BACKGROUND: The clinical trials emerged centromere protein E inhibitor GSK923295 as a promising anticancer drug, but its function in hepatocellular carcinoma (HCC) remain needs to be fully elucidated, especially as chemotherapy after hepatectomy for liver tumors. We aimed to describe anti-HCC activities of GSK923295 and compare its antiproliferative effects on liver regeneration after partial hepatectomy (PH). METHODS: All subjects were randomized to treatment with either vehicle or GSK923295. Antitumor activity of GSK923295 was assessed by xenograft growth assays. The C57BL/6 mice were subjected to 70% PH and the proliferation was calculated by liver coefficient, further confirmed by immunohistochemistry. The proliferation and cell cycle analysis of liver cell AML12 and HCC cells LM3, HUH7, and HepG2 were investigated using the cell counting kit-8 assay and Flow Cytometry. The chromosome misalignment and segregation in AML12 cells were visualized by immunofluorescence. RESULTS: Treatment with GSK923295 induced antiproliferation in HCC cell lines. It also caused delay on HCC tumor growth instead of regression both in a HCC cell line xenograft model and patient-derived tumor xenograft model. With microarray analysis, CENtromere Protein E was gradually increased in mouse liver after PH. Exposure of liver cells to GSK923295 resulted in delay on a cell cycle in mitosis with a phenotype of misaligned chromosomes and chromosomes clustered. In 70% PH mouse model, GSK923295 treatment also remarkably reduced liver regeneration in later stage, in parallel with the mitotic marker phospho-histone H3 elevation. CONCLUSION The anticancer drug GSK923295 causes a significant delay on HCC tumor growth and liver regeneration after PH in later stage.
Animals ; Antineoplastic Agents ; therapeutic use ; Blotting, Western ; Bridged Bicyclo Compounds, Heterocyclic ; therapeutic use ; Carcinoma, Hepatocellular ; drug therapy ; surgery ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Chromosomal Proteins, Non-Histone ; antagonists & inhibitors ; Electrophoresis, Polyacrylamide Gel ; Female ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; Liver Neoplasms ; drug therapy ; surgery ; Liver Regeneration ; physiology ; Mice ; Mice, Inbred C57BL ; Real-Time Polymerase Chain Reaction ; Sarcosine ; analogs & derivatives ; therapeutic use ; Xenograft Model Antitumor Assays

Drug-induced liver injury (DILI) is a significant threat to patient health and a major concern during drug development. Recently, multiple circulating microRNAs (miRNAs) have been reported to be potential biomarkers for DILI. To adapt and validate miRNAs for clinical use, we investigated the time-course changes in miR-122 expression levels in an acetaminophen-induced liver injury model in rats. In addition, miR-155 and miR-21 were evaluated as makers of inflammation and regeneration, respectively, to characterize liver status. Our results revealed that miR-122 is an early and sensitive biomarker of hepatocellular injury at a stage when alanine transaminase, aspartate transaminase, and total bilirubin were not detectable. However, no significant differences in the expression levels of other miRNAs (miR-155 and -21) were observed between treatment and vehicle groups. Collectively, these time-course changes in the expression levels of miRNAs may be useful as markers for clinical decision-making, in the diagnosis and treatment of DILI.
Acetaminophen/*toxicity ; Animals ; Biomarkers/*blood ; Chemical and Drug Induced Liver Injury/*blood/*diagnosis/pathology ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Hepatocytes/*drug effects ; Inflammation/blood/diagnosis ; Liver Regeneration ; MicroRNAs/*blood/genetics ; Predictive Value of Tests ; Rats ; Time

OBJECTIVEThis study was conducted to determine the histopathological and biochemical effects of Thymus algeriensis essential oil (TEO) on hydrogen peroxide (H2O2)-induced oxidative stress in liver and kidney tissues of rats.

METHODSRats were treated in six groups and were exposed for 2 weeks to low (LD; 100 μmol/L) and high doses (HD; 1 mmol/L) of H2O2 in the presence or absence of TEO (180 mg/kg). Liver and kidney atrophy was measured by using biochemical and histopathological assays.

RESULTSOur study demonstrated that H2O2 induced liver and kidney atrophy, as evidenced by the significant elevation of serum aminotransferase, urea, and creatinine levels compared with those in the control rats. Urea levels were estimated by evaluating the activity of serum urease that hydrolyzes urea into CO2 and ammonia. However, TEO treatment significantly alleviated oxidative stress in the H2O2-induced liver and kidney toxicity model by reducing the levels of malondialdehyde concomitantly with marked elevations in superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase, as well as decrease in glutathione activity.

CONCLUSIONOur data demonstrated that TEO protected against H2O2 toxicity by decreasing oxidant levels and DNA damage, as well as increasing antioxidant levels, indicating that TEO has a spectrum of antioxidant and DNA-protective properties.

