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Background: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances., Results: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT., Conclusion: These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.

Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells (HPCs). However, the detailed mechanisms underlying HPC transformation are poorly understood. In this study, we provide evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-β1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-β1 than in those with high HBx or high TGF-β1 and the double-low-expression group. HBx and TGF-β1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-β1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial-mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-β1 exposure. Moreover, activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway was involved in the malignant transformation of HPCs. miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-β1 exposure, which were shown to promote miR-199a-3p expression via c-Jun-mediated activation. Finally, we found that miR-199a-3p was responsible for the malignant transformation of HPCs. In conclusion, our results provide evidence that TGF-β1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway. This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.

In the past 20 years,the advancement and breakthrough of applied basic research,the invention and renewal of medical devices,the popularization and improvement of minimally invasive techniques,the development and debate of innovative surgical methods and the establishment of the diagnosis and treatment standard brought the unprecedented development momentum to traditional liver surgery.This article combined the domestic and foreign related literature and the research results of our team. The current status and progress of the application of preoperative evaluation and surgical planning of liver surgery,surgical techniques of liver resection,laparoscopic and robotic techniques in liver surgery,enhanced recovery after surgery and associating liver partition and portal vein ligation for staged hepatectomy are briefly discussed.

Liver resection is the mainstay of treatment for patients with hepatocellular carcinoma (HCC). Most of HCC patients are associated with varied degrees of liver cirrhosis.Severity of liver cirrhosis adversely affects the outcomes of liver resection, and also plays a vital role in making an appropriate surgical strategy for HCC.In current surgical practice for HCC, liver function and functional reserve are the focus of preoperative evaluation. Liver cirrhosis is still widely regarded as an one-stage entity. The pathological severity of liver cirrhosis is largely ignored. As neither liver function nor functional reserve can reflect the pathological severity of liver cirrhosis when liver function is at the stage of compensation. Preoperative evaluation on the severity of cirrhosis has not been established in a surgical setting.Thus, there is an urgent need to stage the severity of cirrhosis in surgical practice in order to make more precise surgical modalities for individual patients.This article mainly introduces the ongoing research progress in staging the severity of liver cirrhosis while treating HCC at Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and emphasizes the importance of staging the severity of cirrhosis in surgical treatment of HCC.

Non-anatomical liver resection with appropriate resection margin is regarded as a potential curative treatment for selected major hepatic carcinoma due to preserving maximal normal liver, especially in cirrhotic patients. But occurrence of cutting surface related complications becomes a main challenge. From June 2010 to June 2016, 448 patients with major hepatic carcinoma received non-anatomical liver resection in our liver surgery center. After excluding 66 cases that were incongruent with the purpose of study, 235 patients undergoing transparenchymal compressing suture (TCS) to "not good" cutting surface were allocated as study group; 147 patients with exposed surface (ES) were matched as control group. The characteristics of postoperative drainage, postoperative hepatic and renal functions, hospital days, and outcomes were collected retrospectively. We further compared cutting surface related complications under different levels of liver cirrhosis between the two groups. Compared with ES group, patients in TCS group had a decreased incidence of cutting surface related complications (14.3% vs. 6.8%, P=0.011) and a decreased probability of interventions for cutting surface related complications (8.2% vs. 3.4%, P=0.042). TCS application was much more effective to prevent cutting surface related complications in patients with moderate and severe cirrhosis (5.4% vs. 15.8%, P=0.003). Postoperative hepatic and renal function, hospital days and mortality did not differ between the two groups. In conclusion, TCS decreases the probability of cutting surface related complications and postoperative interventions for related complications, especially in patients with moderate and severe cirrhosis.

