID:29343942

  15. 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).

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

    Science.gov (United States)

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

    2014-12-01

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

  17. Saturation toxicokinetics of thioacetamide: role in initiation of liver injury.

    Science.gov (United States)

    Chilakapati, Jaya; Shankar, Kartik; Korrapati, Midhun C; Hill, Ronald A; Mehendale, Harihara M

    2005-12-01

    Thioacetamide (TA), a potent centrilobular hepatotoxicant, undergoes a two-step bioactivation mediated by microsomal CYP2E1 to TA sulfoxide (TASO), and further to TA-S,S-dioxide (TASO2), a reactive metabolite that initiates cellular necrosis. Our earlier studies showed that bioactivation-mediated liver injury of TA is not dose-proportional. The objective of this study was to examine whether increasing doses of TA lead to enzyme saturation, thereby resulting in lack of dose-response for injury: bioactivation of TA --> TASO --> TASO2 may follow zero-order kinetics. A 12-fold dose range of TA (50, 300, and 600 mg/kg i.p.) was injected into male Sprague-Dawley rats. TA and TASO were quantified in plasma, liver, and urine by high-performance liquid chromatography. With increasing doses, the apparent elimination half-lives of TA and TASO increased linearly, indicating that TA bioactivation exhibits saturation kinetics. Increasing TA dose resulted in greater-than-proportional increases in plasma TA and TASO levels. The TASO/TA ratio was inversely proportional to the dose of TA. Covalent binding of 14C-TA-derived radiolabel to liver macromolecules showed a less-than-dose-proportionate increase with a 12-fold higher dose. Less than dose-proportional covalent binding was confirmed in liver microsomal incubations with 14C-TA. Three-fold higher excretion of TASO was seen in urine at the highest dose (600 mg/kg) compared with the lowest dose (50 mg TA/kg). Incubation of TA with rat liver microsomes and purified baculovirus-expressed rat and human CYP2E1 Supersomes, over a concentration range of 0.01 to 10 mM, revealed saturation of TA conversion to TASO at and above 0.05 mM TA concentration, comparable to in vivo plasma and liver levels achieved upon administration of higher doses. Calculated K(m) values for TA (0.1 mM) and TASO (0.6 mM) suggest that the second step of TA bioactivation is 6-fold less efficient. Collectively, the findings indicate saturation of CYP2E1 at the

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

    OpenAIRE

    HAO Kunyan; YU Yuecheng

    2016-01-01

    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. Hepator...

  19. Acute Liver Injury Is Independent of B Cells or Immunoglobulin M.

    Directory of Open Access Journals (Sweden)

    James A Richards

    Full Text Available Acute liver injury is a clinically important pathology and results in the release of Danger Associated Molecular Patterns, which initiate an immune response. Withdrawal of the injurious agent and curtailing any pathogenic secondary immune response may allow spontaneous resolution of injury. The role B cells and Immunoglobulin M (IgM play in acute liver injury is largely unknown and it was proposed that B cells and/or IgM would play a significant role in its pathogenesis.Tissue from 3 models of experimental liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury and patients transplanted following paracetamol overdose were stained for evidence of IgM deposition. Mice deficient in B cells (and IgM were used to dissect out the role B cells and/or IgM played in the development or resolution of injury. Serum transfer into mice lacking IgM was used to establish the role IgM plays in injury.Significant deposition of IgM was seen in the explanted livers of patients transplanted following paracetamol overdose as well as in 3 experimental models of acute liver injury (ischemia-reperfusion injury, concanavalin A hepatitis and paracetamol-induced liver injury. Serum transfer into IgM-deficient mice failed to reconstitute injury (p = 0.66, despite successful engraftment of IgM. Mice deficient in both T and B cells (RAG1-/- mice (p<0.001, but not B cell deficient (μMT mice (p = 0.93, were significantly protected from injury. Further interrogation with T cell deficient (CD3εKO mice confirmed that the T cell component is a key mediator of sterile liver injury. Mice deficient in B cells and IgM mice did not have a significant delay in resolution following acute liver injury.IgM deposition appears to be common feature of both human and murine sterile liver injury. However, neither IgM nor B cells, play a significant role in the development of or resolution from acute liver injury. T cells appear to be key

  20. Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish

    Directory of Open Access Journals (Sweden)

    Changwen Zhang

    2016-11-01

    Full Text Available Alcoholic liver disease (ALD results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the

  1. 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.

  2. Acute kidney injury in liver transplant candidates : A position paper on behalf of the Liver Intensive Care Group of Europe

    NARCIS (Netherlands)

    Angeli, Paolo; Bezinover, Dimitri; Biancofiore, Gianni; Bienholz, Anja; Findlay, James; Paugam Burtz, Catherine; Reyntjens, Koen; Sakai, Tetsuro; Saner, Fuat H; Tomescu, Dana; Wagener, Gebhard; Weiss, Emmanuel

    INTRODUCTION: Acute kidney injury is associated with high mortality in the perioperative period of liver transplantation. The aim of this position paper was to provide an up-to-date overview with special emphases on diagnosis, risk factors, and treatment. EVIDENCE ACQUISITION: The Liver Intensive

  3. 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

  4. Inhibitory effect of TCCE on CCl4-induced overexpression of IL-6 in acute liver injury.

    Science.gov (United States)

    Gao, Jing; Dou, Huan; Tang, Xin-Hui; Xu, Li-Zhi; Fan, Yi-Mei; Zhao, Xiao-Ning

    2004-11-01

    Terminalia catappa L. leaves have been shown to protect against acute liver injury produced by some hepatotoxicants, but the active components and mechanisms are not clear. This study was designed to characterize the protective effects of the chloroform fraction of the ethanol extract of T. catappa leaves (TCCE) against carbon tetrachloride (CCl4)-induced hepatotoxicity in mice, and analyze the changes in expression level of interleukin-6 (IL-6) in the process. It was found that TCCE pretreatment (10 or 30 mg/kg, ig) protected mice from CCl4 toxicity, as evidenced by the reversed alterations in serum alanine aminotransferase (sALT) and serum aspartate aminotransferase (sAST) activities. Additionally liver tissues were subjected to RT-PCR, Western blot and immunohistochemistry to analyze changes in IL-6 expression. It was found that TCCE markedly suppressed the CCl4-induced over-transcription of IL-6 gene. Consistent with the result, the expression of IL-6 protein was also blocked by TCCE in CCl4-stimulated mice, especially in the area around central vein on liver tissue section. In conclusion, TCCE is effective in protecting mice from the hepatotoxicity produced by CCl4, and the mechanisms underlying its protective effects may be related to the inhibition on the overexpression of IL-6 mainly around terminal hepatic vein.

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

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    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.

  6. 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.

  7. Relationship of hyponatremia with degree of liver injury and prognosis in patients with decompensated liver cirrhosis

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    LI Ying

    2016-03-01

    Full Text Available ObjectiveTo investigate the relationship between hyponatremia and degree of liver injury, complications and survival time, and the prognostic value of hyponatremia in patients with decompensated liver cirrhosis. MethodsA total of 218 patients who were diagnosed with decompensated liver cirrhosis for the first time in The First Affiliated Hospital of Dalian Medical University from January 2000 to March 2005 were enrolled in this study, and according to the serum sodium concentration, these patients were divided into group Ⅰ with a serum sodium concentration of ≥130 mmol/L (n=51, group Ⅱ with a serum sodium concentration of ≥120 and <130 mmol/L (n=97, group Ⅲ with a serum sodium concentration of <120 mmol/L (n=70. The patients′sex, age, serum sodium concentration, Child-Pugh class, and complications were analyzed, and the survival time was calculated. The one-way analysis of variance was applied for comparison of continuous data between groups, and the least significant difference t-test was applied for comparison between any two patients; the chi-square test was applied for comparison of categorical data between groups; the Kaplan-Meier method was applied for survival analysis, and the Cox regression model was applied for regression analysis. ResultsCompared with groups Ⅰ and Ⅱ, group Ⅲ had the highest proportion of patients with Child-Pugh C cirrhosis. With the increasing Child-Pugh score, the serum sodium concentration decreased; the serum sodium concentration showed significant differences across the patients with Child-Pugh A, B, and C cirrhosis (F=17.336, P<0.001, and differed significantly between any two groups of these patients (all P <0.05. Compared with groups Ⅰ and Ⅱ, group Ⅲ had the highest incidence rate of complications, and the incidence rates of hepatic encephalopathy and hepatorenal syndrome showed significant differences across the three groups (χ2=17.718 and 6.277, both P<0.05. Group Ⅲ had a

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

    Science.gov (United States)

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

    2017-04-01

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

  9. LLDT-8 protects against cerebral ischemia/reperfusion injury by suppressing post-stroke inflammation

    Directory of Open Access Journals (Sweden)

    Yanke Chen

    2016-06-01

    Conclusion: LLDT-8 exerted anti-inflammatory effects and protected against acute cerebral ischemia/reperfusion injury possibly by acting through the IκB/NF-κB cascade to suppress microglia-mediated neuroinflammation.

  10. Ameliorative Effects of 5-Hydroxymethyl-2-furfural (5-HMF from Schisandra chinensis on Alcoholic Liver Oxidative Injury in Mice

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    Wei Li

    2015-01-01

    Full Text Available The aim of this paper is to evaluate the protective effect of 5-hydroxymethyl-2-furfural (5-HMF on acute alcohol-induced liver oxidative injury in mice. 5-HMF, a maillard reaction product, was isolated from the fruits of Schisandra chinensis for animal experiments. Experimental ICR mice were pretreated with different doses of 5-HMF (7.5, 15, and 30 mg/kg for seven days by gavage feeding. Biochemical markers and enzymatic antioxidants from serum and liver tissue were examined. Our results showed that the activities of ALT (alanine aminotransferase, AST (aspartate transaminase, TC (total cholesterol, TG (triglyceride, L-DLC (low density lipoprotein in serum and the levels of MDA (malondialdehyde in liver tissue, decreased significantly (p < 0.05 in the 5-HMF-treated group compared with the alcohol group. On the contrary, enzymatic antioxidants CAT (catalase, GSH-Px (glutathione peroxidase, and GSH SOD (superoxide dismutase were markedly elevated in liver tissue treated with 5-HMF (p < 0.05. Furthermore, the hepatic levels of pro-inflammatory response marker tumor necrosis factor-alpha (TNF-α and interleukin-1β (IL-1β were significantly suppressed (p < 0.05. Histopathological examination revealed that 5-HMF (30 mg/kg pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It is suggested that the hepatoprotective effects exhibited by 5-HMF on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

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

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    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.

  12. 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 ...

  13. 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.

  14. Quercetin prevents alcohol-induced liver injury through targeting of PI3K/Akt/nuclear factor-κB and STAT3 signaling pathway

    Science.gov (United States)

    Zhu, Minglin; Zhou, Xuefeng; Zhao, Jinping

    2017-01-01

    Quercetin is a type of flavonoid compound, which has potent antioxidant and anti-inflammatory activities, capable of treating a variety of diseases including neurodegenerative diseases, tumors, diabetes and obesity. The present study selected alcohol-induced liver injury model mice and aimed at studying the protective role of quercetin in preventing alcohol-induced liver injury. In alcohol-induced liver injury mice treated with quercetin, it was demonstrated that levels of aspartate transaminase, alanine transaminase, total bilirubin and triglyceride were reduced. In addition to this, the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were increased, malondialdehyde was inhibited, and interleukin (IL)-1β, IL-6, IL-10 and inducible nitric oxide synthase were suppressed. Quercetin additionally suppressed the protein expression levels of B-cell lymphoma (Bcl)-2, Bcl-2 associated X apoptosis regulator, Caspase-3, poly ADP-ribose polymerase, and signal transducer and activator of transcription (STAT) 3 phosphorylation, nuclear factor (NF)-κB and protein kinase B (Akt) phosphorylation levels in alcohol-induced liver injured mice. These results suggested that the protective role of quercetin prevents alcohol-induced liver injury through the phosphoinositide 3-kinase/Akt/NF-κB and STAT3 pathway. PMID:29285175

  15. Tocilizumab-Induced Acute Liver Injury in Adult Onset Still’s Disease

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    Michael Drepper

    2013-01-01

    Full Text Available Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still’s disease (AOSD. Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.

  16. Intestinal Endotoxins as Co-Factors of Liver Injury in Obstructive Jaundice

    OpenAIRE

    Menteş, B. Bülent; Tatlicioğlu, Ertan; Akyol, Gülen; Uluoğlu, Ömer; Sultan, Nedim; Yilmaz, Erdal; Çelebi, Murat; Taneri, Ferit; Ferahköşe, Zafer

    1996-01-01

    The concept of endotoxin-mediated rather than direct liver injury in biliary obsruction was investigated using the experimental rat model of bile duct ligation (BDL) and small bowel bacterial overgrowth (SBBO). Small identical doses of intravenous endotoxin (bacterial LPS) caused a significantly more severe liver injury in rats with BDL, compared with sham-operated rats, suggesting the possible contribution of LPS in this type of liver damage. BDL was then combined with surgica...

  17. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

    Science.gov (United States)

    Ushijima, Kentarou; Tsuruoka, Shu-ichi; Tsuda, Hidetoshi; Hasegawa, Gohki; Obi, Yuri; Kaneda, Tae; Takahashi, Masaki; Maekawa, Tomohiro; Sasaki, Tomohiro; Koshimizu, Taka-aki; Fujimura, Akio

    2009-01-01

    AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. PMID:19694738

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

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    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.

  19. RUCAM in Drug and Herb Induced Liver Injury: The Update

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    Gaby Danan

    2015-12-01

    Full Text Available RUCAM (Roussel Uclaf Causality Assessment Method or its previous synonym CIOMS (Council for International Organizations of Medical Sciences is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI and herb induced liver injury (HILI. Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality

  20. Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt.

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    Heidi L Kenerson

    Full Text Available Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting de novo lipogenesis. However, mTORC1 hyperactivity per se does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the in vivo mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of Tsc1 and/or S6k1 in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6-14 weeks. Following 8 weeks of high-fat diet, the Tsc1-/-;S6k1-/- mice had lower body weights but higher liver TG levels compared to that of the Tsc1-/- mice. However, the loss of S6k1 did not relieve feedback inhibition of Akt activity in the Tsc1-/- livers. To overcome Akt suppression, Pten was deleted in Tsc1-/- livers, and the resultant mice showed improved glucose tolerance compared with the Tsc1-/- mice. However, liver TG levels were significantly reduced in the Tsc1-/-;Pten-/- mice compared to the Pten-/- mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (Srebp1c, Fasn were elevated in the Tsc1-/-;Pten-/- livers, but this was counter-balanced by an up-regulation of Cpt1a involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our in vivo models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism in vivo.

  1. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

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    Chihiro Okuma

    2015-07-01

    Conclusion: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

  2. Burn injury suppresses human dermal dendritic cell and Langerhans cell function

    NARCIS (Netherlands)

    van den Berg, Linda M.; de Jong, Marein A. W. P.; Witte, Lot de; Ulrich, Magda M. W.; Geijtenbeek, Teunis B. H.

    2011-01-01

    Human skin contains epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) that are key players in induction of adaptive immunity upon infection. After major burn injury, suppressed adaptive immunity has been observed in patients. Here we demonstrate that burn injury affects adaptive

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

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    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.

  4. 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.

  5. 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

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

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    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.

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

    NARCIS (Netherlands)

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

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

  8. Molecular mechanism of intracellular lipid accumulation: Suppressive effect of PycnogenolR in liver cells

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    Shoichiro Ikuyama

    2013-09-01

    Full Text Available ABSTRACTCells are physiologically ready to accumulate lipids such as triacylglycerides in the cytoplasm.Five classes of perilipin (PLIN family proteins are known to be involved in the process of intracellular lipid accumulation. PLIN2 is expressed ubiquitously including adipocytes, hepatocytes and macrophages. Over-expression of PLIN2 is demonstrated in the lesions of fatty liver diseases and atherosclerosis. Suppression of PLIN2 expression prevents from developing these pathological conditions in animal models, suggesting that PLIN2 could be a therapeutic target molecule for excessive intracellular lipid accumulation which leads to various metabolic derangements. The PLIN2 gene promoter has two important cis-acting elements in close proximity:AP-1 element which mediates inflammatory signals and PPRE which mediates free fatty acid effect. In NMuLi mouse liver cells, FFA such as oleic acid requires both functional AP-1 and PPRE simultaneously to stimulate the promoter activity, indicating the presence of intimate interaction of inflammatory and metabolic signals on this gene. PycnogenolR, French maritime pine bark extracts, suppressed the oleic acid-induced PLIN2 expression and lipid accumulation in NMuLi cells. We found that PycnogenolR did not suppress the PLIN2 promoter activity or AP-1 binding to DNA. Instead, PycnogenolRfacilitates the PLIN2 mRNA degradation, leading to suppression of lipid accumulation. This effect seems to be independent of antioxidant effect of PycnogenolR.We raise the idea that PLIN2 is a putative target molecule for prevention of pathological condition induced by excessive lipid accumulation, and this class of natural compounds could be putative therapeutic modalities.Key words: PycnogenolR, lipid droplet, perilipin, fatty liver disease

  9. 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...... 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...... 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...

  10. Molecular mechanisms of liver ischemia reperfusion injury: Insights from transgenic knockout models

    Science.gov (United States)

    Datta, Gourab; Fuller, Barry J; Davidson, Brian R

    2013-01-01

    Ischemia reperfusion injury is a major obstacle in liver resection and liver transplantation surgery. Understanding the mechanisms of liver ischemia reperfusion injury (IRI) and developing strategies to counteract this injury will therefore reduce acute complications in hepatic resection and transplantation, as well as expanding the potential pool of usable donor grafts. The initial liver injury is initiated by reactive oxygen species which cause direct cellular injury and also activate a cascade of molecular mediators leading to microvascular changes, increased apoptosis and acute inflammatory changes with increased hepatocyte necrosis. Some adaptive pathways are activated during reperfusion that reduce the reperfusion injury. IRI involves a complex interplay between neutrophils, natural killer T-cells cells, CD4+ T cell subtypes, cytokines, nitric oxide synthases, haem oxygenase-1, survival kinases such as the signal transducer and activator of transcription, Phosphatidylinositol 3-kinases/Akt and nuclear factor κβ pathways. Transgenic animals, particularly genetic knockout models, have become a powerful tool at elucidating mechanisms of liver ischaemia reperfusion injury and are complementary to pharmacological studies. Targeted disruption of the protein at the genetic level is more specific and maintained than pharmacological inhibitors or stimulants of the same protein. This article reviews the evidence from knockout models of liver IRI about the cellular and molecular mechanisms underlying liver IRI. PMID:23555157

  11. Liver Injury Assessment by Vetscan VS2 Analyzer and Most Frequently Used ALT/GTP Reagent.

    Science.gov (United States)

    Vatsalya, Vatsalya; Avila, Diana; Frimodig, Jane C; Barve, Shirish S; McClain, Craig J; Gobejishvili, Leila

    Liver injury is estimated by serum alanine aminotransferases (ALT) levels in experimental animal models. Laboratories use various techniques to measure ALT levels including assay reagents and chemistry analyzers. VetScan VS2 (VS2) is widely used in veterinary clinics and research laboratories for highly reproducible, convenient and effective testing. Alternatively, ALT liquid reagent is used by laboratories to estimate liver injury in animal studies. The aim of this study was to perform comparative analyses of data obtained from these two assays in two different animal models. In this study, we used two different mouse models and compared the ALT levels measured using VetScan VS2 chemistry analyzer and ALT liquid reagent. Immunohistochemical analysis of hepatic tissue was also performed to document liver pathology. The first model is a high fat diet feeding model that results in a mild hepatic steatosis (fat accumulation in the liver) without elevation of ALT levels. For a severe liver injury model, we employed a hepatotoxin-induced liver injury model (carbon tetrachloride, CCl4), which leads to the development of hepatic fibrosis and very high ALT levels. VetScan VS2 and ALT reagent gave different values of ALT for all animal groups. However, linear regression analysis showed a significantly high association between ALT levels obtained by VS2 and ALT liquid reagent in a high-fat feeding model with no liver injury. For the CCl 4 induced liver injury model, serum dilution (5 and 10 times) was performed to obtain accurate results with ALT reagent. ALT levels acquired from both techniques showed a close association. Interestingly, this correlation was closer when serum was diluted 5 fold. This study demonstrates that both methods give similar results when evaluating liver injury in animal studies. However, the serum dilution factor is critical for severe liver injury assessment when using ALT reagent and requires some optimization. In this regard, VetScan VS2 is

  12. Protective effect of aqueous extracts from Rhizopus oryzae on liver injury induced by carbon tetrachloride in rats.

    Science.gov (United States)

    Suzuki, Takehito; Fukuoka, Hideo; Ushikoshi, Setsuo; Sato, Reiichiro; Morita, Hidetoshi; Takizawa, Tatsuya

    2015-05-01

    Hepatoprotective effects of Rhizopus oryzae/ U-1 aqueous extract (RU) were demonstrated in carbon tetrachloride (CCl4 )-induced liver-injured rats. In order to investigate the RU effects, the rats were administered RU at a dose of 10 or 100 mg/kg of body weight for 10 days before induction of the liver injury by oral administration of CCl4 (125 mg/kg body weight). (i) Pretreatment with RU caused a significant decrease in serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities that were increased by the administration of CCl4 . (ii) RU pretreatment (100 mg/kg) increased 5-bromo-2'-deoxyuridine incorporation at 48 h after CCl4 treatment in hepatocytes. (iii) Histological hematoxylin and eosin staining of the liver showed that RU pretreatment reduced the damage induced by CCl4 administration. (iv) Reverse transcriptase PCR analysis showed RU retreatment caused a transient but significant increase in hepatocyte growth factor (HGF) and a sustained and significant increase in insulin-like growth factor-I (IGF-I) gene expression in hepatocytes injured by CCl4 treatment. From these results, we conclude that oral pre-administration of RU was effective to suppress liver injury induced by the subsequent oral CCl4 administration, and RU-induced increase in IGF-I and HGF gene expression may be, even in part, involved in biological actions of RU in rats. © 2014 Japanese Society of Animal Science.

  13. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice.

    Science.gov (United States)

    Chen, Zong; Ding, Tao; Ma, Chuan-Gen

    2017-11-18

    Hepatic ischemia/reperfusion (I/R) injury could arise as a complication of liver surgery and transplantation. No specific therapeutic strategies are available to attenuate I/R injury. NOD-, LRR-and CARD-containing 5 (NLRC5), a member of the NOD-like protein family, has been suggested to negatively regulate nuclear factor kappa B (NF-κB) through interacting with IKKα and blocking their phosphorylation. Dexmedetomidine (DEX) has been shown to attenuate liver injury. In the current study, we investigated the pre-treatment of DEX on hepatic I/R injury in wild type (WT) and NLRC5 knockout (NLRC5 -/- ) mice. Our results indicated that NLRC5 -/- showed significantly stronger histologic damage, inflammatory response, oxidative stress and apoptosis after I/R compared to the WT group of mice, indicating the protective role of NLRC5 against liver I/R injury. Importantly, I/R-induced increase of NLRC5 was reduced by DEX pre-treatment. After hepatic I/R injury, WT and NLRC5 -/- mice pre-treated with DEX exhibited attenuated histological disruption, and reduced pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β and inducible nitric oxide synthase (iNOS), which was associated with the inactivated NF-κB pathway. Moreover, suppression of oxidative stress and apoptosis was observed in DEX-treated mice with I/R injury, probably through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2), reducing mitogen-activated protein kinases (MAPKs) and Caspase-3/poly (ADP-ribose) polymerase (PARP) pathways. In vitro, the results were further confirmed in WT and NLRC5 -/- hepatocytes pre-treated with or without DEX. Together, the findings illustrated that lack of NLRC5 resulted in severer liver I/R injury, which could be alleviated by DEX pre-treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. 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.

  15. Hepatoprotective effects of Micromeria croatica ethanolic extract against CCl4-induced liver injury in mice.

    Science.gov (United States)

    Vladimir-Knežević, Sanda; Cvijanović, Olga; Blažeković, Biljana; Kindl, Marija; Štefan, Maja Bival; Domitrović, Robert

    2015-07-15

    Micromeria croatica (Pers.) Schott is an aromatic plant from Lamiaceae family previously found to possess potent in vitro antioxidant activity which is mainly attributed to the high level of polyphenolic substances. The aim of this study was to investigate the hepatoprotective activity and possible underlying mechanisms of Micromeria croatica ethanolic extract (MC) using a model of carbon tetrachloride (CCl4)-induced liver injury in mice. Male BALB/cN mice were randomly divided into seven groups: control group received saline, MC group received ethanolic extract of M. croatica in 5% DMSO (100 mg/kg b.w., p.o.), and CCl4 group was administered CCl4 dissolved in corn oil (2 mL/kg, 10% v/v, ip). MC50, MC200 and MC400 groups were treated with MC orally at doses of 50, 200 and 400 mg/kg once daily for 2 consecutive days, respectively, 6 h after CCl4 intoxication. The reference group received silymarin at dose of 400 mg/kg. At the end of experiment, blood and liver samples were collected for biochemical, histopathological, immunohistochemical and Western blot analyses. In addition, major phenolic compounds in MC were quantified by HPLC-DAD. CCl4 intoxication resulted in liver cells damage and oxidative stress and triggered inflammatory response in mice livers. MC treatment decreased ALT activity and prevented liver necrosis. Improved hepatic antioxidant status was evident by increased Cu/Zn SOD activity and decreased 4-hydroxynonenal (4-HNE) formation in the livers. Concomitantly, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were overexpressed. The hepatoprotective activity of MC was accompanied by the increase in nuclear factor-kappaB (NF-κB) activation and tumor necrosis factor-alpha (TNF-α) expression, indicating amelioration of hepatic inflammation. Additionally, MC prevented tumor growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) expression, suggesting the potential for suppression of hepatic fibrogenesis. These

  16. Blunt liver injury with intact ribs under impacts on the abdomen: a biomechanical investigation.

    Directory of Open Access Journals (Sweden)

    Yu Shao

    Full Text Available Abdominal trauma accounts for nearly 20% of all severe traffic injuries and can often result from intentional physical violence, from which blunt liver injury is regarded as the most common result and is associated with a high mortality rate. Liver injury may be caused by a direct impact with a certain velocity and energy on the abdomen, which may result in a lacerated liver by penetration of fractured ribs. However, liver ruptures without rib cage fractures were found in autopsies in a series of cases. All the victims sustained punches on the abdomen by fist. Many studies have been dedicated to determining the mechanism underlying hepatic injury following abdominal trauma, but most have been empirical. The actual process and biomechanism of liver injury induced by blunt impact on the abdomen, especially with intact ribs remained, are still inexhaustive. In order to investigate this, finite element methods and numerical simulation technology were used. A finite element human torso model was developed from high resolution CT data. The model consists of geometrically-detailed liver and rib cage models and simplified models of soft tissues, thoracic and abdominal organs. Then, the torso model was used in simulations in which the right hypochondrium was punched by a fist from the frontal, lateral, and rear directions, and in each direction with several impact velocities. Overall, the results showed that liver rupture was primarily caused by a direct strike of the ribs induced by blunt impact to the abdomen. Among three impact directions, a lateral impact was most likely to cause liver injury with a minimum punch speed of 5 m/s (the momentum was about 2.447 kg.m/s. Liver injuries could occur in isolation and were not accompanied by rib fractures due to different material characteristics and injury tolerance.

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    Zheng-xin WANG

    2011-11-01

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

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

    Science.gov (United States)

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

    2016-08-01

    Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaine-induced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges

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    Maria Adriana Rangel

    2017-01-01

    Full Text Available The authors present a case report of antituberculosis drug-induced liver injury that offered diagnostic challenges (namely, the possibility of drug-induced autoimmune hepatitis and treatment difficulties.

  1. 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

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

    Directory of Open Access Journals (Sweden)

    Lance L. Stein

    2011-01-01

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

  3. Oral administration of cilostazol improves survival rate after rat liver ischemia/reperfusion injury.

    Science.gov (United States)

    Fujii, Taku; Obara, Hideaki; Matsubara, Kentaro; Fujimura, Naoki; Yagi, Hiroshi; Hibi, Taizo; Abe, Yuta; Kitago, Minoru; Shinoda, Masahiro; Itano, Osamu; Tanabe, Minoru; Masugi, Yohei; Sakamoto, Michiie; Kitagawa, Yuko

    2017-06-01

    Cilostazol is a type III phosphodiesterase inhibitor used to treat the symptoms of intermittent claudication. Recent studies have shown that cilostazol decreases ischemia/reperfusion (I/R) injury in several organs. We evaluated the effects of cilostazol in a rat model of liver I/R injury. Thirty male Wistar rats with liver I/R injury were divided into a cilostazol or saline (control) group (n = 15 each). Each rat was orally administered cilostazol or saline for 3 d before I/R injury. Liver I/R injury was induced via 1 h of warm ischemia of the median and left lateral liver lobes, followed by 3 h of reperfusion. The rats were then euthanized. Serum aspartate aminotransferase, alanine aminotransferase, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α levels were measured. The Mann-Whitney U test was used to compare the differences between the treatment groups. Histologic examination was performed on the liver tissues. We also conducted a survival study to confirm the effect of cilostazol on the mortality rate in rats. For the survival study, a liver I/R injury model with an ischemia time of 1.5 h was used, and the rats were observed for 1 wk. Serum aspartate aminotransferase, alanine aminotransferase, IL-1β, and IL-6 levels were significantly lower in the cilostazol group than in the saline group. Treatment with cilostazol significantly improved pathological findings associated with liver I/R injury and increased survival rate compared to that in controls. Cilostazol reduced mortality and alleviated the effects of liver I/R injury in Wistar rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Ischemic postconditioning attenuates liver warm ischemia-reperfusion injury through Akt-eNOS-NO-HIF pathway.