Animals ; Antioxidants ; pharmacology ; Hydrogen Peroxide ; metabolism ; toxicity ; Kidney ; drug effects ; physiology ; Lipid Metabolism ; drug effects ; Liver ; drug effects ; physiology ; Male ; Malondialdehyde ; metabolism ; Oils, Volatile ; pharmacology ; Oxidative Stress ; drug effects ; Plant Extracts ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Regeneration ; drug effects ; Thymus Plant ; chemistry

BACKGROUNDConsidering the existence of a large number of liver cell degeneration and necrosis in fibrotic liver, liver function was damaged severely and could not effectively regenerate after partial hepatectomy (PHx). The aim of this study was to investigate whether decorin (DCN) could promote the liver regeneration after PHx in fibrotic mice.

METHODSForty mice (5-week-old, Balb/c) were injected with CCl4 intraperitoneally and liver fibrosis model was established after 5 weeks. The survival mice were randomly divided into two groups: control group and DCN group. Then, we performed 70% PHx on all these mice and injected DCN or phosphate-buffered saline plus normal saline (NS) to each group, respectively, after surgery. Liver body weight ratio (LBR), quantitative real-time polymerase chain reaction, and immunohistochemistry were used to analyze liver regeneration and fibrosis degree in both groups, and to find out whether exogenous protein DCN could promote the regeneration of fibrosis liver after PHx.

RESULTSExpressions of a-smooth muscle actin (SMA) mRNA and LBR had significant increases in the DCN group at postoperative Day 3 (POD 3, P < 0.05). The protein expressions of CD31, a-SMA, and tumor necrosis factor (TNF)-a were higher in the DCN group than those in the control group by immunohistochemistry at POD 3 (P < 0.05).

CONCLUSIONExogenous protein DCN could promote liver regeneration after PHx in fibrotic mice.

Animals ; Decorin ; therapeutic use ; Hepatectomy ; Immunohistochemistry ; Liver Cirrhosis ; drug therapy ; metabolism ; surgery ; Liver Regeneration ; drug effects ; Male ; Mice ; Mice, Inbred BALB C ; Platelet Endothelial Cell Adhesion Molecule-1 ; metabolism

Animals ; Bone Marrow Cells ; cytology ; Cell Differentiation ; drug effects ; Ethanol ; adverse effects ; Hepatocytes ; cytology ; Liver Regeneration ; Mesenchymal Stromal Cells ; cytology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo assess the effect of Danshen on liver regeneration capacity of carbon tetrachloride-induced liver injury rats.

METHODComputer retrieval of data from CJFD, CBM, Chinese science & technology journal full-text database and Chinese medical association digital journals, and such foreign databases as PubMed, EMBASE and SCI was included in the randomized controlled trials (RCT) of rat liver injury induced by carbon tetrachloride,with the search as at May 2012. A Meta analysis was made using Rev-Man 5.1 software. Using the GRADE system to addess five outcomes in stuay.

RESULTTwo hundred and fourteen rats got involved in seven randomized trials. Meta analysis showed there were statistical differences between the Danshen group and the control group in alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-alpha) and hyaluronic acid (HA) after rat liver injury induced by carbon tetrachloride. When we used system to each outcome, because of serious limitations and indirect, they are all very low quality.

CONCLUSIONDanshen shows certain promoting effect to liver regeneration in carbon tetrachloride-induced liver injury rats.

Animals ; Carbon Tetrachloride ; adverse effects ; Chemical and Drug Induced Liver Injury ; etiology ; genetics ; metabolism ; physiopathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Liver Regeneration ; drug effects ; Phenanthrolines ; pharmacology ; Rats ; Salvia miltiorrhiza ; chemistry

OBJECTIVETo observe the effect of D-galactosamine (D-GaIN) and lipopolysaccharide (LPS) on liver tissue regeneration and repair in mice following liver injury induced by partial hepatectomy.

METHODSA total of 40 male BALB/c mice were randomly assigned into 2 equal groups to receive intraperitoneal injections of D-GaIN (500 mg/kg) plus LPS (50 µg/kg, given 1 h later) or two doses of saline 24 h prior to 1/3 hepatectomy. The liver weight/body weight (LW/BW) ratio and liver regeneration rate were observed at different time points after partial hepatectomy. Liver cell injury was assessed using HE staining, hepatocyte proliferation evaluated with BrdU staining, and the oval cell proliferation observed with immunohistochemistry.

RESULTSIn mice receiving saline injection, the liver volume was nearly restored 9 days after partial hepatectomy, while in mice with D-GaIN and LPS injections, the liver failed to recover the normal volume even at 14 days, showing a significant difference in the liver regeneration rate between them [(22.6∓105.93)% vs (9.49∓32.55)%, P<0.001]. Significant degenerative changes of the hepatic cells were found in D-GaIN/LPS-treated group, while only mild inflammatory reaction was observed in saline-treated group after partial hepatectomy. Obvious hepatocyte proliferation was observed at day 7 in saline-treated group but not in D-GaIN/LPS-treated group. Oval cell proliferation in the portal area occurred 3 days after partial hepatectomy in D-GaIN/LPS-treated group.

CONCLUSIOND-GaIN and LPS can obviously inhibit hepatocyte regeneration after liver injury in mice. D-GaIN and LPS combined with partial hepatectomy can induce oval cell proliferation.