Background: This study introduces an innovative stepwise vascular control technique to address the high risk of massive bleeding from main hepatic veins and the retro-hepatic inferior vena cava during hepatectomy involving hepatocaval confluence., Methods: From January 2010 to July 2016, 80 patients underwent stepwise vascular occlusion during complex liver resection involving hepatocaval confluence. Relevant clinical data were collected and compared with those obtained in parallel studies. The protocol has been registered in the Protocol Registration and Results System as protocol NCT02996006., Results: All 80 patients underwent portal triad (PT), infra-hepatic inferior vena cava (IIVC) and supra-hepatic inferior vena cava (SIVC) preparation for occlusion in that order; PT, PT + SIVC and PT + IIVC + SIVC occlusions were performed during liver resection for six, 42 and 32 patients, respectively. The PT, IIVC and SIVC clamping times were 12.9 ± 2.5, 9.1 ± 2.1 and 5.1 ± 1.4 min, respectively. The mean blood loss was 504.1 ± 234.5 mL. Sixteen patients received blood transfusions. Haemodynamic parameters remained stable. No patients had life-threatening complications or died (Clavien-Dindo grade IV or V). Compared with other techniques used in parallel studies, this technique has the advantage of decreased blood loss in less warm ischaemia time., Conclusion: For complex hepatectomy involving hepatocaval confluence, this newly described stepwise vascular control technique was efficacious and feasible for controlling intraoperative bleeding., (© 2017 Royal Australasian College of Surgeons.)

The unique liver immune microenvironment favors resistance to inflammation that promotes normal physiological function. At the same time, it endows the liver with tolerogenic properties that may promote pathological processes. Hepatic dendritic cells (HDCs) initiate and orchestrate immune responses depending on signals they receive from the local environment and are thought to contribute to liver tolerance. Thus, HDCs facilitate impaired T cell responses that are observed in persistent hepatitis C virus (HCV) infection, hepatocellular carcinoma progression, and liver allograft transplantation. HDCs also participate in anti-inflammatory responses in liver ischemia-reperfusion injury (IRI). Moreover, they promote the regression of fibrosis from various fibrogenic liver injuries. These findings suggest that HDCs regulate intrahepatic immune responses, allowing the liver to maintain homeostasis and integrity even under pathological conditions. This review focuses on the tolerogenic properties of HDCs based on recent research and in relation to liver disease pathogenesis and its therapy., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Severity of liver cirrhosis plays a vital role in determining an appropriate surgical strategy for HCC treatment. However, preoperative evaluation of the severity of cirrhosis has not been established in a surgical setting. This study aims to develop a model to predict the severity of cirrhosis., Methods: Overall, 604 patients with hepatocellular carcinoma (HCC) and hepatitis B virus-related cirrhosis undergoing liver resection from Jan 2005 to Jun 2013 were randomly divided into either the model building group (n = 304) or the test group (n = 300). The severity of cirrhosis of the resected specimens was pathologically staged according to the Laennec scoring system, which sub-classified cirrhosis into either stage F4A, F4B, or F4C., Results: A logistic regression analysis showed that varicosity, portal vein diameter, spleen thickness, and platelet count were significantly associated with the histologic sub-classification of cirrhosis in the model building group. Based on these four parameters, a scoring model for predicting the severity of cirrhosis was established. The model was then verified in the test group, the areas under the ROC (AUROC) for predicting mild (F4A), moderate (F4B), and severe cirrhosis (F4C) were 0.861 (95% confidence interval [CI], 0.810-0.911), 0.860 (95% CI, 0.819-0.901), and 0.968 (95% CI, 0.951-0.985), respectively. The accuracy of this model in predicting mild, moderate, and severe cirrhosis is 79.3%, 81.0%, and 85.3%, respectively., Conclusions: By using this model, the severity of cirrhosis can be reliably staged preoperatively, which will provide more information on cirrhotic livers in surgical settings for the treatment of hepatitis B virus-related HCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Liver transplantation (LT) is the only option of treatment for Wilson disease (WD) when chelation therapy fails, but it is limited due to the shortage of donor. Auxiliary partial orthotopic LT (APOLT) has been performed successfully in end-stage WD patients, which expands the donor pool., Methods: Atp7bmice were used as experimental model of WD. Eight- and 20-week-old mice were used as different timepoints to perform APOLT. Serum copper, tissue copper, serum ceruloplasmin (CP), and liver histological examination were observed after operation., Results: Hepatic and serum copper levels in Atp7b mice decreased after APOLT, and copper metabolism disorder of WD mice was relieved at both early and late stages. The progression of pathology in the native liver was delayed only when transplantation was performed at an early stage., Conclusions: Auxiliary partial orthotopic LT can significantly improve copper metabolism disorder in the Atp7b mice, and early transplantation may prevent the disease progression.

