Connective tissue growth factor (CTGF/CCN2) in serum is an indicator of fibrogenic progression and malignant transformation in patients with chronic hepatitis B infection.

Still a challenging medical problem is the non-invasive monitoring of patients with a variety of chronic liver diseases being on risk to develop fibrosis, cirrhosis, and, finally, primary liver cell carcinoma. Previously, we have shown that CTGF/CCN2, a down-stream mediator of TGF-β, in serum might be a promising non-invasive biomarker of fibrosis, which is extended in the following study to cirrhosis and liver cell carcinoma. Healthy individuals (n=56), as well as fibrotic (n=77), cirrhotic (n=17), and HCC-patients (n=72) with chronic hepatitis B (HBV) infection, clinically, biochemically and histopathologically well characterized and classified, were included for the measurements of CTGF-concentrations in serum using a newly developed CTGF-enzyme immunoassay.

Connective tissue growth factor reacts as an IL-6/STAT3-regulated hepatic negative acute phase protein.

Aim: To investigate the mechanisms involved in a possible modulator role of interleukin (IL)-6 signalling on CYR61-CTGF-NOV (CCN) 2/connective tissue growth factor (CTGF) expression in hepatocytes (PC) and to look for a relation between serum concentrations of these two parameters in patients with acute inflammation.

Methods: Expression of CCN2/CTGF, p-STAT3, p-Smad3/1 and p-Smad2 was examined in primary freshly isolated rat or cryo-preserved human PC exposed to various stimuli by Western blotting, electrophoretic mobility shift assay (EMSA), reporter-gene-assays and reverse-transcriptase polymerase chain reaction.

Results: IL-6 strongly down-regulated CCN2/CTGF protein and mRNA expression in PC, enhanceable by extracellular presence of the soluble IL-6 receptor gp80, and supported by an inverse relation between IL-6 and CCN2/CTGF concentrations in patients' sera.

Increased serum xylosyltransferase activity in patients with liver fibrosis.

Background: We investigated the xylosyltransferase (XT) activity in the serum of liver fibrotic patients with hepatitis C virus induced liver fibrosis at different stages as determined according to the scoring system of Desmet and Scheuer.

Methods: Measurement of XT activity was performed by liquid chromatography-tandem mass spectrometry.

Results: We found that serum XT activity in males (n=59, median+/-SD, 27.

Impact of quality control accepted inter-laboratory variations on calculated Fibrotest/Actitest scores for the non-invasive biochemical assessment of liver fibrosis.

Introduction: Non-invasive, i.e. serum-based assessment of liver fibrosis is still an important diagnostic challenge although multiple single and multiparametric panels of biomarkers have been suggested.

BMP-7 as antagonist of organ fibrosis.

Fibrosis is a scarring process that is a common feature of chronic organ injury. It is characterized by elevated activity of transforming growth factor-beta resulting in increased and altered deposition of extracellular matrix and other fibrosis-associated proteins. Recent work has demonstrated that bone morphogenetic protein-7 blocks transforming growth factor-beta signaling.

Non-invasive biomarkers for monitoring the fibrogenic process in liver: a short survey.

The clinical course of chronic liver diseases is significantly dependent on the progression rate and the extent of fibrosis, i.e. the non-structured replacement of necrotic parenchyma by extracellular matrix.

Inverse association between serum concentrations of actin-free vitamin D-binding protein and the histopathological extent of fibrogenic liver disease or hepatocellular carcinoma.

Background And Aim: Next to its role as a carrier protein for vitamin D and its plasma metabolites, the primary function of vitamin D-binding protein (DBP; Gc-globulin) is to serve and to bind and neutralize extracellular monomeric actin (G-actin) released from necrotic cells, which in its long filamentous form (F-actin) triggers coagulation. We, therefore, investigated the kinetics of serum concentrations of actin-free DBP during the pathogenetic sequence from liver fibrosis to hepatocellular carcinoma (HCC) to initiate a discussion on a hypothetical association of serum concentrations of actin-free DBP and, thus, altered actin clearance in the circulation, and an increased risk of thrombosis in patients with functional liver insufficiency.

Results: Our data show that serum levels of actin-free DBP are decreased in patients with liver fibrosis (n=288) and HCC (n=102) compared with healthy controls (n=120 and n=63) and nonliver disease sick (n=312) and that the level of decrease correlates with the severity of disease as determined according to the score by the French METAVIR Cooperative Study Group staging system for hepatic fibrosis or the Edmondson-Steiner's grading system for the assessment of HCC.

Connective tissue growth factor is a Smad2 regulated amplifier of transforming growth factor beta actions in hepatocytes--but without modulating bone morphogenetic protein 7 signaling.