    Science.gov (United States)

    Guo, Jia Y; Yang, Tong; Sun, Xiang G; Zhou, Ni Y; Li, Fu S; Long, Dan; Lin, Tao; Li, Ping Y; Feng, Li

    2011-10-28

    Ischemic postconditioning (IPO) has been demonstrated to attenuate ischemia/reperfusion (I/R) injury in the heart and brain, its roles to liver remain to be defined. The study was undertaken to determine if IPO would attenuate liver warm I/R injury and its protective mechanism. Mice were divided into sham, I/R, IPO+I/R (occlusing the porta hepatis for 60 min, then treated for three cycles of 10 sec brief reperfusion consecutively, followed by a persistent reperfusion); L-NAME+ sham (L-NAME, 16 mg/kg, i.v., 5 min before repefusion); L-NAME+I/R; and L-NAME+ IPO. Blood flow of caudate and left lobe of the liver was blocked. Functional and morphologic changes of livers were evaluated. Contents of nitric oxide, eNOS and iNOS in serum were assayed. Concentration of eNOS, iNOS, malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in hepatic tissue were also measured. Expressions of Akt, p-Akt and HIF-1α protein were determined by western blot. Expressions of TNF-α and ICAM-1 were measured by immunohistochemistry and RT-PCR. IPO attenuated the dramatically functional and morphological injuries. The levels of ALT was significantly reduced in IPO+I/R group (p IPO+I/R group (p IPO also up-regulated the concentration of eNOS, activity of SOD in hepatic tissue (p IPO+I/R group. Protein and mRNA expression of TNF-α and ICAM-1 were markedly suppressed by IPO (p IPO could be abolished by L-NAME. We found that IPO increased the content of NO and attenuated the overproduction of ROS and I/R-induced inflammation. Increased NO contents may contribute to increasing HIF-1α level, and HIF-1α and NO would simultaneously protect liver from I/R injury. These findings suggested IPO may have the therapeutic potential through Akt-eNOS-NO-HIF pathway for the better management of liver I/R injury.

  5. 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.

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

    Directory of Open Access Journals (Sweden)

    Grace Guzman

    2009-01-01

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

  7. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

    Science.gov (United States)

    Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

    2018-03-01

    Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  8. A paradoxical signal intensity increase in fatty livers using opposed-phase gradient echo imaging with fat-suppression pulses

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    Mulkern, Robert V.; Voss, Stephan [Harvard Medical School, Department of Radiology, Children' s Hospital Boston, Boston, MA (United States); Loeb Salsberg, Sandra; Krauel, Marta Ramon; Ludwig, David S. [Harvard Medical School, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States)

    2008-10-15

    With the increase in obese and overweight children, nonalcoholic fatty liver disease has become more prevalent in the pediatric population. Appreciating subtleties of magnetic resonance (MR) signal intensity behavior from fatty livers under different imaging conditions thus becomes important to pediatric radiologists. We report an initially confusing signal behavior - increased signal from fatty livers when fat-suppression pulses are applied in an opposed-phase gradient echo imaging sequence - and seek to explain the physical mechanisms for this paradoxical signal intensity behavior. Abdominal MR imaging at 3 T with a 3-D volumetric interpolated breath-hold (VIBE) sequence in the opposed-phase condition (TR/TE 3.3/1.3 ms) was performed in five obese boys (14{+-}2 years of age, body mass index >95th percentile for age and sex) with spectroscopically confirmed fatty livers. Two VIBE acquisitions were performed, one with and one without the use of chemical shift selective (CHESS) pulse fat suppression. The ratios of fat-suppressed over non-fat-suppressed signal intensities were assessed in regions-of-interest (ROIs) in five tissues: subcutaneous fat, liver, vertebral marrow, muscle and spleen. The boys had spectroscopically estimated hepatic fat levels between 17% and 48%. CHESS pulse fat suppression decreased subcutaneous fat signals dramatically, by more than 85% within regions of optimal fat suppression. Fatty liver signals, in contrast, were elevated by an average of 87% with CHESS pulse fat suppression. Vertebral marrow signal was also significantly elevated with CHESS pulse fat suppression, while spleen and muscle signals demonstrated only small signal increases on the order of 10%. We demonstrated that CHESS pulse fat suppression actually increases the signal intensity from fatty livers in opposed-phase gradient echo imaging conditions. The increase can be attributed to suppression of one partner of the opposed-phase pair that normally contributes to the

  9. A paradoxical signal intensity increase in fatty livers using opposed-phase gradient echo imaging with fat-suppression pulses

    International Nuclear Information System (INIS)

    Mulkern, Robert V.; Voss, Stephan; Loeb Salsberg, Sandra; Krauel, Marta Ramon; Ludwig, David S.

    2008-01-01

    With the increase in obese and overweight children, nonalcoholic fatty liver disease has become more prevalent in the pediatric population. Appreciating subtleties of magnetic resonance (MR) signal intensity behavior from fatty livers under different imaging conditions thus becomes important to pediatric radiologists. We report an initially confusing signal behavior - increased signal from fatty livers when fat-suppression pulses are applied in an opposed-phase gradient echo imaging sequence - and seek to explain the physical mechanisms for this paradoxical signal intensity behavior. Abdominal MR imaging at 3 T with a 3-D volumetric interpolated breath-hold (VIBE) sequence in the opposed-phase condition (TR/TE 3.3/1.3 ms) was performed in five obese boys (14±2 years of age, body mass index >95th percentile for age and sex) with spectroscopically confirmed fatty livers. Two VIBE acquisitions were performed, one with and one without the use of chemical shift selective (CHESS) pulse fat suppression. The ratios of fat-suppressed over non-fat-suppressed signal intensities were assessed in regions-of-interest (ROIs) in five tissues: subcutaneous fat, liver, vertebral marrow, muscle and spleen. The boys had spectroscopically estimated hepatic fat levels between 17% and 48%. CHESS pulse fat suppression decreased subcutaneous fat signals dramatically, by more than 85% within regions of optimal fat suppression. Fatty liver signals, in contrast, were elevated by an average of 87% with CHESS pulse fat suppression. Vertebral marrow signal was also significantly elevated with CHESS pulse fat suppression, while spleen and muscle signals demonstrated only small signal increases on the order of 10%. We demonstrated that CHESS pulse fat suppression actually increases the signal intensity from fatty livers in opposed-phase gradient echo imaging conditions. The increase can be attributed to suppression of one partner of the opposed-phase pair that normally contributes to the

  10. The Diagnosis and Manifestations of Liver Injury Secondary to Off-Label Androgenic Anabolic Steroid Use.

    Science.gov (United States)

    Cabb, Elena; Baltar, Shanna; Powers, David Wes; Mohan, Karthik; Martinez, Antonio; Pitts, Eric

    2016-01-01

    Drug-induced liver injury (DILI) presents as a broad spectrum of adverse drug reactions which can range from a mild elevation in liver enzymes to fulminant liver failure. The primary goal is to identify DILI early when the patient's liver enzymes are elevated and to discontinue the offending agent as soon as possible to prevent further injury. Herbal, dietary supplements and anabolic steroids represent a significant component of the drugs thought to cause DILI in the United States. Unlike all other drugs known to cause DILI, these drugs fall into a category of injury that is neither intrinsic nor idiosyncratic due to overlapping characteristics between the two. Here, we present a case of the off-label use of androgenic anabolic steroids inducing liver injury. A combination of clinical, laboratory, and histologic workup eventually led to the diagnosis of DILI. This can be a diagnostic challenge for practitioners. The American College of Gastroenterology (ACG) published guidelines to aid the clinician in diagnosing DILI. Proving that an episode of liver injury is caused by a drug is difficult in many cases as it requires the exclusion of alternative etiologies. Some of the variables include temporal association, clinical-biochemical features, type of injury (hepatocellular and/or cholestatic), extrahepatic features, and the likelihood that a given agent is the culprit based on its known manifestations with prior cases. This case illustrates the utility of the diagnostic tools used for DILI as recommended by the ACG, along with a supplemental histopathologic diagnosis.

  11. Pronounced effect of minor changes in body temperature on ischemia and reperfusion injury in rat liver

    NARCIS (Netherlands)

    Heijnen, B. H.; van Veen, S. Q.; Straatsburg, I. H.; van Gulik, T. M.

    2001-01-01

    This study examined the effects of 1 degrees C hypo- or hyperthermia on in vivo liver ischemia and reperfusion (I/R) injury in 15 fasted male Wistar rats. Rats were ventilated, and rectal temperature was maintained at 36, 37 (normothermic), or 38 degrees C. In all rats, 70% liver ischemia was

  12. 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.

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

    Science.gov (United States)

    Iwaki, Tomomichi; Ishizaki, Kaoru; Kinoshita, Shuji; Tanaka, Hideki; Fukunari, Atsushi; Tsurufuji, Makoto; Imada, Teruaki

    2007-10-07

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

  14. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge M.; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, M.T.; Groothuis, Geny M. M.

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict

  15. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  16. 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

  17. Protective effect of oligomeric proanthocyanidins against alcohol-induced liver steatosis and injury in mice.

    Science.gov (United States)

    Wang, Zhiguo; Su, Bo; Fan, Sumei; Fei, Haixia; Zhao, Wei

    2015-03-20

    The long-term consumption of alcohol has been associated with multiple pathologies at all levels, such as alcoholism, chronic pancreatitis, malnutrition, alcoholic liver disease (ALD) and cancer. In the current study, we investigated the protective effect of oligomeric proanthocyanidins (OPC) against alcohol-induced liver steatosis and injury and the possible mechanisms using ethanol-induced chronic liver damage mouse models. The results showed that OPC significantly improved alcohol-induced dyslipidemia and alleviated liver steatosis by reducing levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-c) and liver malondialdehyde (MDA), and increasing levels of serum high-density lipoprotein (HDL-c), liver superoxide dismutase (SOD). Further investigation indicated that OPC markedly decreased the expressions of lipid synthesis genes and inflammation genes such as sterol regulatory element-binding protein-1c (Srebp-1c), protein-2 (Srebp2), interleukin IL-1β, IL-6 and TNF-α. Furthermore, AML-12 cells line was used to investigate the possible mechanisms which indicated that OPC might alleviate liver steatosis and damage through AMP-activated protein kinase (AMPK) activation involving oxidative stress. In conclusion, our study demonstrated excellent protective effect of OPC against alcohol-induced liver steatosis and injury, which could a potential drug for the treatment of alcohol-induced liver injury in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. 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.

  19. 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

  20. Silybin Against Liver Ischemia-Reperfusion Injury: Something Old, Something New….

    Science.gov (United States)

    Oltean, Mihai

    2017-09-13

    Ischemia reperfusion injury (IRI) is a life threatening condition that may develop after elective liver surgery or liver transplantation. Numerous surgical and pharmacological approaches have shown varying degrees of protection against liver IRI. A group of protective compounds are the flavonoids but their intestinal absorbtion and bioavailability are low and impredictible. In this issue Tsaroucha et al. reports significantly decreased hepatocellular injury, Fas/FasL expression and inhibited HMGB1 release in rats receiving a hydrosoluble, lyophilized complex of SLB and hydroxypropyl-β-cyclodextrin (SLB-HP-β-CD) intravenously.

  1. Recreational Anabolic-Androgenic Steroid Use Associated With Liver Injuries Among Brazilian Young Men.

    Science.gov (United States)

    Schwingel, Paulo Adriano; Cotrim, Helma Pinchemel; Santos, Crimério Ribeiro dos; Santos, Adriano Oliveira dos; Andrade, Antônio Ricardo Cardia Ferraz de; Carruego, Marcos Vinicius Vilas Boas; Zoppi, Cláudio Cesar

    2015-01-01

    The recreational use of anabolic-androgenic steroids (AAS) has reached alarming levels among healthy people. However, several complications have been related to consumption of these drugs, including liver disorders. To evaluate the prevalence of liver injuries in young Brazilian recreational AAS users. Between February/2007 and May/2012 asymptomatic bodybuilders who were ≥18 years old and reported AAS use for ≥6 months were enrolled. All had clinical evaluations, abdominal ultrasound (AUS), and blood tests. 182 individuals were included in the study. The median age (interquartile range) was 26.0 years (22.0-30.0) and all were male. Elevated liver enzyme levels were observed in 38.5% (n = 70) of AAS users, and creatine phosphokinase was normal in 27.1% (n = 19) of them. Hepatic steatosis was observed by AUS in 12.1% of the sample. One individual had focal nodular hyperplasia and another had hepatocellular adenoma. One case each of hepatitis B and C virus infection was found. A diagnosis of toxic liver injury was suggested in 23 (12.6%) AAS users without a history of alcohol or other medications/drugs consumption, or evidence of other liver diseases. Young Brazilian recreational AAS users presented a wide spectrum of liver injuries that included hepatotoxicity, fatty liver, and liver neoplasm. They also presented risk factors for liver diseases such as alcohol consumption and hepatitis B and C virus infection. The results suggest that the risk of AAS use for the liver may be greater than the esthetic benefits, and demonstrate the importance of screening AAS users for liver injuries.

  2. 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.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Satoru Mitazaki

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lili Ji

    Full Text Available Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection 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. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin.

  6. Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

    Science.gov (United States)

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

    2014-01-01

    Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection 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. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. PMID:24905073

  7. Ethanol extract from portulaca oleracea L. attenuated acetaminophen-induced mice liver injury

    Science.gov (United States)

    Liu, Xue-Feng; Zheng, Cheng-Gang; Shi, Hong-Guang; Tang, Gu-Sheng; Wang, Wan-Yin; Zhou, Juan; Dong, Li-Wei

    2015-01-01

    Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings suggested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. PMID:25901199

  8. Liver trauma from penetrating injuries. Miscellanea, personal series, clinical and CT findings

    International Nuclear Information System (INIS)

    Salzano, A.; Nocera, V.; De Rosa, A.; Vigliotti, A.; Rossi, E.; Carbone, M.; Gatta, G.

    2000-01-01

    Penetrating liver wounds are related to many causes and rank second after blunt abdominal and liver trauma. In this report are examined the clinical and radiological findings of personal series of patients with penetrating trauma, especially by firearms and stab and cut wounds. It will also tried to define the diagnostic workup of these traumas, which is especially based on CT signs of liver damage and associated changes and which is of basic importance for following treatment, both surgical or conservative. In the last seven years it was retrospectively reviewed 31 cases of penetrating liver trauma. The patients were 19 men and 12 women, ranging in age 18 to 73 (mean 42), with penetrating liver injuries from firearms (16 patients) and stab (9 cases) wounds; 6 patients had injuries from different cases. Abdominal CT was carried out in emergency with the CT Angiography (CTA) technique in all patients. In the patients with suspected chest and abdomen involvement CT was performed from the mid-chest for accurate assessment of diaphragm and lung bases and to exclude associated pleuropulmonary damage. Penetrating liver wounds were caused by firearms in 70% of cases, by stabbing in 12% and, in the extant 18%, by other cases such as home accidents, road and work traumas, and liver biopsy. In this series, the liver was most frequently involved, especially by firearms wounds; in the 16 cases the most frequent injuries were hemorrhagic tears. It was found bullets in the liver in 6 cases. In one case of home accident the patient wounded himself while slicing bread with a long knife, which cut into the anterior abdominal wall and tore the anterior liver capsule, as seen at CTA. Penetrating wounds to liver and abdomen are less frequent than those to the chest. In the past decade the use of CT has changed the diagnostic and therapeutic approach to such injuries completely, decreasing the resort to explorative laparotomy and hepatorrhaphy. Indeed, CT provides a clear picture of

  9. Salidroside Suppresses HUVECs Cell Injury Induced by Oxidative Stress through Activating the Nrf2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yao Zhu

    2016-08-01

    Full Text Available Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Salidroside (SAL, one of the main effective constituents of Rhodiola rosea, has been reported to suppress oxidative stress-induced cardiomyocyte injury and necrosis by promoting transcription of nuclear factor E2-related factor 2 (Nrf2-regulated genes such as heme oxygenase-1 (HO-1 and NAD(PH dehydrogenase (quinone1 (NQO1. However, it has not been indicated whether SAL might ameliorate endothelial injury induced by oxidative stress. Here, our study demonstrated that SAL might suppress HUVEC cell injury induced by oxidative stress through activating the Nrf2 signaling pathway. The results of our study indicated that SAL decreased the levels of intercellular reactive oxygen species (ROS and malondialdehyde (MDA, and improved the activities of superoxide dismutase (SOD and catalase (CAT, resulting in protective effects against oxidative stress-induced cell damage in HUVECs. It suppressed oxidative stress damage by inducing Nrf2 nuclear translocation and activating the expression of Nrf2-regulated antioxidant enzyme genes such as HO-1 and NQO1 in HUVECs. Knockdown of Nrf2 with siRNA abolished the cytoprotective effects against oxidative stress, decreased the expression of Nrf2, HO-1, and NQO1, and inhibited the nucleus translocation of Nrf2 in HUVECs. This study is the first to demonstrate that SAL suppresses HUVECs cell injury induced by oxidative stress through activating the Nrf2 signaling pathway.

  10. PARP1-mediated PPARα poly(ADP-ribosyl)ation suppresses fatty acid oxidation in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Huang, Kun; Du, Meng; Tan, Xin; Yang, Ling; Li, Xiangrao; Jiang, Yuhan; Wang, Cheng; Zhang, Fengxiao; Zhu, Feng; Cheng, Min; Yang, Qinglin; Yu, Liqing; Wang, Lin; Huang, Dan; Huang, Kai

    2017-05-01

    PARP1 is a key mediator of cellular stress responses and critical in multiple physiological and pathophysiological processes of cells. However, whether it is involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains elusive. We analysed PARP1 activity in the liver of mice on a high fat diet (HFD), and samples from NAFLD patients. Gain- or loss-of-function approaches were used to investigate the roles and mechanisms of hepatic PARP1 in the pathogenesis of NAFLD. PARP1 is activated in fatty liver of HFD-fed mice. Pharmacological or genetic manipulations of PARP1 are sufficient to alter the HFD-induced hepatic steatosis and inflammation. Mechanistically we identified peroxisome proliferator-activated receptor α (PPARα) as a substrate of PARP1-mediated poly(ADP-ribosyl)ation. This poly(ADP-ribosyl)ation of PPARα inhibits its recruitment to target gene promoters and its interaction with SIRT1, a key regulator of PPARα signaling, resulting in suppression of fatty acid oxidation upregulation induced by fatty acids. Moreover, we show that PARP1 is a transcriptional repressor of PPARα gene in human hepatocytes, and its activation suppresses the ligand (fenofibrate)-induced PPARα transactivation and target gene expression. Importantly we demonstrate that liver biopsies of NAFLD patients display robust increases in PARP activity and PPARα poly(ADP-ribosyl)ation levels. Our data indicate that PARP1 is activated in fatty liver, which prevents maximal activation of fatty acid oxidation by suppressing PPARα signaling. Pharmacological inhibition of PARP1 may alleviate PPARα suppression and therefore have therapeutic potential for NAFLD. PARP1 is activated in the non-alcoholic fatty liver of mice and patients. Inhibition of PARP1 activation alleviates lipid accumulation and inflammation in fatty liver of mice. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Suppression of Sclerostin and Dickkopf-1 levels in patients with fluorine bone injury.

    Science.gov (United States)

    Wang, Wenpeng; Xu, Jian; Liu, Kejian; Liu, Xiaoli; Li, Changcheng; Cui, Caiyan; Zhang, Yuzeng; Li, Huabing

    2013-05-01

    Evidence has been accumulating for the role of Sclerostin and Dickkopf-1 as the antagonists of Wnt/β-Catenin signaling pathway, which suppresses bone formation through inhibiting osteoblastic function. To get deep-inside information about the expression of the antagonists in patients with fluorine bone injury, a case-control study was conducted in two counties in Hubei Province. Urinary and serum fluoride were significantly higher in patients with fluorine bone injury than in healthy controls. Additionally, patients with fluorine bone injury had significantly lower serum Sclerostin and Dickkopf-1 levels compared with healthy controls (Pfluorine bone injury. In conclusion, serum Sclerostin and Dickkopf-1 might be used as important markers of bone metabolism change and potential therapeutic targets to treat fluorine bone injury. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. 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.

  13. 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.

  14. Traumatic Brain Injury in Rats Induces Lung Injury and Systemic Immune Suppression

    NARCIS (Netherlands)

    Vermeij, Jan-Dirk; Aslami, Hamid; Fluiter, Kees; Roelofs, Joris J.; van den Bergh, Walter M.; Juffermans, Nicole P.; Schultz, Marcus J.; Van der Sluijs, Koen; van de Beek, Diederik; van Westerloo, David J.

    2013-01-01

    Traumatic brain injury (TBI) is frequently complicated by acute lung injury, which is predictive for poor outcome. However, it is unclear whether lung injury develops independently or as a result of mechanical ventilation after TBI. Further, TBI is strongly associated with the development of

  15. Concomitant rib fractures and minor liver or spleen injuries in blunt trauma: what is the potential for missed diaphragmatic injuries?

    Science.gov (United States)

    Plurad, David S; Nielsen, Jamison S; Hancock, James; Navaran, Prashanth; Green, Donald J; Lam, Lydia; Inaba, Kenji; Demetriades, Demetrios

    2010-04-01

    Nonoperative management (NOM) of blunt liver or spleen injuries (LSI) is widely accepted, but diaphragmatic injuries (DI) can be elusive. We hypothesize that rib fractures and minor LSI (RF+ minor LSI) are associated with DI. Patients with blunt injury undergoing exploratory laparotomy between January 1, 2000, and December 31, 2007, were identified from our registry. The association between injury variables and DI was examined with logistic regression. Organ Injury Scores of the liver and spleen of Grade I/II were defined as "minor." A potentially nonoperative (PNO) patient had a rib fracture and minor LSI but no bowel injury or hypotension (systolic blood pressure less than 90 mmHg). The incidence of DI was 7.5 per cent (53 of 705) overall but 20 per cent (seven of 35) in patients with RF + minor LSI. Nineteen PNO patients had four (21.1%) DIs. RF + LSI (3.26 [1.74-6.12], P < 0.001) and motor vehicle collisions (4.93 [2.36-10.32], P < 0.001) were independently associated with DI. The incidence of laparotomy in all critically ill blunt injury patients (n = 2177) decreased significantly (P = 0.003). RF + minor LSI are associated with DI even when there are no other operative injuries. Because NOM is increasingly accepted, the potential for missed DI exists. When high-quality imaging is not available or is equivocal, further studies should be considered.

  16. 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

  17. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.

    Science.gov (United States)

    Cohen, Jessica I; Roychowdhury, Sanjoy; McMullen, Megan R; Stavitsky, Abram B; Nagy, Laura E

    2010-08-01

    Complement is involved in the development of alcoholic liver disease in mice; however, the mechanisms for complement activation during ethanol exposure have not been identified. C1q, the recognition subunit of the first complement component, binds to apoptotic cells, thereby activating the classical complement pathway. Because ethanol exposure increases hepatocellular apoptosis, we hypothesized that ethanol-induced apoptosis would lead to activation of complement via the classical pathway. Wild-type and C1qa-/- mice were allowed free access to ethanol-containing diets or pair-fed control diets for 4 or 25 days. Ethanol feeding for 4 days increased apoptosis of Kupffer cells in both wild-type and C1qa-/- mice. Ethanol-induced deposition of C1q and C3b/iC3b/C3c was colocalized with apoptotic Kupffer cells in wild-type, but not C1qa-/-, mice. Furthermore, ethanol-induced increases in tumor necrosis factor-alpha and interleukin-6 expression at this early time point were suppressed in C1q-deficient mice. Chronic ethanol feeding (25 days) increased steatosis, hepatocyte apoptosis, and activity of serum alanine and aspartate aminotransferases in wild-type mice. These markers of hepatocyte injury were attenuated in C1qa-/- mice. In contrast, chronic ethanol (25 days)-induced increases in cytochrome P450 2E1 expression and oxidative stress did not differ between wild-type and C1qa-/- mice. For the first time, these data indicate that ethanol activates the classical complement pathway via C1q binding to apoptotic cells in the liver and that C1q contributes to the pathogenesis of ethanol-induced liver injury. Copyright (c) 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Protection from diclofenac-induced liver injury by Yulangsan polysaccharide in a mouse model.

    Science.gov (United States)

    Huang, Jianchun; Nguyen, Vanphuc; Tang, Xiaojun; Wei, Jinbin; Lin, Xing; Lai, Zefeng; Doan, Vanminh; Xie, Qiuqiao; Huang, Renbin

    2016-12-04

    Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. Yulangsan polysaccharide (YLSPS) is a chief ingredient of its root, which has been used in Chinese traditional medicine with a long history for remedy of acute or chronic hepatitis and jaundice. To investigate the ability of the YLSPS to protect against diclofenac-induced hepatotoxicity in mice. Mice were orally treated with YLSPS daily 1h after the injection of diclofenac for 2 weeks. Dimethyl diphenyl bicarboxylate was used as a reference drug. YLSPS effectively reduced the elevated levels of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and enhanced the reduction of superoxide dismutase, catalase, and glutathione peroxidase activities in the liver. Moreover, the content of malondialdehyde was reduced by treatment with YLSPS, and histological findings also confirmed the anti-hepatotoxic activity. In addition, YLSPS significantly inhibited proinflammatory mediators, such as tumor necrosis factor-alpha and interleukin 1 beta. YLSPS also enhanced mitochondrial antioxidants and inhibited cell death by preventing the down-regulation of Bcl-2 and the up-regulation and release of Bax along with caspase 9 and 3 activity; thus, these findings confirm the involvement of mitochondria in diclofenac-induced apoptosis. The results indicate that protective effects of YLSPS against diclofenac-induced acute hepatic injury may rely on its effect on reducing oxidative stress, suppressing inflammatory responses, and improving drug-metabolizing enzyme activity in the liver. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. 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.

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

    International Nuclear Information System (INIS)

    Massey, Veronica L.; Stocke, Kendall S.; Schmidt, Robin H.; Tan, Min; Ajami, Nadim; Neal, Rachel E.; Petrosino, Joseph F.; Barve, Shirish; Arteel, Gavin E.

    2015-01-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 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

  1. A Novel Small-molecule WNT Inhibitor, IC-2, Has the Potential to Suppress Liver Cancer Stem Cells.

    Science.gov (United States)

    Seto, Kenzo; Sakabe, Tomohiko; Itaba, Noriko; Azumi, Junya; Oka, Hiroyuki; Morimoto, Minoru; Umekita, Yoshihisa; Shiota, Goshi

    2017-07-01

    The presence of cancer stem cells (CSCs) contributes to metastasis, recurrence, and resistance to chemo/radiotherapy in hepatocellular carcinoma (HCC). The WNT signaling pathway is reportedly linked to the maintenance of stemness of CSCs. In the present study, in order to eliminate liver CSCs and improve the prognosis of patients with HCC, we explored whether small-molecule compounds targeting WNT signaling pathway suppress liver CSCs. The screening was performed using cell proliferation assay and reporter assay. We next investigated whether these compounds suppress liver CSC properties by using flow cytometric analysis and sphere-formation assays. A mouse xenograft model transplanted with CD44-positive HuH7 cells was used to examine the in vivo antitumor effect of IC-2. In HuH7 human HCC cells, 10 small-molecule compounds including novel derivatives, IC-2 and PN-3-13, suppressed cell viability and WNT signaling activity. Among them, IC-2 significantly reduced the CD44-positive population, also known as liver CSCs, and dramatically reduced the sphere-forming ability of both CD44-positive and CD44-negative HuH7 cells. Moreover, CSC marker-positive populations, namely CD90-positive HLF cells, CD133-positive HepG2 cells, and epithelial cell adhesion molecule-positive cells, were also reduced by IC-2 treatment. Finally, suppressive effects of IC-2 on liver CSCs were also observed in a xenograft model using CD44-positive HuH7 cells. The novel derivative of small-molecule WNT inhibitor, IC-2, has the potential to suppress liver CSCs and can serve as a promising therapeutic agent to improve the prognosis of patients with HCC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. The role of osteopontin in D-galactosamine-induced liver injury in genetically obese mice

    International Nuclear Information System (INIS)

    Kwon, Hyo-Jung; Won, Young-Suk; Yoon, Won-Kee; Nam, Ki-Hoan; Kim, Dae-Yong; Kim, Hyoung-Chin

    2010-01-01

    Various epidemiological studies have shown that obesity increases the risk of liver disease, but the precise mechanisms through which this occurs are poorly understood. In the present study, we hypothesized that osteopontin (OPN), an extracellular matrix and proinflammatory cytokine, has an important role in making obese mice more susceptible to inflammatory liver injury. After exposure of genetically obese ob/ob and db/db mice to a single dose of D-galactosamine (GalN), the plasma liver enzyme levels, histology and expression levels of cytokines and OPN were evaluated. The ob/ob and db/db mice, which were more sensitive to GalN-induced inflammatory liver injury compared with wild-type mice, had significantly higher plasma and hepatic OPN expression levels. Increased OPN expression was mainly found in hepatocytes and inflammatory cells and was correlated with markedly up-regulated interleukin (IL)-12 and IL-18 levels. Furthermore, pretreatment with a neutralizing OPN (nOPN) antibody attenuated the GalN-induced inflammatory liver injury in ob/ob and db/db mice, which was accompanied by significantly reduced macrophages recruitment and IL-12 and IL-18 productions. Taken together, these results suggest that up-regulated OPN expression is a contributing factor to increased susceptibility of genetically obese mice to GalN-induced liver injury by promoting inflammation and modulating immune response.

