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

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Ivan Ćavar

2011-12-01

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

Role of IRAK-M in alcohol induced liver injury.

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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.

Acetaminophen-induced acute liver injury in HCV transgenic mice

International Nuclear Information System (INIS)

Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

2013-01-01

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.

Acetaminophen-induced acute liver injury in HCV transgenic mice

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

2013-01-15

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

Diphenhydramine as a Cause of Drug-Induced Liver Injury

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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.

Drug-induced liver injuries

African Journals Online (AJOL)

2011-06-02

Jun 2, 2011 ... liver failure in the developed world and a prominent aetiological factor ... most drugs is not known and several epidemiological studies have had major ... eosinophilia, are also pointers towards the cause of the injury and are.

Defining the optimal cut-off values for liver enzymes in diagnosing blunt liver injury.

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Koyama, Tomohide; Hamada, Hirohisa; Nishida, Masamichi; Naess, Paal A; Gaarder, Christine; Sakamoto, Tetsuya

2016-01-25

Patients with blunt trauma to the liver have elevated levels of liver enzymes within a short time post injury, potentially useful in screening patients for computed tomography (CT). This study was performed to define the optimal cut-off values for serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in patients with blunt liver injury diagnosed with contrast enhanced multi detector-row CT (CE-MDCT). All patients admitted from May 2006 to July 2013 to Teikyo University Hospital Trauma and Critical Care Center, and who underwent abdominal CE-MDCT within 3 h after blunt trauma, were retrospectively enrolled. Using receiver operating characteristic (ROC) curve analysis, the optimal cut-off values for AST and ALT were defined, and sensitivity and specificity were calculated. Of a total of 676 blunt trauma patients 64 patients were diagnosed with liver injury (Group LI+) and 612 patients without liver injury (Group LI-). Group LI+ and LI- were comparable for age, Revised Trauma Score, and Probability of survival. The groups differed in Injury Severity Score [median 21 (interquartile range 9-33) vs. 17 (9-26) (p tool for CT scan in patients otherwise eligible for observation only or as a transfer criterion to a facility with CT scan capability.

Assessment of emerging biomarkers of liver injury in human subjects.

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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.

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.

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

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Gregory J Tawa

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

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

Changing Interdigestive Migrating Motor Complex in Rats under Acute Liver Injury

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Mei Liu

2014-01-01

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

Role and mechanisms of autophagy in acetaminophen-induced liver injury.

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Chao, Xiaojuan; Wang, Hua; Jaeschke, Hartmut; Ding, Wen-Xing

2018-04-23

Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[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.

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

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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.

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 ...

Liver Transplantation in the Mouse: Insights Into Liver Immunobiology, Tissue Injury and Allograft Tolerance

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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

Ischemia-reperfusion injury in rat fatty liver: role of nutritional status.

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Caraceni, P; Nardo, B; Domenicali, M; Turi, P; Vici, M; Simoncini, M; De Maria, N; Trevisani, F; Van Thiel, D H; Derenzini, M; Cavallari, A; Bernardi, M

1999-04-01

Fatty livers are more sensitive to the deleterious effects of ischemia-reperfusion than normal livers. Nutritional status greatly modulates this injury in normal livers, but its role in the specific setting of fatty liver is unknown. This study aimed to determine the effect of nutritional status on warm ischemia-reperfusion injury in rat fatty livers. Fed and fasted rats with normal or fatty liver induced by a choline deficient diet underwent 1 hour of lobar ischemia and reperfusion. Rat survival was determined for 7 days. Serum transaminases, liver histology and cell ultrastructure were assessed before and after ischemia, and at 30 minutes, 2 hours, 8 hours, and 24 hours after reperfusion. Survival was also determined in fatty fasted rats supplemented with glucose before surgery. The preischemic hepatic glycogen was measured in all groups. Whereas survival was similar in fasted and fed rats with normal liver (90% vs. 100%), fasting dramatically reduced survival in rats with fatty liver (14% vs. 64%, P nutritional repletion procedure may be part of a treatment strategy aimed to prevent ischemia-reperfusion injury in fatty livers.

Lineage fate of ductular reactions in liver injury and carcinogenesis.

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Jörs, Simone; Jeliazkova, Petia; Ringelhan, Marc; Thalhammer, Julian; Dürl, Stephanie; Ferrer, Jorge; Sander, Maike; Heikenwalder, Mathias; Schmid, Roland M; Siveke, Jens T; Geisler, Fabian

2015-06-01

Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.

Natural history of nonoperative management for grade 4 and 5 liver and spleen injuries in children.

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Yang, Jeannie C; Sharp, Susan W; Ostlie, Daniel J; Holcomb, George W; St Peter, Shawn D

2008-12-01

Nonoperative management is standard treatment of blunt liver or spleen injuries. However, there are few reports outlining the natural history and outcomes of severe blunt hepatic and splenic trauma. Therefore, we reviewed our experience with nonoperative management of grade 4 or 5 liver and spleen injuries. A retrospective analysis was performed on patients with grade 4 or 5 (high-grade) blunt liver and/or spleen injuries from April 1997 to July 2007 at our children's hospital. Demographics, hospital course data, and follow-up data were analyzed. There were 74 high-grade injuries in 72 patients. There were 30 high-grade liver and 44 high-grade spleen injuries. Two patients had both a liver and splenic injury. High-grade liver injuries had a significantly longer length of intensive care and hospital stay compared to high-grade spleen injuries. There were also a significantly higher number of transfusions, radiographs, and total charges in the high-grade liver injuries when compared to the high-grade splenic injuries. The only mortality from solid organ injury was a grade 4 liver injury with portal vein disruption. In contrast, there was only one complication from a high-grade splenic injury-a pleural effusion treated with thoracentesis. There were 5 patients with complications from their liver injury requiring 18 therapeutic procedures. Three patients (10%) with liver injury required readmission as follows: one 5 times, one 3 times, and another one time. Patients with high-grade liver injuries have a longer recovery, more complications, and greater use of resources than in patients with similar injuries to the spleen.

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

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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

Chronic intermittent hypoxia predisposes to liver injury.

Science.gov (United States)

Savransky, Vladimir; Nanayakkara, Ashika; Vivero, Angelica; Li, Jianguo; Bevans, Shannon; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

2007-04-01

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). OSA is associated with nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of obesity. Lean C57BL/6J mice (n = 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n = 15). CIH caused liver injury with an increase in serum ALT (224 +/- 39 U/l versus 118 +/- 22 U/l in the IA group, P fasting serum insulin levels, and mild elevation of fasting serum total cholesterol and triglycerides (TG). Liver TG content was unchanged, whereas cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a malondialdehyde (MDA)/free fatty acids (FFA) ratio of 0.54 +/- 0.07 mmol/mol versus 0.30 +/- 0.01 mmol/mol in control animals (P obesity, CIH leads to mild liver injury via oxidative stress and excessive glycogen accumulation in hepatocytes and sensitizes the liver to a second insult, whereas NASH does not develop.

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

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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.

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.

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.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

International Nuclear Information System (INIS)

Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Energy Technology Data Exchange (ETDEWEB)

Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

2017-01-01

The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

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

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

Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

Science.gov (United States)

Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

2017-12-01

Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Melatonin Protective Effects against Liver Ischemia/Reperfusion Injury

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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.

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...

[Research progress of Chinese herbal medicine and traditional Chinese medicine resulting in liver injury].

Science.gov (United States)

Wang, Jingli; Zhou, Chaofan

2011-12-01

The adverse reactions caused by Chinese herbal medicine and traditional Chinese medicine are reported increased in recent years, among which the acute liver injury caused by Chinese herbal medicine accounts for 21.5% of total liver injuries. Despite the misuse of traditional Chinese medicine not in accordance with differentiation of symptoms and signs, the adverse reaction of Chinese herbal medicine itself can't be little to these adverse events. The paper summarizes the most common categories of traditional Chinese medicine resulting in liver injury, the mechanism, pathological characteristics, clinical symptom of liver injury, the reasons of the reaction and how to prevent. The research aims to enhance the clinical physician recognition of liver injury caused by Chinese herbal medicine, in order to ensure the safe and rational usage of traditional Chinese medicine.

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...... that the detrimental cholestatic liver injury, later characteristic of BA, only begins from the time of birth despite a prenatal occlusive biliary pathology. It may be that tissue injury only occurs with the onset of the perinatal bile surge initiating periductal bile leakage and the triggering of an inflammatory...

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

Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

Science.gov (United States)

Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

2018-05-11

Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

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

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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.

Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports.

Science.gov (United States)

Anno, Takatoshi; Kaneto, Hideaki; Shigemoto, Ryo; Kawasaki, Fumiko; Kawai, Yasuhiro; Urata, Noriyo; Kawamoto, Hirofumi; Kaku, Kohei; Okimoto, Niro

2018-01-01

Hypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non-diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores. It is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia.Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in everyday clinical practice.Herein, we reported similar 2 cases of hypoinsulinemic hypoglycemia without diabetes presumably triggered

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

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

Energy Technology Data Exchange (ETDEWEB)

Geest, Rick van der, E-mail: r.van.der.geest@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Ouweneel, Amber B., E-mail: a.b.ouweneel@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Sluis, Ronald J. van der, E-mail: r.vandersluis@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Groen, Albert K., E-mail: a.k.groen@umcg.nl [University Medical Center Groningen (Netherlands); Van Eck, Miranda, E-mail: m.eck@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands); Hoekstra, Menno, E-mail: hoekstra@lacdr.leidenuniv.nl [Leiden Academic Centre for Drug Research (Netherlands)

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 ± 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

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

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Reza Heidari

2015-03-01

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

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

Science.gov (United States)

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

2010-01-01

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

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

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Bala Miklosh

2012-03-01

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

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

Science.gov (United States)

Bala, Miklosh; Gazalla, Samir Abu; Faroja, Mohammad; Bloom, Allan I; Zamir, Gideon; Rivkind, Avraham I; Almogy, Gidon

2012-03-23

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

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.

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

Multilevel evaluations of potential liver injury of bifenthrin.

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Zhang, Ying; Lu, Meiya; Zhou, Peixue; Wang, Cui; Zhang, Quan; Zhao, Meirong

2015-07-01

The widespread use of pesticides, such as pyrethroids, increases health risks to non-target organisms. The potential toxicity of pyrethroids to the liver remains unclear and could be easily overlooked if only the common clinical indicators of liver disease are examined. In the present study, BALB/c mice were given intraperitoneal injections of 0, 2, 4, or 8 mg/kg bifenthrin (BF) for 7 days. The potential liver injury of BF and its underlying mechanism were then investigated through multilevel evaluations. Histological analyses and serum enzyme activities showed no obvious clinical evidence of liver damage. Oxidative stress was induced and caspases were activated in response to increased BF concentrations. Exposure to BF also significantly altered the expression levels of mitochondrial apoptosis-related genes in dose-dependent relationships. The microarray results showed that BF could disturb the metabolic profile and extensively induce genes related to oxidative stress, including the cytochrome P450 family, glutathione peroxidases, glutathione s-transferases and kinases. In the in vivo model, BF induced liver injury through caspase-mediated mitochondrial-dependent cell death, a process that is closely related to oxidative stress, even in the absence of classical clinical biomarkers of liver dysfunction. The results of this study suggest that classical evaluations are not adequate for liver toxicity of pyrethroids, and highlight the need for more comprehensive assessment of health risks of these widely used pesticides. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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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.

Drug-induced liver injury associated with HIV medications.

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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.

Hepatoprotective effect of kaempferol against alcoholic liver injury in mice.

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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.

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

OpenAIRE

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

2017-01-01

Background 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...

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

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

2017-01-01

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

Saccharomyces boulardii Administration Changes Gut Microbiota and Attenuates D-Galactosamine-Induced Liver Injury

OpenAIRE

Yu, Lei; Zhao, Xue-ke; Cheng, Ming-liang; Yang, Guo-zhen; Wang, Bi; Liu, Hua-juan; Hu, Ya-xin; Zhu, Li-li; Zhang, Shuai; Xiao, Zi-wen; Liu, Yong-mei; Zhang, Bao-fang; Mu, Mao

2017-01-01

Growing evidence has shown that gut microbiome is a key factor involved in liver health. Therefore, gut microbiota modulation with probiotic bacteria, such as Saccharomyces boulardii, constitutes a promising therapy for hepatosis. In this study, we aimed to investigate the protective effects of S. boulardii on D-Galactosamine-induced liver injury in mice. Liver function test and histopathological analysis both suggested that the liver injury can be effectively attenuated by S. boulardii admin...

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

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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.

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.

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

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

2016-07-01

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

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

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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.

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

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

2013-11-01

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

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

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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.

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

DEFF Research Database (Denmark)

Østerballe, Lene; Helgstrand, Frederik; Axelsen, Thomas

2014-01-01

INTRODUCTION: Hepatic pseudoaneurysm (HPA) is a rare complication after liver trauma, yet it is potentially fatal, as it can lead to sudden severe haemorrhage. The risk of developing posttraumatic HPA is one of the arguments for performing follow-up CT of patients with liver injuries. The aim...... no treatment failures. There was no correlation between the severity of the liver injury and development of HPA. 5 out of 7 patients were asymptomatic and would have been discharged without treatment if the protocol did not include a default follow-up CT. CONCLUSIONS: In conclusion, this study shows that HPA...

The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury.

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Joshi, Nikita; Kopec, Anna K; Towery, Keara; Williams, Kurt J; Luyendyk, James P

2014-06-01

Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant α-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1(-/-) mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

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, R.|info:eu-repo/dai/nl/155644033; 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

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

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.

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

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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

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.

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.

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

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Peter Onody

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

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

Liver segment IV hypoplasia as a risk factor for bile duct injury.

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Mercado, Miguel Angel; Franssen, Bernardo; Arriola, Juan Carlos; Garcia-Badiola, Artemio; Arámburo, Rigoberto; Elnecavé, Alejandro; Cortés-González, Rubén

2011-09-01

Bile duct injury remains constant in the era of laparoscopic cholecystectomy and misidentification of structures remains one of the most common causes of such injuries. Abnormalities in liver segment IV, which is fully visible during laparoscopic cholecystectomy, may contribute to misidentification as proposed herein. We describe the case of a 36-year-old female who had a bile duct injury during a laparoscopic cholecystectomy where the surgeon noticed an unusually small distance between the gallbladder and the round ligament. We define hypoplasia of liver segment IV as well as describe the variation of the biliary anatomy in the case. We also intend to fit it in a broader spectrum of developmental anomalies that have both hyopoplasia of some portion of the liver and variations in gallbladder and bile duct anatomy that may contribute to bile duct injury. To our knowledge, hypoplasia of liver segment IV has not been suggested in the literature as a risk factor for bile duct injury except in the extreme case of a left-sided gallbladder. Surgeons should be vigilant during laparoscopic cholecystectomy when they become aware of an unusually small distance between the gallbladder bed and the round ligament prior to beginning their dissection, variations in the common bile duct and cystic duct should be expected.

Amiodarone-Induced Liver Injury and Cirrhosis.

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Buggey, Jonathan; Kappus, Matthew; Lagoo, Anand S; Brady, Carla W

2015-01-01

We present a case report of an 80-year-old woman with volume overload thought initially to be secondary to heart failure, but determined to be amiodarone-induced acute and chronic liver injury leading to submassive necrosis and bridging fibrosis consistent with early cirrhosis. Her histopathology was uniquely absent of steatosis and phospholipidosis, which are commonly seen in AIC.

The protective effect of Nigella sativa against liver injury: a review.

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Mollazadeh, Hamid; Hosseinzadeh, Hossein

2014-12-01

Nigella sativa (Family Ranunculaceae) is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS) and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.

Risk factors for central bile duct injury complicating partial liver resection

NARCIS (Netherlands)

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

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

Eosin fluorescence: A diagnostic tool for quantification of liver injury.

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Ali, Hamid; Ali, Safdar; Mazhar, Maryam; Ali, Amjad; Jahan, Azra; Ali, Abid

2017-09-01

Hepatitis is one of the most common life threatening diseases. The diagnosis is mainly based on biochemical analysis such as liver function test. However, histopathological evaluation of liver serves far better for more accurate final diagnosis. The goal of our study was to evaluate the eosin fluorescence pattern in CCl 4 -induced liver injury model compared with normal and different treatment groups. For this purpose, liver tissues were stained with H/E and examined under bright field microscope but the fluorescence microscopy of H/E stained slides provided an interesting fluorescence pattern and was quite helpful in identifying different structures. Interesting fluorescence patterns were obtained with FITC, Texas Red and Dual channel filter cubes that were quite helpful in identifying different morphological features of the liver. During the course of hepatic injury, liver cells undergo necrosis, apoptosis and overall cellular microenvironment is altered due to the modification of proteins and other intracellular molecules. Intensified eosin fluorescence was observed around the central vein of injured liver compared to normal indicating enhanced binding of eosin to the more exposed amino acid residues. To conclude, eosin fluorescence pattern varies with the health status of a tissue and can be used further for the diagnosis and quantification of severity of various liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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Xinzhi eWang

2016-04-01

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

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

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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.

Intralipid minimizes hepatocytes injury after anoxia-reoxygenation in an ex vivo rat liver model.

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Stadler, Michaela; Nuyens, Vincent; Boogaerts, Jean G

2007-01-01

Ischemia-reperfusion injury is a determinant in liver injury occurring during surgical procedures, ischemic states, and multiple organ failure. The pre-existing nutritional status of the liver, i.e., fasting, might contribute to the extent of tissue injury. This study investigated whether Intralipid, a solution containing soybean oil, egg phospholipids, and glycerol, could protect ex vivo perfused livers of fasting rats from anoxia-reoxygenation injury. The portal vein was cannulated, and the liver was removed and perfused in a closed ex vivo system. Isolated livers were perfused with glucose 5.5 and 15 mM, and two different concentrations of Intralipid, i.e., 0.5:100 and 1:100 (v/v) Intralipid 10%:medium (n = 5 in each group). The experiment consisted of perfusion for 15 min, warm anoxia for 60 min, and reoxygenation during 60 min. Hepatic enzymes, potassium, glucose, lactate, bilirubin, dienes, trienes, and cytochrome-c were analyzed in perfusate samples. The proportion of glycogen in hepatocytes was determined in biopsies. Intralipid attenuated transaminases, lactate dehydrogenase, potassium, diene, and triene release in the perfusate (dose-dependant) during the reoxygenation phase when compared with glucose-treated groups. The concentration of cytochrome-c in the medium was the highest in the 5.5-mM glucose group. The glycogen content was low in all livers at the start of the experiment. Intralipid presents, under the present experimental conditions, a better protective effect than glucose in anoxia-reoxygenation injury of the rat liver.

Remote ischemic preconditioning protects liver ischemia-reperfusion injury by regulating eNOS-NO pathway and liver microRNA expressions in fatty liver rats.

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Duan, Yun-Fei; An, Yong; Zhu, Feng; Jiang, Yong

2017-08-15

Ischemic preconditioning (IPC) is a strategy to reduce ischemia-reperfusion (I/R) injury. The protective effect of remote ischemic preconditioning (RIPC) on liver I/R injury is not clear. This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathway and microRNA expressions in this process. A total of 32 fatty rats were randomly divided into the sham group, I/R group, RIPC group and RIPC+I/R group. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and nitric oxide (NO) were measured. Hematoxylin-eosin staining was used to observe histological changes of liver tissues, TUNEL to detect hepatocyte apoptosis, and immunohistochemistry assay to detect heat shock protein 70 (HSP70) expression. Western blotting was used to detect liver inducible NOS (iNOS) and eNOS protein levels and real-time quantitative polymerase chain reaction to detect miR-34a, miR-122 and miR-27b expressions. Compared with the sham and RIPC groups, serum ALT, AST and iNOS in liver tissue were significantly higher in other two groups, while serum NO and eNOS in liver tissue were lower, and varying degrees of edema, degeneration and inflammatory cell infiltration were found. Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group. Compared with the sham group, HSP70 expressions were significantly increased in other three groups (all Pfatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions. Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.

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).

Study on bone marrow mesenchymal stem cells in repairing of radiation induced acute liver injury of rats

International Nuclear Information System (INIS)

Bao Yongxing; Lou Fan; Zhao Huarong; Zhu Huhu; Ma Yan; Wen Hao

2010-01-01

Objective: To investigate the role of mesenchymal stem cells in the repair of radiation induced liver injury. Methods: 12 female SD rats were irradiated with 20 Gy 6 MV X-rays on the right lobe of the liver, to establish the model of radiation induced liver injury. The rats were divided randomly into two groups as invention group and control group, and transplanted with 1 ml male mesenchymal suspension or 1 ml normal saline in 4 hours after radiotherapy. The morphological changes of liver were observed. The existence of sex determining gene Y(SRY) and the level of alpha-smooth muscle actin (a-SMA) were detected. Results: Some injury of right lobe liver in two groups were observed, and the injury degree of right lobe liver in intervention group were lower than that of control group. The amount of SRY positive cells in the right lobe liver of intervention group was higher than that in the left lobe liver (t = 3.77, P <0.05). The positive expression rate of a-SMA in right lobe liver of intervention group was lower than that of control group. Conclusions: Acute radiation induced liver injury could lead BMSCs' homing in order to decrease the degree of liver fibrosis. (authors)

Effects of defibrotide, a novel oligodeoxyribonucleotide, on ischaemia and reperfusion injury of the rat liver.

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Kim, Kwang Joon; Shin, Yong Kyoo; Song, Jin Ho; Oh, Byung Kwon; Choi, Myung Sup; Sohn, Uy Dong

2002-02-01

1. The purpose of this study was to investigate the protective effects of defibrotide, a single-stranded polydeoxyribonucleotide, on ischaemia-reperfusion injury to the liver using a rat model. 2. Ischaemia of the left and median lobes was created by total inflow occlusion for 30 min followed by 60 min of reperfusion. Hepatic injury was assessed by the release of liver enzymes (alanine transferase, ALT and lactic dehydrogenase, LDH). Hepatic oxidant stress was measured by superoxide production, lipid peroxidation and nitrite/nitrate formation. Leukocyte-endothelium interaction and Kupffer cell mobilization were quantified by measuring hepatic myeloperoxidase (MPO), polymorphonuclear leukocyte adherence to superior mesenteric artery (SMA) and immunostaining of Kupffer cell. 3. Defibrotide treatment resulted in a significant inhibition of postreperfusion superoxide generation, lipid peroxidation, serum ALT activity, serum LDH activity, MPO activity, serum nitrite/nitrate level, leukocyte adherence to SMA, and Kupffer cell mobilization, indicating a significant attenuation of hepatic dysfunction. 4. A significant correlation existed between liver ischaemia/reperfusion and hepatic injury, suggesting that liver ischaemia/reperfusion injury is mediated predominantly by generation of oxygen free radicals and mobilization of Kupffer cells. 5. We conclude that defibrotide significantly protects the liver against liver ischaemia/reperfusion injury by interfering with Kupffer cell mobilization and formation of oxygen free radicals. This study provides strong evidence that defibrotide has important beneficial effects on acute inflammatory tissue injury such as that occurring in the reperfusion of the ischaemic liver.

