Role In Liver Cirrhosis Research Articles

MiR-541 is associated with the prognosis of liver cirrhosis and directly targets JAG2 to inhibit the activation of hepatic stellate cells.

The activation of hepatic stellate cells (HSCs) has been emphasized as a leading event of the pathogenesis of liver cirrhosis, while the exact mechanism of its activation is largely unknown. Furthermore, the novel non-invasive predictors of prognosis in cirrhotic patients warrant more exploration. miR-541 has been identified as a tumor suppressor in hepatocellular carcinoma and a regulator of fibrotic disease, such as lung fibrosis and renal fibrosis. However, its role in liver cirrhosis has not been reported. Real-time PCR was used to detect miR-541 expression in the liver tissues and sera of liver cirrhosis patients and in the human LX-2. Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the activation of LX-2. Bioinformatics analysis and a luciferase reporter assay were conducted to investigate the target gene of miR-541. miR-541 was downregulated in the tissues and sera of patients with liver cirrhosis, which was exacerbated by deteriorating disease severity. Importantly, the lower expression of miR-541 was associated with more episodes of complications including ascites and hepatic encephalopathy, a shorter overall lifespan, and decompensation-free survival. Moreover, multivariate Cox's regression analysis verified lower serum miR-541 as an independent risk factor for liver-related death in cirrhotic patients (HR = 0.394; 95% CI: 0.164-0.947; P = 0.037). miR-541 was also decreased in LX-2 cells activated by TGF-β and the overexpression of miR-541 inhibited the proliferation, activation and hydroxyproline secretion of LX-2 cells. JAG2 is an important ligand of Notch signaling and was identified as a direct target gene of miR-541. The expression of JAG2 was upregulated in the liver tissues of cirrhotic patients and was inversely correlated with miR-541 levels. A rescue assay further confirmed that JAG2 was involved in the function of miR-541 when regulating LX-2 activation and Notch signaling. Dysregulation of miR-541/JAG2 axis might be a as a new mechanism of liver fibrosis, and miR-541 could serve as a novel non-invasive biomarker and therapeutic targets for liver cirrhosis.

Potential of Apolipoprotein A1 (ApoA1) for Detecting Liver Cirrhosis and Hepatocellular Carcinoma.

Objective: Liver cirrhosis and hepatocellular carcinoma (HCC) are chronic liver diseases that can cause serious health problems. Meanwhile, the methods used to detect liver cirrhosis and HCC are limited. Apolipoprotein A1 (ApoA1) is a protein that makes up high-density lipoprotein (HDL), which plays a role in liver cirrhosis and HCC, and can be used as a biomarker. This study aims to determine the ability of ApoA1 to detect and differentiate liver cirrhosis and hepatocellular carcinoma.Methods:This cross-sectional study was conducted on 47 patients with liver cirrhosis and HCC at Margono Soekarjo Regional General Hospital, Purwokerto, Indonesia. This study also involved 33 healthy participants from blood donors at the Blood Transfusion Unit, Indonesian Red Cross, Banyumas. Serum ApoA1 levels were analyzed by ELISA method. Receiver Operating Characteristics (ROC) were used to evaluate the diagnostic power of ApoA1 and differentiate between cirrhotic, HCC, and healthy patients. Multivariate binary logistic regression test to determine the most influential variables on the incidence of cirrhosis, HCC, and health. Results:ApoA1 was able to differentiate cirrhosis from HCC, cirrhosis from healthy and HCC from healthy, with sensitivity 56.7%, 86.7%, 70.6%, specificity 70.6%, 93.9%, 84.9%, respectively, and AUC 68.5%, 92.6%, 75.0%. AFP (p = 0.002, OR 1.004) and bilirubin (p = 0.021, OR 1.259) were variables that contributed to cirrhosis - HCC. Age (p = 0.011, OR 0.766) and AST (p = 0.003, OR 0.834) are variables that play a role in health - cirrhosis. ALT (p = 0.024, OR 0.965) and PT (p = 0.004, OR 0.253) are variables that play a role in healthy - HCC. Conclusion:ApoA1 was best for detecting healthy from cirrhosis, followed by healthy from HCC and cirrhosis from HCC. ApoA1 is not the primary variable determining the incidence of cirrhosis - HCC, healthy - HCC, and healthy – HCC.

Bioinformatics-Based Analysis of lncRNA-mRNA Interaction Network of Mild Hepatic Encephalopathy in Cirrhosis.