  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. Myeloid-derived suppressor cells mediate immune suppression in spinal cord injury.

    Science.gov (United States)

    Wang, Lei; Yu, Wei-bo; Tao, Lian-yuan; Xu, Qing

    2016-01-15

    Spinal cord injury (SCI) is characterized by the loss of motor and sensory functions in areas below the level of the lesion and numerous accompanying deficits. Previous studies have suggested that myeloid-derived suppressor cell (MDSC)-induced immune depression may play a pivotal role in the course of SCI. However, the concrete mechanism of these changes regarding immune suppression remains unknown. Here, we created an SCI mouse model to gain further evidence regarding the relationship between MDSCs following SCI and T lymphocyte suppression. We showed that in the SCI mouse model, the expanding MDSCs have the capacity to suppress T cell proliferation, and this suppression could be reversed by blocking the arginase. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Protective effect of andrographolide against concanavalin A-induced liver injury.

    Science.gov (United States)

    Shi, Guojun; Zhang, Zhijian; Zhang, Rong; Zhang, Xiaofang; Lu, Yan; Yang, Jian; Zhang, Di; Zhang, Zhiguo; Li, Xiaoying; Ning, Guang

    2012-01-01

    This study was designed to investigate the hepatic protective effect and the molecular mechanisms of andrographolide in concanavalin A-induced liver injury model. Results showed that andrographolide (Ag) attenuated concanavalin A (Con-A)-induced liver injury and inhibited hepatocyte apoptosis. Further results showed that oxidative stress response genes were significantly elevated during the pathogenesis induced by Con-A. Meanwhile, gadolinium chloride and N-acetyl-L-cysteine (NAC) treatment, which inactivates Kupffer cells or reduces reactive oxygen species, respectively, prevented the liver injury. So the messenger RNA levels of the oxidative response genes mentioned above were detected, and the following results showed that Ag treatment reduced their expression. Besides, serum lactate dehydrogenase and myeloperoxidase activity was significantly reduced by Ag. Finally, Ag treatment did not further reduce serum tumor necrosis factor-α production compared with NAC treatment alone. Thus, our results indicate that Ag prevents Con-A-induced liver injury and reduced the hepatic oxidative stress response. The hepatic protective effect of Ag indicates that Ag supplementation may be beneficial in the treatment of immune-mediated liver injury.

  6. 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

  7. Eosinophil-induced liver injury: an experimental model using IL-5 transgenic mice.

    Science.gov (United States)

    Tsuda, K; Maeda, T; Tominaga, A; Watanabe, Y; Miyazaki, E; Enzan, H; Akisawa, N; Iwasaki, S; Saibara, T; Onishi, S

    2001-02-01

    In certain liver diseases, activated eosinophils are considered to be important effector cells in addition to T-cell-mediated cytotoxicity. No experimental model, however, has been developed for in vivo analysis of the cytotoxic mechanisms. Interleukin-5 (IL-5) transgenic mice (C3H/HeN-TgN(IL-5)Imeg), which exhibit marked eosinophilia without liver injury, were injected once with 25 microg of lipopolysaccharide (LPS) intraperitoneally. The mice were sacrificed weekly and eosinophilic injuries were assessed microscopically. To clarify the role of Kupffer cells and tumor necrosis factor-alpha (TNF-alpha) in the liver injury, gadolinium chloride (GdCl3) and anti-TNF-alpha neutralizing antibody were administrated before the LPS injection. Two weeks after injection, transgenic mice exhibited marked infiltration of eosinophils and extensive lobular necrosis. Transmigration of eosinophils through vascular endothelium and degranulation of eosinophil cytotoxic granules in inflamed areas were observed. These eosinophilic injuries were transient, but liver-specific. Pre-administration of GdCl3 and anti-TNF-alpha markedly reduced the hepatic inflammation, suggesting that LPS-activated Kupffer cells play a key role in producing the cytotoxicity of eosinophils by releasing TNF-alpha. We have established an experimental model of eosinophil-induced liver injury using IL-5 transgenic mice. Since this model is simple and highly reproducible, it will be useful for analysis of in vivo cytotoxic mechanisms of eosinophils.

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

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    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

  9. 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.

  10. Drug-induced Liver Injury is Frequently Associated with Severe Cutaneous Adverse Drug Reactions: Experience from Two Australian Tertiary Hospitals.

    Science.gov (United States)

    Fang, Wendy C; Adler, Nikki R; Graudins, Linda V; Goldblatt, Caitlin; Goh, Michelle Sy; Roberts, Stuart K; Trubiano, Jason A; Aung, Ar Kar

    2018-01-08

    Drug-induced liver injury can be associated with certain cutaneous adverse drug reactions. We aim to demonstrate the prevalence of drug-induced liver injury in patients with cutaneous adverse drug reactions. Severity and patterns of liver injury, risk factors, causal medications and outcomes are also examined. A retrospective cohort study of patients with cutaneous adverse drug reactions was conducted across two hospitals in Australia. Patients were identified through cross-linkage of multiple databases. 104 patients with cutaneous adverse drug reactions were identified. Of these, 33 (31.7%) had liver injury, representing 50% of patients with drug reaction with eosinophilia and systemic symptoms, and 30.2% of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. Most cases of liver injury (69.7%) were of a cholestatic/mixed pattern with severe disease in 18.2%. No significant risk factors for development of liver injury were noted, but peripheral lymphocytosis may represent a risk in patients with Stevens-Johnson syndrome (OR=6.0, 95% CI:1.8-19.7, p=0.003). Antimicrobials were the most common class to be implicated in drug-induced liver injury. The median length of inpatient stay was longer in patients with liver injury compared to those without (19 vs. 11 days, p=0.002). The mortality rate in those with liver injury was 15.2% and 9.9% in those without. No patients required liver transplantation. Drug-induced liver injury commonly occurs in patients with cutaneous adverse drug reactions and is associated with longer inpatient stay. Patients with Stevens-Johnson/toxic epidermal necrolysis and peripheral lymphocytosis appear to be at higher risk for developing associated liver injury. This article is protected by copyright. All rights reserved.

  11. Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice.

    Science.gov (United States)

    Yu, Su Jong; Bae, Seyeon; Kang, Jae Seung; Yoon, Jung-Hwan; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Yoon Jun; Lee, Wang Jae; Kim, Chung Yong; Lee, Hyo-Suk

    2015-09-05

    Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. 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.

  13. 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

  14. Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

    International Nuclear Information System (INIS)

    Anders, Lisanne C; Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N; Cave, Matt; Arteel, Gavin E; McClain, Craig J

    2016-01-01

    Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE

  15. Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

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    Tomishima Yoshiro

    2013-01-01

    Full Text Available Abstract Background Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2 synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg. The effects of ozagrel (200 mg/kg treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL on cytochrome P450 2E1 (CYP2E1 activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM were evaluated by the WST-1 cell viability assay. Results Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos and C/EBP homologous protein (chop, but did not suppress B-cell lymphoma 2-like protein11 (bim expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest

  16. Histones activate the NLRP3 Inflammasome in Kupffer Cells during Sterile Inflammatory Liver Injury

    Science.gov (United States)

    Huang, Hai; Chen, Hui-Wei; Evankovich, John; Yan, Wei; Rosborough, Brian R.; Nace, Gary W.; Ding, Qing; Loughran, Patricia; Beer-Stolz, Donna; Billiar, Timothy R.; Esmon, Charles T.; Tsung, Allan

    2013-01-01

    Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests it also plays a role in inflammation driven by endogenous danger-associate molecular pattern (DAMP) molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. Here we report that both NLRP3 and its downstream target Caspase-1 are activated I/R and are essential for hepatic I/R injury as both NLRP3 and Caspase-1 KO mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on Caspase-1 expression in liver non-parenchymal cells. While upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through Toll-like Receptor-9 (TLR9). This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and activation of innate immunity during sterile inflammation. PMID:23904166

  17. 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

  18. Implications of microbiota and bile acid in liver injury and regeneration.

    Science.gov (United States)

    Liu, Hui-Xin; Keane, Ryan; Sheng, Lili; Wan, Yu-Jui Yvonne

    2015-12-01

    Studies examining the mechanisms by which the liver incurs injury and then regenerates usually focus on factors and pathways directly within the liver, neglecting the signaling derived from the gut-liver axis. The intestinal content is rich in microorganisms as well as metabolites generated from both the host and colonizing bacteria. Through the gut-liver axis, this complex "soup" exerts an immense impact on liver integrity and function. This review article summarizes data published in the past 30 years demonstrating the signaling derived from the gut-liver axis in relation to liver injury and regeneration. Due to the intricate networks of implicated pathways as well as scarcity of available mechanistic data, it seems that nutrigenomic, metabolomics, and microbiota profiling approaches are warranted to provide a better understanding regarding the interplay and impact between nutrition, bacteria, and host response in influencing liver function and healing. Therefore elucidating the possible molecular mechanisms that link microbiota alteration to host physiological response and vice versa. Published by Elsevier B.V.

  19. 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

  20. Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

    Directory of Open Access Journals (Sweden)

    Weili Yang

    2018-04-01

    Full Text Available Liver ischemia-reperfusion injury (IRI is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ protects the liver against IRI, but with unidentified direct target gene(s and unclear mechanism(s. Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

  1. Intravital Microscopic Evaluation of the Effects of a CXCR2 Antagonist in a Model of Liver Ischemia Reperfusion Injury in Mice.

    Science.gov (United States)

    de Oliveira, Thiago Henrique Caldeira; Marques, Pedro Elias; Poosti, Fariba; Ruytinx, Pieter; Amaral, Flávio Almeida; Brandolini, Laura; Allegretti, Marcello; Proost, Paul; Teixeira, Mauro Martins

    2017-01-01

    Ischemia-reperfusion (IR) is a major contributor to graft rejection after liver transplantation. During IR injury, an intense inflammatory process occurs in the liver. Neutrophils are considered central players in the events that lead to liver injury. CXC chemokines mediate hepatic inflammation following reperfusion. However, few studies have demonstrated in real-time the behavior of recruited neutrophils. We used confocal intravital microscopy (IVM) to image neutrophil migration in the liver and to analyze in real-time parameters of neutrophil recruitment in the inflamed tissue in animals treated or not with reparixin, an allosteric antagonist of CXCR1/2 receptors. WT and LysM-eGFP mice treated with reparixin or saline were subjected to 60 min of ischemia followed by different times of reperfusion. Mice received Sytox orange intravenously to show necrotic DNA in IVM. The effect of reparixin on parameters of local and systemic reperfusion-induced injury was also investigated. IR induced liver injury and inflammation, as evidenced by high levels of alanine aminotransferase and myeloperoxidase activity, chemokine and cytokine production, and histological outcome. Treatment with reparixin significantly decreased neutrophil influx. Moreover, reparixin effectively suppressed the increase in serum concentrations of TNF-α, IL-6, and CCL3, and the reperfusion-associated tissue damage. The number of neutrophils in the liver increased between 6 and 24 h of reperfusion, whereas the distance traveled, velocity, neutrophil size and shape, and cluster formation reached a maximum 6 h after reperfusion and then decreased gradually. In vivo imaging revealed that reparixin significantly decreased neutrophil infiltration and movement and displacement of recruited cells. Moreover, neutrophils had a smaller size and less elongated shape in treated mice. Imaging of the liver by confocal IVM was successfully implemented to describe neutrophil behavior in vivo during liver injury

  2. 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.

  3. Mitochondrial Roles and Cytoprotection in Chronic Liver Injury

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    Davide Degli Esposti

    2012-01-01

    Full Text Available The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.

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

    OpenAIRE

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

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohe...

  5. 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...

  6. Functional role of monocytes and macrophages for the inflammatory response in acute liver injury

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    Henning W Zimmermann

    2012-10-01

    Full Text Available Different etiologies such as drug toxicity, acute viral hepatitis B or acetaminophen poisoning can cause acute liver injury (ALI or even acute liver failure (ALF. Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF, interleukin-6 (IL-6, IL-1-beta or monocyte chemoattractant protein 1 (MCP-1, CCL2 as well as activating other non-parenchymal liver cells, e.g. endothelial or hepatic stellate cells (HSC. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g. via caspase activation, but also activate protective signaling pathways, e.g. via nuclear factor kappa B (NF-kB. Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+ monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1 are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF.

  7. Polysialic Acid/Neural Cell Adhesion Molecule Modulates the Formation of Ductular Reactions in Liver Injury

    OpenAIRE

    Tsuchiya, Atsunori; Lu, Wei-Yu; Weinhold, Birgit; Boulter, Luke; Stutchfield, Benjamin M.; Williams, Michael J.; Guest, Rachel V.; Minnis-Lyons, Sarah E.; MacKinnon, Alison C.; Schwarzer, David; Ichida, Takafumi; Nomoto, Minoru; Aoyagi, Yutaka; Gerardy-Schahn, Rita; Forbes, Stuart J.

    2014-01-01

    In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NC...

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

    African Journals Online (AJOL)

    2013-12-02

    Dec 2, 2013 ... (59.0 -530.8) manifesting severe liver injury. Mean albumin and creatinine were 25.2 g/dl (16.0-32.4) and 162.25 mmol/L (69.8 - 247). Mean platelet count was 128.0X106/L. (20-292). Mean BMI was 18.40 Kg/M2 (16.0 - 31.14). Ultrasound was normal in two, hepatomegally and ascites in six, liver cirrhosis ...

  9. Maresin 1, a Proresolving Lipid Mediator, Mitigates Carbon Tetrachloride-Induced Liver Injury in Mice

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    Ruidong Li

    2016-01-01

    Full Text Available Maresin 1 (MaR 1 was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb and mitogen-activated protein kinases (MAPKs in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway.

  10. Ultra Low Dose Delta 9-Tetrahydrocannabinol Protects Mouse Liver from Ischemia Reperfusion Injury

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    Edith Hochhauser

    2015-07-01

    Full Text Available Background/Aims: Ischemia/reperfusion (I/R injury is the main cause of both primary graft dysfunction and primary non-function of liver allografts. Cannabinoids has been reported to attenuate myocardial, cerebral and hepatic I/R oxidative injury. Delta-9-tetrahydrocannabinol (THC, a cannabinoid agonist, is the active components of marijuana. In this study we examined the role of ultralow dose THC (0.002mg/kg in the protection of livers from I/R injury. This extremely low dose of THC was previously found by us to protect the mice brain and heart from a variety of insults. Methods: C57Bl Mice were studied in in vivo model of hepatic segmental (70% ischemia for 60min followed by reperfusion for 6 hours. Results: THC administration 2h prior to the induction of hepatic I/R was associated with significant attenuated elevations of: serum liver transaminases ALT and AST, the hepatic oxidative stress (activation of the intracellular signaling CREB pathway, the acute proinflammatory response (TNF-α, IL-1α, IL-10 and c-FOS hepatic mRNA levels, and ERK signaling pathway activation. This was followed by cell death (the cleavage of the pro-apoptotic caspase 3, DNA fragmentation and TUNEL after 6 hours of reperfusion. Significantly less hepatic injury was detected in the THC treated I/R mice and fewer apoptotic hepatocytes cells were identified by morphological criteria compared with untreated mice. Conclusion: A single ultralow dose THC can reduce the apoptotic, oxidative and inflammatory injury induced by hepatic I/R injury. THC may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation, liver resection and trauma.

  11. The role of MAP2 kinases and p38 kinase in acute murine liver injury models

    Science.gov (United States)

    Zhang, Jun; Min, Robert W M; Le, Khanh; Zhou, Sheng; Aghajan, Mariam; Than, Tin A; Win, Sanda; Kaplowitz, Neil

    2017-01-01

    c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF/galactosamine (TNF/GalN). Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK. The relative role of MKK4 versus 7 in liver injury is largely unexplored, as is the potential role of p38 kinase, which might be a key mediator of toxicity in addition to JNK. Antisense oligonucleotides (ASO) to MKK4, MKK7 and p38 (versus scrambled control) were used for in vivo knockdown, and in some experiments PMH were used after in vivo knockdown. Mice were treated with APAP or TNF/GalN and injury assessed. MKK4 and MKK7 were expressed in liver and each was efficiently knocked down with two different ASOs. Massive liver injury and ALT elevation were abrogated by MKK4 but not MKK7 ASO pretreatment in both injury models. The protection was confirmed in PMH. Knockdown of MKK4 completely inhibited basal P-p38 in both cytoplasm and mitochondria. However, ALT levels and histologic injury in APAP-treated mice were not altered with p38 knockdown versus scrambled control. p38 knockdown significantly increased P-JNK levels in cytoplasm but not mitochondria after APAP treatment. In conclusion, MKK4 is the major MAP2K, which activates JNK in acute liver injury. p38, the other downstream target of MKK4, does not contribute to liver injury from APAP or TNF/galactosamine. PMID:28661486

  12. [Effects of xiaoyan lidan pian extract on mice with stressive liver injury].

    Science.gov (United States)

    Yin, Xiao-Ping; Kurihara, Hiroshi; Bao, Li

    2009-02-01

    To investigate the protective effects of Xiaoyan Lidan Pian extract (XLP) on restraint stress induced liver injury in mice. Liver injury mouse model was established by restraint stress. Sixty mice were equally divided into 6 groups, the normal control group, the model group, the Thiopronin group, and the three XLP groups treated with low (125 mg/kg), moderate (250 mg/kg) and high dose (500 mg/kg) XLP respectively. Effect of various treatments was evaluated by assessing alanine aminotransferase (ALT) in plasma; malondialdehyde (MDA) content in liver by thiobarbituric acid method; content of nitric oxide (NO) by Griess chemical method; hepatic antioxidant capacity index (ORAC) by fluorescent enzyme immunoassay; glutathione (GSH) content by HPLC; activity of glutathione peroxidase (GPX-Px) and glutathione S-transferase (GST) by colorimetry; activity of hepatic mitochondrial respiratory chain complex enzyme (MRCCE) by ultraviolet spectrophotometry; and contents of cytochrome a, b, c, and c1 by the redox differential spectra. As compared with the model group, in the XLP groups, level of plasma ALT activity, liver content of MDA and NO, and contents of cytochromes were lower, while levels of ORAC index, GSH, GPX-Px and GST in liver, and MRCCE activity were higher. XLP has definite protective effects on stressive liver injury in mice, which may be related to its action in alleviating the oxidative stress condition in mice.

  13. Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury

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    M. Radojkovic

    Full Text Available Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.

  14. Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury.

    Science.gov (United States)

    Radojkovic, M; Stojanovic, M; Stanojevic, G; Radojkovic, D; Gligorijevic, J; Ilic, I; Stojanovic, N

    2017-07-20

    Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Shancai Tan

    2017-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  18. 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

  19. Bone Marrow-Derived Mesenchymal Stem Cells Attenuate Immune-Mediated Liver Injury and Compromise Virus Control During Acute Hepatitis B Virus Infection in Mice.

    Science.gov (United States)

    Qu, Mengmeng; Yuan, Xu; Liu, Dan; Ma, Yuhong; Zhu, Jun; Cui, Jun; Yu, Mengxue; Li, Changyong; Guo, Deyin

    2017-06-01

    Mesenchymal stem cells (MSCs) have been used as therapeutic tools not only for their ability to differentiate toward different cells, but also for their unique immunomodulatory properties. However, it is still unknown how MSCs may affect immunity during hepatitis B virus (HBV) infection. This study was designed to explore the effect of bone marrow-derived MSCs (BM-MSCs) on hepatic natural killer (NK) cells in a mouse model of acute HBV infection. Mice were injected with 1 × 10 6 BM-MSCs, which stained with chloromethyl derivatives of fluorescein diacetate fluorescent probe, 24 h before hydrodynamic injection of viral DNA (pHBV1.3) through the tail vein. In vivo imaging system revealed that BM-MSCs were accumulated in the injured liver, and they attenuated immune-mediated liver injury during HBV infection, as shown by lower alanine aminotransferase levels, reduced proinflammatory cytokine production, and decreased inflammatory cell infiltration in the liver. Importantly, administration of BM-MSCs restrained the increased expression of natural-killer group 2, member D (NKG2D), an important receptor required for NK cell activation in the liver from HBV-infected mice. BM-MSCs also reduced NKG2D expression on NK cells and suppressed the cytotoxicity of NK cells in vitro. Furthermore, BM-MSC-derived transforming growth factor-β1 suppressed NKG2D expression on NK cells. As a consequence, BM-MSC treatment enhanced HBV gene expression and replication in vivo. These results demonstrate that adoptive transfer of BM-MSCs influences innate immunity and limits immune-mediated liver injury during acute HBV infection by suppressing NK cell activity. Meanwhile, the effect of BM-MSCs on prolonging virus clearance needs to be considered in the future.

  20. Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats

    Directory of Open Access Journals (Sweden)

    WeiHeng Wang

    2017-01-01

    Full Text Available Objective. We investigated the hypothesis that methane-rich saline (MS can be used to repair spinal cord injury (SCI in a rat model through suppressing microglial activation related to oxidative, inflammatory, and apoptotic injury. Methods. MS was injected intraperitoneally in rats after SCI. Hematoxylin-eosin (HE staining, oxidative stress, inflammatory parameters, and cell apoptosis were detected 72 h after SCI to determine the optimal dose. Then, we investigated the protective mechanisms and the long-term effects of MS on SCI. HE and microglial activation were observed. Neurological function was evaluated by the Basso, Beattie, and Bresnahan (BBB scale. Results. MS can significantly decrease infarct area and inhibit oxidative stress, inflammation, and cell apoptosis 72 h following SCI. The MS protective effect at a dose of 20 ml/kg was better. Moreover, MS can significantly suppress microglial activation related to oxidative and inflammatory injury after SCI and improve hind limb neurological function. Conclusion. MS could repair SCI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis produced by activated microglia. MS provides a novel and promising strategy for the treatment of SCI.

  1. Validity of diagnostic codes and laboratory measurements to identify patients with idiopathic acute liver injury in a hospital database

    NARCIS (Netherlands)

    Udo, Renate; Maitland-van der Zee, Anke H.; Egberts, Toine C G|info:eu-repo/dai/nl/162850050; den Breeijen, Johanna H.; Leufkens, Hubert G M; van Solinge, Wouter W.|info:eu-repo/dai/nl/106837753; De Bruin, Marie L.

    2016-01-01

    Purpose: The development and validation of algorithms to identify cases of idiopathic acute liver injury (ALI) are essential to facilitate epidemiologic studies on drug-induced liver injury. The aim of this study is to determine the ability of diagnostic codes and laboratory measurements to identify

  2. 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...

  3. Validity of diagnostic codes and laboratory measurements to identify patients with idiopathic acute liver injury in a hospital database

    NARCIS (Netherlands)

    Udo, Renate; Maitland-van der Zee, Anke H.; Egberts, Toine C. G.; den Breeijen, Johanna H.; Leufkens, Hubert G. M.; van Solinge, Wouter W.; de Bruin, Marie L.

    2016-01-01

    PurposeThe development and validation of algorithms to identify cases of idiopathic acute liver injury (ALI) are essential to facilitate epidemiologic studies on drug-induced liver injury. The aim of this study is to determine the ability of diagnostic codes and laboratory measurements to identify

  4. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

    Science.gov (United States)

    Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel

    2014-06-01

    Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Liver injury and disease pathogenesis in chronic hepatitis C.

    Science.gov (United States)

    Yamane, Daisuke; McGivern, David R; Masaki, Takahiro; Lemon, Stanley M

    2013-01-01

    Chronic hepatitis C virus (HCV) infection is a leading cause of liver-specific morbidity and mortality in humans, including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. It has also been associated with altered function in other organs, including those of the endocrine, hematopoietic, and nervous systems. Disease results from both direct regulation of cellular metabolism and signaling pathways by viral proteins as well as indirect consequences of the host response to HCV infection, including inflammatory responses stemming from immune recognition of the virus. Recent in vitro studies have begun to reveal molecular mechanisms responsible for virus-induced changes in cell metabolism and cellular kinase cascades that culminate in pathologic consequences in the liver, such as steatosis, insulin resistance, and carcinogenesis. Here we discuss how these findings may be relevant to disease pathogenesis in patients, and suggest future directions in the field.

  6. 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.

  7. 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

    Directory of Open Access Journals (Sweden)

    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.

  8. Broccoli sprout extract induces detoxification-related gene expression and attenuates acute liver injury.

    Science.gov (United States)

    Yoshida, Kazutaka; Ushida, Yusuke; Ishijima, Tomoko; Suganuma, Hiroyuki; Inakuma, Takahiro; Yajima, Nobuhiro; Abe, Keiko; Nakai, Yuji

    2015-09-21

    To investigate the effects of broccoli sprout extract (BSEx) on liver gene expression and acute liver injury in the rat. First, the effects of BSEx on liver gene expression were examined. Male rats were divided into two groups. The Control group was fed the AIN-76 diet, and the BSEx group was fed the AIN-76 diet containing BSEx. After a 10-d feeding period, rats were sacrificed and their livers were used for DNA microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. Next, the effects of BSEx on acute liver injury were examined. In experiments using acute liver injury models, 1000 mg/kg acetaminophen (APAP) or 350 mg/kg D-galactosamine (D-GalN) was used to induce injury. These male rats were divided into four groups: Control, BSEx, Inducer (APAP or D-GalN), and Inducer+BSEx. The feeding regimens were identical for the two analyses. Twenty-four hours following APAP administration via p.o. or D-GalN administration via i.p., rats were sacrificed to determine serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, hepatic glutathione (GSH) and thiobarbituric acid-reactive substances accumulation and glutathione-S-transferase (GST) activity. Microarray and real-time RT-PCR analyses revealed that BSEx upregulated the expression of genes related to detoxification and glutathione synthesis in normal rat liver. The levels of AST (70.91 ± 15.74 IU/mL vs 5614.41 ± 1997.83 IU/mL, P detoxification enzymes and glutathione synthesis.

  9. The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection

    NARCIS (Netherlands)

    Tang, T J; Kwekkeboom, J; Laman, J D; Niesters, H G M; Zondervan, P E; de Man, R A; Schalm, S W; Janssen, H L A

    Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver

  10. 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.

  11. Pretreatment with mangafodipir improves liver graft tolerance to ischemia/reperfusion injury in rat.

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    Ismail Ben Mosbah

    Full Text Available Ischemia/reperfusion injury occurring during liver transplantation is mainly due to the generation of reactive oxygen species (ROS upon revascularization. Thus, delivery of antioxidant enzymes might reduce the deleterious effects of ROS and improve liver graft initial function. Mangafodipir trisodium (MnDPDP, a contrast agent currently used in magnetic resonance imaging of the liver, has been shown to be endowed with powerful antioxidant properties. We hypothesized that MnDPDP could have a protective effect against liver ischemia reperfusion injury when administrated to the donor prior to harvesting. Livers from Sprague Dawley rats pretreated or not with MnDPDP were harvested and subsequently preserved for 24 h in Celsior® solution at 4°C. Organs were then perfused ex vivo for 120 min at 37°C with Krebs Henseleit solution. In MnDPDP (5 µmol/kg group, we observed that ATP content was significantly higher at the end of the cold preservation period relative to untreated group. After reperfusion, livers from MnDPDP-treated rats showed better tissue integrity, less hepatocellular and endothelial cell injury. This was accompanied by larger amounts of bile production and higher ATP recovery as compared to untreated livers. The protective effect of MnDPDP was associated with a significant decrease of lipid peroxidation, mitochondrial damage, and apoptosis. Interestingly, MnDPDP-pretreated livers exhibited activation of Nfr2 and HIF-1α pathways resulting in a higher catalase and HO-1 activities. MnDPDP also increased total nitric oxide (NO production which derived from higher expression of constitutive NO synthase and lower expression of inducible NO synthase. In conclusion, our results show that donor pretreatment with MnDPDP protects the rat liver graft from cold ischemia/reperfusion injury and demonstrate for the first time the potential interest of this molecule in the field of organ preservation. Since MnDPDP is safely used in liver imaging

  12. 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 ...

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

    African Journals Online (AJOL)

    Serum hepatospecific markers (AST, ALT and ALP) were estimated. The antioxidant status of liver tissues was estimated for GSH, MDA, GST, LDH and vitamin C l, in addition to sodium and potassium. Results: Administration of orogastric dose of ampicillin for 3 weeks induced inhibition of E.coli, yeasts, total anaerobes, and ...

  14. Congenital biliary atresia: liver injury begins at birth

    DEFF Research Database (Denmark)

    Makin, Erica; Quaglia, Alberto; Kvist, Nina

    2009-01-01

    -note review for infants with definite BA who underwent laparotomy within first week of life. RESULTS: Three infants were identified who had occlusive BA evident on the first day of life. In all cases, their liver was grossly normal, and histologic changes were trivial. CONCLUSION: This suggests...