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

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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

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.

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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Z.G. Zhao

2014-02-01

Full Text Available The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL on lipopolysaccharide (LPS-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1, myeloperoxidase (MPO, and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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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.

Effect of WeiJia on carbon tetrachloride induced chronic liver injury

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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

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

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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.

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

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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

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

Extracellular Vesicles from Human Liver Stem Cells Reduce Injury in an Ex Vivo Normothermic Hypoxic Rat Liver Perfusion Model.

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Rigo, Federica; De Stefano, Nicola; Navarro-Tableros, Victor; David, Ezio; Rizza, Giorgia; Catalano, Giorgia; Gilbo, Nicholas; Maione, Francesca; Gonella, Federica; Roggio, Dorotea; Martini, Silvia; Patrono, Damiano; Salizzoni, Mauro; Camussi, Giovanni; Romagnoli, Renato

2018-05-01

The gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV). We established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused for 4 hours without (control group, n = 10) or with HLSC-EV (treated group, n = 9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, alanine aminotransferase, lactate dehydrogenase). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, tissue hypoxia-inducible factor 1-α, and transforming growth factor-beta 1 RNA expression by quantitative reverse transcription-polymerase chain reaction. During hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (P = 0.018) and lactate dehydrogenase (P = 0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (P = 0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes, and EV treatment significantly reduced histological damage (P = 0.030), apoptosis (P = 0.049), and RNA overexpression of hypoxia-inducible factor 1-α (P < 0.0001) and transforming growth factor-beta 1 (P = 0.014). HLSC-EV treatment, even in a short-duration model, was feasible and effectively reduced liver injury during hypoxic NMP.

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.

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Gehrke, Nadine; Nagel, Michael; Straub, Beate K; Wörns, Marcus A; Schuchmann, Marcus; Galle, Peter R; Schattenberg, Jörn M

2018-03-01

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP -/- ) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68 + macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP -/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP -/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological

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

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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.

Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports

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Takatoshi Anno

2018-03-01

Full Text Available Hypoglycemia is induced by many causes, especially over-dose of insulin or oral hypoglycemic agents in diabetic subjects. In such a case, hyperinsulinemic hypoglycemia is usually observed. On the other hand, it is important to classify secondary hypoglycemia and hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia but rarely observed in clinical practice. Herein, we experienced similar 2 cases of non-diabetic hypoinsulinemic hypoglycemia. Both of them were elderly subjects with low body weight. Furthermore, it is likely that hypoinsulinemic hypoglycemia in both subjects was triggered by severe liver injury, at least in part, due to possible limited liver glycogen store. In elderly subjects with low body weight and/or malnutrition, metabolism in the liver is reduced and glycogen accumulation is decreased. Such alteration brings out acute and marked liver injury, which finally leads to the onset of severe hypoglycemia. It is known that not only liver injury but also multiple organ failure could be induced due to extreme emaciation in subjects. It is likely that in elderly subjects with low body weight and/or malnutrition, multiple organ failure including liver failure could be induced due to the similar reason. Therefore, we should be very careful of such subjects in order to avoid the development of multiple organ failure which leads to life-threatening situations. In conclusion, we should keep in mind the possibility of hypoinsulinemic hypoglycemia when we examine severe liver injury, especially in elderly or starving subjects with low body weight and limited liver glycogen stores.

The protective effect of Nigella sativa against liver injury: a review

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Hamid Mollazadeh

2015-12-01

Full Text Available Nigella sativa (Family Ranunculaceae is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.

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.

2012-01-01

. 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

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

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines.

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Zong, L; Yu, Q H; Du, Y X; Deng, X M

2014-02-01

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

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Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q. H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y. X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X. M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

2014-03-03

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

International Nuclear Information System (INIS)

Zong, L.; Yu, Q.H.; Du, Y.X.; Deng, X.M.

2014-01-01

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis

Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis.

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McGreal, Steven R; Bhushan, Bharat; Walesky, Chad; McGill, Mitchell R; Lebofsky, Margitta; Kandel, Sylvie E; Winefield, Robert D; Jaeschke, Hartmut; Zachara, Natasha E; Zhang, Zhen; Tan, Ee Phie; Slawson, Chad; Apte, Udayan

2018-04-01

Overdose of acetaminophen (APAP) results in acute liver failure. We have investigated the role of a posttranslational modification of proteins called O-GlcNAcylation, where the O-GlcNAc transferase (OGT) adds and O-GlcNAcase (OGA) removes a single β-D-N-acetylglucosamine (O-GlcNAc) moiety, in the pathogenesis of APAP-induced liver injury. Hepatocyte-specific OGT knockout mice (OGT KO), which have reduced O-GlcNAcylation, and wild-type (WT) controls were treated with 300 mg/kg APAP and the development of injury was studied over a time course from 0 to 24 h. OGT KO mice developed significantly lower liver injury as compared with WT mice. Hepatic CYP2E1 activity and glutathione (GSH) depletion following APAP treatment were not different between WT and OGT KO mice. However, replenishment of GSH and induction of GSH biosynthesis genes were significantly faster in the OGT KO mice. Next, male C57BL/6 J mice were treated Thiamet-G (TMG), a specific inhibitor of OGA to induce O-GlcNAcylation, 1.5 h after APAP administration and the development of liver injury was studied over a time course of 0-24 h. TMG-treated mice exhibited significantly higher APAP-induced liver injury. Treatment with TMG did not affect hepatic CYP2E1 levels, GSH depletion, APAP-protein adducts, and APAP-induced mitochondrial damage. However, GSH replenishment and GSH biosynthesis genes were lower in TMG-treated mice after APAP overdose. Taken together, these data indicate that induction in cellular O-GlcNAcylation exacerbates APAP-induced liver injury via dysregulation of hepatic GSH replenishment response.

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.

Acute alcohol-induced liver injury

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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.

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

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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.

Hypothermic oxygenated machine perfusion reduces bile duct reperfusion injury after transplantation of donation after circulatory death livers

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van Rijn, Rianne; van Leeuwen, Otto B.; Matton, Alix P. M.; Burlage, Laura C.; Wiersema‐Buist, Janneke; van den Heuvel, Marius C.; de Kleine, Ruben H. J.; de Boer, Marieke T.; Gouw, Annette S. H.

2018-01-01

Dual hypothermic oxygenated machine perfusion (DHOPE) of the liver has been advocated as a method to reduce ischemia/reperfusion injury (IRI). This study aimed to determine whether DHOPE reduces IRI of the bile ducts in donation after circulatory death (DCD) liver transplantation. In a recently performed phase 1 trial, 10 DCD livers were preserved with DHOPE after static cold storage (SCS; http://www.trialregister.nl NTR4493). Bile duct biopsies were obtained at the end of SCS (before DHOPE; baseline) and after graft reperfusion in the recipient. Histological severity of biliary injury was graded according to an established semiquantitative grading system. Twenty liver transplantations using DCD livers not preserved with DHOPE served as controls. Baseline characteristics and the degree of bile duct injury at baseline (end of SCS) were similar between both groups. In controls, the degree of stroma necrosis (P = 0.002) and injury of the deep peribiliary glands (PBG; P = 0.02) increased after reperfusion compared with baseline. In contrast, in DHOPE‐preserved livers, the degree of bile duct injury did not increase after reperfusion. Moreover, there was less injury of deep PBG (P = 0.04) after reperfusion in the DHOPE group compared with controls. In conclusion, this study suggests that DHOPE reduces IRI of bile ducts after DCD liver transplantation. Liver Transplantation 24 655–664 2018 AASLD. PMID:29369470

The safety of low molecular-weight heparin after blunt liver and spleen injuries.

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Rostas, Jack W; Manley, Justin; Gonzalez, Richard P; Brevard, Sidney B; Ahmed, Naveed; Frotan, Mohammad Amin; Mitchell, Ellen; Simmons, Jon D

2015-07-01

Anticoagulation is routinely administered to all trauma patients owing to the high incidence of venous thromboembolism (VTE). However, the timing of administration of anticoagulation is not clearly defined when patients have blunt spleen or liver injuries because of the perceived risk of hemorrhage with early administration. A retrospective chart review was performed of all blunt trauma patients who sustained blunt liver and/or spleen injuries during the 5-year period from 2007 to 2011. Data were collected for all patients managed with nonoperative therapy for these injuries while also receiving routine prophylactic anticoagulation with low molecular-weight heparin. Patients were categorized based on the initiation of enoxaparin therapy after injury: early (72 hours). Primary and secondary outcomes were designated as need for operative or radiologic intervention secondary to spleen or liver hemorrhage, number of transfusions, and incidence of VTE. Three hundred and twenty-eight patients were included. There were no enoxaparin-related hemorrhagic complications or hemorrhage necessitating operative intervention. Patients in the early, intermediate, and late groups received an average of .9, .93, and 1.55 units of blood, respectively. There was 1 pulmonary embolism in the early group, and there were 6 VTE complications in the late group (3 deep venous thromboses and 3 pulmonary embolisms). There are currently no standards for the initiation of prophylactic anticoagulation in trauma patients with blunt liver and spleen injuries. Early administration may be safe and reduce the incidence of thrombotic complications in patients with blunt spleen and liver injuries. Prospective studies in this area are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

Surgical intervention for paediatric liver injuries is almost history - a 12-year cohort from a major Scandinavian trauma centre.

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Koyama, Tomohide; Skattum, Jorunn; Engelsen, Peder; Eken, Torsten; Gaarder, Christine; Naess, Pål Aksel

2016-11-29

Although nonoperative management (NOM) has become standard care, optimal treatment of liver injuries in children is still challenging since many of these patients have multiple injuries. Moreover, the role of angiography remains poorly defined, and a high index of suspicion of complications is warranted. This study reviews treatment and outcomes in children with liver injuries at a major Scandinavian trauma centre over a 12-year period. Patients trauma registry and medical records. A total of 66 children were included. The majority was severely injured as reflected by a median injury severity score of 20.5 (mean 22.2). NOM was attempted in 60 (90.9%) patients and was successful in 57, resulting in a NOM success rate of 95.0% [95% CI 89.3 to 100]. Only one of the three NOM failures was liver related, occurred in the early part of the study period, and consisted in operative placement of drains for bile leak. Two (3.0%) patients underwent angiographic embolization (AE). Complications occurred in 18 (27.3% [95 % CI 16.2 to 38.3]) patients. Only 2 (3.0%) patients had liver related complications, in both cases bile leak. Six (9.1%) patients underwent therapeutic laparotomy for non-liver related injuries. Two (3.0%) patients died secondary to traumatic brain injury. This single institution paediatric liver injury cohort confirms high attempted NOM and NOM success rates even in patients with high grade injuries and multiple accompanying injuries. AE can be a useful NOM adjunct in the treatment of paediatric liver injuries, but is seldom indicated. Moreover, bile leak is the most common liver-related complication and the need for liver-related surgery is very infrequent. NOM is the treatment of choice in almost all liver injuries in children, with operative management and interventional radiology very infrequently indicated.

Chronic liver injury in mice promotes impairment of skin barrier function via tumor necrosis factor-alpha.

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Yokoyama, Satoshi; Hiramoto, Keiichi; Koyama, Mayu; Ooi, Kazuya

2016-09-01

Alcohol is frequently used to induce chronic liver injury in laboratory animals. Alcohol causes oxidative stress in the liver and increases the expression of inflammatory mediators that cause hepatocellular damage. However, during chronic liver injury, it is unclear if/how these liver-derived factors affect distal tissues, such as the skin. The purpose of this study was to evaluate skin barrier function during chronic liver injury. Hairless mice were administered 5% or 10% ethanol for 8 weeks, and damages to the liver and skin were assessed using histological and protein-analysis methods, as well as by detecting inflammatory mediators in the plasma. After alcohol administration, the plasma concentration of the aspartate and alanine aminotransferases increased, while albumin levels decreased. In mice with alcohol-induced liver injury, transepidermal water loss was significantly increased, and skin hydration decreased concurrent with ceramide and type I collagen degradation. The plasma concentrations of [Formula: see text]/[Formula: see text] and tumor necrosis factor-alpha (TNF-α) were significantly increased in mice with induced liver injury. TNF receptor (TNFR) 2 expression was upregulated in the skin of alcohol-administered mice, while TNFR1 levels remained constant. Interestingly, the impairment of skin barrier function in mice administered with 10% ethanol was ameliorated by administering an anti-TNF-α antibody. We propose a novel mechanism whereby plasma TNF-α, via TNFR2 alone or with TNFR1, plays an important role in skin barrier function during chronic liver disease in these mouse models.

Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen

International Nuclear Information System (INIS)

Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

2017-01-01

Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA −/− ). We found that MsrA −/− mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA +/+ ). The central lobule area of the MsrA −/− liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA −/− than in MsrA +/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA −/− than in MsrA +/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA −/− than in MsrA +/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. - Highlights: • MsrA deficiency increases APAP-induced liver damage. • MsrA deletion enhances APAP-induced hepatic GSH depletion and oxidative stress. • MsrA deficiency induces more profound activation of Nrf2 in response to APAP. • MsrA protects the liver from APAP-induced toxicity.

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

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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.

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

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

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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.

Elemental characterization of injuries in fish liver

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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.

Elemental characterization of injuries in fish liver

International Nuclear Information System (INIS)

Stori, E.M.; Rocha, M.L.C.F.; Dias, J.F.; Santos, C.E.I. dos; Souza, C.T. de; Amaral, L; Dias, J.F.

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

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

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

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L. Zong

2014-03-01

Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Acute liver injury associated with a newer formulation of the herbal weight loss supplement Hydroxycut.

Science.gov (United States)

Araujo, James L; Worman, Howard J

2015-05-06

Despite the widespread use of herbal and dietary supplements (HDS), serious cases of hepatotoxicity have been reported. The popular herbal weight loss supplement, Hydroxycut, has previously been implicated in acute liver injury. Since its introduction, Hydroxycut has undergone successive transformations in its formulation; yet, cases of liver injury have remained an ongoing problem. We report a case of a 41-year-old Hispanic man who developed acute hepatocellular liver injury with associated nausea, vomiting, jaundice, fatigue and asterixis attributed to the use of a newer formulation of Hydroxycut, SX-7 Clean Sensory. The patient required hospitalisation and improved with supportive therapy. Despite successive transformations in its formulation, potential liver injury appears to remain an ongoing problem with Hydroxycut. Our case illustrates the importance of obtaining a thorough medication history, including HDS, regardless of new or reformulated product marketing efforts. 2015 BMJ Publishing Group Ltd.

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

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

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Sayed M. Mizar

2015-03-01

Full Text Available Oxidative stress plays a key role in the pathogenesis of hepatic ischemia/reperfusion (I/R-induced injury, one of the leading causes of liver damage post-surgical intervention, trauma and transplantation. This study aimed to evaluate the protective effect of nebivolol and chrysin against I/R-induced liver injury via their vasodilator and antioxidant effects, respectively. Adult male Wister rats received nebivolol (5 mg/kg and/or chrysin (25 mg/kg by oral gavage daily for one week then subjected to ischemia via clamping the portal triad for 30 min then reperfusion for 30 min. Liver function enzymes, alanine transaminase (ALT and aspartate transaminase (AST, as well as hepatic Myeloperoxidase (MPO, total nitrate (NOx, glutathione (GSH and liver malondialdehyde (MDA were measured at the end of the experiment. Liver tissue damage was examined by histopathology. In addition, the expression levels of nitric oxide synthase (NOS subtypes, endothelial (eNOS and inducible (iNOS in liver samples were assessed by Western blotting and confirmed by immunohistochemical analysis. Both chrysin and nebivolol significantly counteracted I/R-induced oxidative stress and tissue damage biomarkers. The combination of these agents caused additive liver protective effect against I/R-induced damage via the up regulation of nitric oxide expression and the suppression of oxidative stress. Chrysin and nebivolol combination showed a promising protective effect against I/R-induced liver injury, at least in part, via decreasing oxidative stress and increasing nitric oxide levels.

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.

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

International Nuclear Information System (INIS)

Uematsu, Yasuaki; Akai, Sho; Tochitani, Tomoaki; Oda, Shingo; Yamada, Toru; Yokoi, Tsuyoshi

2016-01-01

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

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Uematsu, Yasuaki, E-mail: yasuaki-uematsu@ds-pharma.co.jp [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Akai, Sho [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Tochitani, Tomoaki [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Oda, Shingo [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Yamada, Toru [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Yokoi, Tsuyoshi [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

2016-09-15

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

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.

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

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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.

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.

Variation of Traditional Biomarkers of Liver Injury After an Ultramarathon at Altitude.

Science.gov (United States)

Tirabassi, Jill N; Olewinski, Lucianne; Khodaee, Morteza

2018-03-01

Significant elevations of traditional biomarkers of liver injury can occur as a result of running an ultramarathon. Traditional serum biomarker levels of liver injury will significantly increase as the result of participating in this 161-km race at altitude. Prospective cross-sectional study. Level 3. A total of 64 (before) and 83 (after) volunteer runners participated in a prospective observational field-based study at the Leadville 100 ultramarathon race. Changes in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine kinase (CK), and bilirubin levels were measured. Of 669 athletes who started the race, 352 successfully completed the race within the 30-hour cutoff (53%). Of 36 runners who had pre- and postrace blood samples taken, the mean ALT, AST, and bilirubin levels were increased from 23 ± 10 U/L, 23 ± 5 U/L, and 0.60 ± 0.29 mg/dL to 117 ± 106 U/L, 485 ± 500 U/L, and 1.60 ± 0.61 mg/dL, respectively (all P athletes' age, sex, body mass index, or finishing time. Significant positive linear correlations between AST, ALT, and LDH with CK were seen. Athletes in this study did not seek medical attention after the race based on an electronic survey (92% response rate). Significant elevations of traditional biomarkers of liver injury occurred as a result of running an ultramarathon at altitude. These correlated with CK, a marker of muscle injury. When reviewing laboratory studies of traditional biomarkers of liver injury in athletes after an ultramarathon, significant elevations may be seen from baseline but are likely to be of no clinical consequence.

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.

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver.

Science.gov (United States)

Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko

2011-11-01

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.

Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice.

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Iracheta-Vellve, Arvin; Petrasek, Jan; Gyogyosi, Benedek; Bala, Shashi; Csak, Timea; Kodys, Karen; Szabo, Gyongyi

2017-07-01

Inflammation and impaired hepatocyte regeneration contribute to liver failure in alcoholic hepatitis (AH). Interleukin (IL)-1 is a key inflammatory cytokine in the pathobiology of AH. The role of IL-1 in liver regeneration in the recovery phase of alcohol-induced liver injury is unknown. In this study, we tested IL-1 receptor antagonist to block IL-1 signalling in a mouse model of acute-on-chronic liver injury on liver inflammation and hepatocyte regeneration in AH. We observed that inhibition of IL-1 signalling decreased liver inflammation and neutrophil infiltration, and resulted in enhanced regeneration of hepatocytes and increased rate of recovery from liver injury in AH. Our novel findings suggest that IL-1 drives sustained liver inflammation and impaired hepatocyte regeneration even after cessation of ethanol exposure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hepatic injury after whole-liver irradiation in the rat

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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

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

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Ferdinando A. Giannone

2012-01-01

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

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.

Dendritic cells regulate angiogenesis associated with liver fibrogenesis.

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Blois, Sandra M; Piccioni, Flavia; Freitag, Nancy; Tirado-González, Irene; Moschansky, Petra; Lloyd, Rodrigo; Hensel-Wiegel, Karin; Rose, Matthias; Garcia, Mariana G; Alaniz, Laura D; Mazzolini, Guillermo

2014-01-01

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

Saccharomyces boulardii Administration Changes Gut Microbiota and Attenuates D-Galactosamine-Induced Liver Injury.

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Yu, Lei; Zhao, Xue-Ke; Cheng, Ming-Liang; Yang, Guo-Zhen; Wang, Bi; Liu, Hua-Juan; Hu, Ya-Xin; Zhu, Li-Li; Zhang, Shuai; Xiao, Zi-Wen; Liu, Yong-Mei; Zhang, Bao-Fang; Mu, Mao

2017-05-02

Growing evidence has shown that gut microbiome is a key factor involved in liver health. Therefore, gut microbiota modulation with probiotic bacteria, such as Saccharomyces boulardii, constitutes a promising therapy for hepatosis. In this study, we aimed to investigate the protective effects of S. boulardii on D-Galactosamine-induced liver injury in mice. Liver function test and histopathological analysis both suggested that the liver injury can be effectively attenuated by S. boulardii administration. In the meantime, S. boulardii induced dramatic changes in the gut microbial composition. At the phylum level, we found that S. boulardii significantly increased in the relative abundance of Bacteroidetes, and decreased the relative abundance of Firmicutes and Proteobacteria, which may explain the hepatic protective effects of S. boulardii. Taken together, our results demonstrated that S. boulardii administration could change the gut microbiota in mice and alleviate acute liver failure, indicating a potential protective and therapeutic role of S. boulardii.

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

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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.

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

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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)

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

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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

Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines

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Takahashi, Koji; Kanda, Tatsuo; Yasui, Shin; Haga, Yuki; Kumagai, Junichiro; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Nakamura, Masato; Arai, Makoto; Yokosuka, Osamu

2016-01-01

A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID:28100990

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

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Anders, Lisanne C [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Yeo, Heegook; Kaelin, Brenna R; Lang, Anna L; Bushau, Adrienne M; Douglas, Amanda N [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Cave, Matt [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); Arteel, Gavin E [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); McClain, Craig J [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Hepatobiology and Toxicology Program, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Diabetes and Obesity Center, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Robley Rex Louisville VAMC, Louisville, KY 40206 (United States); and others

2016-11-15

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

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

Protection of Liver as a Remote Organ after Renal Ischemia-Reperfusion Injury by Renal Ischemic Postconditioning

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Behjat Seifi

2014-01-01

Full Text Available This study was designed to investigate the protective effects of local renal ischemic postconditioning (POC on liver damage after renal ischemia-reperfusion (IR injury. Male rats were divided into three groups  (n=8. They underwent a right nephrectomy before induction of 45 minutes of left kidney ischemia or sham operation. POC was performed by four cycles of 10 seconds of ischemia and 10 seconds of reperfusion just at the beginning of 24 hours of reperfusion. Then blood and liver samples were collected to measure serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, and liver oxidative stress parameters including superoxide dismutase (SOD activity and malondialdehyde (MDA level. Renal IR caused a significant increase in liver functional indices as demonstrated by increased serum AST and ALT compared to sham group. These parameters reduced significantly in POC group compared to IR group. Liver MDA levels increased and SOD activity decreased in IR group compared to sham group. Induction of POC reduced the elevated liver MDA levels and increased the reduced liver SOD activity. These results revealed that renal IR injury causes liver damage as a remote organ and POC protects liver from renal IR injury by a modification in the hepatic oxidative stress status.