Backgrounds Serum long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) interaction network was discovered to exert an important role in liver cirrhosis while little is known in mild hepatic encephalopathy (MHE). Therefore, we aim to systematically evaluate the serum lncRNA-mRNA network and its regulatory mechanism in MHE. Methods The data of serum mRNAs and lncRNAs were derived from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were calculated between 11 cirrhotic patients with and without MHE. Next, the biological functions and underlined pathways of DEGs were determined through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, an interactive network between lncRNAs and mRNAs was built, and hub genes were identified, respectively. Results A total of 64 differentially expressed lncRNAs (dif-lncRNAs) were found between patients with and without MHE, including 30 up- and 34 downregulated genes. 187 differentially expressed mRNAs (dif-mRNAs) were identified, including 84 up- and 103 downregulated genes. Functional enrichment analysis suggested that the regulatory pathways involved in MHE mainly consisted of a series of immune and inflammatory responses. Several hub mRNAs involved in regulatory network were identified, including CCL5, CCR5, CXCR3, CD274, STAT1, CXCR6, and EOMES. In addition, lnc-FAM84B-8 and lnc-SAMD3-1 were found to regulate these above hub genes through building a lncRNA-mRNA network. Conclusion This is the first study to construct the serum lncRNA-mRNA network in MHE, demonstrating the critical role of lncRNAs in regulating inflammatory and immunological profiles in the developing of MHE, suggesting a latent mechanism in this pathophysiological process.

Serum zonulin levels in patients with liver cirrhosis: Prognostic implications.

BACKGROUNDIncreased gut permeability and bacterial translocation play an important role in liver cirrhosis. Zonulin is a recently recognized protein involved in the disintegration of the intestinal barrier.AIMTo investigate possible differences in serum zonulin levels among patients with different cirrhosis stages and their potential prognostic implications.METHODSConsecutive cirrhotic patients who attended our liver clinic were included in the study. Serum zonulin levels, clinical, radiological and biochemical data were collected at baseline. Patients who accepted participation in a regular surveillance program were followed-up for at least 12 mo.RESULTSWe enrolled 116 cirrhotics [mean Child-Turcotte-Pugh (CTP) score: 6.2 ± 1.6; model for end-stage liver disease score: 11 ± 3.9]. The causes of cirrhosis were viral hepatitis (39%), alcohol (30%), non-alcoholic fatty liver disease (17%), and other (14%). At baseline, 53% had decompensated cirrhosis, 48% had ascites, and 32% had history of hepatic encephalopathy. Mean zonulin levels were significantly higher in patients with CTP-B class than CTP-A class (4.2 ± 2.4 ng/dL vs 3.5 ± 0.9 ng/dL, P = 0.038), with than without ascites (P = 0.006), and with than without history of encephalopathy (P = 0.011). Baseline serum zonulin levels were independently associated with the probability of decompensation at 1 year (P = 0.039), with an area under the receiving operating characteristic of 0.723 for predicting hepatic decompensation. Higher CTP score (P = 0.021) and portal vein diameter (P = 0.022) were independent predictors of mortality.CONCLUSIONSerum zonulin levels are higher in patients with more advanced chronic liver disease and have significant prognostic value in identifying patients who will develop decompensation.

Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals.

Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone.

Prognostic value of serum autotaxin in liver cirrhosis and prediction of hepatocellular carcinoma

BackgroundAutotaxin is a lysophospholipase D related to liver fibrosis; its clinical role in liver cirrhosis is still unknown or limited. In this study we investigate the relation of autotaxin serum levels and prognosis of liver disease and/or prediction of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) patients.Patients and methodsThis observational, prospective case–control study included 180 participants, 60 patients with HCV-related liver cirrhosis, 60 HCV noncirrhotic patients, and 60 healthy controls. They were enrolled from inpatients and clinics of a tertiary-care hospital. Baseline characteristics, serum autotaxin, Child–Turcotte–Pugh and model of end-stage liver disease scores were determined. Abdominal ultrasound and upper gastrointestinal endoscopy were done at the beginning of the study. Cirrhotic patients were prospectively followed up for 6 months.ResultsPatients with liver cirrhosis had the highest level of autotaxin (106±24 μg/ml) compared with noncirrhotic HCV patients (81.9±21 μg/ml) and healthy controls (42.5±11 μg/ml) using one-way analysis of variance test (P=0.000). Spearman’s correlation analysis showed no significant correlation between autotaxin and Child–Turcotte–Pugh score (r=0.02; P<0.70), and model of end-stage liver disease score (r=0.15; P<0.41). At 6 months of follow-up, patients who developed HCC or encephalopathy had significantly higher baseline autotaxin level (141±55 μg/ml; P=0.02, 117±56.6 μg/ml; P=0.000), respectively, than patients who did not (102±34, 90.7±40 μg/ml). Cutoff values of autotaxin for the prediction of HCC and encephalopathy were 95 and 92μg/ml, respectively, with 91 and 92% sensitivity.ConclusionAutotaxin is a sensitive predictor for the development of HCC and encephalopathy in HCV-related cirrhotic patients. However, it was not related to disease severity.