  15. Selective non-operative management of penetrating liver injuries at a UK tertiary referral centre.

    Science.gov (United States)

    MacGoey, P; Navarro, A; Beckingham, I J; Cameron, I C; Brooks, A J

    2014-09-01

    Selective non-operative management (SNOM) of penetrating abdominal injuries has increasingly been applied in North America in the last decade. However, there is less acceptance of SNOM among UK surgeons and there are limited data on UK practice. We aimed to review our management of penetrating liver injuries and, specifically, the application of SNOM. A retrospective review was performed of patients presenting with penetrating liver injuries between June 2005 and November 2013. Thirty-one patients sustained liver injuries due to penetrating trauma. The vast majority (97%) were due to stab wounds. The median injury severity score was 14 and a quarter of patients had concomitant thoracic injuries. Twelve patients (39%) underwent immediate surgery owing to haemodynamic instability, evisceration, retained weapon or diffuse peritonism. Nineteen patients were stable to undergo computed tomography (CT), ten of whom were selected subsequently for SNOM. SNOM was successful in eight cases. Both patients who failed SNOM had arterial phase contrast extravasation evident on their initial CT. Angioembolisation was not employed in either case. All major complications and the only death occurred in the operatively managed group. No significant complications of SNOM were identified and there were no transfusions in the non-operated group. Those undergoing operative management had longer lengths of stay than those undergoing SNOM (median stay 6.5 vs 3.0 days, p<0.05). SNOM is a safe strategy for patients with penetrating liver injuries in a UK setting. Patient selection is critical and CT is a vital triage tool. Arterial phase contrast extravasation may predict failure of SNOM and adjunctive angioembolisation should be considered for this group.

  16. Butyrate protects rat liver against total hepatic ischemia reperfusion injury with bowel congestion.

    Science.gov (United States)

    Liu, Bin; Qian, Jianmin; Wang, Qingbao; Wang, Fangrui; Ma, Zhenyu; Qiao, Yingli

    2014-01-01

    Hepatic ischemia/reperfusion (I/R) injury is an unavoidable consequence of major liver surgery, especially in liver transplantation with bowel congestion, during which endotoxemia is often evident. The inflammatory response aggravated by endotoxin after I/R contributes to liver dysfunction and failure. The purpose of the present study was to investigate the protective effect of butyrate, a naturally occurring four-carbon fatty acid in the body and a dietary component of foods such as cheese and butter, on hepatic injury complicated by enterogenous endotoxin, as well as to examine the underlying mechanisms involved. SD rats were subjected to a total hepatic ischemia for 30 min after pretreatment with either vehicle or butyrate, followed by 6 h and 24 h of reperfusion. Butyrate preconditioning markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathological changes. The inflammatory factors levels, macrophages activation, TLR4 expression, and neutrophil infiltration in live were attenuated by butyrate. Butyrate also maintained the intestinal barrier structures, reversed the aberrant expression of ZO-1, and decreased the endotoxin translocation. We conclude that butyrate inhibition of endotoxin translocation, macrophages activation, inflammatory factors production, and neutrophil infiltration is involved in the alleviation of total hepatic I/R liver injury in rats. This suggests that butyrate should potentially be utilized in liver transplantation.

  17. Intestinal endotoxins as co-factors of liver injury in obstructive jaundice.

    Science.gov (United States)

    Mentes, B B; Tatlicioglu, E; Akyol, G; Uluoglu, O; Sultan, N; Yilmaz, E; Celebi, M; Taneri, F; Ferahkose, Z

    1996-01-01

    The concept of endotoxin-mediated rather than direct liver injury in biliary obstruction was investigated using the experimental rat model of bile duct ligation (BDL) and small bowel bacterial overgrowth (SBBO). Small identical doses of intravenous endotoxin (bacterial LPS) caused a significantly more severe liver injury in rats with BDL, compared with sham-operated rats, suggesting the possible contribution of LPS in this type of liver damage. BDL was then combined with surgically created jejunal self-filling blind loops, which resulted in SBBO. Plasma LPS level increased significantly, and once again a more severe liver injury, determined by liver histology and serum gamma-glutamyl transpeptidase levels, was observed compared with the control group of rats with BDL+self-emptying blind loops. The data presented suggest that small amounts of exogenous LPS and/or the ordinarily innocous amounts of LPS constantly absorbed from the intestinal tract may be critical in the hepatic damage caused by obstruction of the biliary tract.

  18. MicroRNAs as biomarkers for liver injury: Current knowledge, challenges and future prospects.

    Science.gov (United States)

    Lin, Haixia; Ewing, Laura E; Koturbash, Igor; Gurley, Bill J; Miousse, Isabelle R

    2017-12-01

    MicroRNAs (miRNAs) are short regulatory RNAs that are involved in various biological processes that regulate gene expression posttranscriptionally. Changes in miRNA expression can be detected in many physiological and pathological events, such as liver injury. Drug induced liver injury is a life threatening condition that frequently requires organ transplantation. Hepatotoxicity is also one of the major causes of drug failure in clinical trials and of drug withdrawal from the market. The profiling of miRNA expression shows great promise in monitoring liver injury, in the prediction of outcome in patients, and in the identification of liver-reactive compounds in toxicological assessment. Recent studies have demonstrated organ-specificity of some miRNAs (i.e., miR-122), which are released into biological fluids as a result of hepatocyte damage. This attests to the potential of miRNAs as noninvasive biomarkers to detect liver toxicity. This review presents information on miRNA signatures of hepatotoxicity and on the application of promising miRNA biomarkers in preclinical safety assessment. We further discuss the technical challenges associated with these emerging biomarkers for early diagnosis and detection of hepatotoxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Risk assessment of silica nanoparticles on liver injury in metabolic syndrome mice induced by fructose.

    Science.gov (United States)

    Li, Jianmei; He, Xiwei; Yang, Yang; Li, Mei; Xu, Chenke; Yu, Rong

    2018-07-01

    This study aims to assess the effects and the mechanisms of silica nanoparticles (SiNPs) on hepatotoxicity in both normal and metabolic syndrome mouse models induced by fructose. Here, we found that SiNPs exposure lead to improved insulin resistance in metabolic syndrome mice, but markedly worsened hepatic ballooning, inflammation infiltration, and fibrosis. Moreover, SiNPs exposure aggravated liver injury in metabolic syndrome mice by causing serious DNA damage. Following SiNPs exposure, liver superoxide dismutase and catalase activities in metabolic syndrome mice were stimulated, which is accompanied by significantly increased malondialdehyde and 8-hydroxy-2-deoxyguanosine levels as compared to normal mice. Scanning electron microscope (SEM) revealed that SiNPs were more readily deposited in the liver mitochondria of metabolic syndrome mice, resulting in more severe mitochondrial injury as compared to normal mice. We speculated that SiNPs-induced mitochondrial injury might be the cause of hepatic oxidative stress, which further lead to a series of liver lesions as observed in mice following SiNPs exposure. Based on these results, it is likely that SiNPs will increase the risk and severity of liver disease in individuals with metabolic syndrome. Therefore, SiNPs should be used cautiously in food additives and clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. 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.

  1. Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.

    Science.gov (United States)

    Shin, So Youn; Jeong, Sook-Hyang; Sung, Pil Soo; Lee, Jino; Kim, Hyung Joon; Lee, Hyun Woong; Shin, Eui-Cheol

    2016-05-01

    Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.

  2. 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

  3. Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice.

    Science.gov (United States)

    Sanches, Sheila Cristina; Ramalho, Leandra Naira Z; Mendes-Braz, Mariana; Terra, Vânia Aparecida; Cecchini, Rubens; Augusto, Marlei Josiele; Ramalho, Fernando Silva

    2014-05-01

    Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60 min of ischaemia plus saline or riboflavin treatment (30 μmoles/kg BW) followed by 6 h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

    NARCIS (Netherlands)

    Kuijper, I.A.; Yang, H.; Water, van de B.; Beltman, J.B.

    2017-01-01

    Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  7. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice

    International Nuclear Information System (INIS)

    Geest, Rick van der; Ouweneel, Amber B.; Sluis, Ronald J. van der; Groen, Albert K.; Van Eck, Miranda; Hoekstra, Menno

    2016-01-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18 ± 5 ng/ml vs 472 ± 58 ng/ml; P < 0.001) and disrupted the metabolic and anti-inflammatory glucocorticoid function. Adrenal removal did not exacerbate the cholestasis extent. In contrast, the cholestasis-associated liver injury was markedly lower in adrenalectomized mice as compared to controls as evidenced by a 84%–93% decrease in liver necrosis and plasma alanine aminotransferase and bile acid levels (P < 0.001 for all). Gene expression analysis on livers from adrenalectomized mice suggested the absence of bile acid toxicity-associated farnesoid X receptor signaling in the context of a 44% (P < 0.01) and 82% (P < 0.001) reduction in sodium/bile acid cotransporter member 1 transcript level as compared to respectively control and non-diseased mice. Adrenalectomy reduced the expression of the cholesterol synthesis gene HMG-CoA reductase by 70% (P < 0.05), which translated into a 73% lower plasma total cholesterol level (P < 0.05). Treatment of C57BL/6 mice with the glucocorticoid receptor antagonist RU-486 recapitulated the protective effect of adrenalectomy on indices of liver injury and hypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. - Highlights: • Cholestasis is associated with increased plasma glucocorticoid levels in mice. • Adrenalectomy lowers cholestasis-associated liver

  8. Endogenous glucocorticoids exacerbate cholestasis-associated liver injury and hypercholesterolemia in mice.

    Science.gov (United States)

    van der Geest, Rick; Ouweneel, Amber B; van der Sluis, Ronald J; Groen, Albert K; Van Eck, Miranda; Hoekstra, Menno

    2016-09-01

    Cholestatic liver disease is characterized by a disruption of bile flow, bile acid toxicity, liver injury, and hypercholesterolemia. Relatively high secretion of glucocorticoids by the adrenals has been observed under cholestatic conditions. Here we investigated a contribution of the rise in endogenous glucocorticoids to initial stage cholestasis pathology. Adrenalectomized or sham-operated control C57BL/6 mice were given an oral dose of alpha-naphthylisothiocyanate to induce cholestasis. Adrenalectomy effectively lowered plasma corticosterone levels (18±5ng/ml vs 472±58ng/ml; Phypercholesterolemia. In conclusion, we have shown that endogenous glucocorticoids exacerbate the liver injury and hypercholesterolemia associated with acute cholestasis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. [Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis].

    Science.gov (United States)

    Zhao, De-An; Bi, Ling-Yun; Huang, Qian; Zhang, Fang-Min; Han, Zi-Ming

    Isoflurane is halogenated volatile ether used for inhalational anesthesia. It is widely used in clinics as an inhalational anesthetic. Neonatal hypoxic ischemia injury ensues in the immature brain that results in delayed cell death via excitotoxicity and oxidative stress. Isoflurane has shown neuroprotective properties that make a beneficial basis of using isoflurane in both cell culture and animal models, including various models of brain injury. We aimed to determine the neuroprotective effect of isoflurane on hypoxic brain injury and elucidated the underlying mechanism. A hippocampal slice, in artificial cerebrospinal fluid with glucose and oxygen deprivation, was used as an in vitro model for brain hypoxia. The orthodromic population spike and hypoxic injury potential were recorded in the CA1 and CA3 regions. Amino acid neurotransmitters concentration in perfusion solution of hippocampal slices was measured. Isoflurane treatment caused delayed elimination of population spike and improved the recovery of population spike; decreased frequency of hypoxic injury potential, postponed the onset of hypoxic injury potential and increased the duration of hypoxic injury potential. Isoflurane treatment also decreased the hypoxia-induced release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but the levels of γ-aminobutyric acid were elevated. Morphological studies showed that isoflurane treatment attenuated edema of pyramid neurons in the CA1 region. It also reduced apoptosis as evident by lowered expression of caspase-3 and PARP genes. Isoflurane showed a neuro-protective effect on hippocampal neuron injury induced by hypoxia through suppression of apoptosis. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  10. Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis.

    Science.gov (United States)

    Zhao, De-An; Bi, Ling-Yun; Huang, Qian; Zhang, Fang-Min; Han, Zi-Ming

    Isoflurane is halogenated volatile ether used for inhalational anesthesia. It is widely used in clinics as an inhalational anesthetic. Neonatal hypoxic ischemia injury ensues in the immature brain that results in delayed cell death via excitotoxicity and oxidative stress. Isoflurane has shown neuroprotective properties that make a beneficial basis of using isoflurane in both cell culture and animal models, including various models of brain injury. We aimed to determine the neuroprotective effect of isoflurane on hypoxic brain injury and elucidated the underlying mechanism. A hippocampal slice, in artificial cerebrospinal fluid with glucose and oxygen deprivation, was used as an in vitro model for brain hypoxia. The orthodromic population spike and hypoxic injury potential were recorded in the CA1 and CA3 regions. Amino acid neurotransmitters concentration in perfusion solution of hippocampal slices was measured. Isoflurane treatment caused delayed elimination of population spike and improved the recovery of population spike; decreased frequency of hypoxic injury potential, postponed the onset of hypoxic injury potential and increased the duration of hypoxic injury potential. Isoflurane treatment also decreased the hypoxia-induced release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but the levels of γ-aminobutyric acid were elevated. Morphological studies showed that isoflurane treatment attenuated edema of pyramid neurons in the CA1 region. It also reduced apoptosis as evident by lowered expression of caspase-3 and PARP genes. Isoflurane showed a neuro-protective effect on hippocampal neuron injury induced by hypoxia through suppression of apoptosis. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  11. Intermittent Ischemia but Not Ischemic Preconditioning Is Effective in Restoring Bile Flow After Ischemia Reperfusion Injury in the Livers of Aged Rats

    NARCIS (Netherlands)

    Schiesser, Marc; Wittert, Anna; Nieuwenhuijs, Vincent B.; Morphett, Arthur; Padbury, Robert T. A.; Barritt, Greg J.

    BackgroundlAims. Ischemic preconditioning (IPC) and intermittent ischemia (INT) reduce liver injury following ischemia reperfusion in liver resections. Aged livers are at higher risk for ischemia reperfusion injury, but little is known of the effectiveness of IPC and INT in aged livers. The aim of

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

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

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

    International Nuclear Information System (INIS)

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro

    2014-01-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury

  14. Butyrate protects liver against ischemia reperfusion injury by inhibiting nuclear factor kappa B activation in Kupffer cells.

    Science.gov (United States)

    Qiao, Ying-li; Qian, Jian-min; Wang, Fang-rui; Ma, Zhen-yu; Wang, Qian-wei

    2014-04-01

    The inflammatory response after hepatic ischemia reperfusion (I/R) contributes to liver dysfunction and failure after transplantation. Butyrate is a four-carbon fatty acid, normally produced by bacterial fermentation of fiber in mammalian intestines, with anti-inflammatory activities. The purpose of the present study was to investigate the protective effect of butyrate preconditioning, if any, against hepatic I/R injury in rats and the underlying mechanisms involved. Male Sprague-Dawley rats were subjected to a partial (70%) hepatic ischemia for 60 min after pretreatment with either vehicle or butyrate, followed by 3, 6, and 24 h of reperfusion. Hepatic injury was evaluated by biochemical and histopathologic examinations. Neutrophil infiltration was measured by myeloperoxidase (MPO) activity. The expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (Elisa) and Real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The expression of nuclear factor kappa B (NF-κB) p65 was determined by immunohistochemistry and Western blot analysis. Butyrate treatment markedly improved hepatic function and histology, as indicated by reduced transaminase levels and ameliorated tissue pathologic changes. The expression of tumor necrosis factor-alpha, interleukin-6, and myeloperoxidase activity was attenuated by butyrate. Butyrate also reduced I/R-induced nuclear translocation of NF-κB p65 in Kupffer cells. Our results suggest that butyrate alleviates I/R-induced liver injury, possibly by suppressing inflammatory factors production and preventing NF-κB activation in Kupffer cells. Copyright © 2014. Published by Elsevier Inc.

  15. Daily Plasmodium yoelii infective mosquito bites do not generate protection or suppress previous immunity against the liver stage

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    Wong Kurt A

    2011-04-01

    Full Text Available Abstract Background Human populations that are naturally subjected to Plasmodium infection do not acquire complete protection against the liver stage of this parasite despite prolonged and frequent exposure. However, sterile immunity against Plasmodium liver stage can be achieved after repeated exposure to radiation attenuated sporozoites. The reasons for this different response remain largely unknown, but a suppressive effect of blood stage Plasmodium infection has been proposed as a cause for the lack of liver stage protection. Methods Using Plasmodium yoelii 17XNL, the response generated in mice subjected to daily infective bites from normal or irradiated mosquitoes was compared. The effect of daily-infected mosquito bites on mice that were previously immunized against P. yoelii liver stage was also studied. Results It was observed that while the bites of normal infected mosquitoes do not generate strong antibody responses and protection, the bites of irradiated mosquitoes result in high levels of anti-sporozoite antibodies and protection against liver stage Plasmodium infection. Exposure to daily infected mosquito bites did not eliminate the protection acquired previously with a experimental liver stage vaccine. Conclusions Liver stage immunity generated by irradiated versus normal P. yoelii infected mosquitoes is essentially different, probably because of the blood stage infection that follows normal mosquito bites, but not irradiated. While infective mosquito bites do not induce a protective liver stage response, they also do not interfere with previously acquired liver stage protective responses, even if they induce a complete blood stage infection. Considering that the recently generated anti-malaria vaccines induce only partial protection against infection, it is encouraging that, at least in mouse models, immunity is not negatively affected by subsequent exposure and infection with the parasite.

  16. Protective effect of mycelial polysaccharides from Cordyceps sinensis on immunological liver injury in mice

    Directory of Open Access Journals (Sweden)

    Kai-zhong DONG

    2016-04-01

    Full Text Available Objective  To explore the protective effects of mycelial polysaccharides from Cordyceps sinensis (MPCS on BCG+LPS-induced liver injury in mice. Methods  The immunological liver injury mice model was reproduced by giving bacillus Calmette-Guerin (BCG and lipopolysaccharide (LPS. Sixty NIH mice were randomly assigned into 6 groups (10 each: normal control group, model group, mycelium polysaccharide in high (100mg/kg, medium (50mg/kg and low (25mg/kg dose group, and bifendate (150mg/kg treatment group. The serum transaminase levels of alanine ALT and AST were assayed with ELISA, nitric oxide (NO in serum was measured by nitrate reductase method, and the liver homogenate was prepared for the determination of the contents of interleukin-1β(IL-1β and tumor necrosis factor-α(TNF-α. The mRNA expression levels of IL-6 and iNOS in hepatic tissue were assessed using RT-PCR . Results  In the mice of immunological liver injury, mycelial polysaccharides from Cordyceps sinensis obviously lowered the serum ALT and AST levels (P<0.01, high dose MPCS significantly reduced the serum NO and liver tissue IL-1βand TNF-αlevels (P<0.01. Compared with the model group, high and medium dose MPCS significantly reduced the expression levels of IL-6 and iNOS mRNA in hepatic tissues (P<0.01. Conclusion  MPCS shows a certain protective effect on immunological liver injury induced by BCG plus LPS in mice. DOI: 10.11855/j.issn.0577-7402.2016.04.05

  17. Protective effect of gadolinium chloride on early warm ischemia/reperfusion injury in rat bile duct during liver transplantation.

    Directory of Open Access Journals (Sweden)

    Biao Wang

    Full Text Available BACKGROUND: Activation of Kupffer cell (KC is acknowledged as a key event in the initiation and perpetuation of bile duct warm ischemia/reperfusion injury. The inhibitory effect of gadolinium chloride (GdCl(3 on KC activation shows potential as a protective intervention in liver injury, but there is less research with regard to bile duct injury. METHODS: Sixty-five male Sprague-Dawley rats (200-250 g were randomly divided into three experimental groups: a sham group (n = 15, a control group (n = 25, and a GdCl(3 group (n = 25. Specimen was collected at 0.5, 2, 6, 12 and 24 h after operation. Alanine aminotransferase (ALT, alkaline phosphatase (ALP and total bilirubin (TBIL of serum were measured. Tumor necrosis factor-α (TNF-α, Capase-3 activity and soluble Fas (sFas were detected. The pathologic changes of bile duct were observed. Immunochemistry for bile duct Fas was performed. Apoptosis of bile duct cells was evaluated by the terminal UDP nick end labeling assay. RESULTS: GdCl(3 significantly decreased the levels of ALT, ALP and TBIL at 2, 6, 12, and 24 h, and increased serum sFas at 2, 6 and 12 h (P<0.05. TNF-α was lower in the GdCl(3 group than in the control group at 2, 6, 12 and 24 h (P<0.05. Preadministration of GdCl(3 significantly reduced the Caspase-3 activity and bile duct cell apoptosis at 2, 6, 12 and 24 h. After operation for 2, 6 and 12 h, the expression of Fas protein was lower in the GdCl(3 group than in the control group (P<0.05. CONCLUSIONS: GdCl(3 plays an important role in suppressing bile duct cell apoptosis, including decreasing ALT, ALP, TBIL and TNF-α; suppressing Fas-FasL-Caspase signal transduction during transplantation.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Tang, Yuewen; Cheng, Lin

    2017-04-01

    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.

  20. 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...... sacrificed and plasma MP were isolated by ultracentrifugation. HSC and CD133 MP levels were analyzed by fluorescence-activated cell sorting. Patients were enrolled with acute (n=5) and acute on chronic (n=5) liver injury with matched controls (n=7). Blood was collected at admission and plasma CD133 and CD39...... MP subsets were analyzed by fluorescence-activated cell sorting. RESULTS: HSC and CD133 MP levels were significantly increased only in the plasma of wild-type mice with acetaminophen hepatotoxicity (P

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    Peter Onody

    Full Text Available INTRODUCTION: Temporary occlusion of the hepatoduodenal ligament leads to an ischemic-reperfusion (IR injury in the liver. Levosimendan is a new positive inotropic drug, which induces preconditioning-like adaptive mechanisms due to opening of mitochondrial KATP channels. The aim of this study was to examine possible protective effects of levosimendan in a rat model of hepatic IR injury. MATERIAL AND METHODS: Levosimendan was administered to male Wistar rats 1 hour (early pretreatment or 24 hours (late pretreatment before induction of 60-minute segmental liver ischemia. Microcirculation of the liver was monitored by laser Doppler flowmeter. After 24 hours of reperfusion, liver and blood samples were taken for histology, immuno- and enzyme-histochemistry (TUNEL; PARP; NADH-TR as well as for laboratory tests. Furthermore, liver antioxidant status was assessed and HSP72 expression was measured. RESULTS: In both groups pretreated with levosimendan, significantly better hepatic microcirculation was observed compared to respective IR control groups. Similarly, histological damage was also reduced after levosimendan administration. This observation was supported by significantly lower activities of serum ALT (p early = 0.02; p late = 0.005, AST (p early = 0.02; p late = 0.004 and less DNA damage by TUNEL test (p early = 0.05; p late = 0.034 and PAR positivity (p early = 0.02; p late = 0.04. Levosimendan pretreatment resulted in significant improvement of liver redox homeostasis. Further, significantly better mitochondrial function was detected in animals receiving late pretreatment. Finally, HSP72 expression was increased by IR injury, but it was not affected by levosimendan pretreatment. CONCLUSION: Levosimendan pretreatment can be hepatoprotective and it could be useful before extensive liver resection.

  3. Protective effects of total glucosides of paeony and the underlying mechanisms in carbon tetrachloride-induced experimental liver injury

    Science.gov (United States)

    Qin, Ying; Tian, Ya-ping

    2011-01-01

    Introduction We explored the protective effects of total glucosides of paeony (TGP) and the underlying mechanisms in carbon tetrachloride (CCl4)-induced experimental liver injury in mice. Material and methods Chronic liver damage was induced by intraperitoneal injection of CCl4 (0.5 µl/g) three times per week for 8 weeks. Mice also received 25, 50 or 100 mg/kg TGP. Liver sections were stained with haematoxylin/eosin. Serum amino transferases, lipid peroxidation and tumour necrosis factor-α (TNF-α) levels were determined using commercial assays. Quantitative real-time polymerase chain reaction was used to determine the changes in hepatic TNF-α, COX-2, iNOS and HO-1 expression. Protein levels of nitric oxide synthase, cyclooxygenase-2, haem oxygenase-1 and cytochrome P450 2E1 were determined by western blotting. Results Histological results showed that TGP improved the CCl4-induced changes in liver structure and alleviated lobular necrosis. The increases in serum protein and hepatic mRNA expression of TNF-α induced by CCl4 treatment were suppressed by TGP. Total glucosides of paeony also attenuated the increase the expression in iNOS and CYP2E1 but augmented the increase in HO-1.The mRNA and protein expression levels of inducible HO-1 increased significantly after CCl4 treatment. Conclusions Total glucosides of paeony protects hepatocytes from oxidative damage induced by CCl4. Total glucosides of paeony may achieve these effects by enhancing HO-1 expression and inhibiting the expression of proinflammatory mediators. PMID:22291795

  4. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis.

    Science.gov (United States)

    Choi, Yoon Seok; Lee, Jeewon; Lee, Hyun Woong; Chang, Dong-Yeop; Sung, Pil Soo; Jung, Min Kyung; Park, Jun Yong; Kim, Ja Kyung; Lee, Jung Il; Park, Hana; Cheong, Jae Youn; Suh, Kyung-Suk; Kim, Hyung Joon; Lee, June Sung; Kim, Kyung-Ah; Shin, Eui-Cheol

    2015-08-01

    Foxp3(+)CD4(+)CD25(+) regulatory T cells (Tregs) control immune responses, but their role in acute viral hepatitis remains elusive. Herein, we investigated alteration in the peripheral blood Treg population during acute hepatitis A (AHA) and its implication in the immune-mediated liver injury. The study included 71 patients with AHA, and peripheral blood mononuclear cells (PBMCs) were isolated. The suppressive activity of Treg population was determined by assessing anti-CD3/CD28-stimulated proliferation of Treg-depleted and reconstituted PBMCs. Treg cell frequency, phenotype and apoptosis in PBMCs were analysed by flow cytometry. The frequency of circulating Tregs was reduced during AHA. Moreover, the suppressive activity of the total Treg pool in the peripheral blood was attenuated during AHA. Treg frequency and suppressive activity of the Treg population inversely correlated with the serum alanine aminotransferase level. Fas was overexpressed on Tregs during AHA, suggesting their susceptibility to Fas-induced apoptosis. Indeed, increased apoptotic death was observed in Tregs of patients with AHA compared with healthy controls. In addition, agonistic anti-Fas treatment further increased apoptotic death of Tregs from patients with AHA. The decreased Treg frequency and Fas overexpression on Tregs were not observed in other acute liver diseases such as acute hepatitis B, acute hepatitis C and toxic/drug-induced hepatitis. The size of the Treg pool was contracted during AHA, resulting from apoptosis of Tregs induced by a Fas-mediated mechanism. Decrease in Treg numbers led to reduced suppressive activity of the Treg pool and consequently resulted in severe liver injury during AHA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  5. Lansoprazole-induced acute lung and liver injury: a case report.

    Science.gov (United States)

    Atkins, Christopher; Maheswaran, Tina; Rushbrook, Simon; Kamath, Ajay

    2014-12-01

    A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.

  6. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury.

    Science.gov (United States)

    Schwab, Jan M; Zhang, Yi; Kopp, Marcel A; Brommer, Benedikt; Popovich, Phillip G

    2014-08-01

    During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice

    DEFF Research Database (Denmark)

    Ge, Xiadong; Leung, Tung-Ming; Arriazu, Elena

    2014-01-01

    , tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout...... score, and the number of macrophages and TNFα+ cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation...... by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation...

  8. Effect of WeiJia on carbon tetrachloride induced chronic liver injury

    Science.gov (United States)

    Cheung, Pik-Yuen; Zhang, Qi; Zhang, Ya-Ou; Bai, Gan-Rong; Lin, Marie Chia-Mi; Chan, Bernard; Fong, Chi-Chun; Shi, Lin; Shi, Yue-Feng; Chun, Jay; Kung, Hsiang-Fu; Yang, Mengsu

    2006-01-01

    AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model. METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week, Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type IV collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed. RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV, ALT, AST and γ-GT levels after eight weeks of treatment for Group C rats were 58±22 µg/L (P0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in α-SMA expression level was also observed. CONCLUSION: WeiJia could improve liver function and reduce liver

  9. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Medina-Caliz, Inmaculada; Robles-Diaz, Mercedes; Garcia-Muñoz, Beatriz; Stephens, Camilla; Ortega-Alonso, Aida; Garcia-Cortes, Miren; González-Jimenez, Andres; Sanabria-Cabrera, Judith A; Moreno, Inmaculada; Fernandez, M Carmen; Romero-Gomez, Manuel; Navarro, Jose M; Barriocanal, Ana M; Montane, Eva; Hallal, Hacibe; Blanco, Sonia; Soriano, German; Roman, Eva M; Gómez-Dominguez, Elena; Castiella, Agustin; Zapata, Eva M; Jimenez-Perez, Miguel; Moreno, Jose M; Aldea-Perona, Ana; Hernández-Guerra, Manuel; Prieto, Martin; Zoubek, Miguel E; Kaplowitz, Neil; Lucena, M Isabel; Andrade, Raul J

    2016-09-01

    Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (prisk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  10. Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

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    Mitsuhiro Machitani

    2017-12-01

    Full Text Available Telomerase-specific replication-competent adenoviruses (Ads, i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver. We reported that inhibition of nuclear factor-κB (NF-κB leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα expression cassette (TRAD-DNIκBα. Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

  11. Liver Adiposity and Metabolic Profile in Individuals with Chronic Spinal Cord Injury

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    Kathleen C. Rankin

    2017-01-01

    Full Text Available Purpose. To quantify liver adiposity using magnetic resonance imaging (MRI and to determine its association with metabolic profile in men with spinal cord injury (SCI. Materials and Methods. MRI analysis of liver adiposity by fat signal fraction (FSF and visceral adipose tissue (VAT was completed on twenty participants. Intravenous glucose tolerance test was conducted to measure glucose effectiveness (Sg and insulin sensitivity (Si. Lipid panel, fasting glucose, glycated hemoglobin (HbA1c, and inflammatory cytokines were also analyzed. Results. Average hepatic FSF was 3.7%±2.1. FSF was positively related to TG, non-HDL-C, fasting glucose, HbA1c, VAT, and tumor necrosis factor alpha (TNF-α. FSF was negatively related to Si and testosterone. FSF was positively related to VAT (r=0.48, p=0.032 and TNF-α (r=0.51, p=0.016 independent of age, level of injury (LOI, and time since injury (TSI. The associations between FSF and metabolic profile were independent of VAT. Conclusions. MRI noninvasively estimated hepatic adiposity in men with chronic SCI. FSF was associated with dysfunction in metabolic profile, central adiposity, and inflammation. Importantly, liver adiposity influenced metabolic profile independently of VAT. These findings highlight the significance of quantifying liver adiposity after SCI to attenuate the development of metabolic disorders.