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

Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair.

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Sultana, Asma; Powell, James J; Oniscu, Gabriel C

2017-01-01

Liver transplantation is a recognised treatment for extensive bile duct injuries with secondary biliary cirrhosis or recurring sepsis. However, there have been no reports of successful liver transplantation from a donor who sustained a previous bile duct injury. Here we discuss the case of a liver transplant from a 51-year-old brain dead donor who had suffered a Strasberg E1 bile duct injury and had undergone a Roux-en-Y hepaticojejunostomy 24 years prior to donation. The liver was successfully recovered and transplanted into a 56-year-old male recipient with end stage liver disease consequent to alpha 1 antitrypsin deficiency. The graft continues to function well 36 months post-transplant, with normal liver function tests and imaging revealing a patent hepaticojejunostomy. The potential associated vascular injuries should be identified during bench preparation whilst the management of biliary reconstruction at the time of transplant should follow the principles of biliary reconstruction in cases with biliary injuries, extending the hilar opening into the left duct. This case highlights the successful utilisation of a post bile duct injury repair liver, employing an experienced procurement team and careful bench assessment and reconstruction. Copyright © 2017. Published by Elsevier Ltd.

Nrf2 activation prevents cadmium-induced acute liver injury

International Nuclear Information System (INIS)

Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

2012-01-01

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 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 were

Nrf2 activation prevents cadmium-induced acute liver injury

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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

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

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Yu-Jie Zhang

2016-09-01

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

Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

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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.

Fermented Citrus Lemon Reduces Liver Injury Induced by Carbon Tetrachloride in Rats

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Yi Jinn Lillian Chen

2018-01-01

Full Text Available Fermented lemon juice displays a variety of important biological activities, including anti-inflammatory and antioxidant capabilities. The aim of the present study is to investigate hepatic-protective effects of no-sugar-added fermented lemon juice (FLJ for liver inflammation caused by carbon tetrachloride (CCl4 in rats. Rats are divided into six groups: H2O, CCl4 + H2O, CCl4 + silymarin, and CCl4 plus three different FLJ doses by oral administration, respectively. The results show that the contents of plasma ALT and AST, hepatic lipid peroxidation, splenomegaly, and liver water are reduced significantly in rats under FLJ treatment, and pathological examination of liver fibrosis is improved. The reduced hepatic injury by increasing liver soluble protein and glutathione and albumin is observed in FLJ treated groups, and FLJ has comparable efficacies to medicine silymarin in liver therapies. The no-sugar-added FLJ differs from traditional fermentation by adding lots of sugar and prevents any hidden sugar intake while taking it as a complimentary treatment for liver inflammation. The green color and the taste of sourness are both associated with treating and healing the liver based on the five-element theory in traditional Chinese medicine, and the green and sour FLJ may be applied to the ancient theory in preventing hepatic injury accordingly.

Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect

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Helga M. Gretarsdottir

2018-06-01

Full Text Available We describe a case of acute liver injury and migratory arthralgia in a patient receiving bicalutamide treatment for prostate cancer. A 67-year-old male with metastatic prostate cancer presented with a 6-day history of migratory arthralgia. He had been undergoing treatment with bicalutamide for 4 months; 3 weeks prior to symptom appearance the bicalutamide dose had been increased. He had no other symptoms. Liver tests and inflammatory markers were markedly elevated. Serology for hepatitis viruses A, B, and C, CMV, and EBV and autoimmune causes were all negative, and an ultrasound of the upper abdomen was normal. There was no history of blood transfusion, intravenous drug abuse, or alcohol abuse. Due to the suspicion of a drug-induced symptomatology, bicalutamide was discontinued and the patient started on 30 mg prednisolone daily. Three weeks later he was symptom free and after 6 weeks his liver tests were almost normal. The Roussel Uclaf Causality Assessment Method (RUCAM suggested a high probability of liver injury. Bicalutamide has very rarely been reported as a causative agent for liver injury and to our knowledge never for migratory polyarthralgia. The migratory polyarthralgia was attributed to bicalutamide due to the absence of other etiological factors and the disappearance of symptoms after discontinuation of the drug. To our knowledge, this is the first published case report of migratory arthralgia and concomitant liver injury attributed to bicalutamide.

Interferon-Mediated Innate Immune Responses against Malaria Parasite Liver Stages

Directory of Open Access Journals (Sweden)

Jessica L. Miller

2014-04-01

Full Text Available Mosquito-transmitted malaria parasites infect hepatocytes and asymptomatically replicate as liver stages. Using RNA sequencing, we show that a rodent malaria liver-stage infection stimulates a robust innate immune response including type I interferon (IFN and IFNγ pathways. Liver-stage infection is suppressed by these infection-engendered innate responses. This suppression was abrogated in mice deficient in IFNγ, the type I IFN α/β receptor (IFNAR, and interferon regulatory factor 3. Natural killer and CD49b+CD3+ natural killer T (NKT cells increased in the liver after a primary infection, and CD1d-restricted NKT cells, which secrete IFNγ, were critical in reducing liver-stage burden of a secondary infection. Lack of IFNAR signaling abrogated the increase in NKT cell numbers in the liver, showing a link between type I IFN signaling, cell recruitment, and subsequent parasite elimination. Our findings demonstrate innate immune sensing of malaria parasite liver-stage infection and that the ensuing innate responses can eliminate the parasite.

Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.

Science.gov (United States)

Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao

2016-04-14

The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.

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.

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.

Effect of Recombinant FVIIA in Hypothermic, Coagulopathic Pigs with Liver Injuries

National Research Council Canada - National Science Library

Klemcke, Harold G; Delgado, Angel; Holcomb, John B; Ryan, Kathy L; Burke, Allen; DeGuzman, Rodolpho; Scherer, Michael; Cortez, Douglas; Uscilowicz, John; Macaitis, Joseph

2005-01-01

.... Hemodilution was followed by adjustment of body temperature to 32.5 +/- .5 degrees C. Subsequently, a severe liver injury was produced using a specially designed clamp with associated cross-blades...

Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress

Science.gov (United States)

Lu, Yongke; Leung, Tung Ming; Ward, Stephen C.

2012-01-01

Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the l-citrulline/nitric oxide (NO·) salvage pathway to continually supply l-arginine from l-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/− mice (Ass−/− mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/− mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/− compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration. PMID:22052013

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.

Is the Grading of Liver Injuries a Useful Clinical Tool in the Initial Management of Blunt Trauma Patients?

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Helling, Thomas S; Ward, Michael R; Balon, Jennifer

2009-04-01

Computed tomography (CT) has become the preferred method for evaluation of the abdomen for victims of blunt trauma. Grading of liver injuries, primarily by CT, has been advocated as a measure of severity and, by implication, the likelihood for intervention or complications. We have sought to determine if grading of liver injuries, as a clinical tool, affects immediate or extended management of patients. We have retrospectively reviewed all patients sustaining blunt liver injuries as diagnosed by CT over a five-year period at a Level I trauma center to determine if grading of injury influenced management. The AAST organ scaling system was utilized (major grade 4-5, minor grade 1-3), as well as the ISS, AIS, mortality, morbidity, and treatment. There were 133 patients available for review. The patients were grouped into major (n = 20) and minor (n = 113) liver injuries and operative (n = 12) and nonoperative (n = 121) management. Major liver injuries had a higher ISS (39 + 13 vs. 27 + 15, p = 0.001) and were more likely to require operative intervention (5/20 vs. 7/113, p = 0.02). Mortality in this group was not different (major vs. minor), and there were no differences in the incidence of complications. Twelve patients (9%) required operation, all for hemodynamic instability, all within 24 h, and 11/12 within 6 h. At operation 8/12 patients had other sources of bleeding beside the liver injury, and 7/12 had minor hepatic injuries. The operative patients had higher ISS and AIS scores (head/neck, chest, abdomen, extremities) than those managed nonoperatively. More patients died in the operative group (6/12 vs. 8/121, p = 0.0003). There were more pulmonary (6/12 vs. 16/121, p = 0.005), cardiovascular (6/12 vs. 19/121, p = 0.01), and infectious (5/12 vs. 20/121, p = 0.049) complications in the operative group. There were 14 deaths overall; 13/14 were due to traumatic brain injury, and 8/14 required urgent operation for hemorrhage. In conclusion, grading of liver

Role of the Nalp3 inflammasome in acetaminophen-induced sterile inflammation and liver injury

International Nuclear Information System (INIS)

Williams, C. David; Antoine, Daniel J.; Shaw, Patrick J.; Benson, Craig; Farhood, Anwar; Williams, Dominic P.; Kanneganti, Thirumala-Devi; Park, B. Kevin; Jaeschke, Hartmut

2011-01-01

Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300 mg/kg APAP for 24 h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose.

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

Science.gov (United States)

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

2015-01-01

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

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.

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

Assessment of hepatocyte and kupffer cell function using Tc-99m DISIDA/Tc-99m tin colloid in thioacetamide-induced liver injury

International Nuclear Information System (INIS)

Ahn, B. C.; Chun, K. A.; Lee, J.; Lee, K. B.

1997-01-01

Toxic liver injury is not unusual in clinical field and liver biopsy is one of the most accurate method to define the severity of liver injury. But occasionally, it is impossible to obtain liver tissue in patients with acute toxic liver injury. The aim of this study is to evaluate the possibility of liver scintigraphy with Tc-99m DISIDA or Tc-99m tin colloid as a non-invasive tool in predicting functional status of hepatocyte and Kupffer cell and severity of liver injury. Intraperitoneal injection of thioacetamide was performed to make acute liver injury in mice and rats, and liver status was assessed by pathologic specimen and scintigraphic methods. Scintigraphic evaluation were performed by biodistribution of Tc-99m DISIDA or Tc-99m tin colloid in thioacetamide-treated mice. Liver time-activity curves were generated. Comparison between histologic data and scintigraphic data was done with SAS program. Thioacetamide-treated mice demonstrated hepatocyte necrosis in histologic examination and low liver/blood uptake ratios in biodistribution studies using both radiotracers. Biodistribution study using Tc-99m tin colloid revealed increased lung radioactivity in thioacetamide-treated mice. Twenty-four hours after thioacetamide administration, thioacetamide-treated rats demonstrated maximal hepatocyte necrosis and inflammation in histologic finding and delayed maximal uptake time (Tmax) and prolonged half time (T 1/2 ) of liver time-activity curve in liver scintigraphy. Histologic results and scintigraphic data were well correlated, and these two scintigraphic parameters (Tmax T 1/2 ) seemed to be good predictors of histologic change of liver. These data showed that liver injury could be assessed by non-invasive scintigraphic study in rat and mouse. This experimental study might be used as a animal model to evaluate the liver protecting drugs, and this scintigraphic study could be applied to acute toxic hepatitis for assessment of liver status in men

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.

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.

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

Science.gov (United States)

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

2017-12-01

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

DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease.

Science.gov (United States)

Chen, Hanqing; Shen, Feng; Sherban, Alex; Nocon, Allison; Li, Yu; Wang, Hua; Xu, Ming-Jiang; Rui, Xianliang; Han, Jinyan; Jiang, Bingbing; Lee, Donghwan; Li, Na; Keyhani-Nejad, Farnaz; Fan, Jian-Gao; Liu, Feng; Kamat, Amrita; Musi, Nicolas; Guarente, Leonard; Pacher, Pal; Gao, Bin; Zang, Mengwei

2018-02-19

Alcoholic liver disease (ALD) is characterized by lipid accumulation and liver injury. However, how chronic alcohol consumption causes hepatic lipid accumulation remains elusive. The present study demonstrates that activation of the mechanistic target of rapamycin complex 1 (mTORC1) plays a causal role in alcoholic steatosis, inflammation, and liver injury. Chronic-plus-binge ethanol feeding led to hyperactivation of mTORC1, as evidenced by increased phosphorylation of mTOR and its downstream kinase S6 kinase 1 (S6K1) in hepatocytes. Aberrant activation of mTORC1 was likely attributed to the defects of the DEP domain-containing mTOR-interacting protein (DEPTOR) and the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 (SIRT1) in the liver of chronic-plus-binge ethanol-fed mice and in the liver of patients with ALD. Conversely, adenoviral overexpression of hepatic DEPTOR suppressed mTORC1 signaling and ameliorated alcoholic hepatosteatosis, inflammation, and acute-on-chronic liver injury. Mechanistically, the lipid-lowering effect of hepatic DEPTOR was attributable to decreased proteolytic processing, nuclear translocation, and transcriptional activity of the lipogenic transcription factor sterol regulatory element-binding protein-1 (SREBP-1). DEPTOR-dependent inhibition of mTORC1 also attenuated alcohol-induced cytoplasmic accumulation of the lipogenic regulator lipin 1 and prevented alcohol-mediated inhibition of fatty acid oxidation. Pharmacological intervention with rapamycin alleviated the ability of alcohol to up-regulate lipogenesis, to down-regulate fatty acid oxidation, and to induce steatogenic phenotypes. Chronic-plus-binge ethanol feeding led to activation of SREBP-1 and lipin 1 through S6K1-dependent and independent mechanisms. Furthermore, hepatocyte-specific deletion of SIRT1 disrupted DEPTOR function, enhanced mTORC1 activity, and exacerbated alcoholic fatty liver, inflammation, and liver injury in mice. The dysregulation of SIRT1

Proteomic analysis of protective effects of polysaccharides from Salvia miltiorrhiza against immunological liver injury in mice.

Science.gov (United States)

Sun, Xue-Gang; Fu, Xiu-Qiong; Cai, Hong-Bing; Liu, Qiang; Li, Chun-Hua; Liu, Ya-Wei; Li, Ying-Jia; Liu, Zhi-Feng; Song, Yu-Hong; Lv, Zhi-Ping

2011-07-01

This study was designed to investigate mechanisms of the protective effects of Salvia miltiorrhiza polysaccharide (SMPS) against lipopolysaccharide (LPS)-induced immunological liver injury (ILI) in Bacille Calmette-Guérin (BCG)-primed mice. Two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis showed that three proteins are down-regulated and six proteins are up-regulated by SMPS. SMPS reduces the degree of liver injury by up-regulating the enzymes of the citric acid cycle, namely malate dehydrogenase (MDH) and 2-oxoglutarate dehydrogenase complex. LPS significantly increases nuclear factor kappa B (NF-κB) activation, inducible nitric oxide synthase (iNOS) expression and MDA level in BCG primed mice liver, whereas SMPS treatment protects against the immunological liver injury through inhibition of the NF-κB activation by up-regulation of PRDX6 and the subsequent attenuation of lipid peroxidation, iNOS expression and inflammation. Copyright © 2011 John Wiley & Sons, Ltd.

Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

Science.gov (United States)

Devarbhavi, Harshad; Andrade, Raúl J

2014-05-01

Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hepatoprotective effects of setarud against carbon tetrachloride-induced liver injury in rats.

Science.gov (United States)

Khorshid, Hamid Reza Khorram; Azonov, Jahan A; Novitsky, Yury A; Farzamfar, Bardia; Shahhosseiny, Mohammad Hassan

2008-01-01

To assess the hepatoprotective activity of a new herbal drug "setarud" in experimental liver fibrosis, 48 male Wistar rats were divided into four groups: controls, carbon tetrachloride (CCl4) group, and two treatment groups that received CCl4 and setarud at doses of 0.02 or 0.04 g/Kg/day for 30 days. Body weight gain, biochemical liver tests, bile flow rate and composition, and changes in liver morphology in the four groups were studied. CCl4 administration led to morphological and biochemical evidence of liver injury as compared to untreated controls. Setarud administration led to significant protection against CCl4-induced changes in body weight gain, liver morphology, bile flow and concentration. It was also associated with significantly lower serum liver enzyme levels (pliver disease are warranted.

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)

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.

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

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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

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

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

Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

NARCIS (Netherlands)

Geuken, Erwin; Visser, Dorien; Kuipers, Folkert; Blokzijl, Hans; Leuvenink, Henri G. D.; de Jong, Koert P.; Peeters, Paul M. J. G.; Jansen, Peter L. M.; Slooff, Maarten J. H.; Gouw, Annette S. H.; Porte, Robert J.

2004-01-01

BACKGROUND/AIMS: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. METHODS: In 28 liver transplant recipients, bile samples were collected daily

Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation

NARCIS (Netherlands)

Geuken, E; Visser, D; Kuipers, F; Blokzijl, H; Leuvenink, HGD; de Jong, KP; Peeters, PMJG; Jansen, PLM; Slooff, MJH; Gouw, ASH; Porte, RJ

2004-01-01

Background/Aims: Biliary strictures are a serious cause of morbidity after liver transplantation. We have studied the role of altered bile composition as a mechanism of bile duct injury after human liver transplantation. Methods: In 28 liver transplant recipients, bile samples were collected daily

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

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Yuewen Tang

2017-02-01

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

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.

Role of cholangiocyte bile Acid transporters in large bile duct injury after rat liver transplantation.

Science.gov (United States)

Cheng, Long; Zhao, Lijin; Li, Dajiang; Liu, Zipei; Chen, Geng; Tian, Feng; Li, Xiaowu; Wang, Shuguang

2010-07-27

The pathogenesis of nonanastomotic strictures with a patent hepatic artery remains to be investigated. This study focuses on the role of cholangiocyte bile acid transporters in bile duct injury after liver transplantation. Sprague-Dawley rats were divided into three groups (n=20 for each): the sham-operated group (Sham), the transplant group with 1-hr donor liver cold preservation (CP-1h), and the transplant group with 12-hr donor liver cold preservation (CP-12h). Bile was collected for biochemical analysis. The histopathologic evaluation of bile duct injury was performed and the cholangiocyte bile acid transporters apical sodium-dependent bile acid transporter (ASBT), ileal lipid binding protein (ILBP), and Ostalpha/Ostbeta were investigated. RESULTS.: The immunohistochemical assay suggested that ASBT and ILBP were expressed exclusively on large bile duct epithelial cells, whereas Ostalpha and Ostbeta were expressed on both small and large bile ducts. Western blot and quantitative polymerase chain reaction analysis showed that the expression levels of these transporters dramatically decreased after transplantation. It took seven to 14 days for ILBP, Ostalpha, and Ostbeta to recover, whereas ASBT recovered within 3 days and even reached a peak above the normal level seven days after operation. In the CP-12h group, the ratios of the ASBT/ILBP, ASBT/Ostalpha and ASBT/Ostbeta expression levels were correlated with the injury severity scores of large but not small bile ducts. The results suggest that the unparallel alteration of cholangiocyte bile acid transporters may play a potential role in large bile duct injury after liver transplantation with prolonged donor liver preservation.

[The mechanisms of formation of liver injuries associated with the blunt abdominal trauma].

Science.gov (United States)

Pigolkin, Iu I; Dubrovina, I A; Dubrovin, I A

2012-01-01

The mechanisms of liver damage associated with the blunt abdominal trauma are considered based on the analysis of the literature publications. The general characteristic of these mechanisms and the processes underlying the development of liver injuries is presented. It is argued that the mechanisms underlying the formation of damages to the liver differ depending on the form of the traumatic impact, the injurious factor, and the processes leading to the destruction of the hepatic tissue. The main forms of traumatic impact in the case of a blunt abdominal trauma include the strike (blow), pressure, and concussion of the organ while the major traumatic factors are deformation, displacement, and "shock-resistant effects". The mechanisms underlying tissue destruction are compression and stretching. These two mechanisms are responsible for the formation of different variants of liver destruction. The results of the study suggest the necessity of the search for other mechanisms of degradation of the hepatic tissue following a blunt abdominal trauma for the improvement of forensic medical diagnostics of its cause and the underlying mechanism.

Antioxidant and antiapoptotic effects of green tea polyphenols against azathioprine-induced liver injury in rats.

Science.gov (United States)

El-Beshbishy, Hesham A; Tork, Ola M; El-Bab, Mohamed F; Autifi, Mohamed A

2011-04-01

Green tea polyphenols (GTP) is considered to have protective effects against several diseases. The hepatotoxicity of azathioprine (AZA) has been reported and was found to be associated with oxidative damage. This study was conducted to evaluate the role of GTP to protect against AZA-induced liver injury in rats. AZA was administered i.p. in a single dose (50mgkg(-1)) to adult male rats. AZA-intoxicated rats were orally administered GTP (either 100mgkg(-1)day(-1) or 300mgkg(-1)day(-1), for 21 consecutive days, started 7 days prior AZA injection). AZA administration to rats resulted in significant elevation of serum transaminases (sALT and sAST), alkaline phosphatase (sALP), depletion of hepatic reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx), accumulation of oxidized glutathione (GSSG), elevation of lipid peroxides (LPO) expressed as malondialdehyde (MDA), reduction of the hepatic total antioxidant activity (TAA), decrease serum total proteins and elevation of liver protein carbonyl content. Significant rises in liver tumor necrosis factor-alpha (TNF-α) and caspase-3 levels were noticed in AZA-intoxicated rats. Treatment of the AZA-intoxicated rats with GTP significantly prevented the elevations of sALT, sAST and sALP, inhibited depletion of hepatic GSH, GPx, CAT and GSSG and inhibited MDA accumulation. Furthermore, GTP had normalized serum total proteins and hepatic TAA, CAT, TNF-α and caspase-3 levels of AZA-intoxicated rats. In addition, GTP prevented the AZA-induced apoptosis and liver injury as indicated by the liver histopathological analysis. The linear regression analysis showed significant correlation in either AZA-GTP100 or AZA-GTP300 groups between TNF-α and each of serum ALT, AST, ALP and total proteins and liver TAA, GPX, CAT, GSH, GSSG, MDA and caspase-3 levels. However, liver TNF-α produced non-significant correlation with the serum total proteins in both AZA-GTP100 and AZA-GTP300 groups. In conclusion, our data indicate

Liver injury in rhesus monkeys subcutaneously injected with 2.3.7.8-tetrachlorodibenzo-p-dioxin

Energy Technology Data Exchange (ETDEWEB)

Tatsumi, Korenaga; Fukusato, Toshio [Teikyo Univ., Tokyo (Japan). School of Medicine; Kubota, Shunichiro; Ohta, Mari [Tokyo Univ. (Japan); Asaoka, Kazuo [Kyoto Univ., Aichi (Japan); Murata, Nobuo [Teikyo Univ., Kawasaki (Japan). Mizonokuchi Hospital, School of Medicine; Nomizu, Motoyoshi [Hokkaido Univ., Sapporo (Japan); Arima, Akihiro [Shin Nippon Biomedical Laboratories, Ltd., Kagoshima (Japan)

2004-09-15

2.3.7.8-tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of dioxins which are environmentally and biologically stable. Exposure to these compounds results in wide variety of effects including immunological dysfunction, tetragenecity and carcinogenesis. The liver is one of the central organs in which TCDD metabolized after absorption into the human and animal bodies. In experiments using rodents, TCDD accumulates and remains stable in the fatty tissues and liver for a long time. Kinetic profile of TCDD in our experiments using rhesus monkeys demonstrated the higher concentrations of TCDD in the fat, liver, and mammary gland. TCDD-induced liver injury in humans has been reported in Japan (PCB), Taiwan (PCB or PCDF), Italy (Sebeso, TCDD), and Vietnam (TCDD). Considerating the pronounced difference between species observed in some studies on non-human primates to assess effects of relatively low dose of TCDD, in the present study, liver injury in rhesus monkeys after a single subcutaneous administration of low dose of TCDD during pregnancy was investigated.

