138,055 research outputs found

    Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation.

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    Reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate oxidase (NOX) play a key role in liver injury and fibrosis. Previous studies demonstrated that GKT137831, a dual NOX1/4 inhibitor, attenuated liver fibrosis in mice as well as pro-fibrotic genes in hepatic stellate cells (HSCs) as well as hepatocyte apoptosis. The effect of NOX1 and NOX4 deficiency in liver fibrosis is unclear, and has never been directly compared. HSCs are the primary myofibroblasts in the pathogenesis of liver fibrosis. Therefore, we aimed to determine the role of NOX1 and NOX4 in liver fibrosis, and investigated whether NOX1 and NOX4 signaling mediates liver fibrosis by regulating HSC activation. Mice were treated with carbon tetrachloride (CCl4) to induce liver fibrosis. Deficiency of either NOX1 or NOX4 attenuates liver injury, inflammation, and fibrosis after CCl4 compared to wild-type mice. NOX1 or NOX4 deficiency reduced lipid peroxidation and ROS production in mice with liver fibrosis. NOX1 and NOX4 deficiency are approximately equally effective in preventing liver injury in the mice. The NOX1/4 dual inhibitor GKT137831 suppressed ROS production as well as inflammatory and proliferative genes induced by lipopolysaccharide (LPS), platelet-derived growth factor (PDGF), or sonic hedgehog (Shh) in primary mouse HSCs. Furthermore, the mRNAs of proliferative and pro-fibrotic genes were downregulated in NOX1 and NOX4 knock-out activated HSCs (cultured on plastic for 5 days). Finally, NOX1 and NOX4 protein levels were increased in human livers with cirrhosis compared with normal controls. Thus, NOX1 and NOX4 signaling mediates the pathogenesis of liver fibrosis, including the direct activation of HSC

    Diagnostic value of two dimensional shear wave elastography combined with texture analysis in early liver fibrosis.

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    BACKGROUND: Staging diagnosis of liver fibrosis is a prerequisite for timely diagnosis and therapy in patients with chronic hepatitis B. In recent years, ultrasound elastography has become an important method for clinical noninvasive assessment of liver fibrosis stage, but its diagnostic value for early liver fibrosis still needs to be further improved. In this study, the texture analysis was carried out on the basis of two dimensional shear wave elastography (2D-SWE), and the feasibility of 2D-SWE plus texture analysis in the diagnosis of early liver fibrosis was discussed. AIM: To assess the diagnostic value of 2D-SWE combined with textural analysis in liver fibrosis staging. METHODS: This study recruited 46 patients with chronic hepatitis B. Patients underwent 2D-SWE and texture analysis; Young\u27s modulus values and textural patterns were obtained, respectively. Textural pattern was analyzed with regard to contrast, correlation, angular second moment (ASM), and homogeneity. Pathological results of biopsy specimens were the gold standard; comparison and assessment of the diagnosis efficiency were conducted for 2D-SWE, texture analysis and their combination. RESULTS: 2D-SWE displayed diagnosis efficiency in early fibrosis, significant fibrosis, severe fibrosis, and early cirrhosis (AUC \u3e 0.7, P \u3c 0.05) with respective AUC values of 0.823 (0.678-0.921), 0.808 (0.662-0.911), 0.920 (0.798-0.980), and 0.855 (0.716-0.943). Contrast and homogeneity displayed independent diagnosis efficiency in liver fibrosis stage (AUC \u3e 0.7, P \u3c 0.05), whereas correlation and ASM showed limited values. AUC of contrast and homogeneity were respectively 0.906 (0.779-0.973), 0.835 (0.693-0.930), 0.807 (0.660-0.910) and 0.925 (0.805-0.983), 0.789 (0.639-0.897), 0.736 (0.582-0.858), 0.705 (0.549-0.883) and 0.798 (0.650-0.904) in four liver fibrosis stages, which exhibited equivalence to 2D-SWE in diagnostic efficiency (P \u3e 0.05). Combined diagnosis (PRE) displayed diagnostic efficiency (AUC \u3e 0.7, P \u3c 0.01) for all fibrosis stages with respective AUC of 0.952 (0.841-0.994), 0.896 (0.766-0.967), 0.978 (0.881-0.999), 0.947 (0.835-0.992). The combined diagnosis showed higher diagnosis efficiency over 2D-SWE in early liver fibrosis (P \u3c 0.05), whereas no significant differences were observed in other comparisons (P \u3e 0.05). CONCLUSION: Texture analysis was capable of diagnosing liver fibrosis stage, combined diagnosis had obvious advantages in early liver fibrosis, liver fibrosis stage might be related to the hepatic tissue hardness distribution

    M2-like macrophages in the fibrotic liver protect mice against lethal insults through conferring apoptosis resistance to hepatocytes.