Dried roots and rhizomes of Salvia miltiorrhiza (Danshen) are among the most commonly used traditional Chinese medicines in clinic. The material basis for its efficacy mainly includes hydrophobic tanshinones and hydrophilic salvianolic acids. The traditional effects of Danshen are "removing stasis and relieving pain, activating blood to promote menstruation, clearing heart fire and tranquilization". According to modern pharmacological studies, Danshen and its main components have cardiovascular and cerebrovascular protective effect. Recent studies showed that Danshen and its main components also demonstrated protective effects on liver injury models induced by carbon tetrachloride, D-galactosamine, acetaminophen and alcohol. In this paper, the hepatoprotective effect and mechanism of Danshen were summarized and studied.

Activation of hepatic progenitor cells (HPCs) is commonly observed in chronic liver disease and Wnt/β-catenin signaling plays a crucial role in the expansion of HPCs. However, the molecular mechanisms that regulate the activation of Wnt/β-catenin signaling in the liver, especially in HPCs, remain largely elusive. Here, we reported that ectopic expression of Smad6 suppressed the proliferation and self-renewal of WB-F344 cells, a HPC cell line. Mechanistically, we found that Smad6 inhibited Wnt/β-catenin signaling through promoting the interaction of C-terminal binding protein (CtBP) with β-catenin/T-cell factor (TCF) complex to inhibit β-catenin mediated transcriptional activation in WB-F344 cells. We used siRNA targeting β-catenin to demonstrate that Wnt/β-catenin signaling was required for the proliferation and self-renewal of HPCs. Taken together, these results suggest that Smad6 is a regulatory molecule which regulates the proliferation, self-renewal and Wnt/β-catenin signaling in HPCs., (© 2013 Wiley Periodicals, Inc.)

Background: Partial hepatectomy with clear surgical margins is the main curative treatment for hepatic malignancies. The safety of liver resection, to a great extent, depends on the volume of future liver remnant. This manuscript reviews some important strategies that have been developed to increase resectability for patients with borderline volume of future liver remnant, particularly associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)., Methods: To identify potentially relevant articles, we searched Medline and PubMed from January 2010 to December 2013 using the keywords "Associating liver partition and portal vein ligation for staged hepatectomy", "ALPPS", "portal vein embolization", "future liver remnant", "liver hypertrophy", and "liver failure". A number of references from the key articles were also cited. There were no exclusion criteria for published information to the topics., Results: Portal vein ligation (PVL) or embolization (PVE) are traditional approaches to induce liver hypertrophy of the future liver remnant (FLR) prior to hepatectomy in primarily non-resectable liver tumors. However, about 14 percent of patients fail to this approach. Adequate hypertrophy of the FLR using PVL or PVE generally takes more than four weeks. ALPPS can induce rapid growth of the FLR, which is more effective than by portal vein embolization or occlusion alone. Reportedly, the hypertrophy extent of FLR was 40%-80% within 6-9 days in contrast to approximately 8%-27% within 2-60 days by PVL/PVE. However, ALPPS was reported to have high operative morbidity (16%-64% of patients), mortality (12%-23% of patients) and bile leakage rates. Bile leakage and sepsis remain a major cause of morbidity, and the main cause of mortality includes hepatic insufficiency., Conclusion: ALPPS has emerged as a new strategy to increase resectability of hepatic malignancies. Due to high morbidity and mortality rates of ALPPS procedure, the surgical candidates should be selected carefully. Moreover, there are very limited available evidence for its technical feasibility, safety and oncological outcome which are needed for further evaluation in larger scale of studies., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Hepatic stem cell niche plays an important role in hepatic oval cell-mediated liver regeneration. As a component of hepatic stem cell niche, the role of hepatic stellate cells (HSCs) in oval cell proliferation needs further studies. In the present study, we isolated HSCs from rats at indicated time point after partial hepatectomy (PH) in 2-acetylaminofluorene/PH oval cell proliferation model. Conditional medium (CM) from HSCs were collected to detect their effects on proliferation and the mitogen-activated protein kinase pathway activation of two oval cell lines. We found that CM collected from HSCs at early phase of liver regeneration (4 and 9 days group) contained high levels of hepatocyte growth factor (HGF) and stimulated oval cell proliferation via extracellular signal-regulated kinase and p38 pathway. CM collected from HSCs at terminal phase of liver regeneration (12 and 15 days group) contained high levels of transforming growth factor (TGF)-β1, which suppressed DNA synthesis of oval cells. The shift between these two distinct effects depended on the balance between HGF and TGF-β1 secreted by HSCs. Our study demonstrated that HSCs acted as a positive regulator at the early phase and a negative regulator at the terminal phase of the oval cell-mediated liver regeneration., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: To observe the histopathological features of posttransplant complications for hepatic allografts and evaluate their biopsy values., Methods: From January 1999 to May 2011, a total of 268 percutaneous hepatic allograft biopsies were conducted in 207 recipients and the diagnostic procedures for staining, classification and staging performed according to the Banff schema and Chinese Schema on hepatic allograft rejection., Results: Among them, there were ischemia/reperfusion injury (n = 26, 9.7%), acute T cell-mediated rejection (n = 83, 31.0%), acute antibody-mediated rejection (n = 12, 4.5%), chronic posttransplantation rejection (n = 31, 11.6%), immunosuppressive-induced liver injury (n = 70, 26.1%) and recurrent diseases (n = 18, 6.7%). Acute T cell-mediated rejection and drug-induced liver injury were two most common causes of allograft dysfunctions., Conclusion: Percutaneous hepatic allograft biopsy is valuable for the diagnosis and evaluation of various posttransplantation complications.