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

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Seyyed Ali Mard

2017-10-01

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

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

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Qin eDong

2015-10-01

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

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

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).

Hepatic parenchymal atrophy induction for intractable segmental bile duct injury after liver resection.

Science.gov (United States)

Hwang, Shin; Park, Gil-Chun; Ha, Tae-Yong; Ko, Gi-Young; Gwon, Dong-Il; Choi, Young-Il; Song, Gi-Won; Lee, Sung-Gyu

2012-05-01

Liver resection can result in various types of bile duct injuries but their treatment is usually difficult and often leads to intractable clinical course. We present an unusual case of hepatic segment III duct (B3) injury, which occurred after left medial sectionectomy for large hepatocellular carcinoma and was incidentally detected 1 week later due to bile leak. Since the pattern of this B3 injury was not adequate for operative biliary reconstruction, atrophy induction of the involved hepatic parenchyma was attempted. This treatment consisted of embolization of the segment III portal branch to inhibit bile production, induction of heavy adhesion at the bile leak site and clamping of the percutaneous transhepatic biliary drainage (PTBD) tube to accelerate segment III atrophy. This entire procedure, from liver resection to PTBD tube removal took 4 months. This patient has shown no other complication or tumor recurrence for 4 years to date. These findings suggest that percutaneous segmental portal vein embolization, followed by intentional clamping of external biliary drainage, can effectively control intractable bile leak from segmental bile duct injury.

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

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

DEFF Research Database (Denmark)

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

1987-01-01

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

Use of Sengstaken-Blakemore intrahepatic balloon: an alternative for liver-penetrating injuries.

Science.gov (United States)

Fraga, Gustavo Pereira; Zago, Thiago Messias; Pereira, Bruno Monteiro; Calderan, Thiago Rodrigues Araujo; Silveira, Henrique Jose Virgili

2012-09-01

Severe lesions in the liver are associated with a high mortality rate. Alternative surgical techniques such as the use of an intrahepatic balloon may be effective and reduce mortality in severe hepatic lesions. This study aimed to demonstrate the experience of a university hospital in the use of the Sengstaken-Blakemore balloon in patients with transfixing penetrating hepatic injury as an alternative way to treat these challenging injuries. A retrospective study based on the trauma registry of a university hospital was performed. All patients admitted with hepatic penetrating injuries and treated with the Sengstaken-Blakemore balloon within the period 1990-2010 were reviewed. Forty-six patients with transfixing hepatic injuries were treated with the Sengstaken-Blakemore balloon in the study period. The most frequent cause of injury was gunshot wound (87 % of the patients). The mean trauma scores on admission were Revised Trauma Score (RTS) = 7.12 ± 1.46, Injury Severity Score (ISS) = 22.4 ± 9.7, and Abdominal Trauma Index (ATI) = 19.5 ± 11. According to the severity of the hepatic trauma, 71.8 % of patients had grade III, 23.9 % grade IV, and 4.3 % grade V injuries. Associated abdominal injuries were found in 89.1 % of the patients. The most frequent liver-related complications were hepatic abscess postoperative bleeding (8.6 %), biliary fistula (8.6 %), (4.3 %), and biliary peritonitis (2.1 %). Surgical reintervention was necessary in 14 patients (31.1 %). From those 14, only 3 had the balloon removed. The overall morbidity and mortality rates were 56.5 % and 23.9 % (11 patients), respectively. The knowledge of alternative surgical techniques is essential in improving survival in patients with severe penetrating hepatic injuries. The use of intrahepatic balloon is a viable surgical strategy.

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.

S-Adenosylmethionine attenuates bile duct early warm ischemia reperfusion injury after rat liver transplantation.

Science.gov (United States)

Tang, Yong; Chu, Hongpeng; Cao, Guojun; Du, Xiaolong; Min, Xiaobo; Wan, Chidan

2018-03-01

Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are characterized by an excessive inflammatory response. S-Adenosylmethionine (SAM) is an important metabolic intermediate that modulates inflammatory reactions; however, its role in bile duct warm IRI is not known. In this study, male rats were treated with or without SAM (170 μmol/kg body weight) after orthotopic autologous liver transplantation. The histopathological observations showed that bile duct injury in the IRI group was more serious than in the SAM group. The alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DBIL) levels in the serum of the IRI group were significantly increased compared to the SAM group (P liver and bile duct tissues, down-regulated TNF-α levels and up-regulated IL-10 expression in bile duct tissues compared to the IRI group (P livers were much higher compared to those in SAM-treated rats at 24 h after liver transplantation (P bile ducts against warm IRI by suppressing oxidative stress, inflammatory reactions and apoptosis of biliary epithelial cells after liver transplantation.α. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

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

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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.

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

African Journals Online (AJOL)

MIDOU

2013-12-18

Dec 18, 2013 ... induced oxidative liver injury and lipid peroxidation probably due to its antioxidant proprieties. ... enzyme in every enzyme classification (Coyle et al.,. 2002). Others .... control group had a regular histological structure with a.

Chlorpromazine-induced perturbations of bile acids and free fatty acids in cholestatic liver injury prevented by the Chinese herbal compound Yin-Chen-Hao-Tang.

Science.gov (United States)

Yang, Qiaoling; Yang, Fan; Tang, Xiaowen; Ding, Lili; Xu, Ying; Xiong, Yinhua; Wang, Zhengtao; Yang, Li

2015-04-16

Yin-Chen-Hao-Tang (YCHT), a commonly used as a traditional chinese medicine for liver disease. Several studies indicated that YCHT may improving hepatic triglyceride metabolism and anti-apoptotic response as well as decreasing oxidative stress .However, little is known about the role of YCHT in chlorpromazine (CPZ) -induced chlolestatic liver injury. Therefore, we aimed to facilitate the understanding of the pathogenesis of cholestatic liver injury and evaluate the effect of Yin-Chen-Hao-Tang (YCHT) on chlorpromazine (CPZ)-induced cholestatic liver injury in rats based on the change of bile acids (BAs) and free fatty acids (FFAs) alone with the biochemical indicators and histological examination. We conducted an experiment on CPZ-induced cholestatic liver injury in Wistar rats with and without YCHT for nine consecutive days. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C) were measured to evaluate the protective effect of YCHT against chlorpromazine (CPZ)-induced cholestatic liver injury. Histopathology of the liver tissue showed that pathological injuries were relieved after YCHT pretreatment. In addition, ultra-performance lipid chromatography coupled with quadrupole mass spectrometry (UPLC-MS) and gas chromatography coupled with mass spectrometry (GC-MS) was applied to determine the content of bile acids, free fatty acids, respectively. Obtained data showed that YCHT attenuated the effect of CPZ-induced cholestatic liver injury, which was manifested by the serum biochemical parameters and histopathology of the liver tissue. YCHT regulated the lipid levels as indicated by the reversed serum levels of TC, TG, and LDL-C. YCHT also regulated the disorder of BA and FFA metabolism by CPZ induction. Results indicated that YCHT exerted a protective effect on CPZ-induced cholestasis liver injury. The variance of

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

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

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Wei-Lun Wong

2012-01-01

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

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

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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.

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.

Sulfatide-Reactive Natural Killer T Cells Abrogate Ischemia-Reperfusion Injury

OpenAIRE

Yang, Seung Hee; Lee, Jung Pyo; Jang, Hye Ryoun; Cha, Ran-hui; Han, Seung Seok; Jeon, Un Sil; Kim, Dong Ki; Song, Junghan; Lee, Dong-Sup; Kim, Yon Su

2011-01-01

There is a significant immune response to ischemia-reperfusion injury (IRI), but the role of immunomodulatory natural killer T (NKT) cell subtypes is not well understood. Here, we compared the severity of IRI in mice deficient in type I/II NKT cells (CD1d−/−) or type I NKT cells (Jα18−/−). The absence of NKT cells, especially type II NKT cells, accentuated the severity of renal injury, whereas repletion of NKT cells attenuated injury. Adoptively transferred NKT cells trafficked into the tubul...

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.

Subnormothermic ex vivo liver perfusion reduces endothelial cell and bile duct injury after donation after cardiac death pig liver transplantation.

Science.gov (United States)

Knaak, Jan M; Spetzler, Vinzent N; Goldaracena, Nicolas; Boehnert, Markus U; Bazerbachi, Fateh; Louis, Kristine S; Adeyi, Oyedele A; Minkovich, Leonid; Yip, Paul M; Keshavjee, Shaf; Levy, Gary A; Grant, David R; Selzner, Nazia; Selzner, Markus

2014-11-01

An ischemic-type biliary stricture (ITBS) is a common feature after liver transplantation using donation after cardiac death (DCD) grafts. We compared sequential subnormothermic ex vivo liver perfusion (SNEVLP; 33°C) with cold storage (CS) for the prevention of ITBS in DCD liver grafts in pig liver transplantation (n = 5 for each group). Liver grafts were stored for 10 hours at 4°C (CS) or preserved with combined 7-hour CS and 3-hour SNEVLP. Parameters of hepatocyte [aspartate aminotransferase (AST), international normalized ratio (INR), factor V, and caspase 3 immunohistochemistry], endothelial cell (EC; CD31 immunohistochemistry and hyaluronic acid), and biliary injury and function [alkaline phosphatase (ALP), total bilirubin, and bile lactate dehydrogenase (LDH)] were determined. Long-term survival (7 days) after transplantation was similar between the SNEVLP and CS groups (60% versus 40%, P = 0.13). No difference was observed between SNEVLP- and CS-treated animals with respect to the peak of serum INR, factor V, or AST levels within 24 hours. CD31 staining 8 hours after transplantation demonstrated intact EC lining in SNEVLP-treated livers (7.3 × 10(-4) ± 2.6 × 10(-4) cells/μm(2)) but not in CS-treated livers (3.7 × 10(-4) ± 1.3 × 10(-4) cells/μm(2) , P = 0.03). Posttransplant SNEVLP animals had decreased serum ALP and serum bilirubin levels in comparison with CS animals. In addition, LDH in bile fluid was lower in SNEVLP pigs versus CS pigs (14 ± 10 versus 60 ± 18 μmol/L, P = 0.02). Bile duct histology revealed severe bile duct necrosis in 3 of 5 animals in the CS group but none in the SNEVLP group (P = 0.03). Sequential SNEVLP preservation of DCD grafts reduces bile duct and EC injury after liver transplantation. © 2014 American Association for the Study of Liver Diseases.

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...

Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review.

Science.gov (United States)

Wang, Ran; Qi, Xingshun; Yoshida, Eric M; Méndez-Sánchez, Nahum; Teschke, Rolf; Sun, Mingyu; Liu, Xu; Su, Chunping; Deng, Jiao; Deng, Han; Hou, Feifei; Guo, Xiaozhong

2018-04-01

Traditional Chinese medicine (TCM) is becoming increasingly popular and related adverse events are often ignored or underestimated. This systematic review aimed to evaluate the clinical characteristics and outcomes of TCM-induced liver injury (TCM-ILI) and to estimate the proportion of TCM-ILI in all drug-induced liver injuries (DILI). China National Knowledge Infrastructure, Wanfang, VIP, PubMed, and Embase databases were searched. Demographic, clinical, and survival data were extracted and pooled. Factors associated with worse outcomes were calculated. For the proportion meta-analyses, the data were pooled by using a random-effects model. Overall, 21,027 articles were retrieved, of which 625 were finally included. There was a predominance of female and older patients. The proportion of liver transplantation was 2.18% (7/321). The mortality was 4.67% (15/321). Male, higher aspartate aminotransferase and direct bilirubin, and lower albumin were significantly associated with an increased risk of death/liver transplantation in TCM-ILI patients. The proportion of TCM-ILI in all DILI was 25.71%. The proportion was gradually increased with year. Our work summarises current knowledge regarding clinical presentation, disease course, and prognosis of TCM-ILI. TCM can result in hepatotoxicity, even death or necessitate life-saving liver transplantation. Governmental regulation of TCM products should be strictly established.

Hemoretroperitoneum associated with liver bare area injuries: CT evaluation

International Nuclear Information System (INIS)

Miele, V.; Adami, L.; Andreoli, C.; De Cicco, M.L.; David, V.

2002-01-01

In hepatic injury restricted to the postero-superior region of segment VII (bare area), hemoperitoneum may be absent and this condition may be associated with hemoretroperitoneum. The aim of this paper is to present the association between bare area injuries and hemoretroperitoneum evaluated by CT. The CT examinations of 32 patients with blunt liver trauma were reviewed and the number and location of lesions were evaluated. Right lobe involvement was identified, focusing on the bare area lesions. The presence of hemoperitoneum and hemoretroperitoneum were determined. In the 32 patients 44 parenchymal lesions were detected. Segment VII was involved in 16 cases: 5 patients presented an intraparenchymal lesion, 11 patients a lesion emerging to the liver surface. In 8 cases the lesion was localized in the bare area. In the 16 patients presenting a segment-VII lesion, hemoperitoneum was detected in 3 cases, hemoretroperitoneum in 4 cases, and both conditions in 4 cases. A traumatic hepatic lesion may be associated with hemoretroperitoneum rather than hemoperitoneum. This justifies the absence of clinical signals of peritoneal irritation; the negativity of both US scan and peritoneal lavage may cause an inappropriate therapeutic management. Computed tomography yields both the detection of the parenchymal damage and the correct localization of the intraperitoneal and retroperitoneal hemorrhage. (orig.)

Hemoretroperitoneum associated with liver bare area injuries: CT evaluation

Energy Technology Data Exchange (ETDEWEB)

Miele, V.; Adami, L. [Department of Radiology, Camillo Hospital, Rome (Italy); Andreoli, C.; De Cicco, M.L.; David, V. [I Chair of Radiology, University ' ' La Sapienza' ' , Rome (Italy)

2002-04-01

In hepatic injury restricted to the postero-superior region of segment VII (bare area), hemoperitoneum may be absent and this condition may be associated with hemoretroperitoneum. The aim of this paper is to present the association between bare area injuries and hemoretroperitoneum evaluated by CT. The CT examinations of 32 patients with blunt liver trauma were reviewed and the number and location of lesions were evaluated. Right lobe involvement was identified, focusing on the bare area lesions. The presence of hemoperitoneum and hemoretroperitoneum were determined. In the 32 patients 44 parenchymal lesions were detected. Segment VII was involved in 16 cases: 5 patients presented an intraparenchymal lesion, 11 patients a lesion emerging to the liver surface. In 8 cases the lesion was localized in the bare area. In the 16 patients presenting a segment-VII lesion, hemoperitoneum was detected in 3 cases, hemoretroperitoneum in 4 cases, and both conditions in 4 cases. A traumatic hepatic lesion may be associated with hemoretroperitoneum rather than hemoperitoneum. This justifies the absence of clinical signals of peritoneal irritation; the negativity of both US scan and peritoneal lavage may cause an inappropriate therapeutic management. Computed tomography yields both the detection of the parenchymal damage and the correct localization of the intraperitoneal and retroperitoneal hemorrhage. (orig.)

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

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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.

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

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

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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

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 �

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 �

Diagnostic performance of traditional hepatobiliary biomarkers of drug-induced liver injury in the rat.

Science.gov (United States)

Ennulat, Daniela; Magid-Slav, Michal; Rehm, Sabine; Tatsuoka, Kay S

2010-08-01

Nonclinical studies provide the opportunity to anchor biochemical with morphologic findings; however, liver injury is often complex and heterogeneous, confounding the ability to relate biochemical changes with specific patterns of injury. The aim of the current study was to compare diagnostic performance of hepatobiliary markers for specific manifestations of drug-induced liver injury in rat using data collected in a recent hepatic toxicogenomics initiative in which rats (n = 3205) were given 182 different treatments for 4 or 14 days. Diagnostic accuracy of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbili), serum bile acids (SBA), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total cholesterol (Chol), and triglycerides (Trig) was evaluated for specific types of liver histopathology by Receiver Operating Characteristic (ROC) analysis. To assess the relationship between biochemical and morphologic changes in the absence of hepatocellular necrosis, a second ROC analysis was performed on a subset of rats (n = 2504) given treatments (n = 152) that did not cause hepatocellular necrosis. In the initial analysis, ALT, AST, Tbili, and SBA had the greatest diagnostic utility for manifestations of hepatocellular necrosis and biliary injury, with comparable magnitude of area under the ROC curve and serum hepatobiliary marker changes for both. In the absence of hepatocellular necrosis, ALT increases were observed with biochemical or morphologic evidence of cholestasis. In both analyses, diagnostic utility of ALP and GGT for biliary injury was limited; however, ALP had modest diagnostic value for peroxisome proliferation, and ALT, AST, and total Chol had moderate diagnostic utility for phospholipidosis. None of the eight markers evaluated had diagnostic value for manifestations of hypertrophy, cytoplasmic rarefaction, inflammation, or lipidosis.

Liver transplant

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

Predicting renal recovery after liver transplant with severe pretransplant subacute kidney injury: The impact of warm ischemia time.

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Laskey, Heather L; Schomaker, Nathan; Hung, Kenneth W; Asrani, Sumeet K; Jennings, Linda; Nydam, Trevor L; Gralla, Jane; Wiseman, Alex; Rosen, Hugo R; Biggins, Scott W

2016-08-01

Identifying which liver transplantation (LT) candidates with severe kidney injury will have a full recovery of renal function after liver transplantation alone (LTA) is difficult. Avoiding unnecessary simultaneous liver-kidney transplantation (SLKT) can optimize the use of scarce kidney grafts. Incorrect predictions of spontaneous renal recovery after LTA can lead to increased morbidity and mortality. We retrospectively analyzed all LTA patients at our institution from February 2002 to February 2013 (n = 583) and identified a cohort with severe subacute renal injury (n = 40; creatinine <2 mg/dL in the 14-89 days prior to LTA and not on renal replacement therapy [RRT] yet, ≥2 mg/dL within 14 days of LTA and/or on RRT). Of 40 LTA recipients, 26 (65%) had renal recovery and 14 (35%) did not. The median (interquartile range) warm ischemia time (WIT) in recipients with and without renal recovery after LTA was 31 minutes (24-46 minutes) and 39 minutes (34-49 minutes; P = 0.02), respectively. Adjusting for the severity of the subacute kidney injury with either Acute Kidney Injury Network or Risk, Injury, Failure, Loss, and End-Stage Kidney Disease criteria, increasing WIT was associated with lack of renal recovery (serum creatinine <2 mg/dL after LTA, not on RRT), with an odds ratio (OR) of 1.08 (1.01-1.16; P = 0.03) and 1.09 (1.01-1.17; P = 0.02), respectively. For each minute of increased WIT, there was an 8%-9% increase in the risk of lack of renal recovery after LTA. In a separate cohort of 98 LTA recipients with subacute kidney injury, we confirmed the association of WIT and lack of renal recovery (OR, 1.04; P = 0.04). In LT candidates with severe subacute renal injury, operative measures to minimize WIT may improve renal recovery potentially avoiding RRT and the need for subsequent kidney transplant. Liver Transplantation 22 1085-1091 2016 AASLD. © 2016 American Association for the Study of Liver Diseases.

Hydroalcoholic extract of Stevia rebaudiana bert. leaves and stevioside ameliorates lipopolysaccharide induced acute liver injury in rats.

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S, Latha; Chaudhary, Sheetal; R S, Ray

2017-11-01

Oxidative stress and hepatic inflammatory response is primarily implicated in the pathogenesis of LPS induced acute liver injury. Stevioside, a diterpenoidal glycoside isolated from the Stevia rebaudiana leaves, exerts potent anti-oxidant, anti-inflammatory and immunomodulatory activities. The present study was aimed to investigate the hepatoprotective effect of hydroalcoholic extract of Stevia rebaudiana leaves (STE EXT) and its major phytochemical constituent, stevioside (STE) in LPS induced acute liver injury. The hepatoprotective activity of STE EXT (500mg/kg p.o) and STE (250mg/kg p.o) was investigated in lipopolysaccharide (LPS 5mg/kg i.p.) induced acute liver injury in male wistar rats. Our results revealed that both STE EXT and STE treatment ameliorated LPS induced hepatic oxidative stress, evident from altered levels of reduced SOD, Catalase, GSH, MDA, NO. Histopathological observations revealed that both STE EXT and STE attenuated LPS induced structural changes and hepatocellular apoptosis providing additional evidence for its hepatoprotective effect. Further, STE EXT and STE significantly restored the elevated serum and tissue levels of AST and ALT in LPS treated rats. Furthermore, both STE EXT and STE rescued hepatocellular dysfunctions to normal by altering the level of proinflammatory cytokines such as TNF-α, IL-1β and IL-6 exhibiting its anti-inflammatory potential. In conclusion, both STE EXT and STE demonstrated excellent hepatoprotective effects against endotoxemia induced acute liver injury possibly through suppression of hepatic inflammatory response and oxidative stress, attributing to its medicinal importance in treating various liver ailments. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Immune mediated liver failure.