Animals ; Cell Proliferation ; drug effects ; Galactosamine ; pharmacology ; Hepatectomy ; methods ; Lipopolysaccharides ; pharmacology ; Liver ; cytology ; injuries ; physiopathology ; Liver Regeneration ; drug effects ; physiology ; Male ; Mice ; Mice, Inbred BALB C ; Stem Cells ; cytology

OBJECTIVETo investigate the effect of pretreatment with ulinastatin on liver regeneration and TNF-α/IL-6/STAT-3 signal pathway in rats after 70% hepatectomy combined with ischemia-reperfusion injury.

METHODSA total of 120 normal male SD rats weighing 230-280 g were randomized into 3 groups (n=40), namely simple partial hepatectomy (PH) group, partial hepatectomy with ischemia-reperfusion (PHIR) group, and ulinastatin group. All the rats received resection of the left and middle liver lobes. In PHIR group, the remnant right lobes were subjected to blood flow occlusion for 30 min; in UTI group, the rats were given 50 000 U/kg UTI intravenously prior to the occlusion, and in PH group, the blood flow was not occluded. At 1, 6, 12, 24, and 48 after the reperfusion, the remnant liver tissues were examined for regenerated liver weight, PCNA staining, TNF-α and IL-6, STAT-3, cyclin D1, and Cdk4 expressions.

RESULTSThe regenerated liver weight and PCNA positivity rates were significantly higher in ulinastatin group than in PHIR group at 24 h and 48 h after the reperfusion (P<0.05). In ulinastatin group, the levels of TNF-α and IL-6 were significantly lower, and IL-6 level and the expressions of STAT-3, cyclin D1, and Cdk4 mRNA and cyclin D1 and Cdk4 proteins were significantly higher in ulinastatin group than in PHIR group at 24 h and 48 h (P<0.05).

CONCLUSIONUlinastatin can promote liver regeneration after major hepatectomy and ischemia-reperfusion injury, and the effect is possibly related with activation of IL-6/STAT-3 signal pathway, which promotes the synthesis of cyclin Dl-Cdk4 complex and hepatocyte proliferation.

Animals ; Cell Proliferation ; Cyclin D1 ; metabolism ; Cyclin-Dependent Kinase 4 ; metabolism ; Glycoproteins ; pharmacology ; Hepatectomy ; adverse effects ; Hepatocytes ; cytology ; drug effects ; Interleukin-6 ; metabolism ; Liver ; blood supply ; Liver Regeneration ; drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; etiology ; metabolism ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; drug effects ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo evaluate the effect of postoperative intraportally administration of insulin on hepatic regeneration in adult patients underwent living donor right lobe liver transplantation (LDLT).

METHODSFrom July 2005 to September 2007, 15 right lobe LDLT adult recipients voluntarily receiving posttransplant intraportal insulin administration, without postoperative vascular and bile duct complications, without immune rejection, with more than 1 month survival and complete clinical data were enrolled in this study as intraportal insulin-therapy group (Group I). Another consecutive 15 right lobe LDLT adult recipients meeting the upwards referred criteria were enrolled in as non-insulin-therapy control group (Group NI). Recipients in Group I were treated postoperatively with intraportal insulin infusion, as follows: a 18-gauge catheter was inserted into right gastro-omental vein during surgery, regular insulin was administered just after the operation at the rate of 2 units/hour for 7 days. Liver function and serum insulin level were measured at before-operative day 1, postoperative day (POD) 7 and 30. Graft volume (GV) were measured during operation, and at POD 7 and 30.

RESULTSThe rate defined as ratio of POD 7 GV/operation GV in Group I was higher than that of Group NI [(186.1 +/- 35.4)% vs. (160.6 +/- 22.1)%, P < 0.05]. The rate defined as ratio of POD 7 GRWR/operation GRWR was also higher in Group I than Group NI [(179.0 +/- 35.8) % vs. (156.6 +/- 18.5%, P < 0.05], whereas significant differences were not appeared between two groups in terms of regeneration rates at POD 30. Serum levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase in Group I were lower than that in Group NI at POD 7 (P < 0.05). Significant differences were not presented between two groups in terms of post-transplant serum insulin levels and total insulin dosage by subcutaneous administration and venous injection (P > 0.05).

CONCLUSIONSThese results suggest that intraportal insulin administration could augment liver graft regeneration during the first postoperative week.

Adult ; Female ; Humans ; Infusion Pumps ; Insulin ; administration & dosage ; therapeutic use ; Liver Regeneration ; drug effects ; Liver Transplantation ; Living Donors ; Male ; Middle Aged ; Portal Vein ; Postoperative Period ; Retrospective Studies ; Young Adult

Genetic Therapy ; Hepatitis B ; therapy ; virology ; Hepatocytes ; cytology ; Humans ; Interleukin-6 ; genetics ; physiology ; Liver Regeneration ; drug effects ; Receptors, Interleukin-6 ; genetics ; physiology ; Recombinant Fusion Proteins ; genetics ; physiology ; Signal Transduction