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis.

BACKGROUNDClinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIMTo determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension.METHODSA cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals.RESULTSPeripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH.CONCLUSIONPlasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.

Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review.

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

Prognostic significance of vitamin D receptor (VDR) gene polymorphisms in liver cirrhosis

Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1β and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1β levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.

Cyclooxygenase-2 up-regulates hepatic somatostatin receptor 2 expression

Somatostatin and its analogues, which function by binding to somatostatin receptors (SSTRs) 1–5, play a protective role in liver cirrhosis. Hepatic SSTR-2 expression is up-regulated in subjects with liver cirrhosis. However, little is known about the mechanisms underlying this process. In the present study, we observed the up-regulation of hepatic SSTR-2 expression in thioacetamide (TAA)-induced cirrhotic rats and further showed that cyclooxygenase-2 (COX-2) might play a role in this process via the protein kinase C (PKC)–cAMP response element binding protein (CREB) signaling pathway. In vivo, the up-regulated SSTR-2 in liver cirrhosis was inhibited by the addition of a selective COX-2 inhibitor, such as celecoxib. In vitro, the up-regulation of COX-2 by either transfection with COX-2 plasmids or treatment with TAA increased levels of SSTR-2 and phosphorylated CREB (p-CREB) in the human hepatocyte cell line L02. Furthermore, the increase in SSTR-2 expression was inhibited by the addition of celecoxib and a PKC inhibitor. Moreover, for comparable DNA methylation levels in the region upstream of the hepatic SSTR-2 gene in normal and cirrhotic livers, DNA methylation may not contribute to the up-regulation of SSTR-2 expression in cirrhotic livers. In conclusion, the up-regulation of hepatic SSTR-2 might be induced by COX-2 via the PKC-CREB signaling pathway but is probably not induced by DNA methylation.

Systems analysis of key genes and pathways in the progression of hepatocellular carcinoma

The carcinogenesis of hepatocellular carcinoma (HCC) is a complex process, starting from a chronically altered hepatic microenvironment due to liver cirrhosis and ultimately progressing to HCC. However, the sequential molecular alterations driving the malignant transformation in liver cirrhosis are not clearly defined.In this study, we obtained gene expression profiles of HCC, including 268 tumor tissues, 243 adjacent tumor tissues, and 40 cirrhotic tissues (GSE25097) from Gene Expression Omnibus (GEO), to comprehensively define changes in the transcriptome of HCC during the sequential evolution of liver cirrhosis into HCC.We showed that changes in the molecular profiles of cirrhotic and adjacent tumor samples were small and quite uniform, whereas there was a striking increase in the heterogeneity of tumors in HCC tissues at the mRNA level. A massive deregulation of key oncogenic molecules and pathways was observed from cirrhosis to HCC tumors. In addition, we focused on FOXO1 and DCN, 2 critical tumor suppressor genes that play an important role in liver cirrhosis and HCC development. FOXO1 and DCN expression levels were significantly reduced in tumor tissues compared with adjacent tumor tissues in HCC. Kaplan-Meier analysis revealed that FOXO1 and DCN expression was positively correlated with overall survival, defining FOXO1 and DCN as adverse prognostic biomarkers for HCC.This system-level research provided new insights into the molecular mechanisms of HCC carcinogenesis. FOXO1 and DCN may be applied as potential targets for HCC treatment in the future.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis.

Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA+ -M2BP in evaluating liver function and predicting prognosis of cirrhotic patients. We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA+ -M2BP and various biochemical parameters were measured in all patients. With a median follow-up of 23 months, liver-related complications and deaths of 160 patients were recorded. The accuracy of WFA+ -M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively. WFA+ -M2BP levels increased with elevated Child-Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA+ -M2BP for the assessment of liver function using Child-Pugh classification. WFA+ -M2BP was also significantly positively correlated with the model for end-stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA+ -M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876-76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA+ -M2BP as an independent risk factor for liver-related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356-82.820, P = 0.024). Serum WFA+ -M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection.