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Wang, Xiaojing; Ning, Qin

2014-01-01

Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.

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

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

2014-02-01

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

Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide

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Maddox, Jane F.; Luyendyk, James P.; Cosma, Gregory N.; Breau, Alan P.; Bible, Roy H.; Harrigan, George G.; Goodacre, Royston; Ganey, Patricia E.; Cantor, Glenn H.; Cockerell, Gary L.; Roth, Robert A.

2006-01-01

Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferase and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure

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

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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

The experimental study of radiation injury on bile duct and liver tissue

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Cao Guiwen; Wang Bin; Sun Yequan; Shao Xueye; Ning Houfa; Sui Shouguang; Wang Xiuchun; Bai Xuming

2007-01-01

Objective: To investigate the safety, acceptance and the effective extent of 192 Ir-internal irradiation, providing theoretical guidelines for HC. Methods: Sixteen male healthy hybrid dogs enrolled in the experiment were divided into 4 groups of 4 each. The brachytherapy applicator was introduced from gall bladder into the convergence of cystic duct with common hepatic duct during the operation and a small chip of 1 cm 3 liver tissue was cut off and taken for control later on. The animals in group A-D were irradiated by 192 Ir-internal irradiation with 30 Gy, 40 Gy, 50 Gy arid 60 Gy at the correlative dose points respectively. Animals were put to death after 10 days subsequently, with sampling specimens obtained from radiation cystic duct and the in between liver tissue with the distant cystic duct. The radiation injury of the cystic duct and liver tissue near bile ducts were observed and studied by light microscope and transmission election microscope. Results: By the limit of the safest endurance dose(50 Gy) of Bile duct, unreversed injury of the nuclei of liver cells occurred at 0 to 15 mm from bile duct revealed by transmission electron microscope and light microscope. The whole biliary duct wall would be undergone necrosis with irradiation dose over 60 Gy. Conclusions: Normal bile duct possesses good endurance to 192 Ir-internal irradiation. Within the safest endurance limit of 50 Gy the effective irradiation field could reach 15 mm from the involved bile duct. (authors)

[Trends in drug-induced liver injury based on reports of adverse reactions to PMDA in Japan].

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Sudo, Chie; Maekawa, Keiko; Segawa, Katsunori; Hanatani, Tadaaki; Sai, Kimie; Saito, Yoshiro

2012-01-01

Reports on drug-related adverse reactions from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated under the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety measures. Although association between the medicine and the adverse event has not been clearly evaluated, and an incidence may be redundantly reported, this information would be useful to roughly grasp the current status of drug-related adverse reactions. In the present study, we analyzed the incidence of drug-induced liver injury by screening the open-source data publicized by the homepage of Pharmaceutical and Medical Devices Agency from 2005 to 2011 fiscal years. Major drug-classes suspected to cause general drug-induced liver injury were antineoplastics, anti-inflammatory agents/common cold drugs, chemotherapeutics including antituberculous drugs, antidiabetics, antiulcers and antiepileptics. In addition, reported cases for fulminant hepatitis were also summarized. We found that antituberculous isoniazid and antineoplastic tegafur-uracil were the top two suspected drugs. These results might deepen understanding of current situations for the drug-induced liver injury in Japan.

Systematic review of severe acute liver injury caused by terbinafine.

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Yan, Jun; Wang, Xiaolin; Chen, Shengli

2014-08-01

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

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

Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 improves acute liver injury induced by D-galactosamine in rats.

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Lv, Long-Xian; Hu, Xin-Jun; Qian, Gui-Rong; Zhang, Hua; Lu, Hai-Feng; Zheng, Bei-Wen; Jiang, Li; Li, Lan-Juan

2014-06-01

This work investigated the effect of the intragastric administration of five lactic acid bacteria from healthy people on acute liver failure in rats. Sprague-Dawley rats were given intragastric supplements of Lactobacillus salivarius LI01, Lactobacillus salivarius LI02, Lactobacillus paracasei LI03, Lactobacillus plantarum LI04, or Pediococcus pentosaceus LI05 for 8 days. Acute liver injury was induced on the eighth day by intraperitoneal injection of 1.1 g/kg body weight D-galactosamine (D-GalN). After 24 h, samples were collected to determine the level of liver enzymes, liver function, histology of the terminal ileum and liver, serum levels of inflammatory cytokines, bacterial translocation, and composition of the gut microbiome. The results indicated that pretreatment with L. salivarius LI01 or P. pentosaceus LI05 significantly reduced elevated alanine aminotransferase and aspartate aminotransferase levels, prevented the increase in total bilirubin, reduced the histological abnormalities of both the liver and the terminal ileum, decreased bacterial translocation, increased the serum level of interleukin 10 and/or interferon-γ, and resulted in a cecal microbiome that differed from that of the liver injury control. Pretreatment with L. plantarum LI04 or L. salivarius LI02 demonstrated no significant effects during this process, and pretreatment with L. paracasei LI03 aggravated liver injury. To the best of our knowledge, the effects of the three species-L. paracasei, L. salivarius, and P. pentosaceus-on D-GalN-induced liver injury have not been previously studied. The excellent characteristics of L. salivarius LI01 and P. pentosaceus LI05 enable them to serve as potential probiotics in the prevention or treatment of acute liver failure.

Blood Pyrrole-Protein Adducts--A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans.

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Ruan, Jianqing; Gao, Hong; Li, Na; Xue, Junyi; Chen, Jie; Ke, Changqiang; Ye, Yang; Fu, Peter Pi-Cheng; Zheng, Jiang; Wang, Jiyao; Lin, Ge

2015-01-01

Pyrrolizidine alkaloids (PAs) induce liver injury (PA-ILI) and is very likely to contribute significantly to drug-induced liver injury (DILI). In this study we used a newly developed ultra-high performance liquid chromatography-triple quadrupole-mass spectrometry (UHPLC-MS)-based method to detect and quantitate blood pyrrole-protein adducts in DILI patients. Among the 46 suspected DILI patients, 15 were identified as PA-ILI by the identification of PA-containing herbs exposed. Blood pyrrole-protein adducts were detected in all PA-ILI patients (100%). These results confirm that PA-ILI is one of the major causes of DILI and that blood pyrrole-protein adducts quantitated by the newly developed UHPLC-MS method can serve as a specific biomarker of PA-ILI.

Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury.

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Arya J Bahrami

Full Text Available Liver fibrosis is mediated by hepatic stellate cells (HSCs, which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR-mediated signaling, via endothelin-1 (ET-1 and angiotensin II (AngII, increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5, an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs. Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.

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

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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.

Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

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Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

2016-06-01

Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Comparison of British Thoracic Society and American Thoracic Society reintroduction guidelines for anti-tuberculous therapy induced liver injury

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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 significant difference between the two groups (p<0.7). Age was positively related with drug-induced liver injury, while body mass index and serum albumin were negatively associated. Conclusion: There was no significant difference between the two major guidelines though the American Thoracic Society guideline was easier to follow. (author)

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

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Maria E. Linnaus

2016-11-01

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

Preventive effects of indole-3-carbinol against alcohol-induced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms: Role of gut-liver-adipose tissue axis.

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Choi, Youngshim; Abdelmegeed, Mohamed A; Song, Byoung-Joon

2018-05-01

Indole-3-carbinol (I3C), found in Brassica family vegetables, exhibits antioxidant, anti-inflammatory, and anti-cancerous properties. Here, we aimed to evaluate the preventive effects of I3C against ethanol (EtOH)-induced liver injury and study the protective mechanism(s) by using the well-established chronic-plus-binge alcohol exposure model. The preventive effects of I3C were evaluated by conducting various histological, biochemical, and real-time PCR analyses in mouse liver, adipose tissue, and colon, since functional alterations of adipose tissue and intestine can also participate in promoting EtOH-induced liver damage. Daily treatment with I3C alleviated EtOH-induced liver injury and hepatocyte apoptosis, but not steatosis, by attenuating elevated oxidative stress, as evidenced by the decreased levels of hepatic lipid peroxidation, hydrogen peroxide, CYP2E1, NADPH-oxidase, and protein acetylation with maintenance of mitochondrial complex I, II, and III protein levels and activities. I3C also restored the hepatic antioxidant capacity by preventing EtOH-induced suppression of glutathione contents and mitochondrial aldehyde dehydrogenase-2 activity. I3C preventive effects were also achieved by attenuating the increased levels of hepatic proinflammatory cytokines, including IL1β, and neutrophil infiltration. I3C also attenuated EtOH-induced gut leakiness with decreased serum endotoxin levels through preventing EtOH-induced oxidative stress, apoptosis of enterocytes, and alteration of tight junction protein claudin-1. Furthermore, I3C alleviated adipose tissue inflammation and decreased free fatty acid release. Collectively, I3C prevented EtOH-induced liver injury via attenuating the damaging effect of ethanol on the gut-liver-adipose tissue axis. Therefore, I3C may also have a high potential for translational research in treating or preventing other types of hepatic injury associated with oxidative stress and inflammation. Copyright © 2017 Elsevier Inc. All

Role of hypoxia inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury in mice.

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Hong-Min Ni

Full Text Available Chronic alcohol causes liver hypoxia and steatosis, which eventually develops into alcoholic liver disease (ALD. While it has been known that alcohol consumption activates hepatic hypoxia inducing factor-1α (HIF-1α, conflicting results regarding the role of HIF-1α in alcohol-induced liver injury and steatosis in mice have been reported. In the present study, we aimed to use hepatocyte-specific HIF-1β knockout mice to eliminate the possible compensatory effects of the single knockout of the 1α subunit of HIF to study the role of HIFs in ALD. C57BL/6 wild type mice were treated with acute ethanol to mimic human binge drinking. Matched wild-type and hepatocyte specific HIF-1β knockout mice were also subjected to a recently established Gao-binge alcohol model to mimic chronic plus binge conditions, which is quite common in human alcoholics. We found that acute alcohol treatment increased BNIP3 and BNIP3L/NIX expression in primary cultured hepatocytes and in mouse livers, suggesting that HIF may be activated in these models. We further found that hepatocyte-specific HIF-1β knockout mice developed less steatosis and liver injury following the Gao-binge model or acute ethanol treatment compared with their matched wild type mice. Mechanistically, protection against Gao-binge treatment-induced steatosis and liver injury was likely associated with increased FoxO3a activation and subsequent induction of autophagy in hepatocyte-specific HIF-1β knockout mice.

Drug- and herb-induced liver injury: Progress, current challenges and emerging signals of post-marketing risk.

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Raschi, Emanuel; De Ponti, Fabrizio

2015-07-08

Drug-induced liver injury (DILI) and herb-induced liver injury is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications in the past 15 years. This review will first provide clues for clinicians to suspect idiosyncratic (unpredictable) DILI and succeed in diagnosis. Causality assessment remains challenging and requires careful medical history as well as awareness of multifaceted aspects, especially for herbs. Drug discontinuation and therapy reconciliation remain the mainstay in patent's management to minimize occurrence of acute liver failure. The second section will address novel agents associated with liver injury in 2014 (referred to as "signals"), especially in terms of clinical, research and drug development implications. Insights will be provided into recent trends by highlighting the contribution of different post-marketing data, especially registries and spontaneous reporting systems. This literature scrutiny suggests: (1) the importance of post-marketing databases as tools of clinical evidence to detect signals of DILI risk; and (2) the need for joining efforts in improving predictivity of pre-clinical assays, continuing post-marketing surveillance and design ad hoc post-authorization safety studies. In this context, ongoing European/United States research consortia and novel pharmaco-epidemiological tools (e.g., specialist prescription event monitoring) will support innovation in this field. Direct oral anticoagulants and herbal/dietary supplements appear as key research priorities.

Mesenchymal stem cells correct haemodynamic dysfunction associated with liver injury after extended resection in a pig model.

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Tautenhahn, Hans-Michael; Brückner, Sandra; Uder, Christiane; Erler, Silvio; Hempel, Madlen; von Bergen, Martin; Brach, Janine; Winkler, Sandra; Pankow, Franziska; Gittel, Claudia; Baunack, Manja; Lange, Undine; Broschewitz, Johannes; Dollinger, Matthias; Bartels, Michael; Pietsch, Uta; Amann, Kerstin; Christ, Bruno

2017-06-01

In patients, acute kidney injury (AKI) is often due to haemodynamic impairment associated with hepatic decompensation following extended liver surgery. Mesenchymal stem cells (MSCs) supported tissue protection in a variety of acute and chronic diseases, and might hence ameliorate AKI induced by extended liver resection. Here, 70% liver resection was performed in male pigs. MSCs were infused through a central venous catheter and haemodynamic parameters as well as markers of acute kidney damage were monitored under intensive care conditions for 24 h post-surgery. Cytokine profiles were established to anticipate the MSCs' potential mode of action. After extended liver resection, hyperdynamic circulation, associated with hyponatraemia, hyperkalaemia, an increase in serum aldosterone and low urine production developed. These signs of hepatorenal dysfunction and haemodynamic impairment were corrected by MSC treatment. MSCs elevated PDGF levels in the serum, possibly contributing to circulatory homeostasis. Another 14 cytokines were increased in the kidney, most of which are known to support tissue regeneration. In conclusion, MSCs supported kidney and liver function after extended liver resection. They probably acted through paracrine mechanisms improving haemodynamics and tissue homeostasis. They might thus provide a promising strategy to prevent acute kidney injury in the context of post-surgery acute liver failure.

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

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Aida Ortega-Alonso

2016-05-01

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

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2+/- mice

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Hoekstra, H; Porte, RJ; Tian, Y; Jochum, W; Stieger, B; Moritz, W; Slooff, MJH; Graf, R; Clavien, PA

Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug

Sodium 4-phenylbutyrate protects against liver ischemia reperfusion injury by inhibition of endoplasmic reticulum-stress mediated apoptosis.

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Vilatoba, Mario; Eckstein, Christopher; Bilbao, Guadalupe; Smyth, Cheryl A; Jenkins, Stacie; Thompson, J Anthony; Eckhoff, Devin E; Contreras, Juan L

2005-08-01

Evidence is emerging that the endoplasmic reticulum (ER) participates in initiation of apoptosis induced by the unfolded protein response and by aberrant Ca(++) signaling during cellular stress such as ischemia/reperfusion injury (I/R injury). ER-induced apoptosis involves the activation of caspase-12 and C/EBP homologous protein (CHOP), and the shutdown of translation initiated by phosphorylation of eIF2alpha. Sodium 4-phenylbutyrate (PBA) is a low molecular weight fatty acid that acts as a chemical chaperone reducing the load of mutant or unfolded proteins retained in the ER during cellular stress and also exerting anti-inflammatory activity. It has been used successfully for treatment of urea cycle disorders and sickle cell disease. Thus, we hypothesized that PBA may reduce ER-induced apoptosis triggered by I/R injury to the liver. Groups of male C57BL/6 mice were subjected to warm ischemia (70% of the liver mass, 45 minutes). Serum aspartate aminotransferase was assessed 6 hours after reperfusion; apoptosis was evaluated by enzyme-linked immunosorbent assays of caspase-12 and plasma tumor necrosis factor alpha, Western blot analyses of eIF2alpha, and reverse transcriptase-polymerase chain reaction of CHOP expression. A dose-dependent decrease in aspartate aminotransferase was demonstrated in mice given intraperitoneal PBA (1 hour before and 12 hours after reperfusion), compared with vehicle-treated controls; this effect was associated with reduced pyknosis, parenchymal hemorrhages, and neutrophil infiltrates in PBA-treated mice, compared with controls. In a lethal model of total liver I/R injury, all vehicle-treated controls died within 3 days after reperfusion. In contrast, 50% survival (>30 days) was observed in animals given PBA. The beneficial effects of PBA were associated with a greater than 45% reduction in apoptosis, decreased ER-mediated apoptosis characterized by significant reduction in caspase-12 activation, and reduced levels of both phosphorylated

Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis

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Andrea Iorga

2017-05-01

Full Text Available Drug-induced liver injury (DILI can broadly be divided into predictable and dose dependent such as acetaminophen (APAP and unpredictable or idiosyncratic DILI (IDILI. Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER and mitochondrial stress leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI is usually the result of engagement of the innate and adaptive immune system (likely apoptotic, involving death receptors (DR. Here, we review the hepatocyte cell death pathways both in direct hepatotoxicity such as in APAP DILI as well as in IDILI. We examine the known signaling pathways in APAP toxicity, a model of necrotic liver cell death. We also explore what is known about the genetic basis of IDILI and the molecular pathways leading to immune activation and how these events can trigger hepatotoxicity and cell death.

Impaired TFEB-mediated Lysosome Biogenesis and Autophagy Promote Chronic Ethanol-induced Liver Injury and Steatosis in Mice.

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Chao, Xiaojuan; Wang, Shaogui; Zhao, Katrina; Li, Yuan; Williams, Jessica A; Li, Tiangang; Chavan, Hemantkumar; Krishnamurthy, Partha; He, Xi C; Li, Linheng; Ballabio, Andrea; Ni, Hong-Min; Ding, Wen-Xing

2018-05-18

Defects in lysosome function and autophagy contribute to pathogenesis of alcoholic liver disease. We investigated the mechanisms by which alcohol consumption affects these processes, evaluating the functions transcription factor EB (TFEB), which regulates lysosomal biogenesis. We performed studies with GFP-LC3 mice, mice with liver-specific deletion of transcription factor EB (TFEB), mice with disruption of the transcription factor E3 gene (TFE3-knockout mice), mice with disruption of the Tefb and Tfe3 genes (TFEB, TFE3 double-knockout mice), and Tfeb flox/flox albumin cre-negative mice (controls). TFEB was overexpressed from adenoviral vectors or knocked down with small interfering RNAs in mouse livers. Mice were placed on diets of chronic ethanol feeding plus an acute binge to induce liver damage (ethanol diet); some mice were also given injections of torin1, an inhibitor of the kinase activity of the mechanistic target of rapamycin (mTOR). Liver tissues were collected and analyzed by immunohistochemistry, immunoblots, and quantitative real-time PCR to monitor lysosome biogenesis. We analyzed levels of TFEB in liver tissues from patients with alcoholic hepatitis and from healthy donors (controls) by immunohistochemistry. Liver tissues from mice on the ethanol diet had lower levels of total and nuclear TFEB, compared with control mice, and hepatocytes had reduced lysosome biogenesis and autophagy. Hepatocytes from mice on the ethanol diet had increased translocation of mTOR into lysosomes, resulting increased mTOR activation. Administration of torin1 increased liver levels of TFEB and reduced steatosis and liver injury induced by ethanol. Mice that overexpressed TFEB in liver developed less-severe ethanol-induced liver injury and had increased lysosomal biogenesis and mitochondrial bioenergetics compared to mice carrying a control vector. Mice with knockdown of TFEB, as well as TFEB, TFE3 double-knockout mice, developed more severe liver injury in response to the

Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury.

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Dai, Jie; Liu, Mingwei; Ai, Qing; Lin, Ling; Wu, Kunwei; Deng, Xinyu; Jing, Yuping; Jia, Mengying; Wan, Jingyuan; Zhang, Li

2014-06-05

Metformin is a commonly used anti-diabetic drug with AMP-activated protein kinase (AMPK)-dependent hypoglycemic activities. Recent studies have revealed its anti-inflammatory and anti-oxidative properties. In the present study, the anti-oxidative potential of metformin and its potential mechanisms were investigated in a mouse model with carbon tetrachloride (CCl₂)-induced severe oxidative liver injury. Our results showed that treatment with metformin significantly attenuated CCl₂-induced elevation of serum aminotransferases and hepatic histological abnormalities. The alleviated liver injury was associated with decreased hepatic contents of oxidized glutathione (GSSG) and malondialdehyde (MDA). In addition, metformin treatment dose-dependently enhanced the activities of catalase (CAT) and decreased CCl₄-induced elevation of hepatic H₂O₂ levels, but it had no obvious effects on the protein level of CAT. We also found that metformin increased the level of phosphorylated AMP-activated protein kinase (AMPK), but treatment with AMPK activator AICAR had no obvious effects on CAT activity. A molecular docking analysis indicated that metformin might interact with CAT via hydrogen bonds. These data suggested that metformin effectively alleviated CCl₄-induced oxidative liver injury in mice and these hepatoprotective effects might be associated with CAT. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

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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.

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

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Patricia Rivera

2017-10-01

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

Chilean Strawberry Consumption Protects against LPS-Induced Liver Injury by Anti-Inflammatory and Antioxidant Capability in Sprague-Dawley Rats

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Sebastian Molinett

2015-01-01

Full Text Available The Chilean strawberry fruit has high content of antioxidants and polyphenols. Previous studies evidenced antioxidant properties by in vitro methods. However, the antioxidant effect and its impact as functional food on animal health have not been evaluated. In this study, rats were fed with a Chilean strawberry aqueous extract (4 g/kg of animal per day and then subjected to LPS-induced liver injury (5 mg/kg. Transaminases and histological studies revealed a reduction in liver injury in rats fed with strawberry aqueous extract compared with the control group. Additionally, white strawberry supplementation significantly reduced the serum levels and gene expression of TNF-α, IL-6, and IL-1β cytokines compared with nonsupplemented rats. The level of F2-isoprostanes and GSH/GSSG indicated a reduction in liver oxidative stress by the consumption of strawberry aqueous extract. Altogether, the evidence suggests that dietary supplementation of rats with a Chilean white strawberry aqueous extract favours the normalization of oxidative and inflammatory responses after a liver injury induced by LPS.

Chilean Strawberry Consumption Protects against LPS-Induced Liver Injury by Anti-Inflammatory and Antioxidant Capability in Sprague-Dawley Rats.

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Molinett, Sebastian; Nuñez, Francisca; Moya-León, María Alejandra; Zúñiga-Hernández, Jessica

2015-01-01

The Chilean strawberry fruit has high content of antioxidants and polyphenols. Previous studies evidenced antioxidant properties by in vitro methods. However, the antioxidant effect and its impact as functional food on animal health have not been evaluated. In this study, rats were fed with a Chilean strawberry aqueous extract (4 g/kg of animal per day) and then subjected to LPS-induced liver injury (5 mg/kg). Transaminases and histological studies revealed a reduction in liver injury in rats fed with strawberry aqueous extract compared with the control group. Additionally, white strawberry supplementation significantly reduced the serum levels and gene expression of TNF-α, IL-6, and IL-1β cytokines compared with nonsupplemented rats. The level of F2-isoprostanes and GSH/GSSG indicated a reduction in liver oxidative stress by the consumption of strawberry aqueous extract. Altogether, the evidence suggests that dietary supplementation of rats with a Chilean white strawberry aqueous extract favours the normalization of oxidative and inflammatory responses after a liver injury induced by LPS.