Unlabelled: In vivo knockdown of connective tissue growth factor (CTGF/CCN2) was recently shown to attenuate the formation of experimental liver fibrosis. The secreted, cysteine-rich growth factor is proposed to adversely modulate the binding of profibrogenic transforming growth factor beta (TGF-beta) and its natural antagonist bone morphogenetic protein (BMP) to their cognate receptors in several cellular systems, but the functionality of CTGF in modulation of the TGF-beta/BMP signaling pathways is still unknown. This study aims at characterizing a potentially differential modulating role of CTGF on TGF-beta- and BMP7-dependent transactivation of reporter gene [Ad-(CAGA)(12)-MLP-luc, Ad-hCTGF-luc, and Ad-(BRE)(2)-luc reporter gene] expression in rat hepatocytes.

Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells.

Background: Recently, we identified hepatocytes as the major cellular source of profibrogenic connective tissue growth factor (CTGF/CCN2) in the liver. Based on reports of a hepatoprotective effect of coffee consumption, we were the first to provide evidence that caffeine suppresses transforming growth factor (TGF)-beta dependent and -independent CTGF expression in hepatocytes in vitro and in vivo, thus suggesting this xanthine-alkaloid as a potential therapeutic agent.

Aim: This study aims at comparing the inhibitory capacities of caffeine and its three demethylated derivates paraxanthine, theophylline and theobromine on CTGF expression in hepatocytes and hepatic stellate cells (HSC).

Secreted cysteine-rich FGF receptor derives from posttranslational processing by furin-like prohormone convertases.

Cysteine-rich FGF receptor (CFR) was originally identified as a FGF2 receptor and found to be identical to Golgi complex-localized glycoprotein-1 (GLG1), also known as MG-160, and to a murine E-selectin ligand-1 (ESL-1). Although CFR is a 150-kDa integral membrane glycoprotein that is primarily located in the cis-medial Golgi complex, a substantial proportion of CFR is secreted but the underlying mechanism is unknown. CFR contains several possible furin-like proprotein convertase (PC) and matrix metalloproteinase cleavage sites.

Evaluation of serum percent trisialotransferrin as potential predictive biomarker of hepatocellular dedifferentiation in chronic liver disease.

Background And Aim: Chronic hepatitis induced liver fibrogenesis is characterized by epithelial-to-mesenchymal transition of liver parenchymal cells (hepatocytes) to fibroblast (-like cells), i.e. increasing hepatocellular dedifferentiation, ultimatively leading to the development of hepatocellular carcinoma (HCC).

Expression of E-selectin ligand-1 (CFR/ESL-1) on hepatic stellate cells: implications for leukocyte extravasation and liver metastasis.

Leukocytes and tumor cells use E-selectin binding ligands to attach to activated endothelial cells expressing E-selectin during inflammation or metastasis. The cysteine-rich fibroblast growth factor receptor (CFR) represents the main E-selectin ligand (ESL-1) on granulocytes and its expression is exclusively modified by alpha(1,3)-fucosyltransferases IV or VII (FucT4 and FucT7). Hepatic stellate cells (HSC) are pericytes of liver sinusoidal endothelial cells.

Elevated concentrations of 15-deoxy-Delta12,14-prostaglandin J2 in chronic liver disease propose therapeutic trials with peroxisome proliferator activated receptor gamma-inducing drugs.

Background/aims: Current knowledge confers a crucial role to connective tissue growth factor (CTGF/CCN2) in hepatic fibrogenesis. Hepatocytes are likely to be the major cellular source of CTGF in the liver in which CTGF is sensitively upregulated by TGF-beta. Recently, we demonstrated that the methylxanthine derivate caffeine leads to an upregulation of peroxisome proliferator activated receptor gamma (PPARgamma) expression in hepatocytes, thus sensitizing these cells to the well-known inhibitory effect of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15-d-PGJ(2)) on CTGF expression.

Altered factor VII activating protease expression in murine hepatic fibrosis and its influence on hepatic stellate cells.

Background: Platelet-derived growth factor-BB (PDGF-BB) is a profibrotic factor in liver fibrosis through its ability to stimulate hepatic stellate cells (HSC). The liver-derived serine protease factor VII activating protease (FSAP) regulates the activities of PDGF-BB in a cell-specific manner.

Aims: Our aim was to determine the influence of FSAP on the activation of HSC and to analyse the regulation of FSAP in hepatic fibrogenesis.

Questioning the role of actinfree Gc-Globulin as actin scavenger in neurodegenerative central nervous system disease: relationship to S-100B levels and blood-brain barrier function.

Introduction: Preliminary studies report on significantly higher levels of the major cytoskeleton protein actin in CSF of patients with neurodegenerative conditions and that the dynamics of these levels obviously correlates with disease progression and clinical disability. One of the primary functions of actinfree Gc-Globulin is to bind and neutralize extracellular monomeric actin, released into the circulation by necrotic or ruptured cells, and thus ameliorating the clinical outcome in situations of severe organ damage.

Aim And Methods: This is the first study to investigate actinfree Gc-Globulin and S100-B levels (as reliable marker of neurodegeneration) in paired CSF and serum samples of patients with multietiological CNS diseases.