Objective: To determine whether hepatitis B virus X (HBX) protein expression affect the oval cells' response to anti-proliferative effect of transforming growth factor β1 (TGFβ1) in oval cells., Methods: Real-time PCR, Western blot analysis were performed to detect the expression of TGFβRII in HBX-transfected oval cells named HBX-EGFP-LE/6, and EGFP-LE/6, LE/6 control cells. In addition, exogenous TGFβ1 was added into all three oval cell lines, MTT assay was preformed to clarify different responses to the anti-proliferative effect of TGFβ1., Results: The TGFβRII mRNA levels in LE/6 and EGFP-LE/6 cells were (10.2 ± 1.8) and (8.8 ± 0.9) folds of those in HBX-EGFP-LE/6 cells, the difference was significant (P < 0.05). HBX protein expression also reduced the protein levels of TGFβRII in HBX-EGFP-LE/6 oval cells, compared to the control cells. The MTT results exhibited that, after TGFβ1 addition, proliferative inhibition rate in the HBX-EGFP-LE/6 cells was 18.1% ± 1.5% while those in control cells were 42.2% ± 2.8% and 41.9% ± 5.0%, the difference was significant (P < 0.01)., Conclusion: HBX protein expression affects TGFβRII transcriptional activity and protein synthesis, and insensitive oval cells to anti-proliferative effect of TGFβ1.

Background and Aim: The conventional method of anatomical right hemihepatectomy (ARHH) requires hilus dissection. We report a method without hilus dissection to minimize intraoperative bleeding., Methods: We retrospectively evaluated data of 107 patients who received ARHH involving ligation of corresponding inflow and outflow vessels (LCIOV) without hilus dissection between January 2000 and October 2008. Results were compared to those of patients who underwent non-anatomical right hemihepatectomies (NARHH)., Results: The two groups had similar gender and age (both, P>0.05). The LCIOV group had a higher percentage of patients without intrahepatic metastases (94.6% vs 80.3%, P=0.003). Hepatocellular carcinoma (HCC) lesion size (9.3 vs 10.2, P=0.023), durations of inferior vena cava occlusion (4 vs 4.7, P<0.001) and portal triad occlusion (7 vs 11, P<0.001), blood loss (430 vs 580 mL, P=0.001), transfusion volume (300 vs 520 mL, P<0.001), and measures of postoperative liver function (e.g. maximum aspartate aminotransferase [AST]) of the LCIOV group were also significantly less than the NARHH group. Larger hepatic cavernous hemangiomas (HCH) lesion size (16.2 vs 13.0, P<0.001), longer operative time (168 vs 154 min, P=0.017), and a lower percentage of patients with inferior vena cava occlusion (17.8% vs 35.2%, P=0.001), pleural effusions (19.3% vs 30.9%, P=0.042), and blood transfusions (10.3% vs 75.0%, P<0.001) were found in the LCIOV group., Conclusion: The reported method is a safe and bloodless technique for right hemihepatectomy in select patients., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Objective: To investigate the changes of oval cell proliferation rate in the rat 2-acetylaminofluorene/partial hepatectomy (2-AAF/PH) model., Methods: Livers were collected from 2-AAF/PH rats at different time points after hepatectomy. Paraffin sections were investigated by double immunofluorescent staining with confocal microscopy for oval cell marker epithelial cell adhesion molecule and proliferative index proliferating cell nuclear antigen, or epithelial cell adhesion molecule and alpha-smooth muscle actin. Deposition of matrix in liver tissue was detected by sirius red staining., Results: Response of ductular oval cells could be observed in portal area at 2 days after PH, and the number of oval cells reached its peak at 9 days and then gradually declined. Oval cell proliferation rate decreased from (91.3 +/- 1.6)% at 2 days after PH to (53.6 +/- 4.4)% at 12 days (P < 0.01). In addition, oval cells infiltrating into liver parenchyma were closely associated with activated hepatic stellate cells and extracellular matrix., Conclusions: Oval cell proliferation rate starts decreasing before its number reaches a peak in 2-AAF/PH model. Hepatic stellate cells probably tightly regulate oval cell number through secreting several factors and producing extracellular matrix.