Preventive effects of dexmedetomidine on the liver in a rat model of acid-induced acute lung injury.

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Sen, Velat; Güzel, Abdulmenap; Şen, Hadice Selimoğlu; Ece, Aydın; Uluca, Unal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

2014-01-01

The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

Salecan protected against concanavalin A-induced acute liver injury by modulating T cell immune responses and NMR-based metabolic profiles

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Sun, Qi; Xu, Xi, E-mail: xuxi@njust.edu.cn; Yang, Xiao; Weng, Dan; Wang, Junsong; Zhang, Jianfa

2017-02-15

Salecan, a water-soluble extracellular β-glucan produced by Agrobacterium sp. ZX09, has been reported to exhibit a wide range of biological effects. The aims of the present study were to investigate the protective effect of salecan against Concanavalin A (ConA)-induced hepatitis, a well-established animal model of immune-mediated liver injury, and to search for possible mechanisms. C57BL/6 mice were pretreated with salecan followed by ConA injection. Salecan treatment significantly reduced ConA-induced acute liver injury, and suppressed the expression and secretion of inflammatory cytokines including interferon (IFN)-γ, interleukin (IL)-6 and IL-1β in ConA-induced liver injury model. The high expression levels of chemokines and adhesion molecules such as MIP-1α, MIP-1β, ICAM-1, MCP-1 and RANTES in the liver induced by ConA were also down-regulated after salecan treatment. Salecan inhibited the infiltration and activation of inflammatory cells, especially T cells, in the liver induced by ConA. Moreover, salecan reversed the metabolic profiles of ConA-treated mice towards the control group by partly recovering the metabolic perturbations induced by ConA. Our results suggest the preventive and therapeutic potential of salecan in immune-mediated hepatitis. - Highlights: • Salecan treatment significantly reduced ConA-induced liver injury. • Salecan suppressed the expression and secretion of inflammatory cytokines. • Salecan decreased the expression of chemokines and adhesion molecules in liver. • Salecan inhibited the infiltration and activation of T cells induced by ConA. • Salecan partly recovered the metabolic perturbations induced by ConA.

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.

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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.

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

THE LAWFUL CONSEQUENCES OF BIRTH CERTIFICATE ON CHILDREN ABROGATION

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Natasya Immanuela Sandjojo

2017-12-01

Full Text Available Research due to the law on the abrogation of birth certificates against children aims to know the effect of law affecting the child, as well as review of the determination and judgment in court that play a role in the birth certificate abrogation. This research describes the importance of birth certificate because of the low public awareness to perform birth registration. The study uses normative juridical research, which faces legal issues with the process of discovering legal rules, principles, and legal doctrines, with deductive methods, starting from the general thing and then generating specific and legitimate answers. Based on the results of the study, that the abrogation of birth certificate brings great lawful consequences for the child, especially the status and position of the child, as well as the right of alimentation,  which in this study included some examples of determination and court decision about the birth certificate abrogation.

Comparative Study on the Cytoprotective Effects of Activated Protein C Treatment in Nonsteatotic and Steatotic Livers under Ischemia-Reperfusion Injury

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Akitoshi Matsuda

2015-01-01

Full Text Available Activated protein C (APC has cytoprotective effects on liver ischemia-reperfusion injury (IRI. However, it is unclear whether APC is beneficial in steatotic liver IRI. We compared the cytoprotective effects of APC in nonsteatotic and steatotic liver IRI. Methods. Mice fed either normal diets (ND mice or high fat diets (HF mice, were treated with APC or saline (control and were performed 60 min partial IRI. Moreover, primary steatotic hepatocytes were either untreated or treated with APC and then incubated with H2O2. Results. APC significantly reduced serum transaminase levels and the inflammatory cells infiltration compared with control at 4 h in ND mice and at 24 h in HF mice. APC inhibited sinusoidal endothelial injury in ND mice, but not in HF mice. In contrast, APC activated adenosine monophosphate-activated protein kinase (AMPK phosphorylation in HF mice, but not in ND mice. In the in vitro study, APC significantly increased AMPK phosphorylation, ATP concentration, and survival rates of hepatocytes compared with control. Conclusion. During IRI in normal liver, APC attenuated initial damage by inhibiting inflammatory cell infiltration and sinusoidal endothelial injury, but not in steatotic liver. However, in steatotic liver, APC might attenuate late damage via activation of AMPK.

GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

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Hui Zhang

2014-01-01

Full Text Available Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK- 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP, and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB but enhanced the transcriptional activity of cAMP response element binding protein (CREB in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

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Kim, Young C.; Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

2007-01-01

Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards

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

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Di Zhao

2017-11-01

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

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

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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......(6266) (p edema in mice with ALF....

MANAGEMENT OF LIVER TRAUMA

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Dova Subba

2016-03-01

Full Text Available AIM To estimate the incidence of Liver Trauma injuries and grade their severity of injury. To assess the factors responsible for morbidity and mortality after Liver Trauma. To study the postoperative complications and the management of Liver Trauma. MATERIALS AND METHODS The present prospective study was conducted on 100 patients who were admitted to Department of General Surgery for treatment who were managed operatively or non-operatively for abdominal trauma and having liver injury forms the material of the study. This study was conducted over a span of 24 months from June 2013 to November 2015. RESULTS Maximum number of patients are in the age group of 21-30 years (46%. 85% patients (85/100 are males and 15% of patients (15/100 are females. Lapse time of injury and admission varied from 25 minutes to 66 hours and 30 minutes. 75 % of the patients (75/100 presented within 24 hours after injury. Death rate of patients who reached hospital after 24 hours of injury was higher than the patients who reached hospital within 24 hours of injury. 28% of patients (28/100 had associated bony injuries, out of which 5% of patients (5/100 expired due to primary haemorrhage of fractured femur. More than one segment was injured in many patients. Segment V is involved commonly making 55% (55/100 of patients. Next common segment involved is segment VII, making 39% (39/100. CONCLUSION Mechanism of injury is the important factor which is responsible for morbidity in liver injury. Nonoperative management proved to be safe and effective and often has been used to treat patients with liver trauma.

Drug-Induced Liver Injury Network Causality Assessment: Criteria and Experience in the United States

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Paul H. Hayashi

2016-02-01

Full Text Available Hepatotoxicity due to drugs, herbal or dietary supplements remains largely a clinical diagnosis based on meticulous history taking and exclusion of other causes of liver injury. In 2004, the U.S. Drug-Induced Liver Injury Network (DILIN was created under the auspices of the U.S. National Institute of Diabetes and Digestive and Kidney Diseases with the aims of establishing a large registry of cases for clinical, epidemiological and mechanistic study. From inception, the DILIN has used an expert opinion process that incorporates consensus amongst three different DILIN hepatologists assigned to each case. It is the most well-established, well-described and vigorous expert opinion process for DILI to date, and yet it is an imperfect standard. This review will discuss the DILIN expert opinion process, its strengths and weaknesses, psychometric performance and future.

Glechoma hederacea extracts attenuate cholestatic liver injury in a bile duct-ligated rat model.

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Wang, Ya-Yu; Lin, Shih-Yi; Chen, Wen-Ying; Liao, Su-Lan; Wu, Chih-Cheng; Pan, Pin-Ho; Chou, Su-Tze; Chen, Chun-Jung

2017-05-23

In traditional Chinese medicine, Glechoma hederacea is frequently prescribed to patients with cholelithiasis, dropsy, abscess, diabetes, inflammation, and jaundice. Polyphenolic compounds are main bioactive components of Glechoma hederacea. This study was aimed to investigate the hepatoprotective potential of hot water extract of Glechoma hederacea against cholestatic liver injury in rats. Cholestatic liver injury was produced by ligating common bile ducts in Sprague-Dawley rats. Saline and hot water extract of Glechoma hederacea were orally administrated using gastric gavages. Liver tissues and bloods were collected and subjected to evaluation using histological, molecular, and biochemical approaches. Using a rat model of cholestasis caused by bile duct ligation (BDL), daily oral administration of Glechoma hederacea hot water extracts showed protective effects against cholestatic liver injury, as evidenced by the improvement of serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Glechoma hederacea extracts alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), connective tissue growth factor, and collagen expression, and the anti-fibrotic effects were accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad2/3 activity. Glechoma hederacea extracts attenuated BDL-induced inflammatory cell infiltration/accumulation, NF-κB and AP-1 activation, and inflammatory cytokine production. Further studies demonstrated an inhibitory effect of Glechoma hederacea extracts on the axis of high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) intracellular signaling pathways. The hepatoprotective, anti-oxidative, anti-inflammatory, and anti-fibrotic effects of Glechoma hederacea extracts seem to be multifactorial. The beneficial effects of daily Glechoma hederacea extracts supplementation were associated with anti-oxidative, anti-inflammatory, and anti-fibrotic potential, as well as down

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

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Kamran Qureshi

2014-01-01

Full Text Available Hepatitis associated aplastic anemia (HAAA is a rare syndrome in which severe aplastic anemia (SAA complicates the recovery of acute hepatitis (AH. HAAA is described to occur with AH caused by viral infections and also with idiopathic cases of AH and no clear etiology of liver injury. Clinically, AH can be mild to fulminant and transient to persistent and precedes the onset SAA. It is assumed that immunologic dysregulation following AH leads to the development of SAA. Several observations have been made to elucidate the immune mediated injury mechanisms, ensuing from liver injury and progressing to trigger bone marrow failure with the involvement of activated lymphocytes and severe T-cell imbalance. HAAA has a very poor outcome and often requires bone marrow transplant (BMT. The findings of immune related myeloid injury implied the use of immunosuppressive therapy (IST and led to improved survival from HAAA. We report a case of young male who presented with AH resulting from the intake of muscle building protein supplements and anabolic steroids. The liver injury slowly resolved with supportive care and after 4 months of attack of AH, he developed SAA. He was treated with IST with successful outcome without the need for a BMT.

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

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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.

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

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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

Factors affecting drug-induced liver injury: antithyroid drugs as instances

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Reza Heidari

2014-09-01

Full Text Available Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

Chilean Strawberry Consumption Protects against LPS-Induced Liver Injury by Anti-Inflammatory and Antioxidant Capability in Sprague-Dawley Rats

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Molinett, Sebastian; Nuñez, Francisca; Moya-León, María Alejandra; Zúñiga-Hernández, Jessica

2015-01-01

The Chilean strawberry fruit has high content of antioxidants and polyphenols. Previous studies evidenced antioxidant properties by in vitro methods. However, the antioxidant effect and its impact as functional food on animal health have not been evaluated. In this study, rats were fed with a Chilean strawberry aqueous extract (4 g/kg of animal per day) and then subjected to LPS-induced liver injury (5 mg/kg). Transaminases and histological studies revealed a reduction in liver injury in rats...

Acetaminophen-induced Liver Injury is Attenuated in Transgenic fat-1 Mice Endogenously Synthesizing Long-chain n-3 Fatty Acids.

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Feng, Ruibing; Wang, Yang; Liu, Conghui; Yan, Chunyan; Zhang, Hang; Su, Huanxing; Kang, Jing X; Shang, Chang-Zhen; Wan, Jian-Bo

2018-04-18

Acetaminophen (APAP) overdose-caused hepatotoxicity is the most commonly cause of drugs-induced liver failurecharacterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1) / mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-κB) - mediated inflammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose. Copyright © 2018 Elsevier Inc. All rights reserved.

Preventive Effects of Dexmedetomidine on the Liver in a Rat Model of Acid-Induced Acute Lung Injury

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Velat Şen

2014-01-01

Full Text Available The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300–350 g were allocated randomly to four groups. In group 1, normal saline (NS was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI was found to be associated with increased malondialdehyde (MDA, total oxidant activity (TOA, oxidative stress index (OSI, and decreased total antioxidant capacity (TAC. Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P<0.05. The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

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Woolbright, Benjamin L. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Antoine, Daniel J.; Jenkins, Rosalind E. [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Bajt, Mary Lynn [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Park, B. Kevin [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

2013-12-15

Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given D-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. - Highlights: • The mechanism of cell death during cholestasis remains a controversial topic. • Plasma biomarkers offer new insight into cell death after bile duct ligation. • Cytokeratin-18, microRNA-122 and HMGB

Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

International Nuclear Information System (INIS)

Woolbright, Benjamin L.; Antoine, Daniel J.; Jenkins, Rosalind E.; Bajt, Mary Lynn; Park, B. Kevin; Jaeschke, Hartmut

2013-01-01

Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given D-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. - Highlights: • The mechanism of cell death during cholestasis remains a controversial topic. • Plasma biomarkers offer new insight into cell death after bile duct ligation. • Cytokeratin-18, microRNA-122 and HMGB

Thromboxane A{sub 2} receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment

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Minamino, Tsutomu [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ito, Yoshiya [Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ohkubo, Hirotoki [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Surgery, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Hosono, Kanako; Suzuki, Tatsunori [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Sato, Takehito [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Ae, Takako; Shibuya, Akitaka [Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Sakagami, Hiroyuki [Departments of Anatomy, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Narumiya, Shuh [Department of Pharmacology, Kyoto University School of Medicine, Kyoto, 606-8315 (Japan); Koizumi, Wasaburo [Departments of Gastroenterology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan); Majima, Masataka, E-mail: mmajima@med.kitasato-u.ac.jp [Departments of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374 (Japan)

2012-02-15

It is thought that thromboxane A{sub 2} (TxA{sub 2}) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA{sub 2} is involved in liver repair. The objective of the present study was to examine the role of TxA{sub 2} receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl{sub 4}) was used to induce liver injury in TP knockout (TP{sup −/−}) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48 h, respectively, and then declined. In TP{sup −/−} mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP{sup −/−} mice, the accumulation of hepatic CD11b{sup +}/F4/80{sup +} macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C―C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl{sub 4}-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression. -- Highlights: ► TP enhances liver regeneration by CCl{sub 4}. ► TP accumulates macrophages. ► TP up-regulates MCP-1.

Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

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Francis, Ben; Clarke, Joanna I; Walker, Lauren E; Brillant, Nathalie; Jorgensen, Andrea L; Park, B Kevin; Pirmohamed, Munir; Antoine, Daniel J

2018-05-02

The potential of mechanistic biomarkers to improve the prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration as well as to characterize their natural variability and impact of diurnal variation. Serum samples from 200 healthy volunteers were recruited as part of a cross sectional study; of these, 50 subjects had weekly serial sampling over 3 weeks, while 24 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), high mobility group box-1 (HMGB1), total keratin-18 (FL-K18), caspase cleaved keratin-18 (cc-K18), glutamate dehydrogenase (GLDH) and colony stimulating factor-1 (CSF-1) were assessed by validated assays. Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models (ALT 50 (41-50) U/l, miR-122 3548 (2912-4321) copies/µl, HMGB1 2.3 (2.2-2.4) ng/ml, FL-K18 475 (456-488) U/l, cc-K18 272 (256-291) U/l, GLDH 27 (26-30) U/l and CSF-1 2.4 (2.3-2.9) ng/ml). There was a small but significant intra-individual time random effect detected but no significant impact of diurnal variation was observed, with the exception of GLDH. Reference intervals for novel DILI biomarkers have been described for the first time. An upper limit of a reference range might represent the most appropriate method to utilize these data. Regulatory authorities have published letters of support encouraging further qualification of leading candidate biomarkers. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification. Drug-induced liver injury (DILI) has a big impact on patient health and the development of new medicines. Unfortunately, currently used blood-based tests to assess liver injury and recovery suffer from insufficiencies. Newer blood

Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.

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Barbara Renga

Full Text Available BACKGROUND: The farnesoid-x-receptor (FXR is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. PRINCIPAL FINDINGS: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTα, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. CONCLUSIONS: FXR antagonism in vivo

The effects of somatostatin and ursodeoxycholic acid in preventing the ischemic injury of the liver following Pringle maneuver in obstructive jaundice-rat model.

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Pergel, Ahmet; Zengin, Kagan; Cercel, Ali; Aki, Hilal; Kaya, Safiye

2007-01-01

In our study, the effects of somatostatin (SS) and ursodeoxycholic acid (UDCA) on ischemic liver injury were studied in (obstructive) jaundice-rat model. For this purpose, jaundice was produced in the first four groups by binding of their choleducts. We performed just laparotomy to the other four groups of animals. To groups 1 and 5, SS was given 15 mcg/kg/day intraperitoneally, and to groups 2 and 6, UDCA was given 20 mg/kg/day enterally. No drugs were given to any other group. At the end of one week, a procedure with ischemia of the liver for 60 minutes followed by reperfusion for 2 hours, was performed to each rat except for groups 4 and 8. Following this procedure, they were sacrificed. The blood samples were taken to measure SGOT, SGPT, ALP, LDH, total and direct bilirubin levels, while liver biopsies were taken for histopathological evaluation. Under normothermic conditions, following 60-minute liver ischemia period, no irreversible histopathological changes were detected. However, increases in liver necrosis parameters were noted biochemically. SS and UDCA were thought to be effective in preventing the injury by decreasing the liver enzymes levels to a significant degree. The damage of the hepatic ischemic injury was found to be more meaningful and prominent in liver with jaundice. In this study, it was noted that SS and UDCA decrease the effects of cholestatic hepatic injury especially and improve the condition.

Human Parvovirus B19 NS1 Protein Aggravates Liver Injury in NZB/W F1 Mice

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Tsai, Chun-Chou; Chiu, Chun-Ching; Hsu, Jeng-Dong; Hsu, Huai-Sheng; Tzang, Bor-Show; Hsu, Tsai-Ching

2013-01-01

Human parvovirus B19 (B19) has been associated with a variety of diseases. However, the influence of B19 viral proteins on hepatic injury in SLE is still obscure. To elucidate the effects of B19 viral proteins on livers in SLE, recombinant B19 NS1, VP1u or VP2 proteins were injected subcutaneously into NZB/W F1 mice, respectively. Significant expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were detected in NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Markedly hepatocyte disarray and lymphocyte infiltration were observed in livers from NZB/WF 1 mice receiving B19 NS1 as compared to those mice receiving PBS. Additionally, significant increases of Tumor Necrosis Factor –α (TNF-α), TNF-α receptor, IκB kinase –α (IKK-α), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) and nuclear factor-kappa B (NF-κB) were detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Accordingly, significant increases of matrix metalloproteinase-9 (MMP9) and U-plasminogen activator (uPA) were also detected in livers from NZB/W F1 mice receiving B19 NS1 as compared to those mice receiving PBS. Contrarily, no significant variation on livers from NZB/W F1 mice receiving B19 VP1u or VP2 was observed as compared to those mice receiving PBS. These findings firstly demonstrated the aggravated effects of B19 NS1 but not VP1u or VP2 protein on hepatic injury and provide a clue in understanding the role of B19 NS1 on hepatic injury in SLE. PMID:23555760

Quercetin protects liver injury induced by bile duct ligation via attenuation of Rac1 and NADPH oxidase1 expression in rats.

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Kabirifar, Razieh; Ghoreshi, Zohreh-Al-Sadat; Safari, Fatemeh; Karimollah, Alireza; Moradi, Ali; Eskandari-Nasab, Ebrahim

2017-02-01

Bile duct ligation (BDL) and subsequent cholestasis are correlated with oxidative stress, hepatocellular injury and fibrosis. Quercetin is a flavonoid with antifibrotic, and hepatoprotective properties. However, the molecular mechanism underlying quercetin-mediated hepatoprotection is not fully understood. The current study was to evaluate mechanisms of hepatoprotective effect of quercetin in BDL rat model. We divided male Wistar rats into 4 groups (n=8 for each): sham, sham+quercetin (30 mg/kg per day), BDL, and BDL+quercetin (30 mg/kg per day). Four weeks later, the rats were sacrificed, the blood was collected for liver enzyme measurements and liver for the measurement of Rac1, Rac1-GTP and NOX1 mRNA and protein levels by quantitative PCR and Western blotting, respectively. Quercetin significantly alleviated liver injury in BDL rats as evidenced by histology and reduced liver enzymes. Furthermore, the mRNA and protein expression of Rac1, Rac1-GTP and NOX1 were significantly increased in BDL rats compared with those in the sham group (Pliver injury through increasing antioxidant capacity of the liver tissue, while preventing the production of Rac1, Rac1-GTP and NOX1 proteins.

Schisandra sphenanthera extract (Wuzhi Tablet protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

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Xuezhen Zeng

2017-09-01

Full Text Available Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ, a preparation of extract from Schisandra sphenanthera that is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.

Livers from fasted rats acquire resistance to warm and cold ischemia injury.

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Sumimoto, R; Southard, J H; Belzer, F O

1993-04-01

Successful liver transplantation is dependent upon many factors, one of which is the quality of the donor organ. Previous studies have suggested that the donor nutritional status may affect the outcome of liver transplantation and starvation, due to prolonged stay in the intensive care unit, may adversely affect the liver. In this study we have used the orthotopic rat liver transplant model to measure how fasting the donor affects the outcome of liver transplantation. Rat livers were preserved with UW solution either at 37 degrees C (warm ischemia for 45-60 min) or at 4 degrees C (cold ischemia for 30 or 44 hr). After preservation the livers were orthotopically transplanted and survival (for 7 days) was measured, as well as liver functions 6 hr after transplantation. After 45 min of warm ischemia 50% (3 of 6) animals survived when the liver was obtained from a fed donor about 80% (4 of 5) survived when the liver was obtained from a three-day-fasted donor. After 60 min warm ischemia no animal survived (0 of 8, fed group). However, if the donor was fasted for 3 days 89% (8 of 9) of the animals survived for 7 days. Livers cold-stored for 30 hr were 50% viable (3 of 6) and fasting for 1-3 days did not affect this outcome. However, if the donor was fasted for 4 days 100% (9 of 9) survival was obtained. After 44-hr preservation only 29% (2/7) of the recipients survived for 7 days. If the donor was fasted for 4 days, survival increased to 83% (5/6). Liver functions, bile production, and serum enzymes were better in livers from the fasted rats than from the fed rats. Fasting caused a 95% decrease in liver glycogen content. Even with this low concentration of glycogen, liver viability (animal survival) after warm or cold ischemia was not affected, and livers with a low glycogen content were fully viable. Thus liver glycogen does not appear to be important in liver preservation. This study shows that fasting the donor does not cause injury to the liver after warm or cold

Role of liver progenitors in liver regeneration.

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Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A; Canbay, Ali

2015-02-01

During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

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

Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice.