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

    International Nuclear Information System (INIS)

    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J.

    2014-01-01

    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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    Javier A. Cienfuegos

    2014-03-01

    Full Text Available Liver regeneration (LR is one of the most amazing tissue injury response. Given its therapeutic significance has been deeply studied in the last decades. LR is an extraordinary complex process, strictly regulated, which accomplishes the characteristics of the most evolutionary biologic systems (robustness and explains the difficulties of reshaping it with therapeutic goals. TH reproduces the physiological tissue damage response pattern, with a first phase of priming of the hepatocytes -cell-cycle transition G0-G1-, and a second phase of proliferation -cell-cycle S/M phases- which ends with the liver mass recovering. This process has been related with the tissue injury response regulators as: complement system, platelets, inflammatory cytokines (TNF-α, IL-1β, IL-6, growth factors (HGF, EGF, VGF and anti-inflammatory factors (IL-10, TGF-β. Given its complexity and strict regulation, illustrates the unique alternative to liver failure is liver transplantation. The recent induced pluripotential cells (iPS description and the mesenchymal stem cell (CD133+ plastic capability have aroused new prospects in the cellular therapy field. Those works have assured the cooperation between mesenchymal and epithelial cells. Herein, we review the physiologic mechanisms of liver regeneration.

  17. 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.

  18. Polyethylene glycols: An effective strategy for limiting liver ischemia reperfusion injury.

    Science.gov (United States)

    Pasut, Gianfranco; Panisello, Arnau; Folch-Puy, Emma; Lopez, Alexandre; Castro-Benítez, Carlos; Calvo, Maria; Carbonell, Teresa; García-Gil, Agustín; Adam, René; Roselló-Catafau, Joan

    2016-07-28

    Liver ischemia-reperfusion injury (IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ (ischemia) is exacerbated following the return of oxygen delivery (reperfusion). IRI is a major cause of primary non-function after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions (antioxidants, anti-cytokines, etc.) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols (PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI.

  19. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    International Nuclear Information System (INIS)

    Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

    2016-01-01

    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.

  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. Protective Effects of Quercetin and Quercetin-5',8-Disulfonate against Carbon Tetrachloride-Caused Oxidative Liver Injury in Mice

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    Yanmang Cui

    2013-12-01

    Full Text Available Oxidative stress is one of the major factors in the pathogenesis of liver disease. Quercetin is a plant-based antioxidant traditionally used as a treatment for hepatic injury, but its poor solubility affects its bioavailability. We here report the regulative effects on hepatoprotection and absorption in mice of quercetin sulfation to form quercetin-5',8-disulfonate (QS, a novel synthetic compound. Oral administration of both QS and the parent quercetin at 100, 200 and 500 mg/kg·bw prior to acute CCl4 oxidative damage in mice, effectively attenuated serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and lactate dehydrogenase (LDH activities and hepatic malondialdehyde (MDA levels (p < 0.05, and suppressed the CCl4-induced depletion of glutathione peroxidase (GSH-Px and total superoxide dismutase (T-SOD. Selective 5',8-sulfation of quercetin increased the hepatoprotective effect, and its relative absorption relative to quercetin (p < 0.05 as indicated by an improved 24-hour urinary excretion and a decreased fecal excretion determined by HPLC. These results and histopathological observations collectively demonstrate that quercetin sulfation increases its hepatoprotective effects and absorption in mice, and QS has potential as a chemopreventive and chemotherapeutic agent for liver diseases.

  2. Aloin protects against chronic alcoholic liver injury via attenuating lipid accumulation, oxidative stress and inflammation in mice.

    Science.gov (United States)

    Cui, Yan; Ye, Qing; Wang, Heya; Li, Yingchao; Xia, Xiuhua; Yao, Weirong; Qian, He

    2014-12-01

    The present study was designed to investigate the protective effect of aloin against alcoholic liver disease in a chronic alcohol feeding mouse model. Mice were given alcohol twice a day by intragastric administration for 11 weeks (4.0, 4.7, 5.5 g/kg bw/day for the first 3 weeks respectively, 6.3 g/kg bw/day for the following 8 weeks). Aloin (10, 30 mg/kg bw) or vehicle was given by gavage to mice after each alcohol administration. Alcohol elevated the serum transaminases alanine aminotransferase, aspartate aminotransferase, total cholesterol and triglyceride levels which were significantly attenuated by the co-administration of aloin (p aloin significantly suppressed the alcohol-dependent induction of sterol regulatory element-binding protein-1c expression (p aloin supplementation significantly inhibited the alcohol-dependent elevation of malondialdehyde and cytochrome P4502E1 expression (p aloin (p aloin may represent a novel, protective strategy against chronic alcoholic liver injury by attenuating lipid accumulation, oxidative stress and LPS-induced inflammatory response.

  3. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice.

    Science.gov (United States)

    Lin, Chih-Wen; Zhang, Hao; Li, Min; Xiong, Xiwen; Chen, Xi; Chen, Xiaoyun; Dong, Xiaocheng C; Yin, Xiao-Ming

    2013-05-01

    Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. In both acute and chronic ethanol condition, macroautophagy was activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  4. 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.

  5. Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.

    Science.gov (United States)

    Volarevic, Vladislav; Markovic, Bojana Simovic; Bojic, Sanja; Stojanovic, Maja; Nilsson, Ulf; Leffler, Hakon; Besra, Gurdyal S; Arsenijevic, Nebojsa; Paunovic, Verica; Trajkovic, Vladimir; Lukic, Miodrag L

    2015-02-01

    Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Participation of nuclear factor (erythroid 2-related), factor 2 in ameliorating lithocholic acid-induced cholestatic liver injury in mice.

    Science.gov (United States)

    Tan, K P; Wood, G A; Yang, M; Ito, S

    2010-11-01

    Lithocholic acid (LCA), the most toxic bile acid, induces cholestatic liver injury in rodents. We previously showed that LCA activates the oxidative stress-responsive nuclear factor (erythroid-2 like), factor 2 (Nrf2) in cultured liver cells, triggering adaptive responses that reduce cell injury. In this study, we determined whether Nrf2 protects the liver against LCA-induced toxicity in vivo. Nrf2 disrupted (Nrf2(-/-) ) and wild-type mice were treated with LCA (125 mg·kg(-1) body weight) to induce liver injury. Levels of mRNA, protein and function of important Nrf2 target genes coupled with liver histology and injury biomarkers of mice were examined. In 4 day LCA treatments, we observed a significantly higher hepatic induction of Nrf2 target, cytoprotective genes including thioredoxin reductase 1, glutamate cysteine ligase subunits, glutathione S-transferases, haeme oxygenase-1 and multidrug resistance-associated proteins 3 and 4 in the wild type as compared with the Nrf2(-/-) mice. Moreover, basal and LCA-induced hepatic glutathione and activities of glutathione S-transferases and thioredoxin reductases were higher in wild-type than in Nrf2(-/-) mice. This reduced production of cytoprotective genes against LCA toxicity rendered Nrf2(-/-) mice more susceptible to severe liver damage with the presence of multifocal liver necrosis, inflamed bile ducts and elevation of lipid peroxidation and liver injury biomarkers, such as alanine aminotransferase and alkaline phosphatase. Nrf2 plays a crucial cytoprotective role against LCA-induced liver injury by orchestrating adaptive responses. The pharmacological potential of targeting liver Nrf2 in the management of cholestatic liver diseases is proposed. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  7. 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...

  8. Anti-apoptotic effects of tamarind leaves against ethanol-induced rat liver injury.

    Science.gov (United States)

    Ghoneim, Asser I; Eldahshan, Omayma A

    2012-03-01

    The leaf decoctions of Tamarindus indica (TI) have long been traditionally used in liver ailments. The aim of this study was to investigate the anti-apoptotic activity of TI leaf extract against acute ethanol (EtOH)-induced liver injury. The major constituents of the extract were also examined for standardization purposes. Rats (n = 5-7) were orally pretreated with TI leaf extract (25, 50 and 100 mg/kg) for seven days. Silymarin was used as a positive control. Liver tissue biochemical assays included key markers of apoptosis and its redox signalling. Serum enzyme levels were also determined. All graded doses of TI leaf extract mitigated the EtOH-induced liver caspase-3 activation (42, 57 and 64%) as well as DNA fragmentation (32, 47 and 50%), respectively. The highest dose of the extract demonstrated membrane-stabilizing (38%) in addition to glutathione-replenishing (88%) effects. Also, the leaves improved the liver histopathological alterations. Moreover, major plant bioactive polyphenolics, that might be responsible for the extract's observed effects, were isolated and identified. TI leaf extract demonstrated promising anti-apoptotic hepatoprotective effects in rats. The use of TI leaves in different liver diseases, having apoptosis as the underlying pathology, hence warrants further clinical investigation. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  9. 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.)

  10. Hepatoprotective effect of ghrelin on carbon tetrachloride-induced acute liver injury in rats.

    Science.gov (United States)

    Cetin, Ebru; Kanbur, Murat; Cetin, Nazmi; Eraslan, Gökhan; Atasever, Ayhan

    2011-11-10

    Recent studies have revealed that ghrelin may be an antioxidant and antiinflammatory agent. Oxidative stress are considered to play a prominent causative role in the development of various hepatic disorders. We investigated whether ghrelin plays a protective role against carbon tetrachloride (CCl(4))-induced acute liver injury in rats. Forty adult male Sprague-Dawley rats were randomly divided into four equal groups as; control, ghrelin, CCl(4) and ghrelin plus CCl(4). Evaluations were made for lipid peroxidation, enzyme activities and biochemical parameters. Pathological histology was also performed. CCl(4) treatment increased plasma and liver tissue malondialdehyde (MDA) content and plasma nitric oxide (NO) level, and decreased erythrocyte and liver tissue superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities when compared to control group. At the same time, CCl(4) treatment increased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alcaline phosphatase (ALP) activities. By contrast, ghrelin pretreatment reduced plasma and liver MDA content and plasma NO level, and increased erythrocyte and liver tissue SOD, CAT and GPx activities when compared with CCl(4)-treated group. Moreover, both ghrelin alone and ghrelin plus CCl(4) treatment elevated serum glucose level. The CCl(4)-induced histopathological changes were also reduced by the ghrelin pretreatment. Our results show that ghrelin can be proposed to protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effect may be correlated with its antioxidant and free radical scavenger effects. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Influence Of Whey Protein For Abrogating Liver Injury In Female Rats

    International Nuclear Information System (INIS)

    ANWAR, M.M.; MOHAMED, N.E.

    2009-01-01

    The objective of this study was to determine the possible benefits of whey protein concentrate (44% protein, 5% fat and 4.6% ash in dry weight) against liver injury induced by CCl 4 . It was carried out by evaluating the effect of the daily feeding of female rats on diet containing 15% whey protein instead of soybean protein for four weeks on some biochemical and histological changes in liver of female rats.The data showed that injection with CCl 4 (1 ml /kg body weight 3 times / week) caused significant decrease in body weight with disturbances in liver functions as significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and bilirubin and significant decrease in serum albumin, FT3 and an increase in AFP levels. A marked significant decrease in glutathione content and significant increase in lipid peroxidation was also observed in hepatic tissues. The histological examination revealed that CCl 4 treatment showed marked degenerative changes in liver hepatocytes and sinusoids.The results also showed that feeding on diet containing whey protein for two or four weeks during CCl 4 treatment minimized the disturbance of the liver functions and liver histology.

  12. Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation.

    Science.gov (United States)

    Yue, Shi; Rao, Jianhua; Zhu, Jianjun; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

    2014-06-01

    Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation. Copyright © 2014 by The American Association of Immunologists, Inc.

  13. Oligonol Ameliorates CCl4-Induced Liver Injury in Rats via the NF-Kappa B and MAPK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Jeonghyeon Bak

    2016-01-01

    Full Text Available Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl4- induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg reduced CCl4-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl4-induced production of inflammatory mediators, including TNF-α, IL-1β, cyclooxygenase-2 (COX-2, and inducible nitric oxide synthase (iNOS mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-κB p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK, c-Jun NH2-terminal kinase (JNK, and p38 mitogen-activated protein kinases (MAPKs as well as Akt. Oligonol exhibited strong antioxidative activity in vitro and in vivo, and hepatoprotective activity against t-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream kinases including MAPKs and Akt.

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

    Science.gov (United States)

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

    2001-04-01

    .u.). IRFI 042 (100 mg/kg, 30 min after CCl4 injection) blunted liver MAL (0.32 +/- 0.17 nmol/mg protein), decreased the serum levels of ALT (128.71 +/- 13.23 U/L), and restored the hepatic concentrations of VE (9.52 +/- 3.21 nmol/g tissue), inhibited OH* production (2,3-DHBA= 3.54 +/- 1.31 microM; 2,5-DHBA= 7.37 +/- 2.46 microM), restored the endogenous antioxidant GSH (12.77 +/- 3.73 mmol/g protein) and improved histology. Furthermore IRFI 042 treatment suppressed plasma TNF-alpha concentrations (31.47 +/- 18.25 IU/ml) and hepatic TNF-alpha mRNA levels (11.65 +/- 3.21 a.u.). The acute treatment with vitamin E failed to exert any protective effect against CCl4 -induced hepatotoxicity. These investigations suggest that IRFI 042 treatment may be of benefit during free radical-mediated liver injury.

  15. 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...

  16. Antioxidant Activity of The Ancient Herb, Holy Basil in CCl4-Induced Liver Injury in Rats.

    Science.gov (United States)

    Ponnusam, Yuvaraj; Louis, Therasilin; Madhavachandran, V; Kumar, Suresh; Thoprani, Neelam; Hamblin, Michael R; Lakshmanan, Shanmugamurthy

    2015-11-01

    An herbal preparation called "holy basil plus herbal powder" (HBPP) containing Ocimum santum, Withania somnifera, Pongamia pinnata, Plumbago indica, Emblica officinalis and Curcuma longa was investigated as an antioxidant and hepatoprotect ive agent. The antioxidant activity of HBPP was investigated in rats with liver injury induced by oral administration of carbon tetrachloride:olive oil (1:1). HBPP was administered orally at 500 mg/kg daily for 7 days before. HBPP exhibited statistically significant antioxidant activity, as shown by increased levels of glutathione peroxidase (GPX), glutathione S-transferase (GST), glutathione reductase (GRD), superoxide dismutase (SOD) and catalase (CAT) and decreased level of lipid peroxidation (LPO). HBPP performed equally well as silymarin, a well-established antioxidant preparation used to protect against liver injury.

  17. Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury.

    Science.gov (United States)

    Borlak, Jürgen; Chatterji, Bijon; Londhe, Kishor B; Watkins, Paul B

    2013-01-01

    Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI). Healthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays. One-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs

  18. The Effect of Recombinant Factor VIIa and Fibrinogen on Bleeding from Grade V Liver Injuries in Coagulopathic Swine

    National Research Council Canada - National Science Library

    Brundage, Susan

    2003-01-01

    This was a 2 part study. The first part of the study was performed to determine if recombinant factor VIIa would reduce bleeding after a grade V liver injury in hypothermic, dilutionally coagulopathic pigs when used...

  19. [Construction of a subtracted cDNA library of chronic intermittent hypoxia rabbit liver by suppression subtractive hybridization].

    Science.gov (United States)

    Wu, Yue-tao; Liu, Rui-hong; Yang, Yu; Luo, Ying-quan; Rong, Yao

    2007-12-01

    To construct a subtracted cDNA library of chronic intermittent hypoxia (CIH) rabbit liver by suppression subtractive hybridization (SSH). Twenty-four rabbits were divided into 4 groups: ordinary feeding group, full-fat food group, ordinary feeding in chronic intermittent hypoxia group, and full-fat food in chronic intermittent hypoxia group. The mRNAs were extracted from different rabbit livers and converted into double-strand cDNA. After digestion with restriction enzyme, the cDNA of hyperlipidemia-sensitive rabbit group was subdivided into 2 portions and each one was lighted with different adaptors. Two rounds of both hybridization and suppression PCR obtained the differentially expressed cDNA. The PCR products were inserted into T/A vector to set up the subtractive cDNA library. The clones were selected and amplified by PCR and identified. Based on the pathology of the abdominal aorta and liver, and the amplified library contained 500 positive bacteria clones, including 462 clones, which had inserts from 250 to 700 bp by PCR analysis. A novel rabbit gene, Cthrc1, involved in CHI had been cloned. The GenBank Accession Number is XM_418373. The molecular mechanism of CIH promoting atherogenesis formation is made clear.

  20. 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...

  1. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis.

    Science.gov (United States)

    Karidis, Nikolaos P; Delladetsima, Ioanna; Theocharis, Stamatios

    2015-01-01

    Chronic hepatitis C virus (HCV) infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even "similar" causes, such as hepatitis B virus- (HBV-) related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.

  2. 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.

  3. 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.

  4. 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.

  5. Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Merema, Marjolijn T; Groothuis, Geny M M

    2012-09-17

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine

  6. Protective effect of linalool against lipopolysaccharide/D-galactosamine-induced liver injury in mice.

    Science.gov (United States)

    Li, Jingyuan; Zhang, Xiaoyu; Huang, Haiying

    2014-12-01

    Linalool, a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. The aim of this study was to investigate the effects of linalool against lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced liver injury in mice. Mice were administered with linalool 1h before receiving LPS (50 μg/kg) and GalN (800 mg/kg). The results demonstrated that linalool had a protective effect on LPS/GalN-induced acute liver injury, as evidenced by the attenuation of hepatic pathological damage, malondialdehyde (MDA) content, MPO activity and serum ALT and AST levels. Linalool alleviated serum and hepatic TNF-α and IL-6 production, as well as hepatic iNOS and COX-2 expression by inhibiting NF-κB activation. Treatment of linalool increased bcl-2 expression and inhibited caspase-3 and caspase-8 expression. In addition, linalool increased Nrf2 and heme oxygenase-1 expression up-regulation by LPS/GalN. In conclusion, our results suggested that linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Temporal trends of dialysis requiring acute kidney injury after orthotopic cardiac and liver transplant hospitalizations.

    Science.gov (United States)

    Nadkarni, Girish N; Chauhan, Kinsuk; Patel, Achint; Saha, Aparna; Poojary, Priti; Kamat, Sunil; Patel, Shanti; Ferrandino, Rocco; Konstantinidis, Ioannis; Garimella, Pranav S; Menon, Madhav C; Thakar, Charuhas V

    2017-07-19

    The epidemiology and outcomes of acute kidney injury (AKI) in prevalent non-renal solid organ transplant recipients is unknown. We assessed the epidemiology of trends in acute kidney injury (AKI) in orthotopic cardiac and liver transplant recipients in the United States. We used the Nationwide Inpatient Sample to evaluate the yearly incidence trends (2002 to 2013) of the primary outcome, defined as AKI requiring dialysis (AKI-D) in hospitalizations after cardiac and liver transplantation. We also evaluated the trend and impact of AKI-D on hospital mortality and adverse discharge using adjusted odds ratios (aOR). The proportion of hospitalizations with AKI (9.7 to 32.7% in cardiac and 8.5 to 28.1% in liver transplant hospitalizations; p trend <0.01) and AKI-D (1.63 to 2.33% in cardiac and 1.32 to 2.65% in liver transplant hospitalizations; p trend <0.01) increased from 2002-2013. This increase in AKI-D was explained by changes in race and increase in age and comorbidity burden of transplant hospitalizations. AKI-D was associated with increased odds of in hospital mortality (aOR 2.85; 95% CI 2.11-3.80 in cardiac and aOR 2.00; 95% CI 1.55-2.59 in liver transplant hospitalizations) and adverse discharge [discharge other than home] (aOR 1.97; 95% CI 1.53-2.55 in cardiac and 1.91; 95% CI 1.57-2.30 in liver transplant hospitalizations). This study highlights the growing burden of AKI-D in non-renal solid organ transplant recipients and its devastating impact, and emphasizes the need to develop strategies to reduce the risk of AKI to improve health outcomes.

  10. The paradox of chronic neuroinflammation, systemic immune suppression and autoimmunity after traumatic chronic spinal cord injury

    Science.gov (United States)

    Kopp, Marcel A.; Brommer, Benedikt; Popovich, Phillip G.

    2014-01-01

    During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the “immune privileged/specialized” milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of “SCI disease” and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because nflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, “compartmentalized” investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS is influenced by systemic immune challenges and that the immune system is hardwired into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the face of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and ‘neurogenic’ spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired ‘host-defense’ and trauma-induced autoimmunity. PMID:25017893

  11. Acute kidney injury in liver cirrhosis: new definition and application

    Directory of Open Access Journals (Sweden)

    Florence Wong

    2016-12-01

    Full Text Available The traditional diagnostic criteria of renal dysfunction in cirrhosis are a 50% increase in serum creatinine (SCr with a final value above 1.5 mg/dL. This means that patients with milder degrees of renal dysfunction are not being diagnosed, and therefore not offered timely treatment. The International Ascites Club in 2015 adapted the term acute kidney injury (AKI to represent acute renal dysfunction in cirrhosis, and defined it by an increase in SCr of 0.3 mg/dL (26.4 µmoL/L in <48 hours, or a 50% increase in SCr from a baseline within ≤3 months. The severity of AKI is described by stages, with stage 1 represented by these minimal changes, while stages 2 and 3 AKI by 2-fold and 3-fold increases in SCr respectively. Hepatorenal syndrome (HRS, renamed AKI-HRS, is defined by stage 2 or 3 AKI that fulfils all other diagnostic criteria of HRS. Various studies in the past few years have indicated that these new diagnostic criteria are valid in the prediction of prognosis for patients with cirrhosis and AKI. The future in AKI diagnosis may include further refinements such as inclusion of biomarkers that can identify susceptibility for AKI, differentiating the various prototypes of AKI, or track its progression.

  12. MicroRNA-122 is involved in oxidative stress in isoniazid-induced liver injury in mice.

    Science.gov (United States)

    Song, L; Zhang, Z R; Zhang, J L; Zhu, X B; He, L; Shi, Z; Gao, L; Li, Y; Hu, B; Feng, F M

    2015-10-27

    Many studies have shown that the pathogenesis of liver injury includes oxidative stress. MicroRNA-122 may be a marker for the early diagnosis of drug-induced liver injury. However, the relationship between microRNA-122 and oxidative stress in anti-tuberculosis drug-induced liver injury remains unknown. We measured changes in tissue microRNA-122 levels and indices of oxidative stress during liver injury in mice after administration of isoniazid, a first-line anti-tuberculosis drug. We quantified microRNA-122 expression and indices of oxidative stress at 7 time points, including 1, 3, and 5 days and 1, 2, 3, and 4 weeks. The tissue microRNA-122 levels and oxidative stress significantly changed at 3 and 5 days, suggesting that isoniazid-induced liver injury reduces oxidative stress and microRNA-122 expression compared to in the control group (P microRNA-122, began to change at 5 days (P microRNA-122 profile may affect oxidative stress by regulating mitochondrial ribosome protein S11 gene during isoniazid-induced liver injury, which may contribute to the response mechanisms of microRNA-122 and oxidative stress.

  13. Quantitative evaluation of 99mTc-GSA for fatty liver and ischemia-reperfusion injury in rats

    International Nuclear Information System (INIS)

    Kimoto, Mitsunori

    1996-01-01

    99m Tc-GSA (GSA) liver scintigraphy was performed in rats with fatty liver and ischemia-reperfusion injury to study the usefulness of GSA in evaluating these pathological processes. Fatty liver was produced by feeding rats a choline-deficient diet. The rats with fatty liver were divided into five groups according to the length of the diet (controls, two weeks, six weeks, 10 weeks, and 12 weeks). In the rats dieted for two weeks and six weeks, regional hepatic ischemia was also induced by clamping the left hepatic artery and the left portal vein for 10 minutes, then reperfusion was performed for 15 minutes. GSA was administered via the IVC. t 90 , or the time at which the liver time activity curve reached ninety percent of its peak value, was used as an index of GSA hepatic uptake, Ku and Kd, determined by two compartment analysis, were also used as indices. In rats of the fatty liver group, we confirmed microscopically that various degrees of fatty infiltration existed according to the diet period, and t 90 became significantly longer according to the severity of fatty infiltration. Ku and Kd also decreased according to the severity of fatty infiltration. In the rats with fatty infiltration and ischemia-reperfusion injury, t 90 also increased according to the severity of fatty infiltration, becoming longer than in the rats without ischemia-reperfusion injury. Quantitative analysis of GSA liver scintigraphy was useful for evaluating fatty liver and ischemia-reperfusion injury. (author)

  14. Associations of coffee consumption with markers of liver injury in the insulin resistance atherosclerosis study.

    Science.gov (United States)

    Dickson, J C; Liese, A D; Lorenzo, C; Haffner, S M; Watkins, S M; Hamren, S J; Stiles, J K; Wagenknecht, L E; Hanley, A J

    2015-07-28

    Coffee consumption has been associated with reduced risk of developing type 2 diabetes mellitus (T2DM) however, the mechanism for this association has yet to be elucidated. Non-alcoholic fatty liver disease (NAFLD) characterizes and predicts T2DM yet the relationship of coffee with this disorder remains unclear. Our aim was to investigate the associations of coffee with markers of liver injury in 1005 multi-ethnic, non-diabetic adults in the Insulin Resistance Atherosclerosis Study. Dietary intake was assessed using a validated 114-item food frequency questionnaire. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and fetuin-A were determined in fasting blood samples and the validated NAFLD liver fat score was calculated. Multivariate linear regression assessed the contribution of coffee to variation in markers of liver injury. Caffeinated coffee showed significant inverse associations with ALT (β = -0.08, p = 0.0111), AST (β = -0.05, p = 0.0155) and NAFLD liver fat score (β = -0.05, p = 0.0293) but not with fetuin-A (β = 0.04, p = 0.17). When the highest alcohol consumers were excluded, these associations remained (ALT β = -0.11, p = 0.0037; AST β = -0.05, p = 0.0330; NAFLD liver fat score β = -0.06, p = 0.0298). With additional adjustment for insulin sensitivity, the relationship with ALT remained significant (ALT β = -0.08, p = 0.0400; AST β = -0.03, p = 0.20; NAFLD liver fat score β = -0.03, p = 0.27). There were no significant associations of decaffeinated coffee with liver markers. These analyses indicate a beneficial impact of caffeinated coffee on liver morphology and/or function, and suggest that this relationship may mediate the well-established inverse association of coffee with risk of T2DM.

  15. ZYZ-772 Prevents Cardiomyocyte Injury by Suppressing Nox4-Derived ROS Production and Apoptosis

    Directory of Open Access Journals (Sweden)

    Ying Wang

    2017-02-01

    Full Text Available Nox-dependent signaling plays critical roles in the development of heart failure, cardiac hypertrophy, and myocardial infarction. NADPH oxidase 4 (Nox4 as a major source of oxidative stress in the heart offers a new therapeutic target in cardiovascular disease. In the present work, a novel flavonoid was isolated from Zanthoxylum bungeanum. Its structure was elucidated as Quercetin-3-O-(6′′-O-α-l-rhamnopyransoyl-β-d-glucopyranoside-7-O-β-d-glucopyranoside (ZYZ-772 for the first time. ZYZ-772 exhibited significant cardio-protective property against CoCl2 induced H9c2 cardiomyocyte cells injury. In CoCl2 stimulated cardiomyocyte injury, ZYZ-772 inhibited expression of Nox4, and alleviated ROS overproduction. Importantly, ROS triggered MAPKs phosphorylation and P53 signaling mediated apoptosis were restored by ZYZ-772. Our findings present the first piece of evidence for the therapeutic properties of ZYZ-772 in preventing cardiomyocyte injury, which could be attributed to the suppression of Nox4/MAPKs/P53 axis. This will offer a novel therapeutic strategy for the treatment of cardiac ischemia disease.