Hepatic oval cells are thought to represent facultative hepatic epithelial stem cells in liver in which damage inhibits hepatocyte proliferation and liver regeneration. The LE/6 hepatic stem cell line was derived from the liver of male Sprague-Dawley rats fed a choline-deficient diet containing 0.1% ethionine. They are histochemically characterized by their expression of hepatocytic (hepPar1), cholangiocytic cytokeratin (CK19), hepatic progenitor cell (OV-6), and hematopoietic stem cell (c-kit) markers. In this study, we transplanted LE/6 cells by subcutaneous injection into adult female nude mice, and examined their engraftment and differentiation potential in the subcutaneous microenvironment in vivo. Our results demonstrated that following subcutaneous transplantation, differentiation of LE/6 cells into mesenchymal tumor tissue (MTT) was associated with reduced E-cadherin expression, upregulation of E-cadherin repressor molecules (Snail proteins), and increased expression of vimentin and N-cadherin, all of these events are characteristic of the epithelial-mesenchymal transition (EMT).

Objective: To investigate the role of hepatic stellate cells in the differentiation of hepatic oval cells into adult hepatocyte., Methods: The oval cell were cocultured with primary hepatic stellate cells (HSC) in the same well (M-coculture) or separately cultured with HSC by millIcell (S-coculture). Oval cells were cultured alone as control; the expression of adult hepatocyte marker HNF-4alpha, albumin, and oval cell marker AFP, CK-19 in each group were detected by real-time PCR and western-blot. Phenotype changes were observed by transmission electron microscope (TEM); PAS staining was used to detect the quantity of glycogen granule in oval cell. Albumin level in supernatant was detected using ELISA kit., Result: (1) The relative level of HNF-4alpha and albumin mRNA expression compared with pre-coculture: M-coculture: HNF-4a: 1.9+/-0.2, 10.7+/-1.2, 12.0+/-1.3; albumin: 5.7+/-1.6, 110.7+/-13.7, 173.6+/-22.3. S-coculture: 1.4+/-0.1, 3.2+/-0.6, 8.9+/-1.4 times; albumin: 2.9+/-1.4, 22.3+/-8.5, 96.3+/-16.3. The relative level of HNF-4a and albumin mRNA expression in coculture group (M- and S-coculture) were higher than control group (LSD-t: 32.98, 10.08, 13.38, 7.96; P less than 0.01); and a higher level of HNF-4a and albumin was found in M-coculture group compared to S-coculture group (LSD-t: 32.98, 25.65; P less than 0.01). The relative level of AFP and CK-19 mRNA expression compared with pre-coculture: M-coculture: 1.1+/-0.2, 0.2+/-0.0, 0.0+/-0.0; S-coculture group: AFP: 1.0+/-0.2, 0.2+/-0.1, 0.1+/-0.0; CK-19: 0.6+/-0.1, 0.1+/-0.0, 0.0+/-0.0; control group: AFP: 1.0+/-0.1, 1.0+/-0.1, 1.1+/-0.1, CK-19: 1.0+/-0.1, 1.1+/-0.1, 1.0+/-0.1. The relative level of AFP and CK-19 mRNA expression in coculture group (M- and S-coculture) were lower than that in control group (LSD-t: 37.99, 34.50, 13.59, 22.46; P less than 0.01). (2) The albumin secretion was detected in M-coculture: 14 day: (15.30+/-0.09) ng/ml, 21: (20.98+/-0.12) ng/ml; S-coculture: 14 day: (11.41+/-0.13) ng/ml, 21 day:(15.12+/-0.17) ng/ml. (3) It showed more organelles such as endoplasmic reticulum, mitochondrion and Golgi apparatus in oval cells cocultured with HSC. And cholangiole-like structure appeared between oval cells cocultured with HSC. (4) PAS staining showed glycogen granules could be observed in coculture groups., Conclusion: HSC can induce differentiation of oval cell into mature hepatocyte.