Connective tissue growth factor: a fibrogenic master switch in fibrotic liver diseases.

Connective tissue growth factor (CTGF=CCN2), one of six members of cysteine-rich, secreted, heparin-binding proteins with a modular structure, is recognized as an important player in fibrogenic pathways as deduced from findings in non-hepatic tissues and emerging results from liver fibrosis. Collectively, the data show strongly increased expression in fibrosing tissues and transforming growth factor (TGF-beta)-stimulated expression in hepatocytes, biliary epithelial cells and stellate cells. Functional activity as a mediator of fibre-fibre, fibre-matrix and matrix-matrix interactions, as an enhancer of profibrogenic TGF-beta and several secondary effects owing to TGF-beta enhancement, and as a down-modulator of the bioactivity of bone morphogenetic protein-7 has been proposed.

Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury.

Platelet-derived growth factor (PDGF) has an essential role in liver fibrogenesis, as PDGF-B and -D both act as potent mitogens on culture-activated hepatic stellate cells (HSCs). Induction of PDGF receptor type-beta (PDGFR beta) in HSC is well documented in single-dose carbon tetrachloride (CCl(4))-induced acute liver injury. Of the newly discovered isoforms PDGF-C and -D, only PDGF-D shows significant upregulation in bile duct ligation (BDL) models.

Maternal factor V Leiden mutation is associated with HELLP syndrome in Caucasian women.

Objective: There is growing evidence that hypertensive pregnancy complications and other adverse pregnancy outcomes are associated with the presence of inherited or acquired thrombophilias. As hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is one of the most severe forms of pre-eclampsia we aimed to assess the prevalence of the factor V Leiden, the prothrombin 20210G >A mutation and the methylenetetrahydrofolate reductase (MTHFR) 677C >T polymorphism in women with HELLP syndrome and in their fetuses from the same index pregnancy.

Design: The study was performed retrospectively in a case-control design.

Transforming growth factor beta 1 gene variants increase transcription and are associated with liver cirrhosis in Chinese.

Background And Aims: Transforming growth factor beta1 (TGFbeta1) acts as an important profibrogenic cytokine in liver fibrogenesis. The aim of this study was to explore the association between TGFbeta1 gene polymorphisms and liver cirrhosis.

Methods: Totally 118 Chinese suffering from liver cirrhosis induced by HBV infection and 104 healthy controls were recruited.

Changing the pathogenetic roadmap of liver fibrosis? Where did it start; where will it go?

The pathophysiology of liver injury has attracted the interest of experimentalists and clinicians over many centuries. With the discovery of liver-specific pericytes - formerly called fat-storing cells, Ito-cells, lipocytes, and currently designated as hepatic stellate cells (HSC) - the insight into the cellular and molecular pathobiology of liver fibrosis has evolved and the pivotal role of HSC as a precursor cell-type for extracellular matrix-producing myofibroblasts has been established. Although activation and transdifferentiation of HSC to myofibroblasts is still regarded as the pathogenetic key mechanism of fibrogenesis, recent studies point to a prominent heterogeneity of the origin of myofibroblasts.

Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways.

Background/aims: Epidemiological studies suggest that coffee drinking is inversely correlated with the risk of development of liver fibrosis but the molecular basis is unknown.

Methods: We investigated the pharmacological mechanisms involved in caffeine-dependent regulation of CTGF expression, an important modulator protein of fibrogenic TGF-beta, in rat hepatocytes using Western-blot, co-immunoprecipitations, reporter-gene-assays and ELISAs.

Results: It is demonstrated that caffeine, similar to 8-Br-cAMP, suppresses CTGF expression, decreases SMAD2 protein levels and inhibits SMAD1/3-phosphorylation.

Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression.

Background/aims: Up to now, the effect of activin A on the expression of the important transforming growth factor (TGF)-beta downstream modulator connective tissue growth factor (CTGF) is not known, but might be of relevance for the functional effects of this cytokine on several liver cell types.

Methods: In this study, activin A-dependent CTGF expression in hepatocytes (PC) primed by exogenous activin A and in PC maintained under complete activin-free culture conditions was analysed by Western blots, metabolic labelling, gene silencing, reverse transcriptase-polymerase chain reaction (RT-PCR) and CTGF reporter gene assays. This study was supplemented by immunocytochemical staining of activin A and CTGF in PC of injured liver.

Evaluation of a novel reverse-hybridization StripAssay for typing DNA variants useful in diagnosis of adult-type hypolactasia.

Background: Adult-type hypolactasia is a genetically determined inability to digest lactose after weaning. Two single-nucleotide polymorphisms (C-13910T, G-22018A) located upstream of the lactase gene (LCT) within the gene MCM6 are associated with the lactase persistence/non-persistence trait in patients of European descent. Therefore, the genotyping of these SNPs has been established as a diagnostic tool for adult-type hypolactasia.