  16. NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases.

    Science.gov (United States)

    Sadegh, Leila; Chen, Peter W; Brown, Joseph R; Han, Zhiqiang; Niederkorn, Jerry Y

    2015-09-01

    Uveal melanoma (UM) is the most common intraocular tumor in adults and liver metastasis is the leading cause of death in UM patients. We have previously shown that NKT cell-deficient mice develop significantly fewer liver metastases from intraocular melanomas than do wild-type (WT) mice. Here, we examine the interplay between liver NKT cells and NK cells in resistance to liver metastases from intraocular melanomas. NKT cell-deficient CD1d(-/-) mice and WT C57BL/6 mice treated with anti-CD1d antibody developed significantly fewer liver metastases than WT mice following either intraocular or intrasplenic injection of B16LS9 melanoma cells. The increased number of metastases in WT mice was associated with reduced liver NK cytotoxicity and decreased production of IFN-γ. However, liver NK cell-mediated cytotoxic activity was identical in non-tumor bearing NKT cell-deficient mice and WT mice, indicating that liver metastases were crucial for the suppression of liver NK cells. Depressed liver NK cytotoxicity in WT mice was associated with production of IL-10 by bone marrow-derived liver cells that were neither Kupffer cells nor myeloid-derived suppressor cells and by increased IL-10 receptor expression on liver NK cells. IL-10(-/-) mice had significantly fewer liver metastases than WT mice, but were not significantly different from NKT cell-deficient mice. Thus, development of melanoma liver metastases is associated with upregulation of IL-10 in the liver and an elevated expression of IL-10 receptor on liver NK cells. This impairment of liver NK activity is NKT cell-dependent and only occurs in hosts with melanoma liver metastases. © 2015 UICC.

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

    International Nuclear Information System (INIS)

    Lee, Jae Hyun; Cho, Kyung Ja; Lee, Sun Joo; Jang, Won Suk

    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

  18. AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development

    Directory of Open Access Journals (Sweden)

    Nadia Boudaba

    2018-02-01

    Full Text Available Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease.

  19. Protective effect of gadolinium chloride on early warm ischemia/reperfusion injury in rat bile duct during liver transplantation.

    Science.gov (United States)

    Wang, Biao; Zhang, Qi; Zhu, Bili; Cui, Zhonglin; Zhou, Jie

    2013-01-01

    Activation of Kupffer cell (KC) is acknowledged as a key event in the initiation and perpetuation of bile duct warm ischemia/reperfusion injury. The inhibitory effect of gadolinium chloride (GdCl(3)) on KC activation shows potential as a protective intervention in liver injury, but there is less research with regard to bile duct injury. Sixty-five male Sprague-Dawley rats (200-250 g) were randomly divided into three experimental groups: a sham group (n = 15), a control group (n = 25), and a GdCl(3) group (n = 25). Specimen was collected at 0.5, 2, 6, 12 and 24 h after operation. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL) of serum were measured. Tumor necrosis factor-α (TNF-α), Capase-3 activity and soluble Fas (sFas) were detected. The pathologic changes of bile duct were observed. Immunochemistry for bile duct Fas was performed. Apoptosis of bile duct cells was evaluated by the terminal UDP nick end labeling assay. GdCl(3) significantly decreased the levels of ALT, ALP and TBIL at 2, 6, 12, and 24 h, and increased serum sFas at 2, 6 and 12 h (Pbile duct cell apoptosis at 2, 6, 12 and 24 h. After operation for 2, 6 and 12 h, the expression of Fas protein was lower in the GdCl(3) group than in the control group (Pbile duct cell apoptosis, including decreasing ALT, ALP, TBIL and TNF-α; suppressing Fas-FasL-Caspase signal transduction during transplantation.

  20. Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate-induced liver injury in rats.

    Science.gov (United States)

    Hfaiedh, Mbarka; Brahmi, Dalel; Zourgui, Lazhar

    2016-03-01

    Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases. © 2014 Wiley Periodicals, Inc.

  1. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury.

    Science.gov (United States)

    Moustafa, Tarek; Fickert, Peter; Magnes, Christoph; Guelly, Christian; Thueringer, Andrea; Frank, Sasa; Kratky, Dagmar; Sattler, Wolfgang; Reicher, Helga; Sinner, Frank; Gumhold, Judith; Silbert, Dagmar; Fauler, Günter; Höfler, Gerald; Lass, Achim; Zechner, Rudolf; Trauner, Michael

    2012-01-01

    The liver controls central processes of lipid and bile acid homeostasis. We aimed to investigate whether alterations in lipid metabolism contribute to the pathogenesis of chronic cholestatic liver disease in mice. We used microarray and metabolic profiling analyses to identify alterations in systemic and hepatic lipid metabolism in mice with disruption of the gene ATP-binding cassette sub-family B member 4 (Abcb4(-/-) mice), a model of inflammation-induced cholestatic liver injury, fibrosis, and cancer. Alterations in Abcb4(-/-) mice, compared with wild-type mice, included deregulation of genes that control lipid synthesis, storage, and oxidation; decreased serum levels of cholesterol and phospholipids; and reduced hepatic long-chain fatty acyl-CoAs (LCA-CoA). Feeding Abcb4(-/-) mice the side chain-modified bile acid 24-norursodeoxycholic acid (norUDCA) reversed their liver injury and fibrosis, increased serum levels of lipids, lowered phospholipase and triglyceride hydrolase activities, and restored hepatic LCA-CoA and triglyceride levels. Additional genetic and nutritional studies indicated that lipid metabolism contributed to chronic cholestatic liver injury; crossing peroxisome proliferator-activated receptor (PPAR)-α-deficient mice with Abcb4(-/-) mice (to create double knockouts) or placing Abcb4(-/-) mice on a high-fat diet protected against liver injury, with features similar to those involved in the response to norUDCA. Placing pregnant Abcb4(-/-) mice on high-fat diets prevented liver injury in their offspring. However, fenofibrate, an activator of PPARα, aggravated liver injury in Abcb4(-/-) mice. Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease in mice. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  2. Drug-induced liver injury associated with high-dose ceftriaxone: a retrospective cohort study adjusted for the propensity score.

    Science.gov (United States)

    Nakaharai, Kazuhiko; Sakamoto, Yohei; Yaita, Kenichiro; Yoshimura, Yukihiro; Igarashi, Shun; Tachikawa, Natsuo

    2016-08-01

    Ceftriaxone has been recognized as a well-tolerated drug; however, in some instances, liver dysfunction occurs after using high-dose ceftriaxone. We aimed to assess the incidence of liver injury due to high-dose ceftriaxone and to determine whether there is a dose-dependent risk of liver injury with this drug. We conducted a retrospective cohort study of hospitalized adult patients treated with ceftriaxone at a tertiary care hospital from January 2012 to October 2013. We collected demographic and clinical data by reviewing their medical records. The incidence of liver injury based on biochemical criteria, defined as a primary outcome, was compared between patients treated with high-dose ceftriaxone (4 g/day) and those treated with a normal dose of ceftriaxone (2 g/day) for ≥5 consecutive days. A propensity score for the use of high-dose ceftriaxone was calculated from five factors. We identified 37 patients treated with high-dose ceftriaxone and 434 patients treated with a normal dose of ceftriaxone. Among these 471 patients, 15 patients (3.2 %) experienced liver injury, of whom six patients (6/37, 16.2 %) had received high-dose ceftriaxone and nine patients (9/434, 2.1 %) had received normal doses of ceftriaxone. In the multivariate analysis adjusted for the propensity score, high-dose ceftriaxone was independently associated with liver injury (odds ratio, 7.23; 95 % confidence interval, 2.01-26.0). The present study revealed that high-dose ceftriaxone was associated with a significantly higher incidence of liver injury compared with the normal-dose regimen. Therefore, clinicians should carefully observe for signs of liver injury after high-dose ceftriaxone use.

  3. Protective effect of Rabdosia amethystoides (Benth Hara extract on acute liver injury induced by Concanavalin A in mice through inhibition of TLR4-NF-κB signaling pathway

    Directory of Open Access Journals (Sweden)

    Ke-Feng Zhai

    2016-02-01

    Full Text Available Extract of Rabdosia amethystoides (Benth Hara (ERA, a traditional Chinese medicine has antibacterial, antiviral, anti-tumor, anti-hepatitis and anti-inflammatory properties. However, the hepatoprotective effects and molecular mechanisms of ERA on acute liver injury have not been fully elucidated. This study aims to investigate the anti-inflammatory effect and liver protection of ERA against the acute liver injury induced by Concanavalin A (Con A and its underlying molecular mechanisms in mice. Mice received ERA (50, 100, 150 mg/kg body weight by gavage before Con A intravenous administration. We found that ERA pretreatment was able to significantly reduce the elevated serum alanine and aspartate aminotransferase levels and liver necrosis in Con A-induced hepatitis. In addition, ERA treatment significantly decreased the myeloperoxidase, malondialdehyde levels and augmented superoxide dismutase level in the liver tissue, and also suppressed the secretion of proinflammatory cytokines in the serum, compared with Con A group by enzyme linked immunosorbent assay. Furthermore, we observed that ERA pretreatment can significantly decrease the expression level of Toll-like receptor (TLR 4 mRNA or protein in liver tissues. Further results showed that ERA pretreatment was capable of attenuating the activation of the NF-κB pathway by inhibiting IκBα kinase and p65 phosphorylation in Con A-induced liver injury. Our results demonstrate that ERA pretreatment has hepatoprotective property against Con A-induced liver injury through inhibition of inflammatory mediators in mice. The beneficial effect of ERA may be mediated by the downregulation of TLR4 expression and the inhibition of NF-κB activation.

  4. Resveratrol, an antioxidant, protects spinal cord injury in rats by suppressing MAPK pathway

    Directory of Open Access Journals (Sweden)

    Song Fu

    2018-02-01

    Full Text Available Resveratrol, a polyphenol found in various plants, including grapes, plums and peanuts has shown various medIRInal properties, including antioxidant, protection of cardiovascular disease and cancer risk. However, the effects of resveratrol on spinal cord reperfusion injury have not been investigated. Hence, the present study was designed to evaluate the effect of resveratrol on nitric oxide synthase (iNOS/p38MAPK signaling pathway and to elucidate its regulating effect on the protection of spinal cord injury. Spinal cord ischemia–reperfusion injury (IRI was performed by the infrarenal abdominal aorta with mini aneurysm clip model. The expressions of iNOS and p38MAPK and the levels of biochemical parameters, including nitrite/nitrate, malondialdehyde (MDA, advanced oxidation products (AOPP, reduced glutathione (GSH, superoxide dismutase (SOD and catalase (CAT were measured in control and experimental groups. IRI-induced rats treated with 10 mg/kg resveratrol protected spinal cord from ischemia injury as supported by improved biological parameters measured in spinal cord tissue homogenates. The resveratrol treatment significantly decreased the levels of plasma nitrite/nitrate, iNOS mRNA and protein expressions and phosphorylation of p38MAPK in IRI-induced rats. Further, IRI-produced free radicals were reduced by resveratrol treatment by increasing enzymatic and non-enzymatic antioxidant levels such as GSH, SOD and CAT. Taken together, administration of resveratrol protects the damage caused by spinal cord ischemia with potential mechanism of suppressing the activation of iNOS/p38MAPK pathway and subsequent reduction of oxidative stress due to IRI.

  5. Parboiled Germinated Brown Rice Protects Against CCl4-Induced Oxidative Stress and Liver Injury in Rats.

    Science.gov (United States)

    Wunjuntuk, Kansuda; Kettawan, Aikkarach; Charoenkiatkul, Somsri; Rungruang, Thanaporn

    2016-01-01

    Parboiled germinated brown rice (PGBR) of Khao Dawk Mali 105 variety was produced by steaming germinated paddy rice, which is well-known for its nutrients and bioactive compounds. In this study we determined the in vivo antioxidant and hepatoprotective effects of PGBR in carbon tetrachloride (CCl(4))-induced oxidative stress in rats. Male Sprague-Dawley rats, (weight 200-250 g) were randomly divided into (1) control, (2) CCl(4), (3) white rice (WR)+CCl(4), (4) brown rice (BR)+CCl(4), and (5) PGBR+CCl(4) groups. PGBR, BR, and WR diets were produced by replacing corn starch in the AIN76A diet with cooked PGBR, BR, and WR powders, respectively. All rats except the control group were gavaged with 50% CCl4 in olive oil (v/v, 1 mL/kg) twice a week for 8 weeks. CCl(4)-treated rats exhibited significant liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as obvious changes to liver histopathology compared to control. In addition, CCl(4) treatment decreased the activities of CYP2E1 and antioxidant enzymes: glutathione S-transferase, glutathione peroxidase, superoxide dismutase and catalase, and glutathione (GSH) content. However, the PGBR+CCl(4) group exhibited less liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as better antioxidant enzyme activities and GSH content. Furthermore, PGBR inhibited degradation of CYP2E1 in CCl(4)-induced decrease of CYP2E1 activity. These data suggest that PGBR may prevent CCl(4)-induced liver oxidative stress and injury through enhancement of the antioxidant capacities, which may be due to complex actions of various bioactive compounds, including phenolic acids, γ-oryzanol, tocotrienol, and GABA.

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

    Science.gov (United States)

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

    2015-01-01

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

  7. Influence of acidosis and hypoxia on liver ischemia and reperfusion injury in an in vivo rat model

    NARCIS (Netherlands)

    Heijnen, Bob H. M.; Elkhaloufi, Yasser; Straatsburg, Irene H.; van Gulik, Thomas M.

    2002-01-01

    The contribution of acidosis to the development of reperfusion injury is controversial. In this study, we examined the effects of respiratory acidosis and hypoxia in a frequently used in vivo liver ischemia and reperfusion (I/R) injury rat model. Rats were anesthetized with intraperitoneal

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Brain expression of the water channels Aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema

    DEFF Research Database (Denmark)

    Eefsen, Martin; Jelnes, Peter; Schmidt, Lars E

    2010-01-01

    Cerebral edema is a feared complication to acute liver failure (ALF), but the pathogenesis is still poorly understood. The water channels Aquaporin-1 (Aqp1) and -4 (Aqp4) has been associated with brain edema formation in several neuropathological conditions, indicating a possible role of Aqp1 and....../or Aqp4 in ALF mediated brain edema. We induced acute liver injury and hyperammonemia in mice, to evaluate brain edema formation and the parallel expression of Aqp1 and Aqp4 in ALF. Liver injury and hyperammonemia were induced by +D-galactosamine (GLN) plus lipopolysaccharide (LPS) intraperitoneally...

  10. Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Derdak, Zoltan; Villegas, Kristine A; Harb, Ragheb; Wu, Annie M; Sousa, Aryanna; Wands, Jack R

    2013-04-01

    p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays. PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells. The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Olson, Erik R; Besselsen, David G; Klaassen, Curtis D; Dvorak, Katerina; Cherrington, Nathan J

    2009-07-10

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.

  12. The effects of epidural bupivacaine on ischemia/reperfusion-induced liver injury.

    Science.gov (United States)

    Sarikus, Z; Bedirli, N; Yilmaz, G; Bagriacik, U; Bozkirli, F

    2016-01-01

    Several animal studies showed beneficial effects of thoracic epidural anesthesia (TEA) in hippocampal, mesenteric and myocardial IR injury (2-4). In this study, we investigated the effects of epidural bupivacaine on hepatic ischemia reperfusion injury in a rat model. Eighteen rats were randomly divided into three groups each containing 6 animals. The rats in Group C had sham laparotomy. The rats in the Group S were subjected to liver IR through laparotomy and 20 mcg/kg/h 0.9% NaCl was administered to these rats via an epidural catheter. The rats in the Group B were subjected to liver IR and were given 20 mcg/kg/h bupivacaine via an epidural catheter. Liver tissue was harvested for MDA analysis, apoptosis and histopathological examination after 60 minutes of ischemia followed by 360 minutes of reperfusion. Blood samples were also collected for TNF-α, IL-1β, AST and ALT analysis. The AST and ALT levels were higher in ischemia and reperfusion group, which received only normal saline via the thoracic epidural catheter, compared to the sham group. In the ischemia reperfusion group, which received bupivacaine via the epidural catheter, IL-1 levels were significantly higher than in the other groups. TNF-α levels were higher in the Groups S and B compared to the sham group. Bupivacaine administration induced apoptosis in all animals. These results showed that thoracic epidural bupivacaine was not a suitable agent for preventing inflammatory response and lipid peroxidation in experimental hepatic IR injury in rats. Moreover, epidural bupivacaine triggered apoptosis in hepatocytes. Further research is needed as there are no studies in literature investigate the effects of epidural bupivacaine on hepatic ischemia reperfusion injury (Tab. 3, Fig. 3, Ref. 34).

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

    Science.gov (United States)

    Harris, J Kirk; El Kasmi, Karim C; Anderson, Aimee L; Devereaux, Michael W; Fillon, Sophie A; Robertson, Charles E; Wagner, Brandie D; Stevens, Mark J; Pace, Norman R; Sokol, Ronald J

    2014-01-01

    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 alter

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

    Directory of Open Access Journals (Sweden)

    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. Effect of recombinant FVIIa in hypothermic, coagulopathic pigs with liver injuries.

    Science.gov (United States)

    Klemcke, Harold G; Delgado, Angel; Holcomb, John B; Ryan, Kathy L; Burke, Allen; DeGuzman, Rodolpho; Scherer, Michael; Cortez, Douglas; Uscilowicz, John; Macaitis, Joseph M; Bliss, Jason; Wojtaszczyk, Jennifer; Christensen, Suzanne; Currier, Heather; Pusateri, Anthony E

    2005-07-01

    Previous experiments with diverse pig models to evaluate the ability of rFVIIa to reduce hemorrhage have provided divergent results. The current study was conducted to address concerns related to previous work by using larger sample sizes, and an extended observational period of 4 hours post-injury. The objectives were to evaluate further the hemostatic efficacy and safety of rFVIIa administration after traumatic, uncontrolled hemorrhage. Anesthetized, splenectomized pigs (36.6 +/- 0.3 kg; n = 18/group) underwent an approximately 50% isovolemic blood exchange with 33 degrees C 6% hetastarch, and body temperature was adjusted to 32.5 +/- 0.5 degrees C. Subsequently, a Grade V liver injury was inflicted. After 30 seconds, either vehicle or treatment (180 microg/kg or 720 microg/kg rFVIIa) was administered intravenously as a bolus. Concomitantly, laparotomy pads were packed around the liver. Resuscitation with 33 degrees C lactated Ringer's solution (260 mL/min) was initiated and pigs were monitored for 4 hour post-injury or until death. Tissues were collected and examined histologically to assess the presence of disseminated intravascular coagulation (DIC). Liver injuries were comparable among all groups (p = 0.89). Measures associated with in vitro coagulation (prothrombin time, activated partial thromboplastin time, thromboelastographic split-point and R times) were enhanced by rFVIIa administration (p < 0.05). However, neither percent survival (p = 0.82), survival time (p = 0.56), nor blood loss (p = 0.63) were affected by treatment. DIC was not evident in lung or kidney tissue. These data indicate an inability of rFVIIa at these doses to reduce blood loss, or to increase survival time or percent survival in this pig model. Absence of DIC provides evidence for safe use of rFVIIa under conditions specific to this study.

  16. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    International Nuclear Information System (INIS)

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  17. microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation.

    Science.gov (United States)

    Jin, Xiu-Li; Sun, Qin-Sheng; Liu, Feng; Yang, Hong-Wei; Liu, Min; Liu, Hong-Xia; Xu, Wei; Jiang, Yu-Yang

    2013-07-01

    Transcriptional repressor Pokemon is a critical factor in embryogenesis, development, cell proliferation, differentiation, and oncogenesis, thus behaving as an oncogene. Oncomine database suggests a potential correlation between the expressions of Pokemon and Sprouty1. This study investigated the regulatory role of Pokemon in Sprouty1 expression and the effect on liver cancer cell growth and proliferation, revealing a novel miR-21-mediated regulatory circuit. In normal (HL-7702) and cancer (QGY-7703) liver cell lines, Sprouty1 expression is inversely correlated with Pokemon levels. Targeted expression or siRNA-mediated silencing showed that Pokemon is a repressor of Sprouty1 expression at both mRNA and protein levels, but Pokemon cannot affect the promoter activity of Sprouty1. Sprouty1 is a target of miR-21 and interestingly, we found that miR-21 is up-regulated by Pokemon in liver cancer cells. Luciferase reporter assays showed that Pokemon up-regulated miR-21 transcription in a dose-dependent manner, and ChIP assay exhibited a direct binding of Pokemon to the miR-21 promoter at -747 to -399 bp. Site-directed mutagenesis of the GC boxes at -684 to -679 bp and -652 to -647 bp of miR-21 promoter abolished the regulatory activity by Pokemon. Furthermore, we found that the modulation of Pokemon and miR-21 expression affected the growth and proliferation of liver cancer cells QGY-7703. In summary, our findings demonstrate that Pokemon suppresses Sprouty1 expression through a miR-21-mediated mechanism, affecting the growth and proliferation of liver cancer cells. This study recognized miR-21 and Sprouty1 as novel targets of the Pokemon regulatory network. Copyright © 2013 Wiley Periodicals, Inc.

  18. Differential expression of genes identified by suppression subtractive hybridization in liver and adipose tissue of gerbils with diabetes

    Science.gov (United States)

    Li, Zhenkun; Li, Xiaohong; Guo, Meng; Lu, Jing; Wang, Ying; Chen, Zhenwen

    2018-01-01

    Objectives We aimed at identifying genes related to hereditary type 2 diabetes expressed in the liver and the adipose tissue of spontaneous diabetic gerbils using suppression subtractive hybridization (SSH) screening. Methods Two gerbil littermates, one with high and the other with normal blood glucose level, from our previously bred spontaneous diabetic gerbil strain were used in this study. To identify differentially expressed genes in the liver and the adipose tissue, mRNA from these tissues was extracted and SSH libraries were constructed for screening. After sequencing and BLAST analyzing, up or down-regulated genes possibly involved in metabolism and diabetes were selected, and their expression levels in diabetic gerbils and normal controls were analyzed using quantitative RT-PCR and Western blotting. Results A total of 4 SSH libraries were prepared from the liver and the adipose tissue of gerbils. There are 95 up or down-regulated genes were identified to be involved in metabolism, oxidoreduction, RNA binding, cell proliferation, and differentiation or other function. Expression of 17 genes most possibly associated with diabetes was analyzed and seven genes (Sardh, Slc39a7, Pfn1, Arg1, Cth, Sod1 and P4hb) in the liver and one gene (Fabp4) in the adipose tissue were identified that were significantly differentially expressed between diabetic gerbils and control animals. Conclusions We identified eight genes associated with type 2 diabetes from the liver and the adipose tissue of gerbils via SSH screening. These findings provide further insights into the molecular mechanisms of diabetes and imply the value of our spontaneous diabetic gerbil strain as a diabetes model. PMID:29394254

  19. 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...

  20. Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation.

    Science.gov (United States)

    Park, Jeong Woo; Cho, Jung Won; Joo, Soo Yeon; Kim, Chang Seong; Choi, Joon Seok; Bae, Eun Hui; Ma, Seong Kwon; Kim, Suhn Hee; Lee, JongUn; Kim, Soo Wan

    2012-05-15

    The present study was performed to examine whether paricalcitol may prevent the cisplatin-induced kidney injury. Furthermore, potential molecular mechanisms underlying the protective effect of paricalcitol were explored. Male Sprague-Dawley rats were treated with vehicle (n=12), cisplatin (n=12, 6 mg/kg/day, i.p.), or cisplatin+paricalcitol (n=12, 0.2 μg/kg/day, s.c.) for 4 days. In another series of experiment, HK-2 cells were treated with cisplatin (50 μM), with or without paricalcitol (0.2 ng/ml). Paricalcitol counteracted the cisplatin-induced decline in renal function. Paricalcitol also suppressed the expression of TGF-β1, Smad signaling, and the subsequent epithelial-to-mesenchymal process in cisplatin-treated rats. The expression of P-p53 and p21 was increased in cisplatin-induced nephropathy. These changes were completely prevented or significantly attenuated with paricalcitol co-treatment. The expression of p27(kip1) was increased in cisplatin-treated rats, which was, however, further augmented by the paricalcitol co-treatment. In HK-2 cells, cisplatin increased the expression of p-ERK1/2 and P-p38. Cisplatin also increased the expression of fibronectin and CTGF. Cisplatin increased the expression of pro-apoptotic markers. The expression of CDK2 and Cyclin E as well as that of PCNA was increased. These changes were completely prevented or significantly attenuated by the paricalcitol pretreatment. In contrast, cisplatin increased the expression of p27(kip1), which was further augmented by the paricalcitol-pretreatment. These results suggest that paricalcitol may ameliorate cisplatin-induced renal injury by suppressing the fibrotic, apoptotic and proliferative factors. Its underlying mechanisms may include inhibition of TGF-β1, mitogen-activated protein kinase signaling, p53-induced apoptosis, and augmentation of p27(kip1). Copyright © 2012 Elsevier B.V. All rights reserved.

  1. MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Mitchell R. McGill

    2015-05-01

    Full Text Available Drug-induced liver injury (DILI is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs has advanced our knowledge of DILI in two ways: (1 possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified, and (2 circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

  2. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    Science.gov (United States)

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  3. 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.

  4. [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.

  5. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens.

    Science.gov (United States)

    Tsai, Meng-Tsz; Chen, Ching-Yi; Pan, Yu-Hui; Wang, Siou-Huei; Mersmann, Harry J; Ding, Shih-Torng

    2015-01-01

    Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p.) until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  6. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

    Directory of Open Access Journals (Sweden)

    Meng-Tsz Tsai

    2015-01-01

    Full Text Available Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4- induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p. until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  7. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Obara, Akio; Fujita, Yoshihito; Abudukadier, Abulizi; Fukushima, Toru; Oguri, Yasuo; Ogura, Masahito; Harashima, Shin-ichi; Hosokawa, Masaya; Inagaki, Nobuya, E-mail: inagaki@metab.kuhp.kyoto-u.ac.jp

    2015-05-15

    Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti-cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR-dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. - Highlights: • We elucidated a novel pathway of metformin's anti-cancer action in HCC cells. • DEPTOR is involved in the suppressing effect of metformin on mTOR signaling. • Metformin increases DEPTOR protein levels via suppression of proteasome activity. • DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action.

  8. Protective effect of Cordyceps militaris polypeptide against acute alcoholic liver injury in rats

    Directory of Open Access Journals (Sweden)

    CAI Qi

    2016-04-01

    Full Text Available ObjectiveTo investigate the protective effect of Cordyceps militaris polypeptide against acute alcoholic liver injury in rats and related mechanism. MethodsA total of 60 Wistar rats were randomly divided into blank control group, model group, and low-, medium-, and high-dose Cordyceps militaris polypeptide groups. All rats except those in the blank control group were given 10 ml/kg 56° liquor by gavage once a day; the rats in the blank control group were given distilled water of the same dose by gavage once a day. At 1 hour after gavage with liquor, the rats in the model group and low-, medium-, and high-dose Cordyceps militaris polypeptide groups were given distilled water or Cordyceps militaris polypeptide solution (6 ml/kg by gavage. Blood samples were collected from the orbit 4 weeks later. The serum levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST and the activity of superoxide dismutase (SOD and level of malondialdehyde (MDA in the liver were measured for each group, and the pathological changes in the liver were observed under a light microscope. Analysis of variance was applied for comparison between multiple groups, and the SNK-q test was applied for comparison between any two groups. ResultsCompared with the model group, the low-, medium-, and high-dose Cordyceps militaris polypeptide groups showed significant reductions in the serum levels of ALT and AST and the level of MDA in the liver (all P<0.05, as well as a significant increase in the activity of SOD in the liver (all P<0.05, while these indices showed significant differences between the low-, medium-, and high-dose Cordyceps militaris polypeptide groups (all P<0.05. The liver pathological sections from the low-, medium-, and high-dose Cordyceps militaris polypeptide groups showed alleviated hepatocyte fatty degeneration and necrosis induced by alcohol under a light microscope. ConclusionCordyceps militaris polypeptide has a protective effect

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chaoyun [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Huang, Qingxian [Department of Hepatobiliary Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong 264000 (China); Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China); Bai, Xianyong, E-mail: xybai2012@163.com [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, Shandong 264003 (China)

    2013-11-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO{sub 2}), carbon dioxide tension, pH, and the PaO{sub 2}/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22{sup phox} levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may

  11. Hydroxysafflor yellow A suppress oleic acid-induced acute lung injury via protein kinase A

    International Nuclear Information System (INIS)

    Wang, Chaoyun; Huang, Qingxian; Wang, Chunhua; Zhu, Xiaoxi; Duan, Yunfeng; Yuan, Shuai; Bai, Xianyong

    2013-01-01

    Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO 2 ), carbon dioxide tension, pH, and the PaO 2 /fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22 phox levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. - Highlights: • Oleic acid (OA) cause acute lung injury (ALI) via inhibiting cAMP/PKA signal pathway. • Blocking protein kinase A (PKA) activation may enhance Cytokine

  12. Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Meng-Xi; Jin, Lei; Sun, Si-Jia; Liu, Peng; Feng, Xu; Cheng, Zhou-Li; Liu, Wei-Ren; Guan, Kun-Liang; Shi, Ying-Hong; Yuan, Hai-Xin; Xiong, Yue

    2018-03-01

    Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting step in hepatic gluconeogenesis pathway to maintain blood glucose levels. Mammalian cells express two PCK genes, encoding for a cytoplasmic (PCPEK-C or PCK1) and a mitochondrial (PEPCK-M or PCK2) isoforms, respectively. Increased expressions of both PCK genes are found in cancer of several organs, including colon, lung, and skin, and linked to increased anabolic metabolism and cell proliferation. Here, we report that the expressions of both PCK1 and PCK2 genes are downregulated in primary hepatocellular carcinoma (HCC) and low PCK expression was associated with poor prognosis in patients with HCC. Forced expression of either PCK1 or PCK2 in liver cancer cell lines results in severe apoptosis under the condition of glucose deprivation and suppressed liver tumorigenesis in mice. Mechanistically, we show that the pro-apoptotic effect of PCK1 requires its catalytic activity. We demonstrate that forced PCK1 expression in glucose-starved liver cancer cells induced TCA cataplerosis, leading to energy crisis and oxidative stress. Replenishing TCA intermediate α-ketoglutarate or inhibition of reactive oxygen species production blocked the cell death caused by PCK expression. Taken together, our data reveal that PCK1 is detrimental to malignant hepatocytes and suggest activating PCK1 expression as a potential treatment strategy for patients with HCC.