Aim: To elucidate the interaction between non-parenchymal cells, extracellular matrix and oval cells during the restituting process of liver injury induced by partial hepatectomy (PH)., Methods: We examined the localization of oval cells, non-parenchymal cells, and the extracellular matrix components using immunohistochemical and double immunofluorescent analysis during the proliferation and differentiation of oval cells in N-2-acetylaminofluorene (2-AAF)/PH rat model., Results: By day 2 after PH, small oval cells began to proliferate around the portal area. Most of stellate cells and laminin were present along the hepatic sinusoids in the periportal area. Kupffer cells and fibronectin markedly increased in the whole hepatic lobule. From day 4 to 9, oval cells spread further into hepatic parenchyma, closely associated with stellate cells, fibronectin and laminin. Kupffer cells admixed with oval cells by day 6 and then decreased in the periportal zone. From day 12 to 15, most of hepatic stellate cells (HSCs), laminin and fibronectin located around the small hepatocyte nodus, and minority of them appeared in the nodus. Kupffer cells were mainly limited in the pericentral sinusoids. After day 18, the normal liver lobule structures began to recover., Conclusion: Local hepatic microenvironment may participate in the oval cell-mediated liver regeneration through the cell-cell and cell-matrix interactions.

Objective: Clinical and liver pathological features of 60 primary biliary cirrhosis (PBC) patients were reviewed to identify prognostic factors in order to improve the diagnosis and treatment of the disease., Methods: The general conditions, clinical manifestations, serum biochemical and immunological changes, and liver pathological findings were assessed in 60 PBC patients. All cases were followed up and 5 variables were studied by univariate analysis; the variables linked with survival were included in a Cox model., Results: Forty-eight patients were females (80%), 12 were males (20%), and the mean age at their diagnoses was (52.5+/-9.4). The symptoms most frequently complained about were jaundice (61.6%), fatigue (51.6%), anorexia (43.3%) and pruritus (25%). Serum alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) levels were markedly elevated in the majority of the patients [(242.3+/-137.1) U/L and (250.6+/-216.1) U/L, respectively], whereas ALT and AST levels were mildly to moderately elevated [(185.8+/-269.1) U/L and (172.5+/-163.6) U/L, respectively]. Thirty-two patients (53.3%) had a total bilirubin level of > or = 34.2 micromol/L. Twenty-eight patients (59.5%) had elevated serum IgM and 41 patients (68.3%) were anti-mitochondrial antibody AMA/AMA-M2 positive. Forty-two of the 60 patients had liver biopsies. The liver pathological changes: 33.3% of the cases were in I or II stage and 66.6% in III or IV stage. The follow up results: Five patients died of liver failure or massive upper gastrointestinal bleeding; 45 were still alive; the average survival period was 3.92 years; 10 patients were lost in the follow-up. With multivariate analysis (Cox model), age, level of total bilirubin and the stage of the liver pathological changes were found to be independent factors linked to the survival of the patients., Conclusion: PBC may not be a rare liver disease in China. The awareness to recognize PBC is important in making an early diagnosis and treatment.

Background: Mesohepatectomy is a rarely used operative procedure to treat liver cancer because of its technical complexity. In patients with hepatocellular carcinoma (HCC) with a viral hepatitic/cirrhotic background, this procedure can be used to resect the tumor with adequate margins, while at the same time preserve as much functioning hepatic parenchyma as possible. This retrospective study aimed to evaluate the early results and late survival outcomes of mesohepatectomy in HCC., Materials and Methods: From 1996 to 2005, 256 patients with HCC situated at the central liver segments (Couinaud segments IV, V, VIII+/-I) were treated with mesohepatectomy. The treatment outcomes of these patients were retrospectively analyzed., Results: The in-hospital mortality rate was 0.4%, but the postoperative morbidity rate was 28.1%. The 1-, 3-, and 5-year overall survival rates were 77.0, 49.8, and 35.1%, while the 1-, 3-, and 5-year disease-free survival rates were 59.1, 28.8, and 17.0%, respectively. Multivariate analyses showed the significant factors for overall survival were tumor size>8 cm, vascular invasion, and alpha fetoprotein (AFP)>5,000 ng/ml; and for disease-free survival were tumor size>8 cm, vascular invasion, tumor number (three or more), AFP>5,000 ng/ml., Conclusion: Mesohepatectomy is a safe and effective treatment for a centrally situated HCC with a viral hepatitic/cirrhotic background.