Cytokinome profile evaluation in patients with hepatitis C virus infection.

The ''omics sciences'' (genomics, transcriptomics, proteomics) are often used to study living organisms as a whole system by evaluating the complex expression patterns of genes, miRNA, proteins, and metabolites. This study aimed, through bioinformatics and systems biology, to decipher the cytokinome profile in the evolution of inflammatory processes leading to cancer. The cytokinome was defined as the totality of cytokines and their interactions in and around biological cells. The system biology approach would provide a better understanding of the complex interaction network of cytokines, especially in cancer patients. Acquired knowledge would enable health providers with tools to evaluate disease onset through progression as well as identifying innovative therapeutic strategies. Understanding the role each cytokine plays in the metabolic network is of great importance. This paper reviews our group's ''omics'' work. In particular, it addresses the role cytokines play in liver disease in six different scenarios. The first is the role the cytokines play in chronic inflammatory diseases and cancers. The second is the significance of the cytokinome profile. The third is the role of liver cirrhosis as an inflammatory disease. The fourth is the comparison of cytokine levels evaluated in patients with chronic hepatitis C virus (HCV) or with HCV-related cirrhosis. The fifth is the comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of type 2 diabetes. And lastly, we present a comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of hepatocellular carcinoma.

Protein Recommendations for Older Adults with Cirrhosis: A Review

Protein intake has a key role in liver cirrhosis in older adults. However, types and amounts of protein intake in cirrhosis have been controversial. The aim of this paper is to investigate the optimal protein intake for management of cirrhosis and prevention of hepatic encephalopathy in older adults. Protein restriction of 0.6 g/kg/d has traditionally been used as medical nutrition therapy in liver cirrhosis. However, recent evidence has shown that protein restrictions have many negative consequences for older adults with cirrhosis. Current research indicates protein intakes of 1.2-1.5 g/kg/d in liver cirrhosis; however, many older adults do not consume this amount. Strategies to help increase protein intake and manage cirrhosis include ensuring adequate protein at every meal through either regular intake or supplementation, protein supplementation prior to bedtime or overnight, and supplementation with branched-chain amino acids. An emphasis on vegetable protein versus animal protein is probably not an advantageous treatment option because of lack of conclusive evidence regarding benefits and potential negative side effects.

Mass spectrometric characterization of human serum albumin dimer: A new potential biomarker in chronic liver diseases

Human serum albumin (HSA) undergoes several structural alterations affecting its properties in pro-oxidant and pro-inflammatory environments, as it occurs during liver cirrhosis. These modifications include the formation of albumin dimers. Although HSA dimers were reported to be an oxidative stress biomarker, to date nothing is known about their role in liver cirrhosis and related complications. Additionally, no high sensitive analytical method was available for HSA dimers assessment in clinical settings.Thus the HSA dimeric form in human plasma was characterized by mass spectrometry using liquid chromatography tandem mass spectrometry (LC-ESI-Q-TOF) and matrix assisted laser desorption time of flight (MALDI-TOF) techniques. N-terminal and C-terminal truncated HSA, as well as the native HSA, undergo dimerization by binding another HSA molecule. This study demonstrated the presence of both homo- and hetero-dimeric forms of HSA. The dimerization site was proved to be at Cys-34, forming a disulphide bridge between two albumin molecules, as determined by LC–MS analysis after tryptic digestion. Interestingly, when plasma samples from cirrhotic subjects were analysed, the dimer/monomer ratio resulted significantly increased when compared to that of healthy subjects. These isoforms could represent promising biomarkers for liver disease. Additionally, this analytical approach leads to the relative quantification of the residual native HSA, with fully preserved structural integrity.

Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.

Measurement of Transporter Associated with Antigen Processing 1 and Tumor Necrosis Factor Alpha Expression in Hepatitis B Virus-Related Hepatocellular Carcinoma and Peritumor Cirrhosis Tissues using Tissue Chip Technology

The objective of this study was to explore the associations of expression of transporter associated with antigen processing 1 (TAP1) and tumor necrosis factor alpha (TNF-α with the occurrence and development of HBV-related hepatocellular carcinoma (HCC). The expression of TAP1 and TNF-α in 38 HCC, 32 peritumor liver cirrhosis and 28 normal liver tissues, were assessed by immunohistochemical assay using tissue microarray technology. TAP1 and TNF-α were negative in normal liver tissue hut positive in HCC and peritumor cirrhosis tissue. There were no significant differences in the rates of positivity for TAP1 and TNF-α between HCC and peritumor cirrhosis tissue (p>0.05), but there was a significant difference when rates in HCC and peritumor cirrhosis tissue were compared with those in normal liver tissue (p<0.0001, p<0.01, respectively). The degree of differentiation of HCC was correlated with TNF-α expression (p<0.05), but not TAP1 expression (p>0.05), CONCLUSIONS: Major histocompatibility complex class I molecules are involved in HBV-related HCC. TNF-α plays an important role in liver cirrhosis and in formation and development of HCC following HBV infection. TNF-α can be used as an indicator of the degree of differentiation of HCC.