  13. Acute kidney injury following liver transplantation: a systematic review of published predictive models.

    Science.gov (United States)

    Caragata, R; Wyssusek, K H; Kruger, P

    2016-03-01

    Acute kidney injury is a frequent postoperative complication amongst liver transplant recipients and is associated with increased morbidity and mortality. This systematic review analysed the existing predictive models, in order to solidify current understanding. Articles were selected for inclusion if they described the primary development of a clinical prediction model (either an algorithm or risk score) to predict AKI post liver transplantation. The database search yielded a total of seven studies describing the primary development of a prediction model or risk score for the development of AKI following liver transplantation. The models span thirteen years of clinical research and highlight a gradual change in the definitions of AKI, emphasising the need to employ standardised definitions for subsequent studies. Collectively, the models identify a diverse range of predictive factors with several common trends. They emphasise the impact of preoperative renal dysfunction, liver disease severity and aetiology, metabolic risk factors as well as intraoperative variables including measures of haemodynamic instability and graft quality. Although several of the models address postoperative parameters, their utility in predictive modelling seems to be of questionable relevance. The common risk factors identified within this systematic review provide a minimum list of variables, which future studies should address. Research in this area would benefit from prospective, multi-site studies with larger cohorts as well as the subsequent internal and external validation of predictive models. Ultimately, the ability to identify patients at high risk of post-transplant AKI may enable early intervention and perhaps prevention.

  14. 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

  15. Chloride-liberal fluids are associated with acute kidney injury after liver transplantation.

    Science.gov (United States)

    Nadeem, Ashraf; Salahuddin, Nawal; El Hazmi, Alyaa; Joseph, Mini; Bohlega, Balsam; Sallam, Hend; Sheikh, Yasser; Broering, Dieter

    2014-11-19

    Acute kidney injury (AKI) occurs frequently after liver transplantation and is associated with significant morbidity and mortality. Recent evidence has linked the predominant usage of 'chloride-liberal' intravenous fluids, such as 0.9% saline to the development of renal dysfunction in general critically ill patients. We compared the effects of perioperative fluid types on AKI in liver transplant recipients. An observational analysis of liver transplant recipients over a 33-month period, between January 2010 and September 2013, was performed. Intensive care unit database and patient records were analyzed for determinants of early postoperative AKI. Univariate and multivariate regression analysis was carried out using a two-tailed P value less than 0.05 to establish significance. The institutional Research Ethics Committee approved the study methodology (RAC no. 2131 073). One hundred and fifty-eight liver transplants were performed, AKI developed in 57 (36.1%) patients: 39 (68.4%) fully recovered, 13 (22.8%) developed chronic renal failure and 10 (17.5%) required long-term hemodialysis. On univariate regression analysis, AKI was significantly associated with greater than 3,200 ml of chloride-liberal fluids infused within the first postoperative day (HR 5.9, 95% CI 2.64, 13.2, P liberal fluids (HR 6.25, 95% CI 2.69, 14.5, P liberal fluids and preoperative status was associated with an increased risk for postoperative AKI.

  16. Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

    International Nuclear Information System (INIS)

    Lee, Ye-Ji; Lee, Seung-Hae; Youn, Young-So; Choi, Ji-Yeon; Song, Keung-Sub; Cho, Min-Sun; Kang, Jihee Lee

    2012-01-01

    Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

  17. Role of gamma-irradiated Rosemary against Ethanol Induced Liver Injury in Rats

    International Nuclear Information System (INIS)

    Hamzaa, R.G.; El shahat, A.N.; Mekawey, H.M.S.

    2013-01-01

    Among natural antioxidants, rosemary contains several antioxidant oil and phenolic compounds that may be possessed hepato protective effect. This study aimed to investigate the effect of dietary supplementation with gamma irradiated rosemary on ethanol induced liver injury in rats. Rosemary essential oil was analyzed by gas chromatography/mass spectrometry (GC/MS). The results of biological study revealed that dietary supplementation of either raw or gamma-irradiated rosemary following ethanol administration exerts remarkable modulating effect by reducing the level of total bilirubin, the activity of transaminases, gamma glutamyl transferase and serum alkaline phosphatase, decreasing the concentration of some lipid fractions and malondialdehyde content and xanthine oxidase activity. Also, supplementation of dietary rosemary induced an increase of high density lipoprotein and reduced glutathione content and enhances the activity of xanthine dehydrogenase, superoxide dismutase and catalase activities. Thus, gamma-irradiated rosemary could be incorporated to the diet as a nutritional supplement, to augment the liver's defenses against oxidative stress

  18. Idiosyncratic Drug-Induced Liver Injury (IDILI: Potential Mechanisms and Predictive Assays

    Directory of Open Access Journals (Sweden)

    Alexander D. Roth

    2017-01-01

    Full Text Available Idiosyncratic drug-induced liver injury (IDILI is a significant source of drug recall and acute liver failure (ALF in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME- mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA. We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

  19. Precision-cut mouse liver slices as an ex vivo model to study the mechanism of inflammatory stress-related idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Y.; Starokozhko, Viktoriia; Merema, Maja; Groothuis, Genoveva

    2012-01-01

    Idiosyncratic drug reactions (IDRs) can be defined as adverse drug reactions that occur in a small minority of the patients taking clinically-relevant doses and do not involve the known pharmacological effects of the drug. IDR related to hepatotoxicity or idiosyncratic drug-induced liver injury

  20. Activation of a novel c-Myc-miR27-prohibitin 1 circuitry in cholestatic liver injury inhibits glutathione synthesis in mice.

    Science.gov (United States)

    Yang, Heping; Li, Tony W H; Zhou, Yu; Peng, Hui; Liu, Ting; Zandi, Ebrahim; Martínez-Chantar, María Luz; Mato, José M; Lu, Shelly C

    2015-01-20

    We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factor-erythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Myc-mediated induction of microRNA 27a/b (miR27a/b), which target both PHB1 and Nrf2 to reduce their expression. Knockdown of c-Myc or miR27a/b attenuated LCA-mediated suppression of Nrf2, PHB1, and GCL subunit expression, whereas overexpression of PHB1 protected against the fall in Nrf2 and GCL subunits. Both c-Myc and PHB1 directly interact with Nrf2 but c-Myc lowers Nrf2 binding to ARE while PHB1 enhances it. This is the first work that shows how activation of this circuit in cholestatic liver injury inhibits GCL expression. LCA feeding and BDL activate c-Myc-miR27a/b-PHB1 circuit, with the consequence of inhibiting Nrf2 expression and ARE binding, resulting in decreased reduced glutathione synthesis and antioxidant capacity.

  1. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

    International Nuclear Information System (INIS)

    Boelsterli, Urs A.

    2003-01-01

    The nonsteroidal antiinflammatory drug diclofenac causes rare but significant cases of serious hepatotoxicity, typically with a delayed onset (>1-3 months). Because there is no simple dose relationship and because liver injury cannot be reproduced in current animal models, individual patient-specific susceptibility factors have been evoked to account for the increased risk. While these patient factors have remained undefined, a number of molecular hazards have been characterized. Among these are metabolic factors (bioactivation by hCYP2C9 or hCYP3A4 to thiol-reactive quinone imines, activation by hUGT2B7 to protein-reactive acyl glucuronides and iso-glucuronides, and 4'-hydroxylation secondary to diclofenac glucuronidation), as well as kinetic factors (Mrp2-mediated concentrative transport of diclofenac metabolites into bile). From the toxicodynamic view, both oxidative stress (caused by putative diclofenac cation radicals or nitroxide and quinone imine-related redox cycling) and mitochondrial injury (protonophoretic activity and opening of the permeability transition pore) alone or in combination have been implicated in diclofenac toxicity. In some cases, immune-mediated liver injury is involved, inferred from inadvertent rechallenge data and from a number of experiments demonstrating T cell sensitization. Why certain underlying diseases (e.g., osteoarthritis) also increase the susceptibility to diclofenac hepatotoxicity is not clear. To date, cumulative damage to mitochondrial targets seems a plausible putative mechanism to explain the delayed onset of liver failure, perhaps even superimposed on an underlying silent mitochondrial abnormality. Increased efforts to identify both patient-specific risk factors and disease-related factors will help to define patient subsets at risk as well as increase the predictability of unexpected hepatotoxicity in drug development

  2. Tbx3 Promotes Liver Bud Expansion During Mouse Development by Suppression of Cholangiocyte Differentiation

    NARCIS (Netherlands)

    Lüdtke, Timo H.-W.; Christoffels, Vincent M.; Petry, Marianne; Kispert, Andreas

    2009-01-01

    After specification of the hepatic endoderm, mammalian liver organogenesis progresses through a series of morphological stages that culminate in the migration of hepatocytes into the underlying mesenchyme to populate the hepatic lobes. Here, we show that in the mouse the transcriptional repressor

  3. Protective effect of recombinant human IL-1Ra on CCl4-induced acute liver injury in mice

    Science.gov (United States)

    Zhu, Run-Zhi; Xiang, Di; Xie, Chao; Li, Jing-Jing; Hu, Jian-Jun; He, Hong-Lin; Yuan, Yun-Sheng; Gao, Jin; Han, Wei; Yu, Yan

    2010-01-01

    AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl4). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a

  4. 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.

  5. 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. 

  6. The Effect of Recombinant Factor VIIa on Noncoagulopathic Pigs with Grade V Liver Injuries

    Science.gov (United States)

    2003-05-01

    mimicking haemophilia A or B conditions. Thromb Hemost 1999;82(S1):303; abstract 951. 22. Rao VM, Rapaport SI. Factor VIIa-catalyzed activation of Fac- tor...The Effect of Recombinant Factor VIIa on Noncoagulopathic Pigs with Grade V Liver Injuries Martin A Schreiber, MD, FACS, John B Holcomb, MD, FACS...5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Schreiber, M. A. Holcomb, J. B . Hedner, U. Brundage, S. I. Macaitis, J. M. Aoki, N. Meng

  7. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury[S

    OpenAIRE

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W.; Flanders, Kathleen C.; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M.; Gonzalez, Frank J.

    2012-01-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohisto...

  8. 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.

  9. Hepatoprotective Effects of Total Triterpenoids and Total Flavonoids from Vitis vinifera L against Immunological Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Tao Liu

    2012-01-01

    Full Text Available Suosuo grape (the fruits of Vitis vinifera L has been used for prevention and treatment of liver diseases in Uighur folk medicine in China besides its edible value. In this study, the hepatoprotective effects of total triterpenoids (VTT and total flavonoids (VTF from Suosuo grape were evaluated in Bacille-Calmette-Guerin- (BCG- plus-lipopolysaccharide- (LPS- induced immunological liver injury (ILI in mice. Various dose groups (50, 150, and 300 mg/kg of VTT and VTF alleviated the degree of liver injury of ILI mice, effectively reduced the BCG/LPS-induced elevated liver index and spleen index, hepatic nitric oxide (NO, and malondialdehyde (MDA content, increased liver homogenate alanine aminotransferase (ALT and aspartate aminotransferase (AST levels, and restored hepatic superoxide dismutase (SOD activity in ILI mice. VTT and VTF also significantly inhibited intrahepatic expression of Th1 cytokines (IFN-γ and IL-2 in ILI mice and increased intrahepatic expression of Th2 cytokines (IL-4 and IL-10. Moreover, the increased Bax/Bcl-2 ratio was significantly downregulated by VTT and VTF in liver tissue of ILI mice. These results are comparable to those of biphenyl dicarboxylate (DDB, the reference hepatoprotective agent and suggest that VTT and VTF play a protective role against immunological liver injury, which may have important implications for our understanding of the immunoregulatory mechanisms of this plant.

  10. 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

  11. 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

  12. Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

    International Nuclear Information System (INIS)

    Mosedale, Merrie; Wu, Hong; Kurtz, C. Lisa; Schmidt, Stephen P.; Adkins, Karissa; Harrill, Alison H.

    2014-01-01

    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

  13. miR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jun [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Tao, Zhong-Hua [Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai 200032 (China); Wen, Duo; Wan, Jin-Liang; Liu, Dong-Li; Zhang, Shu; Cui, Jie-Feng; Sun, Hui-Chuan; Wang, Lu [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Zhou, Jian; Fan, Jia [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China); Institute of Biomedical Sciences of Fudan University, Shanghai 200032 (China); Wu, Wei-Zhong, E-mail: wu.weizhong@zs-hospital.sh.cn [Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032 (China)

    2014-04-25

    Highlights: • miR-612 suppresses tumorsphere and clone formation of HCC cells. • miR-612 reduces drug resistance of HCC cells. • miR-612 suppresses tumorigenesis of HCC in NOD/SCID mice. • miR-612 inhibits an invasive frontier of HCC xenografts. • miR-612 suppresses Wnt/β-catenin signaling. - Abstract: Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.

  14. miR-612 suppresses the stemness of liver cancer via Wnt/β-catenin signaling

    International Nuclear Information System (INIS)

    Tang, Jun; Tao, Zhong-Hua; Wen, Duo; Wan, Jin-Liang; Liu, Dong-Li; Zhang, Shu; Cui, Jie-Feng; Sun, Hui-Chuan; Wang, Lu; Zhou, Jian; Fan, Jia; Wu, Wei-Zhong

    2014-01-01

    Highlights: • miR-612 suppresses tumorsphere and clone formation of HCC cells. • miR-612 reduces drug resistance of HCC cells. • miR-612 suppresses tumorigenesis of HCC in NOD/SCID mice. • miR-612 inhibits an invasive frontier of HCC xenografts. • miR-612 suppresses Wnt/β-catenin signaling. - Abstract: Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612

  15. A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways

    International Nuclear Information System (INIS)

    Furuya, Shinji; Chappell, Grace A.; Iwata, Yasuhiro; Uehara, Takeki; Kato, Yuki; Kono, Hiroshi; Bataller, Ramon; Rusyn, Ivan

    2016-01-01

    Clinical data strongly indicate that acute kidney injury (AKI) is a critical complication in alcoholic hepatitis, an acute-on-chronic form of liver failure in patients with advanced alcoholic fibrosis. Development of targeted therapies for AKI in this setting is hampered by the lack of an animal model. To enable research into molecular drivers and novel therapies for fibrosis- and alcohol-associated AKI, we aimed to combine carbon tetrachloride (CCl 4 )-induced fibrosis with chronic intra-gastric alcohol feeding. Male C57BL/6J mice were administered a low dose of CCl 4 (0.2 ml/kg 2 × week/6 weeks) followed by alcohol intragastrically (up to 25 g/kg/day for 3 weeks) and with continued CCl 4 . We observed that combined treatment with CCl 4 and alcohol resulted in severe liver injury, more pronounced than using each treatment alone. Importantly, severe kidney injury was evident only in the combined treatment group. This mouse model reproduced distinct pathological features consistent with AKI in human alcoholic hepatitis. Transcriptomic analysis of kidneys revealed profound effects in the combined treatment group, with enrichment for damage-associated pathways, such as apoptosis, inflammation, immune-response and hypoxia. Interestingly, Havcr1 and Lcn2, biomarkers of AKI, were markedly up-regulated. Overall, this study established a novel mouse model of fibrosis- and alcohol-associated AKI and identified key mechanistic pathways. - Highlights: • Acute kidney injury (AKI) is a critical complication in alcoholic hepatitis • We developed a novel mouse model of fibrosis- and alcohol-associated AKI • This model reproduces key molecular and pathological features of human AKI • This animal model can help identify new targeted therapies for alcoholic hepatitis

  16. 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.

  17. Myocardial injury in patients with hemodynamic derangements during and/or after liver transplantation.

    Science.gov (United States)

    Huang, Shun; Apinyachon, Worapot; Agopian, Vatche G; Wray, Christopher L; Busuttil, Ronald W; Steadman, Randolph H; Xia, Victor W

    2016-12-01

    Myocardial injury, defined as an elevation of cardiac troponin (cTn) resulting from ischemia, is associated with substantial mortality in surgical patients, and its incidence, risk factors, and impact on patients undergoing liver transplantation (LT) are poorly understood. In this study, adult patients who experienced perioperative hemodynamic derangements and had cTn measurements within 30 days after LT between 2006 and 2013 were studied. Of 502 patients, 203 (40.4%) met the diagnostic criteria (cTn I ≥0.1 ng/mL) of myocardial injury. The majority of myocardial injury occurred within the first three postoperative days and presented without clinical signs or symptoms of myocardial infarction. Thirty-day mortality in patients with myocardial injury was 11.4%, significantly higher compared with that in patients without myocardial injury (3.4%, P<.01). Cox analysis indicated the peak cTn was significantly associated with 30-day mortality. Multivariable logistic analysis identified three independent risk factors: requirement of ventilation before transplant (odds ratios (OR) 1.6, P=.006), RBC≥15 units (OR 1.7, P=.006), and the presence of PRS (OR 2.0, P=.028). We concluded that post-LT myocardial injury in this high-risk population was common and associated with mortality. Our findings may be used in pretransplant stratification. Further studies to investigate this postoperative cardiac complication in all LT patients are warranted. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. 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.).

  19. Tanshinone IIA protects against immune-mediated liver injury through activation of T-cell subsets and regulation of cytokines.

    Science.gov (United States)

    Qin, Xiao-Yan; Li, Tang; Yan, Li; Liu, Qing-Shan; Tian, Yu

    2010-03-01

    Tanshione IIA (TSN) is the major active component of Salvia miltiorrhiza, a traditional Chinese Medicine. TSN protects against antioxidant-induced liver injury, although the exact mechanism is not well understood. In this study, the protective effects of TSN was examined by enzyme-linked immunosorbent assay (ELISA) and histochemistry of several cytokines. TSN is found to significantly reduce plasma alanin aminotransferase and aspartate amino transferase levels in mice with concanavalin A-induced immune-mediated liver injury. TSN increases T lymphocyte subset CD3+, CD4+ and CD8+ ratios.Also, TSN significantly reduces inflammatory cytokines, including interleukin-2, interleukin-4, interferon-gamma and tumor necrosis factor alpha, while elevates anti-inflammatory cytokine, interleukin-10. TSN may provide a potential drug candidate for liver injury therapeutics.

  20. 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

    2014-11-07

    To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury. 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. 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 the saline group. The

  1. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

    Science.gov (United States)

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics. PMID:25631039

  2. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach.

    Science.gov (United States)

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-29

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics.

  3. 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.

  4. The essential oil of Artemisia capillaris protects against CCl4-induced liver injury in vivo

    Directory of Open Access Journals (Sweden)

    Qinghan Gao

    Full Text Available Abstract To study the hepatoprotective effect of the essential oil of Artemisia capillaris Thunb., Asteraceae, on CCl4-induced liver injury in mice, the levels of serum aspartate aminotransferase and alanine aminotransferase, hepatic levels of reduced glutathione, activity of glutathione peroxidase, and the activities of superoxide dismutase and malondialdehyde were assayed. Administration of the essential oil of A. capillaris at 100 and 50 mg/kg to mice prior to CCl4 injection was shown to confer stronger in vivo protective effects and could observably antagonize the CCl4-induced increase in the serum alanine aminotransferase and aspartate aminotransferase activities and malondialdehyde levels as well as prevent CCl4-induced decrease in the antioxidant superoxide dismutase activity, glutathione level and glutathione peroxidase activity (p < 0.01. The oil mainly contained β-citronellol, 1,8-cineole, camphor, linalool, α-pinene, β-pinene, thymol and myrcene. This finding demonstrates that the essential oil of A. capillaris can protect hepatic function against CCl4-induced liver injury in mice.

  5. Recent Progress on Liver Kinase B1 (LKB1: Expression, Regulation, Downstream Signaling and Cancer Suppressive Function

    Directory of Open Access Journals (Sweden)

    Ren-You Gan

    2014-09-01

    Full Text Available Liver kinase B1 (LKB1, known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK, salt-inducible kinase (SIK, sucrose non-fermenting protein-related kinase (SNRK and brain selective kinase (BRSK signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of this molecular and its significance in cancers.

  6. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis

    Directory of Open Access Journals (Sweden)

    Nikolaos P. Karidis

    2015-01-01

    Full Text Available Chronic hepatitis C virus (HCV infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even “similar” causes, such as hepatitis B virus- (HBV- related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.

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

    Directory of Open Access Journals (Sweden)

    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

  8. Cytoprotective Mechanisms in Fatty Liver Preservation against Cold Ischemia Injury: A Comparison between IGL-1 and HTK

    Directory of Open Access Journals (Sweden)

    Arnau Panisello-Roselló

    2018-01-01

    Full Text Available Institute Goeorges Lopez 1 (IGL-1 and Histidine-Tryptophan-Ketoglutarate (HTK preservation solutions are regularly used in clinical for liver transplantation besides University of Wisconsin (UW solution and Celsior. Several clinical trials and experimental works have been carried out comparing all the solutions, however the comparative IGL-1 and HTK appraisals are poor; especially when they deal with the underlying protection mechanisms of the fatty liver graft during cold storage. Fatty livers from male obese Zücker rats were conserved for 24 h at 4 °C in IGL-1 or HTK preservation solutions. After organ recovery and rinsing of fatty liver grafts with Ringer Lactate solution, we measured the changes in mechanistic target of rapamycin (mTOR signaling activation, liver autophagy markers (Beclin-1, Beclin-2, LC3B and ATG7 and apoptotic markers (caspase 3, caspase 9 and TUNEL. These determinations were correlated with the prevention of liver injury (aspartate and alanine aminostransferase (AST/ALT, histology and mitochondrial damage (glutamate dehydrogenase (GLDH and confocal microscopy findings. Liver grafts preserved in IGL-1 solution showed a marked reduction on p-TOR/mTOR ratio when compared to HTK. This was concomitant with significant increased cyto-protective autophagy and prevention of liver apoptosis, including inflammatory cytokines such as HMGB1. Together, our results revealed that IGL-1 preservation solution better protected fatty liver grafts against cold ischemia damage than HTK solution. IGL-1 protection was associated with a reduced liver damage, higher induced autophagy and decreased apoptosis. All these effects would contribute to limit the subsequent extension of reperfusion injury after graft revascularization in liver transplantation procedures.

  9. 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

  10. Hepatoprotective Evaluation of Ganoderma lucidum Pharmacopuncture: In vivo Studies of Ethanol-induced Acute Liver Injury

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    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.

  11. [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 technology was feasible. The new extraction could protect the liver injury in rats, which was better than extraction of current preparation technology.

  12. Construction and analysis of liver suppression subtractive hybridization library of silver carp (Hypophthalmichthys molitrix) intraperitoneally injected with microcystin-LR.

    Science.gov (United States)

    Qu, Xiancheng; Zhang, Kaiyue; Cui, Zhihui; Zhang, Yong; Jiang, Jiaoyun; Feng, Long; Liu, Qigen

    2011-09-01

    Microcystin-LR (MC-LR) is the most frequently studied cyclic heptapeptide hepatotoxin produced by cyanobacteria. The toxin accumulates rapidly in the liver where it exerts most of its damage, but the molecular mechanisms behind its toxicity remain unclear. Here, suppression subtractive hybridization (SSH) was used to identify alterations in gene transcription of the silver carp (Hypophthalmichthys molitrix) after exposure to MC-LR. After hybridization and cloning, the forward and reverse subtractive cDNA libraries were obtained. At random, 150 positive clones (70 forward and 80 reverse) were selected and sequenced from the subtractive libraries, which gave a total of 88 gene fragment sequences (48 forward and 40 reverse). Sequencing analysis and homology searches showed that these ESTs represented 75 unique genes and 13 duplicates. Of the 75 unique genes, 38 shared high homology with fish genes of known functions, including immune-related genes, transporters and some involved in cell metabolism. Four sequenced genes (Fs59, Fs70, Rs2 and Rs15) were analyzed further using semi-quantitative RT-PCR. The genes from the forward library (Fs59 and Fs70) were found to be transcriptionally upregulated, while the genes from the reverse library (Rs2 and Rs15) were found to be transcriptionally downregulated. These results confirmed the successful construction of the subtractive cDNA library that was enriched for genes that were differentially transcribed in the silver carp liver challenged with MC-LR. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney.

    Science.gov (United States)

    Ebrahimkhani, Mohammad R; Daneshmand, Ali; Mazumder, Aprotim; Allocca, Mariacarmela; Calvo, Jennifer A; Abolhassani, Nona; Jhun, Iny; Muthupalani, Sureshkumar; Ayata, Cenk; Samson, Leona D

    2014-11-11

    Inflammation is accompanied by the release of highly reactive oxygen and nitrogen species (RONS) that damage DNA, among other cellular molecules. Base excision repair (BER) is initiated by DNA glycosylases and is crucial in repairing RONS-induced DNA damage; the alkyladenine DNA glycosylase (Aag/Mpg) excises several DNA base lesions induced by the inflammation-associated RONS release that accompanies ischemia reperfusion (I/R). Using mouse I/R models we demonstrate that Aag(-/-) mice are significantly protected against, rather than sensitized to, I/R injury, and that such protection is observed across three different organs. Following I/R in liver, kidney, and brain, Aag(-/-) mice display decreased hepatocyte death, cerebral infarction, and renal injury relative to wild-type. We infer that in wild-type mice, Aag excises damaged DNA bases to generate potentially toxic abasic sites that in turn generate highly toxic DNA strand breaks that trigger poly(ADP-ribose) polymerase (Parp) hyperactivation, cellular bioenergetics failure, and necrosis; indeed, steady-state levels of abasic sites and nuclear PAR polymers were significantly more elevated in wild-type vs. Aag(-/-) liver after I/R. This increase in PAR polymers was accompanied by depletion of intracellular NAD and ATP levels plus the translocation and extracellular release of the high-mobility group box 1 (Hmgb1) nuclear protein, activating the sterile inflammatory response. We thus demonstrate the detrimental effects of Aag-initiated BER during I/R and sterile inflammation, and present a novel target for controlling I/R-induced injury.

  14. Suppression of liver receptor homolog-1 by microRNA-451 represses the proliferation of osteosarcoma cells

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    Li, Zhiyong; Wu, Shuwen; Lv, Shouzheng; Wang, Huili; Wang, Yong; Guo, Qiang, E-mail: qiangguo_gq@163.com

    2015-06-05

    Liver receptor homolog-1 (LRH-1) plays an important role in the onset and progression of many cancer types. However, the role of LRH-1 in osteosarcoma has not been well investigated. In this study, the critical role of LRH-1 in osteosarcoma cells was described. Quantitative polymerase chain reaction and Western blot analysis results revealed that LRH-1 was highly overexpressed in osteosarcoma cells. LRH-1 was knocked down by small interfering RNA (siRNA), and this phenomenon significantly inhibited osteosarcoma cell proliferation. Bioinformatics analysis results showed that LRH-1 contained putative binding sites of microRNA-451 (miR-451); this result was further validated through a dual-luciferase activity reporter assay. miR-451 was overexpressed in osteosarcoma cells through transfection of miR-451 mimics; miR-451 overexpression then significantly inhibited LRH-1 expression and cell proliferation. The loss of LRH-1 by siRNA or miR-451 mimics significantly impaired Wnt/β-catenin activity, leading to G0/G1 cell cycle arrest. Results showed that LRH-1 is implicated in osteosarcoma. Therefore, miR-451-induced suppression of LRH-1 can be a novel therapy to treat osteosarcoma. - Highlights: • LRH-1 was highly overexpressed in osteosarcoma cells. • Knockdown of LRH-1 inhibited osteosarcoma cell proliferation. • miR-451 directly targeted and regulated LRH-1 expression. • Overexpression of miR-451 suppressed Wnt activity.

  15. Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation

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    Stefania Bruno

    2016-01-01

    Full Text Available Human liver stem cells (HLSCs are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs, and dendritic cells (DCs in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2 and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs, HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.

  16. Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through Class IIa Histone Deacetylase 4.

    Science.gov (United States)

    Wang, Yangmeng; Paulo, Esther; Wu, Dongmei; Wu, Yixuan; Huang, Wendong; Chawla, Ajay; Wang, Biao

    2017-12-01

    Uncoupling protein 1 + beige adipocytes are dynamically regulated by environment in rodents and humans; cold induces formation of beige adipocytes, whereas warm temperature and nutrient excess lead to their disappearance. Beige adipocytes can form through de novo adipogenesis; however, how "beiging" characteristics are maintained afterward is largely unknown. In this study, we show that beige adipocytes formed postnatally in subcutaneous inguinal white adipose tissue lost thermogenic gene expression and multilocular morphology at the adult stage, but cold restored their beiging characteristics, a phenomenon termed beige adipocyte renaissance. Ablation of these postnatal beige adipocytes inhibited cold-induced beige adipocyte formation in adult mice. Furthermore, we demonstrated that beige adipocyte renaissance was governed by liver kinase b1 and histone deacetylase 4 in white adipocytes. Although neither presence nor thermogenic function of uncoupling protein 1 + beige adipocytes contributed to metabolic fitness in adipocyte liver kinase b1-deficient mice, our results reveal an unexpected role of white adipocytes in maintaining properties of preexisting beige adipocytes. © 2017 by the American Diabetes Association.