Background: Massive bleeding remains one of main factors of morbidity and death in liver resections. For this reason, the Pringle maneuver or total vascular exclusion is commonly used during liver resection. However, ischemic damage is still a major problem. Some surgeons used the "glissonean" approach for bleeding control, but the technique is tedious and also time consuming, with high incidence of bile leaks in the postoperative period. The aim of this paper is to describe a new bleeding control technique, rapid ligation of the corresponding inflow and outflow vessels without hilus dissection before the parenchyma transection during anatomical left liver resection and to analyze the feasibility, blood loss, transfusion requirements, and postoperative complications., Materials and Methods: During the past 18 years, we used the new hemorrhage control technique in left liver resection in 630 patients with malignant or benign tumors., Results: The median blood loss in all 630 patients was 110 +/- 250 ml (range 50-750), and no patient required blood transfusion. The median total operative time was 77 +/- 35 min (range 25-155). No bile leaks and liver failure of the patients occurred postoperatively. There was no death within 30 postoperative days., Conclusion: The rapid ligation of the corresponding inflow and outflow vessels without hilus dissection before the parenchyma transection is a feasible, safe, and bloodless technique during the left liver resection.

The interleukin-1 receptor-like protein ST2 exists in both membrane-bound (ST2L) and soluble form (sST2). ST2L has been found to play an important regulatory role in Th2-type immune response, but the function of soluble form of ST2 remains to be elucidated. In this study, we report the protective effect of soluble ST2 on warm hepatic ischemia/reperfusion injury. We constructed a eukaryotic expression plasmid, psST2-Fc, which expresses functional murine soluble ST2-human IgG1 Fc (sST2-Fc) fusion protein. The liver damage after ischemia/reperfusion was significantly attenuated by the expression of this plasmid in vivo. sST2-Fc remarkably inhibited the activation of Kupffer cells and the production of proinflammatory mediators TNF-alpha and IL-6. Furthermore, the levels of TLR4 mRNA and the nuclear translocation of NF-kappaB were also suppressed by pretreatment with sST2-Fc. These results thus identified soluble ST2 as a negative regulator in hepatic I/R injury, possibly via ST2-TLR4 pathway.

Background: Hepatic veins remain patent during complete inflow occlusion (CIO) and bleeding from them may continue. Occlusion of the inferior vena cava (ICV) during CIO may reduce blood loss from hepatic veins. This study was designed to compare the overall outcomes after application of CIO with or without occlusion of the ICV below the liver in complex mesohepatectomy for hepatocellular carcinoma (HCC) patients with cirrhosis., Materials and Methods: One hundred and eighteen (118) patients were randomly assigned to CIO or a modified technique of hepatic vascular exclusion (MTHVE). Hemodynamic parameters were evaluated and the amount of blood loss, measurement of liver enzymes, and postoperative progress were recorded., Results: Blood loss during liver transection in CIO groups was significantly greater than that in MTHVE group (P=0.046). Thus, incidence of blood transfusion was significantly greater in patients of the CIO group (P=0.041). There were no significant differences in liver enzyme changes, bilirubin, or morbidity in the postoperative period between the two groups., Conclusions: CIO with occlusion of the ICV below the liver is a safe, effective, and feasible technique during mesohepatectomy in HCC patients with cirrhosis. Excellent results were obtained with minimized bleeding, limited hepatic function damage, and low rate of postoperative complications.