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Peng, Wen-Huang; Chen, Yi-Wen; Lee, Meng-Shiou; Chang, Wen-Te; Tsai, Jen-Chieh; Lin, Ying-Chih; Lin, Ming-Kuem

2016-12-07

Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CC EtOH ). The hepatoprotective effect of CC EtOH (20, 100 and 500 mg/kg) was evaluated on carbon tetrachloride (CCl₄)-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CC EtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl₄ were significantly reduced by CC EtOH . In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA) and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRd) in the liver. We demonstrate that the hepatoprotective mechanisms of CC EtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury.

Hepatoprotective Effect of Cuscuta campestris Yunck. Whole Plant on Carbon Tetrachloride Induced Chronic Liver Injury in Mice

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Wen-Huang Peng

2016-12-01

Full Text Available Cuscuta seeds and whole plant have been used to nourish the liver and kidney. This study was aimed to investigate the hepatoprotective activity of the ethanol extract of Cuscuta campestris Yunck. whole plant (CCEtOH. The hepatoprotective effect of CCEtOH (20, 100 and 500 mg/kg was evaluated on carbon tetrachloride (CCl4-induced chronic liver injury. Serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol were measured and the fibrosis was histologically examined. CCEtOH exhibited a significant inhibition of the increase of serum alanine aminotransferase, aspartate aminotransferase, triglyceride and cholesterol. Histological analyses showed that fibrosis of liver induced by CCl4 were significantly reduced by CCEtOH. In addition, 20, 100 and 500 mg/kg of the extract decreased the level of malondialdehyde (MDA and enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD, glutathione peroxidase (GPx and glutathione reductase (GRd in the liver. We demonstrate that the hepatoprotective mechanisms of CCEtOH were likely to be associated to the decrease in MDA level by increasing the activities of antioxidant enzymes such as SOD, GPx and GRd. In addition, our findings provide evidence that C. campestris Yunck. whole plant possesses a hepatoprotective activity to ameliorate chronic liver injury.

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

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Yumin Xu

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

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

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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.

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.

Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.

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Baghdasaryan, Anna; Fuchs, Claudia D; Österreicher, Christoph H; Lemberger, Ursula J; Halilbasic, Emina; Påhlman, Ingrid; Graffner, Hans; Krones, Elisabeth; Fickert, Peter; Wahlström, Annika; Ståhlman, Marcus; Paumgartner, Gustav; Marschall, Hanns-Ulrich; Trauner, Michael

2016-03-01

Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. Eight week old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1week of ASBT inhibitor feeding. A4250 improved sclerosing cholangitis in Mdr2(-/-) mice and significantly reduced serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of pro-inflammatory (Tnf-α, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct proliferation (mRNA and immunohistochemistry for cytokeratin 19 (CK19)). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly A4250 significantly reduced biliary BA secretion but preserved HCO3(-) and biliary phospholipid secretion resulting in an increased HCO3(-)/BA and PL/BA ratio. In addition, A4250 profoundly increased fecal BA excretion without causing diarrhea and altered BA pool composition, resulting in diminished concentrations of primary BAs tauro-β-muricholic acid and taurocholic acid. Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA

Serum neopterin and soluble CD163 as markers of macrophage activation in paracetamol (acetaminophen)-induced human acute liver injury.

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Craig, D G; Lee, P; Pryde, E A; Hayes, P C; Simpson, K J

2013-12-01

Macrophage activation is implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS) following paracetamol (acetaminophen) overdose (POD). Neopterin is synthesised from macrophages and reflects the intensity of monocyte/macrophage activation. Soluble CD163 (sCD163) is a marker of alternatively activated M2 macrophages. To examine neopterin and sCD163 levels in a cohort of acute liver injury patients. Consecutive patients (n = 41, (18 (43.9%) male) with acute liver injury were enrolled. Neopterin and sCD163 levels were measured by ELISA. A total of 24/33 (72.7%) POD patients developed hepatic encephalopathy (HE), and therefore acute liver failure. Both neopterin and sCD163 levels were significantly higher in PODs compared with chronic liver disease (neopterin P paracetamol overdose, and reflect the degree of macrophage activation in this condition. Serum neopterin in particular may have value as an early proxy marker of macrophage activation following paracetamol overdose. © 2013 John Wiley & Sons Ltd.

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

Breviscapine ameliorates CCl4‑induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation.

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Liu, Yu; Wen, Pei-Hao; Zhang, Xin-Xue; Dai, Yang; He, Qiang

2018-05-02

Acute liver injury is characterized by fibrosis, inflammation and apoptosis, leading to liver failure, cirrhosis or cancer and affecting the clinical outcome in the long term. However, no effective therapeutic strategy is currently available. Breviscapine, a mixture of flavonoid glycosides, has been reported to have multiple biological functions. The present study aimed to investigate the effects of breviscapine on acute liver injury induced by CCl4 in mice. C57BL/6 mice were subjected to intraperitoneal injection with CCl4 for 8 weeks with or without breviscapine (15 or 30 mg/kg). Mice treated with CCl4 developed acute liver injury, as evidenced by histological analysis, Masson trichrome and Sirius Red staining, accompanied with elevated levels of alanine aminotransferase and aspartate aminotransferase. Furthermore, increases in pro‑inflammatory cytokines, chemokines and apoptotic factors, including caspase‑3 and poly(ADP ribose) polymerase‑2 (PARP‑2), were observed. Breviscapine treatment significantly and dose‑dependently reduced collagen deposition and the fibrotic area. Inflammatory cytokines were downregulated by breviscapine through inactivating Toll‑like receptor 4/nuclear factor-κB signaling pathways. In addition, co‑administration of breviscapine with CCl4 decreased the apoptotic response by enhancing B‑cell lymphoma-2 (Bcl‑2) levels, while reducing Bcl‑2‑associated X protein, apoptotic protease activating factor 1, caspase‑3 and PARP activity. Furthermore, CCl4‑induced oxidative stress was blocked by breviscapine through improving anti‑oxidants and impeding mitogen‑activated protein kinase pathways. The present study highlighted that breviscapine exhibited liver‑protective effects against acute hepatic injury induced by CCl4 via suppressing inflammation and apoptosis.

Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

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Nakagawa, Shin-ichiro; Hirata, Yuichi; Kameyama, Takeshi; Tokunaga, Yuko; Nishito, Yasumasa; Hirabayashi, Kazuko; Yano, Junichi; Ochiya, Takahiro; Tateno, Chise; Tanaka, Yasuhito; Mizokami, Masashi; Tsukiyama-Kohara, Kyoko; Inoue, Kazuaki; Yoshiba, Makoto; Takaoka, Akinori; Kohara, Michinori

2013-01-01

The interferon (IFN) system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV) and hepatitis B virus (HBV). This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC). Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs) in the livers and sera of these humanized chimeric mice. Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level) of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic) tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS) and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1), suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet

International Nuclear Information System (INIS)

Tryndyak, Volodymyr P.; Latendresse, John R.; Montgomery, Beverly; Ross, Sharon A.; Beland, Frederick A.; Rusyn, Ivan; Pogribny, Igor P.

2012-01-01

MicroRNAs (miRNAs) are a class of small, conserved, tissue-specific regulatory non-coding RNAs that modulate a variety of biological processes and play a fundamental role in the pathogenesis of major human diseases, including nonalcoholic fatty liver disease (NAFLD). However, the association between inter-individual differences in susceptibility to NAFLD and altered miRNA expression is largely unknown. In view of this, the goals of the present study were (i) to determine whether or not individual differences in the extent of NAFLD-induced liver injury are associated with altered miRNA expression, and (ii) assess if circulating blood miRNAs may be used as potential biomarkers for the noninvasive evaluation of the severity of NAFLD. A panel of seven genetically diverse strains of inbred male mice (A/J, C57BL/6J, C3H/HeJ, 129S/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) were fed a choline- and folate-deficient (CFD) diet for 12 weeks. This diet induced liver injury in all mouse strains; however, the extent of NAFLD-associated pathomorphological changes in the livers was strain-specific, with A/J, C57BL/6J, and C3H/HeJ mice being the least sensitive and WSB/EiJ mice being the most sensitive. The morphological changes in the livers were accompanied by differences in the levels of hepatic and plasma miRNAs. The levels of circulating miR-34a, miR-122, miR-181a, miR-192, and miR-200b miRNAs were significantly correlated with a severity of NAFLD-specific liver pathomorphological features, with the strongest correlation occurring with miR-34a. These observations suggest that the plasma levels of miRNAs may be used as biomarkers for noninvasive monitoring the extent of NAFLD-associated liver injury and susceptibility to NAFLD. -- Highlights: ► Choline- and folate-deficiency induces a strain-specific fatty liver injury in mice. ► The extent of liver pathology was accompanied by the changes in microRNA expression. ► The levels of circulating microRNAs mirror the magnitude of

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

OpenAIRE

Zahra Hesami; Maryam Ayatollahi; Bita Geramizadeh; Akram Jamshidzadeh; Akbar Vahdati

2016-01-01

Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4), we used immunohistochemical analysis ...

Surgical management and outcome of blunt major liver injuries: experience of damage control laparotomy with perihepatic packing in one trauma centre.

Science.gov (United States)

Lin, Being-Chuan; Fang, Jen-Feng; Chen, Ray-Jade; Wong, Yon-Cheong; Hsu, Yu-Pao

2014-01-01

This retrospective study aimed to assess the clinical experience and outcome of damage control laparotomy with perihepatic packing in the management of blunt major liver injuries. From January 1998 to December 2006, 58 patients of blunt major liver injury, American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) equal or greater than III, were operated with perihepatic packing at our institute. Demographic data, intra-operative findings, operative procedures, adjunctive managements and outcome were reviewed. To determine whether there was statistical difference between the survivor and non-survivor groups, data were compared by using Mann-Whitney U test for continuous variables, either Pearson's chi-square test or with Yates continuity correction for contingency tables, and results were considered statistically significant if phepatic artery ligation (n=11) and 7 patients required post-laparotomy hepatic transarterial embolization. Of the 58 patients, 28 survived and 30 died with a 52% mortality rate. Of the 30 deaths, uncontrolled liver bleeding in 24-h caused 25 deaths and delayed sepsis caused residual 5 deaths. The mortality rate versus OIS was grade III: 30% (6/20), grade IV: 54% (13/24), and grade V: 79% (11/14), respectively. On univariate analysis, the significant predictors of mortality were OIS grade (p=0.019), prolonged initial prothrombin time (PT) (p=0.004), active partial thromboplastin time (APTT) (p<0.0001) and decreased platelet count (p=0.005). The mortality rate of surgical blunt major liver injuries remains high even with perihepatic packing. Since prolonged initial PT, APTT and decreased platelet count were associated with high risk of mortality, we advocate combination of damage control resuscitation with damage control laparotomy in these major liver injuries. Copyright © 2013 Elsevier Ltd. All rights reserved.

Revisiting acute liver injury associated with herbalife products.

Science.gov (United States)

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

2011-10-27

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

MR T1{rho} as an imaging biomarker for monitoring liver injury progression and regression: an experimental study in rats with carbon tetrachloride intoxication

Energy Technology Data Exchange (ETDEWEB)

Zhao, Feng; Wang, Yi-Xiang J.; Yuan, Jing; Deng, Min; Ahuja, Anil T. [Chinese University of Hong Kong, Department of Imaging and Interventional Radiology, Prince of Wales Hospital, Hong Kong SAR (China); Wong, Hing Lok [School of Public Health and Primary Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Jockey Club Centre for Osteoporosis Care and Control, Hong Kong SAR (China); Chu, Eagle S.H.; Go, Minnie Y.Y.; Yu, Jun [Chinese University of Hong Kong, Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong SAR (China); Teng, Gao-Jun [Southeast University, Department of Radiology, Zhongda Hospital, Nanjing (China)

2012-08-15

Recently it was shown that the magnetic resonance imaging (MRI) T1{rho} value increased with the severity of liver fibrosis in rats with bile duct ligation. Using a rat carbon tetrachloride (CCl{sub 4}) liver injury model, this study further investigated the merit of T1{rho} relaxation for liver fibrosis evaluation. Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl{sub 4} twice weekly for up to 6 weeks. Then CCl{sub 4} was withdrawn and the animals were allowed to recover. Liver T1{rho} MRI and conventional T2-weighted images were acquired. Animals underwent MRI at baseline and at 2 days, 2 weeks, 4 weeks and 6 weeks post CCl{sub 4} injection, and they were also examined at 1 week and 4 weeks post CCl{sub 4} withdrawal. Liver histology was also sampled at these time points. Liver T1{rho} values increased slightly, though significantly, on day 2, and then increased further and were highest at week 6 post CCl{sub 4} insults. The relative liver signal intensity change on T2-weighted images followed a different time course compared with that of T1{rho}. Liver T1{rho} values decreased upon the withdrawal of the CCl{sub 4} insult. Histology confirmed the animals had typical CCl{sub 4} liver injury and fibrosis progression and regression processes. MR T1{rho} imaging can monitor CCl{sub 4}-induced liver injury and fibrosis. (orig.)

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

NARCIS (Netherlands)

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

2010-01-01

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

Cilostazol attenuates cholestatic liver injury and its complications in common bile duct ligated rats.

Science.gov (United States)

Abdel Kawy, Hala S

2015-04-05

Cilostazol is a phosphodiesterase III inhibitor increases adenosine 3', 5'-cyclic monophosphate (cyclic AMP) level which inhibits hepatic stellate cell activation. Its pharmacological effects include vasodilation, inhibition of vascular smooth muscle cell growth, inhibition of platelet activation and aggregation. The aim of the current study was to determine the effects of early administration of low dose cilostazol on cholestatic liver injury induced by common bile duct ligation (CBDL) in rat. Male Wistar rats (180-200g) were divided into three groups: Group A; simple laparotomy group (sham). Group B; CBDL, Group C; CBDL rats treated with cilostazol (9mg/kg daily for 21 days). Six rats from each group were killed by the end of weeks one and three after surgery, livers and serum were collected for biochemical and histopathological studies. Aspartate aminotransferase, alanine aminotransferase, gama glutamyl transferase, alkaline phosphatase and total bilirubin serum levels decreased in the cilostazol treated rats, when compared with CBDL rats. The hepatic levels of tumor necrosis factor-alpha, transforming growth factor-beta, and platelet derived growth factor-B were significantly lower in cilostazol treated rats than that in CBDL rats. Cilostazol decreased vascular endothelial growth factor level and hemoglobin content in the livers. Cilostazol significantly lowered portal pressure, inhibited ductular proliferation, portal inflammation, hepatic fibrosis and decreased hepatic hydroxyproline contents. Administration of cilostazol in CBDL rats improved hepatic functions, decreased ductular proliferation, ameliorated portal inflammation, lowered portal hypertension and reduced fibrosis. These effects of cilostazol may be useful in the attenuation of liver injury in cholestasis. Copyright © 2015 Elsevier B.V. All rights reserved.

Ebselen abrogates TNFα induced pro‐inflammatory response in glioblastoma

OpenAIRE

Tewari, Richa; Sharma, Vivek; Koul, Nitin; Ghosh, Abhishek; Joseph, Christy; Hossain Sk, Ugir; Sen, Ellora

2008-01-01

We investigated the pro‐inflammatory response mediated by TNFα in glioblastoma and whether treatment with organoselenium Ebselen (2‐phenyl‐1,2‐benzisoselenazol‐3[2H]one) can affect TNFα induced inflammatory response. Exposure to TNFα increased the expression of pro‐inflammatory mediator interleukin IL‐6, IL‐8, monocyte chemoattractant protein‐1 (MCP‐1) and cyclooxygenase (COX‐2). Treatment with Ebselen abrogated TNFα induced increase in pro‐inflammatory mediators. Ebselen not only abrogated T...

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

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

2017-03-08

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

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

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

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Shanzheng Lu

2016-10-01

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

A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

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Roxanne Lim

2014-01-01

Full Text Available Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM, Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.

Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature Swine.

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Liang, Tiebing; Alloosh, Mouhamad; Bell, Lauren N; Fullenkamp, Allison; Saxena, Romil; Van Alstine, William; Bybee, Phelan; Werling, Klára; Sturek, Michael; Chalasani, Naga; Masuoka, Howard C

2015-01-01

Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet) develop metabolic syndrome and nonalcoholic steatohepatitis (NASH) characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model. Ossabaw swine were fed standard chow (control group; n = 6) or NASH diet (n = 6) for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24. The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a) hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes), (b) hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c) Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides. This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a) hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b) hepatocyte ballooning generally precedes the development of fibrosis; (c) there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.

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

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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.

Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury.

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Igami, Kentaro; Shimojo, Yosuke; Ito, Hisatomi; Miyazaki, Toshitsugu; Kashiwada, Yoshiki

2015-04-01

This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)). Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K. Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells. FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver. © 2014 Royal Pharmaceutical Society.

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

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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

Targeted induction of interferon-λ in humanized chimeric mouse liver abrogates hepatotropic virus infection.

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Shin-ichiro Nakagawa

Full Text Available BACKGROUND & AIMS: The interferon (IFN system plays a critical role in innate antiviral response. We presume that targeted induction of IFN in human liver shows robust antiviral effects on hepatitis C virus (HCV and hepatitis B virus (HBV. METHODS: This study used chimeric mice harboring humanized livers and infected with HCV or HBV. This mouse model permitted simultaneous analysis of immune responses by human and mouse hepatocytes in the same liver and exploration of the mechanism of antiviral effect against these viruses. Targeted expression of IFN was induced by treating the animals with a complex comprising a hepatotropic cationic liposome and a synthetic double-stranded RNA analog, pIC (LIC-pIC. Viral replication, IFN gene expression, IFN protein production, and IFN antiviral activity were analyzed (for type I, II and III IFNs in the livers and sera of these humanized chimeric mice. RESULTS: Following treatment with LIC-pIC, the humanized livers of chimeric mice exhibited increased expression (at the mRNA and protein level of human IFN-λs, resulting in strong antiviral effect on HBV and HCV. Similar increases were not seen for human IFN-α or IFN-β in these animals. Strong induction of IFN-λs by LIC-pIC occurred only in human hepatocytes, and not in mouse hepatocytes nor in human cell lines derived from other (non-hepatic tissues. LIC-pIC-induced IFN-λ production was mediated by the immune sensor adaptor molecules mitochondrial antiviral signaling protein (MAVS and Toll/IL-1R domain-containing adaptor molecule-1 (TICAM-1, suggesting dual recognition of LIC-pIC by both sensor adaptor pathways. CONCLUSIONS: These findings demonstrate that the expression and function of various IFNs differ depending on the animal species and tissues under investigation. Chimeric mice harboring humanized livers demonstrate that IFN-λs play an important role in the defense against human hepatic virus infection.

Overexpression of the long noncoding RNA TUG1 protects against cold-induced injury of mouse livers by inhibiting apoptosis and inflammation.

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Su, Song; Liu, Jiang; He, Kai; Zhang, Mengyu; Feng, Chunhong; Peng, Fangyi; Li, Bo; Xia, Xianming

2016-04-01

Hepatic injury provoked by cold storage is a major problem affecting liver transplantation, as exposure to cold induces apoptosis in hepatic tissues. Long noncoding RNAs (lncRNAs) are increasingly understood to regulate apoptosis, but the contribution of lncRNAs to cold-induced liver injury remains unknown. Using RNA-seq, we determined the differential lncRNA expression profile in mouse livers after cold storage and found that expression of the lncRNA TUG1 was significantly down-regulated. Overexpression of TUG1 attenuated cold-induced apoptosis in mouse hepatocytes and liver sinusoidal endothelial cells LSECs, in part by blocking mitochondrial apoptosis and endoplasmic reticulum (ER) stress pathways. Moreover, TUG1 attenuated apoptosis, inflammation, and oxidative stress in vivo in livers subjected to cold storage. Overexpression of TUG1 also improved hepatocyte function and prolonged hepatic graft survival rates in mice. These results suggest that the lncRNA TUG1 exerts a protective effect against cold-induced liver damage by inhibiting apoptosis in mice, and suggests a potential role for TUG1 as a target for the prevention of cold-induced liver damage in liver transplantation. RNA-seq data are available from GEO using accession number GSE76609. © 2016 Federation of European Biochemical Societies.

Experience with managing liver trauma in southeastern Nigeria.

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Chianakwana, Gu; Umeh, Ku; Chianakwana, Jo

2011-04-01

All over the world, liver trauma occurs as a result of blunt or penetrating abdominal injury. To review the management, morbidity and mortality of liver trauma in our resource-deprived centre, and to see how we can improve these outcomes, our poor facilities notwithstanding. This is a descriptive epidemiology. Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria. Patients who were treated for liver trauma in our centre between 2004 and 2010 were reviewed for aetiology of injury, management, morbidity and mortality. Of the 162 patients who were treated for liver trauma during the period, only 156 patients were recruited into the study. One hundred and nineteen (119) were males and 37 were females. Majority were blunt injuries while others were penetrating injuries. The blunt injuries were usually solitary, affecting only the liver whereas the penetrating injuries occasionally involved both the liver and some other organ(s). The commonest cause of blunt injuries was road traffic accident followed by fall from height. The commonest cause of penetrating injury was gunshot wound, followed by stab wound. Morbidity and mortality following liver trauma can be reduced by applying prompt and appropriate management modalities within the ambit of available resources. However, outcome will improve if adequate facilities are available.

The role of the hemostatic system in murine liver injury induced by coexposure to lipopolysaccharide and trovafloxacin, a drug with idiosyncratic liability

International Nuclear Information System (INIS)

Shaw, Patrick J.; Fullerton, Aaron M.; Scott, Michael A.; Ganey, Patricia E.; Roth, Robert A.

2009-01-01

The use of the fluoroquinolone antibiotic trovafloxacin (TVX) was severely restricted in 1999 due to its association with idiosyncratic hepatotoxicity. Previously, we reported that a nontoxic dose of TVX interacts with a nontoxic dose of lipopolysaccharide (LPS) to cause robust hepatocellular injury in mice. This interaction with LPS was not seen in mice treated with levofloxacin (LVX), a fluoroquinolone not associated with hepatotoxicity in people. TVX/LPS-coexposure caused an increase in plasma alanine aminotransferase (ALT) activity as early as 4.5 h after LPS administration which progressed through 15 h. We examined the role of the hemostatic system in TVX/LPS-induced liver injury. At the onset of liver injury, coexposure to TVX/LPS, but not exposure to TVX, LVX, LPS or LVX/LPS, caused increased plasma concentration of thrombin-antithrombin dimers and decreased plasma circulating fibrinogen. LPS treatment induced a small increase in plasma plasminogen activator inhibitor-1 (PAI-1) concentration, and TVX pretreatment enhanced this effect. TVX/LPS coexposure also resulted in hepatic fibrin deposition. Anticoagulant heparin administration reduced TVX/LPS-induced hepatic fibrin deposition and liver injury. PAI-1 -/- mice treated with TVX/LPS exhibited similar fibrin deposition to wild-type mice but had significantly reduced hepatocellular injury. PAI-1 -/- mice, but not heparin-treated mice, had reduced plasma concentrations of several cytokines compared to TVX/LPS-treated controls. In summary, TVX/LPS-coexposure caused an imbalance in the hemostatic system, resulting in thrombin activation increased, plasma concentration of PAI-1 and hepatic fibrin deposition. Both thrombin activation and PAI-1 play critical roles in the progression of TVX/LPS-induced liver injury, but through different modes of action.