  17. Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells.

    Directory of Open Access Journals (Sweden)

    Raimundo Fernandes de Araújo Júnior

    type III (PCIII, and NF-κB were decreased in the alcohol-CARV 5 mg/kg group relative to the alcohol-only group.CARV can reduce the stress oxidative, inflammatory response and fibrosis in ethanol-induced liver injury in a rat model by downregulating signalling of Kuppfer cells and hepatic stellate cells (HSCs through suppression of inflammatory cytokines.

  18. Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages.

    Directory of Open Access Journals (Sweden)

    Yiannis N Kallis

    Full Text Available Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1 is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1-deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow-derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment.

  19. Effects of Contrast-Enhanced Ultrasonography in Monitoring Hepatic Microcirculation After Rat Liver Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Zhang, Yun-Fei; Li, Hong; Zhang, Bao-Hui; Fang, Xiu-Bin

    2016-06-01

    Our objective was to evaluate the effects of contrast-enhanced ultrasonography in monitoring microcirculation after rat liver ischemia-reperfusion injury. Male Wistar rats (n = 36) were divided into sham-operated and ischemia-reperfusion groups. Rats in the ischemia-reperfusion groups underwent normothermic liver ischemia for 15 minutes followed by 1, 6, or 24 hours of reperfusion. At different time points, contrast-enhanced ultrasonography was performed to determine peak intensity in monitoring hepatic microcirculation. In addition, serum levels of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor α, and interleukin 1β levels were measured. Histopathologic changes were also observed. One hour after reperfusion, peak intensity values decreased, and serum levels of alanine aminotransferase, tumor necrosis factor α, and interleukin 1β increased significantly in the ischemia-reperfusion group compared with the sham-operated group. Histology results showed mild injury. Six hours after reperfusion, peak intensity values decreased continuously, serum levels of alanine aminotransferase, tumor necrosis factor α, and interleukin 1β decreased, and aspartate aminotransferase levels increased. Histology results showed severe injury compared with 1 hour after reperfusion. Twenty-four hours after reperfusion, peak intensity values increased, alanine aminotransferase and aspartate aminotransferase levels decreased, and histology results showed moderate injury compared with 6 hours after reperfusion. Peak intensity values were negatively correlated to alanine aminotransferase (P liver ischemia-reperfusion injury can be monitored by contrast-enhanced ultrasonography. The perfusion of contrast agents negatively correlates to the severity of injuries.

  20. Panax notoginseng saponins preconditioning protects rat liver grafts from ischemia/reperfusion injury via an antiapoptotic pathway.

    Science.gov (United States)

    Zhang, Yi; Ye, Qi-Fa; Lu, Li; Xu, Xian-Lin; Ming, Ying-Zi; Xiao, Jian-Sheng

    2005-05-01

    Ischemia/reperfusion (I/R) injury is a major cause of primary graft dysfunction and renders an allograft more immunogenic in orthotopic liver transplantation (OLT). Panax notoginseng saponins (PNS) has been reported to exert protective effects against I/R injury to various organs. The objective of this study is to investigate whether PNS preconditioning protects rat liver grafts from I/R injury via an antiapoptotic pathway. Male Sprague-Dawley rats were used as donors and recipients of orthotopic liver transplantation (OLT) and were divided into PNS preconditioning group(group P) and normal saline control group (group N) randomly according to whether PNS (50 mg/kg) was injected intravenously 1 hour before liver grafts harvesting, and sham group (group S). The animals were separately killed 2, 6 and 24 hours after reperfusion. Plasma samples were collected for test of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver tissues were collected to detect histological changes, apoptosis and the expression of TNF-alpha, Bcl-2 and Caspase-3 mRNA. The serum levels of ALT and AST and the apoptosis index (AI) of liver tissue in group P were lower than in group N significantly 2, 6 and 24 hours after reperfusion. Compared with group N, the expression of TNF-alpha and Caspase-3 mRNA was reduced significantly in group P 2 and 6 hours after reperfusion and the expression of Bcl-2 mRNA was enhanced significantly in group P 6 and 24 hours after reperfusion. PNS preconditioning protects liver grafts from I/R injury effectively in rat OLT via an antiapoptotic pathway. The antiapoptotic mechanisms of PNS may include inhibiting the expression of TNF-alpha and Caspase-3 and enhancing the expression of Bcl-2.

  1. [Protective effect of Angelica sinensis polysaccharide against liver injury induced by D-galactose in aging mice and its mechanisms].

    Science.gov (United States)

    Xia, J Y; Fan, Y L; Jia, D Y; Zhang, M S; Zhang, Y Y; Li, J; Jing, P W; Wang, L; Wang, Y P

    2016-03-20

    To investigate the protective effect of Angelica sinensis polysaccharide (ASP) against liver injury induced by D-galactose in aging mice and its mechanisms. Male C57BL/6J were randomly divided into three groups with 10 mice in each group. In the D-galactose model group, the mice were subcutaneously injected with D-galactose (120 mg/kg) qd×42; in the ASP+D-galactose group, from the 8th day of the establishment of D-galactose model, the mice were subcutaneously injected with ASP (120 mg/kg) qd×35. In the normal control group, the mice were subcutaneously injected with isotonic saline of the same volume at the same time point. On the 2nd day after the injection was finished, the ocular blood was collected to prepare serum and measure the content of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil). The liver tissue homogenate was prepared to measure the content of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), and advanced glycation end products (AGEs). A paraffin section of liver tissue was prepared; HE staining was performed to observe the pathomorphological changes of the liver, periodic acid-Schiff staining (PAS) was used to observe the changes in glycogen in the liver, and a transmission electron microscope was used to observe the hepatocyte ultrastructure. The D-galactose model group had increased content of ALT, AST, and TBil, reduced activities of SOD and GSH-Px, an increased content of MDA, and severe liver injuries; the hepatocytes showed degenerative changes, the amount of glycogen in the liver decreased, and the accumulation of AGEs increased. The ASP+D-galactose group had reduced content of ALT, AST, and TBil, increased activities of SOD and GSH-Px, and reduced content of MDA and AGEs; the amount of glycogen in the liver increased, and liver injury and hepatocyte injury were alleviated. ASP can antagonize the liver injury induced by D-galactose in aging mice, and its

  2. 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

  3. Heme oxygenase-1 protects rat liver against warm ischemia/reperfusion injury via TLR2/TLR4-triggered signaling pathways.

    Science.gov (United States)

    Huang, Han-Fei; Zeng, Zhong; Wang, Kun-Hua; Zhang, Hai-Yan; Wang, Shuai; Zhou, Wen-Xiang; Wang, Zhan-Bo; Xu, Wang-Gang; Duan, Jian

    2015-03-14

    To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury. Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies. HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the

  4. Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo.

    Science.gov (United States)

    Wang, Jun-ming; Sheng, Yu-chen; Ji, Li-li; Wang, Zheng-tao

    2014-06-01

    The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity.

  5. Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo *

    Science.gov (United States)

    Wang, Jun-ming; Sheng, Yu-chen; Ji, Li-li; Wang, Zheng-tao

    2014-01-01

    The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity. PMID:24903991

  6. A Network-Based Pharmacology Study of the Herb-Induced Liver Injury Potential of Traditional Hepatoprotective Chinese Herbal Medicines.

    Science.gov (United States)

    Hong, Ming; Li, Sha; Tan, Hor Yue; Cheung, Fan; Wang, Ning; Huang, Jihan; Feng, Yibin

    2017-04-14

    Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one-Xiao-Chai-Hu-Tang (XCHT)-a composite formula, and the other- Radix Polygoni Multiflori (Heshouwu) -a single herb, were analyzed by network pharmacology study. Based on the network pharmacology framework, we exploited the potential HILI effects of XCHT and Heshouwu by predicting the molecular mechanisms of HILI and identified the potential hepatotoxic ingredients in XCHT and Heshouwu . According to our network results, kaempferol and thymol in XCHT and rhein in Heshouwu exhibit the largest number of liver injury target connections, whereby CASP3, PPARG and MCL1 may be potential liver injury targets for these herbal medicines. This network pharmacology assay might serve as a useful tool to explore the underlying molecular mechanism of HILI. Based on the theoretical predictions, further experimental verification should be performed to validate the accuracy of the predicted interactions between herbal ingredients and protein targets in the future.

  7. Alleviation of lipopolysaccharide/d-galactosamine-induced liver injury in leukocyte cell-derived chemotaxin 2 deficient mice

    Directory of Open Access Journals (Sweden)

    Akinori Okumura

    2017-12-01

    Full Text Available Leukocyte cell-derived chemotaxin 2 (LECT2 is a secreted pleiotropic protein that is mainly produced by the liver. We have previously shown that LECT2 plays an important role in the pathogenesis of inflammatory liver diseases. Lipopolysaccharide/d-galactosamine (LPS/d-GalN-induced acute liver injury is a known animal model of fulminant hepatic failure. Here we found that this hepatic injury was alleviated in LECT2-deficient mice. The levels of TNF-α and IFN-γ, which mediate this hepatitis, had significantly decreased in these mice, with the decrease in IFN-γ production notably greater than that in TNF-α. We therefore analyzed IFN-γ-producing cells in liver mononuclear cells. Flow cytometric analysis showed significantly reduced IFN-γ production in hepatic NK and NKT cells in LECT2-deficient mice compared with in wild-type mice. We also demonstrated a decrease in IFN-γ production in LECT2-deficient mice after systemic administration of recombinant IL-12, which is known to induce IFN-γ in NK and NKT cells. These results indicate that a decrease of IFN-γ production in NK and NKT cells was involved in the alleviation of LPS/d-GalN-induced liver injury in LECT2-deficient mice.

  8. 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

  9. [Approach to liver, spleen and pancreatic injuries including damage control surgery of terrorist attacks].

    Science.gov (United States)

    Stavrou, G A; Lipp, M J; Oldhafer, K J

    2017-10-01

    Terrorist attacks have outreached to Europe with more and more attacks on civilians. Derived from war surgery experience and from lessons learned from major incidents, it seems mandatory for every surgeon to improve understanding of the special circumstances of trauma following a terrorist attack and its' management. A short literature review is followed by outlining the damage control surgery (DCS) principle for each organ system with practical comments from the perspective of a specialized hepatobiliary (HPB) surgery unit. Every surgeon has to become familiar with the new entities of blast injuries and terrorist attack trauma. This concerns not only the medical treatment but also tailoring surgical treatment with a view to a lack of critical resources under these circumstances. For liver and pancreatic trauma, simple treatment strategies are a key to success.

  10. 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Fullerton, Aaron M., E-mail: fuller22@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, 1129 Farm Lane, Room 215, East Lansing, MI 48824 (United States); Roth, Robert A., E-mail: rothr@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, Food Safety and Toxicology Building, 1129 Farm Lane, Room 221, East Lansing, MI 48824 (United States); Ganey, Patricia E., E-mail: ganey@msu.edu [Department of Pharmacology and Toxicology, Center for Integrative Toxicology, Michigan State University, Food Safety and Toxicology Building, 1129 Farm Lane, Room 214, East Lansing, MI 48824 (United States)

    2013-01-15

    Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four. Mice treated with TCDD did not develop liver injury; however, TCDD pretreatment increased liver injury resulting from moderate doses of Con A (4–10 mg/kg). TCDD-pretreated mice had altered plasma concentrations of inflammatory cytokines, including interferon gamma (IFNγ), and TCDD/Con A-induced hepatotoxicity was attenuated in IFNγ knockout mice. At various times after treatment, intrahepatic immune cells were isolated, and expression of cell activation markers as well as cytolytic proteins was determined. TCDD pretreatment increased the proportion of activated natural killer T (NKT) cells and the percent of cells expressing Fas ligand (FasL) after Con A administration. In addition FasL knockout mice and mice treated with CD18 antiserum were both protected from TCDD/Con A-induced hepatotoxicity, suggesting a requirement for direct cell–cell interaction between effector immune cells and parenchymal cell targets in the development of liver injury from TCDD/Con A treatment. In summary, exposure to TCDD increased NKT cell activation and exacerbated immune-mediated liver injury induced by Con A through a mechanism involving IFNγ and FasL expression. -- Highlights: ► TCDD pretreatment sensitizes mice to Con A-induced hepatotoxicity. ► TCDD pretreatment increased concentration of IFNγ in plasma after Con A. ► Con A-induced activation of NKT cells was increased by TCDD pretreatment. ► Fas

  11. 2,3,7,8-TCDD enhances the sensitivity of mice to concanavalin A immune-mediated liver injury

    International Nuclear Information System (INIS)

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

    2013-01-01

    Inflammation plays a major role in immune-mediated liver injury, and exposure to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reported to alter the inflammatory response as well as affect immune cell activity. In this study, we tested the hypothesis that TCDD pretreatment exacerbates hepatotoxicity in a murine model of immune-mediated liver injury induced by concanavalin A (Con A) administration. Mice were pretreated with 30 μg/kg TCDD or vehicle control on day zero and then given either Con A or saline intravenously on day four. Mice treated with TCDD did not develop liver injury; however, TCDD pretreatment increased liver injury resulting from moderate doses of Con A (4–10 mg/kg). TCDD-pretreated mice had altered plasma concentrations of inflammatory cytokines, including interferon gamma (IFNγ), and TCDD/Con A-induced hepatotoxicity was attenuated in IFNγ knockout mice. At various times after treatment, intrahepatic immune cells were isolated, and expression of cell activation markers as well as cytolytic proteins was determined. TCDD pretreatment increased the proportion of activated natural killer T (NKT) cells and the percent of cells expressing Fas ligand (FasL) after Con A administration. In addition FasL knockout mice and mice treated with CD18 antiserum were both protected from TCDD/Con A-induced hepatotoxicity, suggesting a requirement for direct cell–cell interaction between effector immune cells and parenchymal cell targets in the development of liver injury from TCDD/Con A treatment. In summary, exposure to TCDD increased NKT cell activation and exacerbated immune-mediated liver injury induced by Con A through a mechanism involving IFNγ and FasL expression. -- Highlights: ► TCDD pretreatment sensitizes mice to Con A-induced hepatotoxicity. ► TCDD pretreatment increased concentration of IFNγ in plasma after Con A. ► Con A-induced activation of NKT cells was increased by TCDD pretreatment. ► Fas

  12. FGF receptors 1 and 2 control chemically-induced injury and compound detoxification in regenerating livers of mice

    Science.gov (United States)

    Böhm, Friederike; Speicher, Tobias; Hellerbrand, Claus; Dickson, Clive; Partanen, Juha M.; Ornitz, David M.; Werner, Sabine

    2010-01-01

    Background & Aims Fibroblast growth factor receptor (FGFR) 4 controls bile acid metabolism and protects the liver from fibrosis, but the roles of FGFR1 and FGFR2 in the adult liver are largely unknown. We investigated the functions and mechanisms of action of these receptors in liver homeostasis, regeneration, and fibrosis. Methods We generated mice with hepatocytes that lack FGFR1 and FGFR2 and subjected them to acute and chronic carbon tetrachloride-induced liver injury and partial hepatectomy; mice were also injected with FGF7. We performed histology, histomorphometry, real-time reverse transcription PCR, and immunoblot analyses. Results In hepatocytes, loss of FGFR1 and FGFR2 eliminated responsiveness to FGF7 and related FGF family members, but did not affect toxin-induced liver injury and fibrosis. However, mortality after partial hepatectomy increased because of severe hepatocyte necrosis. These effects appeared to be mediated by a failure of hepatocyes to induce the expression of the transcriptional regulators Dbp and Tef upon liver surgery; this affected expression of their target genes, which encode detoxifying cytochrome P450 enzymes. We found that Dbp and Tef expression was directly controlled by FGFR signalling in hepatocytes. As a consequence of the reduced expression of genes that control detoxification, the liver tissue that remained after partial hepatectomy failed to efficiently metabolize endogenous compounds and the drugs applied for anaesthesia/analgesia. Conclusions We identified a new, cytoprotective effect of FGFR1 and FGFR2 in the regenerating liver and suggest the use of recombinant FGF7 to increase survival of patients after surgical resection of large amounts of liver tissue. PMID:20603121

  13. 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.

  14. Minocycline-Suppression of Early Peripheral Inflammation Reduces Hypoxia-Induced Neonatal Brain Injury

    Directory of Open Access Journals (Sweden)

    Yingjun Min

    2017-09-01

    Full Text Available While extensive studies report that neonatal hypoxia-ischemia (HI induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d rat pups to systemic hypoxia (3.5 h, a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg was injected intraperitoneally (i.p. 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS, indicated by presence of C-C chemokine receptor type 2 (CCR2+/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker. Interrupted blood-brain barrier (BBB, hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response.

  15. Minocycline-Suppression of Early Peripheral Inflammation Reduces Hypoxia-Induced Neonatal Brain Injury

    Science.gov (United States)

    Min, Yingjun; Li, Hongchun; Xu, Kaiyu; Huang, Yilong; Xiao, Jie; Wang, Weizhou; Li, Longjun; Yang, Ting; Huang, Lixuan; Yang, Ling; Jiang, Hong; Wang, Qian; Zhao, Min; Hua, HaiRong; Mei, Rong; Li, Fan

    2017-01-01

    While extensive studies report that neonatal hypoxia-ischemia (HI) induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg) was injected intraperitoneally (i.p.) 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg) minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response. PMID:28955196

  16. Comparative study of fast T 2-weighted images using respiratory triggered, breath-hold, fat suppression and phased array multi coil for liver evaluation by magnetic resonance imaging

    International Nuclear Information System (INIS)

    Abbehusen, Cristiane L.; D'Ippolito, Giuseppe; Palacio, Glaucia A.S.; Szejnfeld, Jacob

    2003-01-01

    The objective of this study was to compare both qualitatively and quantitatively six T 2-weighted turbo spin-echo sequences varying the respiratory compensation technique, associating or not fat tissue suppression and using different types of coils. We performed a prospective study of 71 consecutive patients that were submitted to MRI of the liver using a 1.5 T magnet. The six following pulse sequences were used: fat-suppressed respiratory triggered with conventional body coil; breath-hold fat-suppressed with conventional body coil; non-suppressed respiratory triggered with conventional body coil; breath-hold non fat-suppressed with conventional body coil; fat-suppressed respiratory triggered with phased-array multi coil; breath-hold fat-suppressed with phased-array multi coil. Images were analyzed quantitatively by measuring the signal-to-noise ratios and qualitatively by evaluating the sharpness of hepatic contours, visibility of intrahepatic vessels and other segmental landmarks, and the presence of artifacts. Results: the qualitative analysis showed that the mean values obtained with the six sequences were 7.8, 4.6, 7.9, 5.2, 6.7 and 4.6 respectively. The respiratory-triggered sequences were better than the breath-hold sequences in both qualitative and quantitative analysis (p < 0.001). No significant differences in the values of signal-to-noise ratios and in overall image quality were found between the sequences with and without fat suppression (p . 0.05). The sequences using the body coil were similar in terms of image quality (p . 0.05) and better regarding signal-to-noise ratios than those obtained with the phased=array multi coil (p ,0.001). Our qualitative and quantitative results suggest that the best MRI sequences for the valuation of the liver are the sequences with respiratory triggering using a conventional body coil, with or without fat suppression. (author)

  17. [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.

  18. Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series

    Directory of Open Access Journals (Sweden)

    Castellote José

    2011-07-01

    Full Text Available Abstract Background Acute liver injury (ALI induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug. The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. Methods Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. Results In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8 and of 10 per million paracetamol users-year (95% CI 4.3-19.4. Conclusions Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

  19. Prediction of liver injury using the BP-ANN model with metabolic parameters in overweight and obese Chinese subjects.

    Science.gov (United States)

    Hu, Lufeng; Wang, Fan; Xu, Jinzhong; Wang, Xiaofang; Lin, Hong; Zhang, Yi; Yu, Yang; Wang, Youpei; Pang, Lingxia; Zhang, Xi; Liu, Qi; Qiu, Guoshi; Jiang, Yongsheng; Xie, Longteng; Liu, Yanlong

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is often associated with dyslipidemia. Metabolic disequilibrium, resulting from being overweight and obesity, increases risk to cardiovascular system and chronic liver disease. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) are standard clinical markers for liver injury. In this study, we examined association of body mass index (BMI) and metabolic markers with serum ALT, AST and GGT activity in an overweight and obese Chinese population. A total of 421 overweight and obese Chinese adults (211 males and 210 females) from The First Affiliated Hospital of Wenzhou Medical University were recruited in this study in 2014. All participants underwent anthropometric measures and phlebotomy after an overnight fast. Elevated ALT, AST and GGT levels were found in 17%, 5% and 24%, respectively. There were significant correlations between ALT and BMI, plasma triglycerides (TG), cholesterol, HDL and glucose, and between AST and plasma TG and cholesterol. GGT also correlated with plasma TG, cholesterol and glucose. The levels of ALT, AST and GGT could be predicted by BMI, plasma TG, cholesterol, HDL and glucose using the back propagation artificial neural network model (BP-ANN). These data suggest that abnormal metabolic markers could be used to monitor liver function to determine whether liver damage has occurred in overweight and obese individuals. This approach has clinical utility with respect to early scanning of liver injury or NAFLD based on routinely available metabolic data in overweight and obese population.

  20. Polydatin Protects Rat Liver against Ethanol-Induced Injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-κB p65 Pathway

    Directory of Open Access Journals (Sweden)

    Qiong-Hui Huang

    2017-01-01

    Full Text Available Excessive alcohol consumption leads to serious liver injury, associating with oxidative stress and inflammatory response. Previous study has demonstrated that polydatin (PD exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage, but the research remained insufficient. Hence, this experiment aimed to evaluate the hepatoprotective effect and potential mechanisms of PD on ethanol-induced hepatotoxicity. Our results showed that PD pretreatment dramatically decreased the levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, and lactate dehydrogenase (LDH in the serum, suppressed the malonaldehyde (MDA and triglyceride (TG content and the production of reactive oxygen species (ROS, and enhanced the activities of superoxide dismutase (SOD, glutathione peroxidase (GSH-Px, catalase (CAT, andalcohol dehydrogenase (ADH, and aldehyde dehydrogenase (ALDH, paralleled by an improvement of histopathology alterations. The protective effect of PD against oxidative stress was probably associated with downregulation of cytochrome P450 2E1 (CYP2E1 and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2 and its target gene haem oxygenase-1 (HO-1. Moreover, PD inhibited the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6 via downregulating toll-like receptor 4 (TLR4 and nuclear factor kappa B (NF-κB p65. To conclude, PD pretreatment protects against ethanol-induced liver injury via suppressing oxidative stress and inflammation.

  1. IgA against gut-derived endotoxins: does it contribute to suppression of hepatic inflammation in alcohol-induced liver disease?

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Schäfer, C.; Bode, C.

    2002-01-01

    , endotoxin, and acute-phase proteins were measured in patients with different stages of alcoholic liver disease and in healthy controls. Antibodies of type IgA, but not IgG, against fecal endotoxins were significantly increased in patients with alcohol-induced liver disease. IgA antibodies against fecal......Endotoxins of intestinal origin are supposed to play an important role in the development of alcoholic hepatitis in man. To estimate the role of immunoglobulin response to gut-derived endotoxin in the development of alcohol-induced liver disease, serum levels of IgA and IgG against fecal endotoxin...... endotoxin were found to be closely correlated with the plasma concentrations of alanine aminotransferase, gamma-glutamyl transferase, and C-reactive protein in patients with alcoholic liver disease. In conclusion, as IgA located in body tissue was shown to suppress the inflammatory process, enhanced...

  2. Does Citrulline Have Protective Effects on Liver Injury in Septic Rats?

    Directory of Open Access Journals (Sweden)

    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.

  3. Exploration of Biomarkers for Amoxicillin/Clavulanate‐Induced Liver Injury: Multi‐Omics Approaches

    Science.gov (United States)

    Lee, J; Ji, SC; Kim, B; Yi, S; Shin, KH; Cho, JY; Lim, KS; Lee, SH; Yoon, SH; Chung, JY; Yu, KS; Park, HS

    2016-01-01

    To explore potential biomarkers for amoxicillin/clavulanate‐induced liver injury (AC‐DILI), we conducted a clinical trial in 32 healthy subjects based on multi‐omics approaches. Every subject was administered amoxicillin/clavulanate for 14 days. The liver‐specific microRNA‐122 (miR‐122) level increased prior to and correlated well with the observed alanine aminotransferase (ALT) level increase. This result indicates its potential as a sensitive early marker for AC‐DILI. We also identified urinary metabolites, such as azelaic acid and 7‐methylxanthine, with levels that significantly differed among the groups classified by ALT elevation level on day 8 after drug administration (P < 0.05). Lymphocyte proliferation in response to the drug was also observed. These findings demonstrate sequential changes in the process of AC‐DILI, including metabolic changes, increased miR‐122 level, increased liver enzyme activity, and enhanced lymphocyte proliferation after drug administration. In conclusion, this study provides potential biomarkers for AC‐DILI based on currently known mechanisms using comprehensive multi‐omics approaches. PMID:27785887

  4. Severe Aplastic Anemia following Acute Hepatitis from Toxic Liver Injury: Literature Review and Case Report of a Successful Outcome

    Directory of Open Access Journals (Sweden)

    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.

  5. 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. Histological findings were consistent with acute hepatitis in all cases (n=10) for which liver biopsy was performed. Twenty-three patients (91.6%) recovered with conservative management, 1 patient (4%) had a liver transplant, and 1 patient (4%) died of hepatic failure. Conclusions In our cases, we found that P. multiflorum Thunb could be hepatotoxic and could lead to severe drug-induced liver injury, and even death. PMID:22195249

  6. Schisandrol B protects against cholestatic liver injury through pregnane X receptors.

    Science.gov (United States)

    Zeng, Hang; Jiang, Yiming; Chen, Pan; Fan, Xiaomei; Li, Dongshun; Liu, Aiming; Ma, Xiaochao; Xie, Wen; Liu, Peiqing; Gonzalez, Frank J; Huang, Min; Bi, Huichang

    2017-04-01

    Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera. Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases. © 2017 The British Pharmacological Society.

  7. Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug-Induced Liver Injury?

    Science.gov (United States)

    Holman, Natalie S; Mosedale, Merrie; Wolf, Kristina K; LeCluyse, Edward L; Watkins, Paul B

    2016-06-01

    Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal. To examine HDE alterations as a function of drug-induced stress, this work utilized prototypical hepatotoxicant acetaminophen (APAP) in male Sprague-Dawley (SD) rats, SD rat hepatocytes, and primary human hepatocytes. HDE were isolated using ExoQuick precipitation reagent and analyzed by quantification of the liver-specific RNAs albumin and microRNA-122 (miR-122). In vivo, significant elevations in circulating exosomal albumin mRNA were observed at subtoxic APAP exposures. Significant increases in exosomal albumin mRNA were also observed in primary rat hepatocytes at subtoxic APAP concentrations. In primary human hepatocytes, APAP elicited increases in both exosomal albumin mRNA and exosomal miR-122 without overt cytotoxicity. However, the number of HDE produced in vitro in response to APAP did not increase with exosomal RNA quantity. We conclude that significant drug-induced alterations in the liver-specific RNA content of HDE occur at subtoxic APAP exposures in vivo and in vitro, and that these changes appear to reflect selective packaging rather than changes in exosome number. The current findings demonstrate that translationally relevant HDE alterations occur in the absence of overt hepatocellular toxicity, and support the hypothesis that HDE released by stressed hepatocytes may mediate early immune responses in DILI. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. Comparison of British Thoracic Society and American Thoracic Society reintroduction guidelines for anti-tuberculous therapy induced liver injury

    International Nuclear Information System (INIS)

    Zuberi, B. F.; Alvi, H.; Zuberi, F. F.; Salahuddin, J.

    2014-01-01

    Objective: To compare the efficacy of British Thoracic Society and American Thoracic Society guidelines for re-introduction of anti-tuberculous therapy after drug-induced liver injury, and to assess the ease of administration of each guideline on a scale of 1-10. Methods: The randomised prospective interventional study was conducted at the Department of Medicine and Pulmonology, Dow University of Health Sciences, Karachi, from December 2011 to November 2013. Patients with anti-tuberculous therapy drug-induced liver injury were selected. Hepatotoxic anti-tuberculous therapy was stopped and modified anti-tuberculous therapy was started. Patients were followed weekly till clinical and biochemical parameters got stabilised. After stabilisation, the patients were randomised to one of the two groups to receive re-introduction of anti-tuberculous therapy under the guidelines of British Thoracic Society (Group I) or those of American Thoracic Society (Group II). Means of the groups were analysed by Student's t test and proportions were compared by chi-square test. Multivariate analysis was done for age, body mass index and serum albumin for recurrence of drug-induced liver injury after the re-introduction. P value <0.05 was taken as significant. Results: Of the total 325 patients, 163(50.15%) were in Group I, while 162(49.84%) were in Group II. The frequency of recurrence of drug-induced liver injury in Group I was 16 (9.8%) and in Group II it was 18 (11.1%). There was no statistically sign