Objective: To study the relationship between hepatic insulin resistance induced by high fat diet and the expression of genes involving hepatic glucose output., Methods: Normal 8-week-old male SD rats were randomly divided into two groups, i.e, normal chow group (NC, n = 10) and high fat diet group (HF, n = 10). They were fed for 28 weeks. Body weight and fasting blood glucose (FBG) were measured. At the end of the experiment, the rats were sacrificed and their fasting insulin (INS) and triglycerides (TG) were measured. Hepatic insulin sensitivity was measured by tissue uptake of 3H-2-deoxyglucose and the content of hepatic glycogen was measured using the anthrone method. Gene expression was investigated by using the semi-quantitative RT-PCR method., Results: As compared with NC group, CF group rats developed visceral obesity which was accompanied by higher plasma TG. FBG in CF group increased starting from the 18th week (NC 4.77+/-63 mmol/L vs HF 5.45+/-87 mmol/L, P < 0.05). The rate of uptake of 3H-2-deoxyglucose in livers decreased by 51% in the HF group. The content of hepatic glycogen increased by 92.4% (P < 0.01). The level of phosphoenolpyruvate carboxykinase (PEPCK) and PGC-1a mRNA increased by 41.5% and 30.8%, respectively (P < 0.05)., Conclusion: A high fat diet induced expressions of PGC-1a and PEPCK. It suggests that gluconeogenesis may play a role in the increase of hepatic glucose output and FBG.

Background: The high mortality of patients with severe acute pancreatitis (SAP) is due to multiorgan dysfunction. The mechanisms of SAP are still obscure. The aim of this study was to investigate the role of nuclear factor-kappa B (NF-kappaB) activation in rats with SAP associated with liver injury and the protection effect of triptolide against liver injury in rats with SAP., Methods: Ninety Wistar rats were randomly divided into three groups (n=30 each group): severe acute pancreatitis (group P), treatment with triptolide (group T), and sham operation (group S). SAP models were induced by retrograde injection of 5% sodium taurocholate to the pancreatic duct. After the model was successfully established, no treatment was given to group P. In group T, triptolide (0.05 mg/ml) was injected intraperitoneally (0.2 mg/kg). In group S, the abdominal walls of rats were opened, sutured, but not treated. The rats were sacrificed after operation at 2, 6, and 12 hours, respectively. The serum levels of amylase (AMY), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined at three time points (10 rats for each time point). Liver tissues were obtained to detect the activity of NF-kappaB and to observe their pathological changes with light and electron microscopes., Results: The serum levels of AMY and ALT were higher in groups P and T than in group S. The serum AMY levels were significantly lower in group T than in group P at 12 hours after operation. The serum ALT levels were significantly lower in group T than in group P at 6, 12 hours after operation. At the three time points, the levels of TNF-alpha and IL-6 in groups P and T increased more significantly than in group S. In group T they were decreased more significantly than in group P at the three time points. In groups P and T, NF-kappaB activity in liver tissue increased more significantly than in group S at the three time points. The activity of NF-kappaB was higher in group P than in groups S and T at the three time points. Liver pathological damages were milder in group T than in group P under light and electron microscopes., Conclusions: NF-kappaB plays an important role in the pathogenesis of liver injury in rats with SAP. Triptolide can reduce pathological damage to the liver. Its mechanism is to inhibit the activity of NF-kappaB and to decrease the release of inflammatory mediators.

Aim: To determine the role and effect of nitric oxide synthase type II (NOSII) in cirrhotic rats., Methods: Expression of NOSII mRNA was detected by real time RT-PCR. The activity of nitric oxide synthase and serum levels of NO, systemic and portal hemodynamics and degrees of cirrhosis were measured with high sensitive methods. Chinese traditional medicine tetrandrine was used to treat cirrhotic rats and to evaluate the function of NO. Double-blind method was applied during the experiment., Results: The concentration of NO and the activity of NOS were increased markedly at all stages of cirrhosis, and iNOSmRNA was greatly expressed. Meanwhile the portal-venous-pressure (PVP), and portal-venous-flow (PVF) were significantly increased. NO, NOS and iNOSmRNA were positively correlated to the quantity of hepatic fibrosis. Tetrandrine significantly inhibited NO production and the expression of iNOSmRNA., Conclusion: Increased hepatic expression of NOSII is one of the important causes of hepatic cirrhosis and portal hypertension.

Aims: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects., Methods: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography., Results: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively., Conclusions: The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.

In the past 37 years, 207 patients with hepatic injuries were managed in our hospital. Of them, 5 patients died during the preparation for emergency laparotomy. 191 patients were surgically treated, with 11 (5.8%) postoperative deaths, while all 11 patients treated nonsurgically were cured. Finally, we discussed operative methods of hepatic injuries and indications for conservative therapy.