Hepatitis C Virus Infection Is Blocked by HMGB1 Released from Virus-Infected Cells

High-mobility group box 1 (HMGB1), an abundant nuclear protein that triggers host immune responses, is an endogenous danger signal involved in the pathogenesis of various infectious agents. However, its role in hepatitis C virus (HCV) infection is not known. Here, we show that HMGB1 protein is translocated from the nucleus to cytoplasm and subsequently is released into the extracellular milieu by HCV infection. Secreted HMGB1 triggers antiviral responses and blocks HCV infection, a mechanism that may limit HCV propagation in HCV patients. Secreted HMGB1 also may have a role in liver cirrhosis, which is a common comorbidity in HCV patients. Further investigations into the roles of HMGB1 in the diseases caused by HCV infection will shed light on and potentially help prevent these serious and prevalent HCV-related diseases.

Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis

Introduction Monocytes are the cells that play a crucial role in the pathogenesis of liver damage and liver cirrhosis (LC), and as platelets, by connecting hemostasis and inflammatory processes, participate in pathogenesis of chronic liver diseases, we aimed to investigate the presence of monocyte-platelet aggregates and platelet micro-particles (PMPs) and their role in LC. Patients and methods The study included 60 patients with post-hepatitic LC and 20 healthy controls. Activated monocytes (CD11b, HLA-DR, CD14, CD16), monocyte-platelet aggregates (CD41/CD14), activated platelets (CD41/CD62) and PMPs were analyzed by flow cytometry. Their relations to the clinical and laboratory data were assessed in the studied group. Results Patients with LC had higher levels of activated platelets, activated monocytes and monocyte-platelet aggregations as compared to healthy controls. PMPs percentage showed no significant differences between patients and controls but significantly increased in both patients with no bleeding and patients with splenomegaly compared to patients without. All studied markers showed no significant differences between patients with thrombocytopenia and those with normal platelet counts and also between patients with different disease stages. Positive correlations between monocyte-platelet aggregates and both activated platelets and monocytes were demonstrated. There were significant negative correlations between PMPs and both age and prothrombin time among patients. Conclusions The stage of post-hepatitic LC is not the only factor that affects the level of activated platelets, activated monocytes and monocyte-platelet aggregates. PMPs have no influence on thrombocytopenia but may have the potential to influence the progression of clotting activity in LC.

Does the right inferior phrenic artery has a supplying role in liver cirrhosis without HCC?: 64-slice CT evaluation

To investigate whether the right inferior phrenic artery (RIPA) has a role in supplying the liver in cirrhotic patients without hepatocellular carcinoma (HCC) using 64-slice computed tomography (CT). Fifty-eight consecutive cirrhotic patients were categorized into two groups in regard to the absence (group 1, n=33) or presence of portal vein thrombosis (group 2, n=25). In addition, 35 patients without liver disease were included as a control group (group 0). The diameters of the RIPA and left inferior phrenic artery (LIPA) were measured in the ascending portion of these vessels using arterial-phase CT images. The discrepancy between the diameters of the RIPA and LIPA were calculated. The diameters of the RIPA and LIPA and the discrepancy between the diameters of the RIPA and LIPA were then compared. The characteristics of all RIPA and LIPA were visualized. The diameter of the LIPA among the three groups was not significantly different (P = 0.363). The mean diameters of the LIPA were 1.8±0.19, 1.8±0.22, and 1.7±0.38 mm for groups 0, 1, and 2, respectively. The diameter of the RIPA was significantly greater (2.1±0.54 mm) in groups 1 and 2 (1.9±0.19 mm) than in group 0 (1.8±0.18 mm). There was significantly difference between groups 0 and 2 (P = 0.003), and groups 1 and 2 (P = 0.01) with regard to the discrepancy of the diameters of RIPA and LIPA. The RIPA may contribute to the blood supply of the liver in cirrhotic patients, especially those with portal venous thrombosis.