Etiology and Outcome of Acute Liver Failure: Experience from a Liver Transplantation Centre in Montreal

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Geneviève Tessier

2002-01-01

Full Text Available BACKGROUND: Acute liver failure is a rare condition in which massive liver injury is associated with the rapid development of hepatic encephalopathy. Although viral hepatitis and drug-induced liver injury are the most common causes, no specific etiology is found in a substantial proportion of cases reported from Europe and the United States.

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

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Fuyang Zhang

2016-11-01

Full Text Available The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR, inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.

Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

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Zhou, Rui-Jun; Ye, Hua; Wang, Feng; Wang, Jun-Long; Xie, Mei-Lin

2017-11-04

Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

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Weaver, Richard J; Betts, Catherine; Blomme, Eric A G; Gerets, Helga H J; Gjervig Jensen, Klaus; Hewitt, Philip G; Juhila, Satu; Labbe, Gilles; Liguori, Michael J; Mesens, Natalie; Ogese, Monday O; Persson, Mikael; Snoeys, Jan; Stevens, James L; Walker, Tracy; Park, B Kevin

2017-07-01

The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

KAUST Repository

Diaz Rua, Ruben

2017-04-19

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

Long-term intake of a high protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

KAUST Repository

Diaz Rua, Ruben; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M.; Oliver, Paula

2017-01-01

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid–base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid–base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences.

Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats.

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Díaz-Rúa, Rubén; Keijer, Jaap; Palou, Andreu; van Schothorst, Evert M; Oliver, Paula

2017-08-01

Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acid-base maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acid-base equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatoprotective effect of Scoparia dulcis on carbon tetrachloride induced acute liver injury in mice.

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Tsai, Jen-Chieh; Peng, Wen-Huang; Chiu, Tai-Hui; Huang, Shun-Chieh; Huang, Tai-Hung; Lai, Shang-Chih; Lai, Zhen-Rung; Lee, Chao-Ying

2010-01-01

This study aims to investigate the hepatoprotective activity and active constituents of the ethanol extract of Scoparia dulcis (SDE). The hepatoprotective effect of SDE (0.1, 0.5 and 1 g/kg) was evaluated on the carbon tetrachloride (CCl(4))-induced acute liver injury. The active constituents were detected by high performance liquid chromatography (HPLC). Mice pretreated orally with SDE (0.5 and 1.0 g/kg) and silymarin (200 mg/kg) for five consecutive days before the administering of a single dose of 0.2% CCl(4) (10 ml/kg of bw, ip) showed a significant inhibition of the increase of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Histological analyses also showed that SDE (0.5 and 1.0 g/kg) and silymarin reduced the extent of liver lesions induced by CCl(4), including vacuole formation, neutrophil infiltration and necrosis. Moreover, SDE decreased the malondialdehyde (MDA) level and elevated the content of reduced glutathione (GSH) in the liver as compared to those in the CCl(4) group. Furthermore, SDE (0.5 and 1.0 g/kg) enhanced the activities of anti-oxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd) and glutathione-S-transferase (GST). The quantities of active constituents in SDE were about 3.1 mg luteolin/g extract and 1.1 mg apigenin/g extract. The hepatoprotective mechanisms of SDE were likely associated to the decrease in MDA level and increase in GSH level by increasing the activities of antioxidant enzymes such as SOD, GPx, GRd and GST. These results demonstrated that SDE could alleviate CCl(4)-induced acute liver injury in mice.

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

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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.

Liver injury and fibrosis induced by dietary challenge in the Ossabaw miniature Swine.

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Tiebing Liang

Full Text Available Ossabaw miniature swine when fed a diet high in fructose, saturated fat and cholesterol (NASH diet develop metabolic syndrome and nonalcoholic steatohepatitis (NASH characterized by liver injury and fibrosis. This study was conducted to further characterize the development of NASH in this large animal model.Ossabaw swine were fed standard chow (control group; n = 6 or NASH diet (n = 6 for 24 weeks. Blood and liver tissue were collected and liver histology were characterized at 0, 8, 16 and 24 weeks of dietary intervention. Hepatic apoptosis and lipid levels were assessed at week 24.The NASH diet group developed metabolic syndrome and progressive histologic features of NASH including: (a hepatocyte ballooning at 8 weeks which progressed to extensive ballooning (>90% hepatocytes, (b hepatic fibrosis at week 16, which progressed to moderate fibrosis, and (c Kupffer cell accumulation with vacuolization at 8 weeks which progressed through week 24. The NASH diet group showed increased hepatocyte apoptosis that correlated with hepatic total and free cholesterol and free fatty acids, but not esterified cholesterol or triglycerides.This report further characterizes the progression of diet-induced NASH in the Ossabaw swine model. In Ossabaw swine fed the NASH diet: (a hepatocyte injury and fibrosis can occur without macrovesicular steatosis or excess triglyceride accumulation; (b hepatocyte ballooning generally precedes the development of fibrosis; (c there is increased hepatocyte apoptosis, and it is correlated more significantly with hepatic free cholesterol than hepatic free fatty acids and had no correlation with hepatic triglycerides.

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

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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

IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

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A. E. Shcherba

2013-01-01

Full Text Available Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury. 

Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

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Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

2016-10-01

Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. Copyright © 2016 by the Research Society on Alcoholism.

Swertianlarin, an Herbal Agent Derived from Swertia mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Common Bile Duct-Ligated Rats

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Liangjun Zhang

2015-01-01

Full Text Available Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL. Serum alanine aminotransferase (ATL and aspartate aminotransferase (AST levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P<0.05. The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα were decreased by swertianlarin in BDL rats for 3 and 7 days (P<0.05. Moreover, reductions in serum interleukins IL-1β and IL-6 levels were also observed in BDL rats treated with swertianlarin (P<0.05. In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA and deoxycholic acid (DCA in cholestatic rats were decreased by swertianlarin (P<0.05. In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

Retrospective study of paracetamol poisoning in children aged zero to six years found no cases of liver injury

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Dan-Nielsen, S; Bisgaard, A S; Jans, S R

2018-01-01

AIM: This study focused on children aged zero to six years with suspected single-dose paracetamol poisoning, which has not been investigated in Denmark. We evaluated the incidence of liver injuries and the use of activated charcoal and N-acetylcysteine treatment. METHODS: Our retrospective study.......67 ± 1.05 years. Activated charcoal treatment was given in 87% of cases, but only 15% of the children received treatment within one hour of the suspected paracetamol poisoning. Although 80% of the children received N-acetylcysteine treatment, only one case (0.5%) had a toxic plasma paracetamol level...... children aged zero to six years with suspected paracetamol poisoning. Vomiting or abdominal pain was associated with elevated plasma paracetamol levels. No liver injuries were reported....

Diagnosis and nonsurgical management of bile leak complicated by biloma after blunt liver injury: report of two cases

Energy Technology Data Exchange (ETDEWEB)

Backer, A. de; Schepper, A. de [Department of Radiology, University Hospital of Antwerp (Belgium); Fierens, H.; Pelckmans, P. [Department of Gastroenterology, University Hospital of Antwerp (Belgium); Jorens, P.G. [Intensive Care Unit, University Hospital of Antwerp (Belgium); Vaneerdeweg, W. [Department of Surgery, University Hospital of Antwerp (Belgium)

1998-12-01

We report on two patients with biliary tract injury and associated biloma following blunt abdominal trauma. Both patients underwent emergency surgery because of hemodynamic instability and bloody peritoneal aspiration. Computed tomography in the postoperative days showed severe hepatic parenchymal injury and the presence of hypodense collections with intraparenchymal and subcapsular extension, suggestive for biloma, but otherwise failed to demonstrate the exact location of the bile duct injury. One of them underwent temporary percutaneous drainage. Bile duct injury was well demonstrated on endoscopic retrograde cholangiography (ERCP) and treated by endobiliary stent placement. This report advocates the use of ERCP and endobiliary stenting in the management of biliary injury resulting from liver trauma. (orig.) With 2 figs., 9 refs.

Diagnosis and nonsurgical management of bile leak complicated by biloma after blunt liver injury: report of two cases

International Nuclear Information System (INIS)

Backer, A. de; Schepper, A. de; Fierens, H.; Pelckmans, P.; Jorens, P.G.; Vaneerdeweg, W.

1998-01-01

We report on two patients with biliary tract injury and associated biloma following blunt abdominal trauma. Both patients underwent emergency surgery because of hemodynamic instability and bloody peritoneal aspiration. Computed tomography in the postoperative days showed severe hepatic parenchymal injury and the presence of hypodense collections with intraparenchymal and subcapsular extension, suggestive for biloma, but otherwise failed to demonstrate the exact location of the bile duct injury. One of them underwent temporary percutaneous drainage. Bile duct injury was well demonstrated on endoscopic retrograde cholangiography (ERCP) and treated by endobiliary stent placement. This report advocates the use of ERCP and endobiliary stenting in the management of biliary injury resulting from liver trauma. (orig.)

Effect of heme oxygenase-1 on the protection of ischemia reperfusion injury of bile duct in rats after liver transplantation.

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Zhan, Xi; Zhang, Zhiqing; Huang, Hanfei; Zhang, Yujun; Zeng, Zhong

2018-06-01

To investigate the effect of heme oxygenase-1 (HO-1) on the ischemic reperfusion injury (IRI) of bile duct in rat models after liver transplantation. 320 SD rats were equally and randomly divided into 5 groups, which were group A receiving injection of 3×10 8 /pfu/ml adenovirus (adv), group B with donor receiving Adv-HO-1 and recipient receiving Adv-HO-1-siRNA, group C with donor and recipient both receiving Adv-HO-1, group D with donor receiving Adv-HO-1-siRNA and recipient receiving Adv-HO-1, and group E with donor and recipient both receiving Adv-HO-1-siRNA at 24h before liver transplantation. Donor liver was stored in UW liquid at 4°C followed by measuring HO-1 level by western blot before transplantation. On d1, d3, d7 and d14, serum and liver was isolated for analysis of liver function, inflammatory cell infiltration by H&E staining, ultrastructure of liver by transmission electron microscopy as well as the expression of HO-1, Bsep, Mrp2 and Ntcp by western blot. Compared with group D and E, group B and C displayed improved liver function as demonstrated by lower level of ALT, AST, LDH, TBIL, ALP and GGT, increased secretion of TBA and PL as well as expression of transporter proteins (Bsep, Mrp2 and Ntcp), reduced inflammatory cells infiltration and liver injury. Our study demonstrated that overexpression of HO-1 in donor liver can ameliorate the damage to bile duct and liver, and improved liver function, suggesting HO-1 might be a new therapeutic target in the treatment of IRI after liver transplantation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

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Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

2016-11-01

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright © 2016. Published by Elsevier

SB203580 Modulates p38 MAPK Signaling and Dengue Virus-Induced Liver Injury by Reducing MAPKAPK2, HSP27, and ATF2 Phosphorylation.

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Gopinathan Pillai Sreekanth

Full Text Available Dengue virus (DENV infection causes organ injuries, and the liver is one of the most important sites of DENV infection, where viral replication generates a high viral load. The molecular mechanism of DENV-induced liver injury is still under investigation. The mitogen activated protein kinases (MAPKs, including p38 MAPK, have roles in the hepatic cell apoptosis induced by DENV. However, the in vivo role of p38 MAPK in DENV-induced liver injury is not fully understood. In this study, we investigated the role of SB203580, a p38 MAPK inhibitor, in a mouse model of DENV infection. Both the hematological parameters, leucopenia and thrombocytopenia, were improved by SB203580 treatment and liver transaminases and histopathology were also improved. We used a real-time PCR microarray to profile the expression of apoptosis-related genes. Tumor necrosis factor α, caspase 9, caspase 8, and caspase 3 proteins were significantly lower in the SB203580-treated DENV-infected mice than that in the infected control mice. Increased expressions of cytokines including TNF-α, IL-6 and IL-10, and chemokines including RANTES and IP-10 in DENV infection were reduced by SB203580 treatment. DENV infection induced the phosphorylation of p38MAPK, and its downstream signals including MAPKAPK2, HSP27 and ATF-2. SB203580 treatment did not decrease the phosphorylation of p38 MAPK, but it significantly reduced the phosphorylation of MAPKAPK2, HSP27, and ATF2. Therefore, SB203580 modulates the downstream signals to p38 MAPK and reduces DENV-induced liver injury.

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

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

2017-01-01

We compared the relative protective abilities of silymarin and l-methionine pre-treatment in acetaminophen overdose injuries of the liver, kidney and cerebral cortex by assessing behaviours, antioxidant status, tissue histological changes and biochemical parameters of hepatic/renal function. Rats were divided into six groups of ten each; animals in five of these groups were pre-treated with oral distilled water, silymarin (25mg/kg) or l-methionine (2.5, 5 and 10mg/kg body weight) for 14days; and then administered intraperitoneal (i.p.) acetaminophen at 800mg/kg/day for 3days. Rats in the sixth group (normal control) received distilled water orally for 14days and then i.p. for 3days. Neurobehavioural tests were conducted 7days after last i.p treatment, and animals sacrificed on the 8th day. Plasma was assayed for biochemical markers of liver/kidney function; while sections of the liver, kidney and cerebral cortex were either homogenised for assay of antioxidant status or processed for histology. Acetaminophen overdose resulted in locomotor retardation, excessive self-grooming, working-memory impairment, anxiety, derangement of liver/kidney biochemistry, antioxidant imbalance, and histological changes in the liver, kidney and cerebral cortex. Administration of silymarin or increasing doses of l-methionine counteracted the behavioural changes, reversed biochemical indices of liver/kidney injury, and improved antioxidant activity. Silymarin and l-methionine also conferred variable degrees of tissue protection, on histology. Either silymarin or l-methionine can protect vulnerable tissues from acetaminophen overdose injury; however, each offers variable protection to different tissues. This study highlights an obstacle to seeking the 'ideal' protective agent against acetaminophen overdose. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury

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Burra Patrizia

2012-07-01

Full Text Available Abstract Background Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs, a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model. Methods Mesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion. To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification. Data were analyzed by Mann–Whitney U-test, Kruskal-Wallis test and Cuzick’s test followed by Bonferroni correction for multiple comparisons. Results We have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However

New therapeutic strategies for canine liver disease; Growth factors and liver progenitor cells

NARCIS (Netherlands)

Arends, B.

2008-01-01

The liver has the unique capacity to regulate its mass after loss of functional liver cells due to liver disease, injury, and/or toxicity. Unfortunately, in the course of chronic liver disease this meticulously regulated regeneration process is imbalanced resulting in a decreased regenerative

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

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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.

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

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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.

NRF2 Protection against Liver Injury Produced by Various Hepatotoxicants

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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.

Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures

International Nuclear Information System (INIS)

Woźny, Maciej; Lewczuk, Bogdan; Ziółkowska, Natalia; Gomułka, Piotr; Dobosz, Stefan; Łakomiak, Alicja; Florczyk, Maciej; Brzuzan, Paweł

2016-01-01

To date, there has been no systematic approach comprehensively describing the sequence of pathological changes in fish during prolonged exposure to microcystin-LR (MC-LR). Towards this aim, juvenile whitefish individuals received an intraperitoneal injection with pure MC-LR, and the injection was repeated every week to maintain continuous exposure for 28 days. During the exposure period, growth and condition of the fish were assessed based on biometric measurements. Additionally, selected biochemical markers were analysed in the fishes' blood, and their livers were carefully examined for morphological, ultrastructural, and molecular changes. The higher dose of MC-LR (100 μg·kg −1 ) caused severe liver injury at the beginning of the exposure period, whereas the lower dose (10 μg·kg −1 ) caused less, probably reversible injury, and its effects began to be observed later in the exposure period. These marked changes were accompanied by substantial MC-LR uptake by the liver. However, starting on the 7th day of exposure, cell debris began to be removed by phagocytes, then by 14th day, proliferation of liver cells had markedly increased, which led to reconstruction of the liver parenchyma at the end of the treatment. Surprisingly, despite weekly-repeated intraperitoneal injections, MC-LR did not accumulate over time of exposure which suggests its limited uptake in the later phase of exposure. In support, mRNA expression of the membrane transport protein oatp1d was decreased at the same time as the regenerative processes were observed. Our study shows that closing of active membrane transport may serve as one defence mechanism against further MC-LR intoxication. - Highlights: • The study presents pathological changes in whitefish during prolonged MC-LR exposure. • After early, severe injury, the damaged liver parenchyma of the fish regenerated. • Endoplasmic reticulum, cytoskeleton, and chromatin were the main targets for MC-LR. • MC-LR did not

Patients with HBV-related acute-on-chronic liver failure have increased concentrations of extracellular histones aggravating cellular damage and systemic inflammation.

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Li, X; Gou, C; Yao, L; Lei, Z; Gu, T; Ren, F; Wen, T

2017-01-01

Acute-on-chronic liver failure (ACLF) is the most common type of liver failure and associated with grave consequences. Systemic inflammation has been linked to its pathogenesis and outcome, but the identifiable triggers are absent. Recently, extracellular histones, especially H4, have been recognized as important mediators of cell damage in various inflammatory conditions. This study aimed to investigate whether extracellular histones have clinical implications in patients with hepatitis B virus (HBV)-related ACLF. One hundred and twelve patients with HBV-related ACLF, 90 patients with chronic hepatitis B, 88 patients with HBV-related liver cirrhosis and 40 healthy volunteers were entered into this study. Plasma histone H4 levels, cytokine profile and clinical data were obtained. Besides, patient's sera were incubated overnight with human L02 hepatocytes or monocytic U937 cells in the presence or absence of antihistone H4 antibody, and cellular damage and cytokine production were evaluated. We found that plasma histone H4 levels were greatly increased in patients with ACLF as compared with chronic hepatitis B, liver cirrhosis and healthy control subjects and were significantly associated with disease severity, systemic inflammation and outcome. Notably, ACLF patients' sera incubation decreased cultured L02 cell integrity and induced profound cytokine production in the supernatant of U937 cells. Antihistone H4 antibody treatment abrogated these adverse effects, thus confirming a cause-effect relationship between extracellular histones and organ injury/dysfunction. The data support the hypothesis that the increased extracellular histone levels in ACLF patients may aggravate disease severity by inducing cellular injury and systemic inflammation. Histone-targeted therapies may have potentially interventional value in clinical practice. © 2016 John Wiley & Sons Ltd.

Using multiphoton fluorescence lifetime imaging to characterize liver damage and fluorescein disposition in liver in vivo

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Thorling, Camilla A.; Studier, Hauke; Crawford, Darrell; Roberts, Michael S.

2016-03-01

Liver disease is the fifth most common cause of death and unlike many other major causes of mortality, liver disease rates are increasing rather than decreasing. There is no ideal measurement of liver disease and although biopsies are the gold standard, this only allows for a spot examination and cannot follow dynamic processes of the liver. Intravital imaging has the potential to extract detailed information over a larger sampling area continuously. The aim of this project was to investigate whether multiphoton and fluorescence lifetime imaging microscopy could detect early liver damage and to assess whether it could detect changes in metabolism of fluorescein in normal and diseased livers. Four experimental groups were used in this study: 1) control; 2) ischemia reperfusion injury; 3) steatosis and 4) steatosis with ischemia reperfusion injury. Results showed that multiphoton microscopy could visualize morphological changes such as decreased fluorescence of endogenous fluorophores and the presence of lipid droplets, characteristic of steatosis. Fluorescence lifetime imaging microscopy showed increase in NADPH in steatosis with and without ischemia reperfusion injury and could detect changes in metabolism of fluorescein to fluorescein monoglurcuronide, which was impaired in steatosis with ischemia reperfusion injury. These results concluded that the combination of multiphoton microscopy and fluorescence lifetime imaging is a promising method of assessing early stage liver damage and that it can be used to study changes in drug metabolism in the liver as an indication of liver disease and has the potential to replace the traditional static liver biopsy currently used.

Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses.

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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.

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

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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.

Ameliorative effects of 5-hydroxymethyl-2-furfural (5-HMF) from Schisandra chinensis on alcoholic liver oxidative injury in mice.

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Li, Wei; Qu, Xin-Nan; Han, Ye; Zheng, Si-Wen; Wang, Jia; Wang, Ying-Ping

2015-01-22

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.

Differential Effects of Three Techniques for Hepatic Vascular Exclusion during Resection for Liver Cirrhosis on Hepatic Ischemia-Reperfusion Injury in Rats

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Changjun Jia

2018-01-01

Full Text Available Background/Aims. Hepatic ischemia-reperfusion (I/R injury is a serious concern during hepatic vascular occlusion. The objectives of this study were to assess effects of three techniques for hepatic vascular occlusion on I/R injury and to explore the underlying mechanisms. Methods. Liver cirrhotic rats had undertaken Pringle maneuver (PR, hemihepatic vascular occlusion (HH, or hepatic blood inflow occlusion without hemihepatic artery control (WH. Levels of tumor necrosis factor alpha (TNF-α, nuclear factor kappa B (NF-κB, toll-like receptor 4 (TLR4, TIR-domain-containing adapter-inducing interferon-β (TRIF, and hemeoxygenase 1 (HMOX1 were assayed. Results. The histopathologic analysis displayed that liver harm was more prominent in the PR group, but similar in the HH and WH groups. The HH and WH groups responded to hepatic I/R inflammation similarly but better than the PR group. Mechanical studies suggested that TNF-α/NF-κB signaling and TLR4/TRIF transduction pathways were associated with the differential effects. In addition, the HH and WH groups had significantly higher levels of hepatic HMOX1 (P<0.05 than the PR group. Conclusions. HH and WH confer better preservation of liver function and protection than the Pringle maneuver in combating I/R injury. Upregulation of HMOX1 may lead to better protection and clinical outcomes after liver resection.