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    Acute injury in the setting of liver fibrosis is an interesting and still unsettled issue. Most recently, several prominent studies have indicated the favourable effects of liver fibrosis against acute insults. Nevertheless, the underlying mechanisms governing this hepatoprotection remain obscure. In the present study, we hypothesized that macrophages and their M1/M2 activation critically involve in the hepatoprotection conferred by liver fibrosis. Our findings demonstrated that liver fibrosis manifested a beneficial role for host survival and apoptosis resistance. Hepatoprotection in the fibrotic liver was tightly related to innate immune tolerance. Macrophages undertook crucial but divergent roles in homeostasis and fibrosis: depleting macrophages in control mice protected from acute insult; conversely, depleting macrophages in fibrotic liver weakened the hepatoprotection and gave rise to exacerbated liver injury upon insult. The contradictory effects of macrophages can be ascribed, to a great extent, to the heterogeneity in macrophage activation. Macrophages in fibrotic mice exhibited M2-preponderant activation, which was not the case in acutely injured liver. Adoptive transfer of M2-like macrophages conferred control mice conspicuous protection against insult. In vitro, M2-polarized macrophages protected hepatocytes against apoptosis. Together, M2-like macrophages in fibrotic liver exert the protective effects against lethal insults through conferring apoptosis resistance to hepatocytes

    The evaluation of liver fibrosis regression in chronic hepatitis C patients after the treatment with direct-acting antiviral agents – A review of the literature

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    The second-generation of direct-acting antiviral agents are the current treatment for chronic viral hepatitis C infection. To evaluate the regression of liver fibrosis in patients receiving this therapy, liver biopsy remains the most accurate method, but the invasiveness of this procedure is its major drawback. Different non-invasive tests have been used to study changes in the stage of liver fibrosis in patients with chronic viral hepatitis treated with the second-generation of direct-acting antiviral agents: liver stiffness measurements (with transient elastography or acoustic radiation force impulse elastography) or different scores that use serum markers to calculate a fibrosis score. We prepared a literature review of the available data regarding the long-term evolution of liver fibrosis after the treatment with direct-acting antiviral agents for chronic viral hepatitis C

    Diagnostic value of combined serum biomarkers for the evaluation of liver fibrosis in chronic hepatitis C infection: A multicenter, noninterventional, observational study

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    Background/Aims: The hepatitis C virus (HCV) infection is important cause of chronic hepatitis. Liver biopsy is considered the gold standard for assessment of fibrosis but this procedure is an invasive procedure. We aimed to evaluate the diagnostic efficiency of non-invasive serum biomarkers, separately and in combinations, on liver fibrosis in treatment-naive chronic hepatitis C (CHC) patients. Materials and Methods: Two hundred and sixteen treatment-naive CHC patients were enrolled from 32 locations across Turkey in this open-labelled, non-interventional prospective observational study. FibroTest®, aspartate aminotransferase-to-platelet ratio index(APRI), aspartate aminotransferase and alanine aminotransferase ratio (AAR), fibrosis index based on four factors (FIB-4), Age-platelet(AP) index and Forns index were measured and compared with Metavir scores got from liver biopsies. Results: Data from 182 patients with baseline liver biopsy were suitable for analysis. One hundred and twenty patients (65.9%) had F0-F1 fibrosis and 62 patients (34.1%) had F2-F4 fibrosis. APRI 0.732 area under the curve(AUC) indicated advanced fibrosis with 69% sensitivity and 77% specificity. FIB-4 0.732 AUC and FibroTest 0.715 AUC indicated advanced fibrosis with 69% and 78.4% sensitivity, and 75% and 71.4% specificity, respectively. The combined use of tests also led to an increase in AUC and specificity. Combinations of FibroTest with APRI and/or FIB-4, and FIB-4 with APRI were optimal for the evaluation of liver fibrosis. Conclusion: Fibrotest, FIB-4, APRI, AP index and Forns index exhibit good diagnostic performance for determining liver fibrosis in CHC patients, and the use of at least two tests together will increase their diagnostic value still further. © Copyright 2018 by The Turkish Society of Gastroenterology

    Modulation of the unfolded protein response by tauroursodeoxycholic acid counteracts apoptotic cell death and fibrosis in a mouse model for secondary biliary liver fibrosis

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    The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death

    Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B

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    Background: HBV infection is a serious global heath problem. It is crucial to monitor this disease more closely with a non-invasive marker in clinical trials. We aimed to evaluate the predictive value of serum hyaluronate for the presence of extensive liver fibrosis and inflammation. Methods: 28 healthy volunteers and 65 patients with HBeAg negative chronic hepatitis B were enrolled. Liver biopsies scored according to Ishak system. Association of serum hyaloronate with liver fibrosis and inflammation were assessed, and cut off points for serum hyaluronate levels were identified by receiver operating characteristics (ROC) curves and their values for prediction of fibrosis and inflammation were assessed. Results: In patients with CHB serum hyaluronate had the most significant correlation and predictive values for the liver fibrosis and inflammation comparing to the other variables. At the cut off point of 126.4 ngm/ml it could discriminate extensive fibrosis from milder ones with sensitivity of 90.9% and specificity of 98.1%. With the same value it could discriminate extensive inflammation from their milder counterparts with sensitivity of 63.6% and specificity of 92.6%. Conclusion: Serum hyaluronate was the best predictor of extensive liver fibrosis and inflammation and it could discriminate subgroups of patients with chronic hepatitis B. It could be used as a non-invasive test to monitor these patients more closely with developing anti viral agents in clinical trials
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