Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. The fact that HCC is resistant to conventional chemotherapy and is rarely amenable to radiotherapy leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver diseases, most of which culminate in cirrhosis, such as alcoholic cirrhosis and chronic hepatitis B and C infections. This review outlines recent findings on the progression of liver disease, including our knowledge of the role of apoptotic processes, with an emphasis on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The proapoptotic and antiapoptotic properties of TRAIL, its involvement in liver injury, and its potential as a therapeutic agent in fibrosis and HCC are discussed. Several contradictory and confusing data have not yet been resolved or placed into perspective, such as the influence of factors that determine the TRAIL sensitivity of target cells, including the tumor microenvironment or cirrhotic tissue. Therefore, we assess these data from the perspectives of gastroenterologists (P.S. and M.W.B.) and a molecular oncologist (I.H.) with research interests in liver injury, apoptosis, and experimental therapeutics.
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PMID:On the TRAIL to therapeutic intervention in liver disease. 1759 86

alpha-lipoic acid (alpha-LA) is an antioxidant used in a number of conditions related to liver diseases. Herein, we investigated the effect of alpha-LA on the development of rat pre-neoplastic lesions generated by a model of hepatocarcinogenesis, which has similarities in its histopathological sequence to human hepatocellular carcinoma development with cirrhosis. Initiation of hepatocytes was achieved by treatment with a single dose of diethylnitrosamine and promotion by feeding a choline-methionine-deficient diet (CMD), with or without alpha-LA. Pre-neoplastic lesions were identified by their positivity to the placental form of glutathione S-transferase (GSTP) or to gamma glutamyl transpeptidase. alpha-LA given to rats fed a CMD for 6 weeks dramatically increased the number of GSTP-positive foci as compared with rats fed a CMD alone (96/cm(2) versus 7/cm(2)), the mean foci area (0.033 versus 0.008 mm(2)) and the percentage of GSTP-positive liver tissue (3.01 versus 0.07%). Essentially similar results were obtained after 10 weeks of treatment. Co-treatment with CMD + alpha-LA also resulted in the enhancement of fat accumulation, lipid peroxidation and hepatocyte death; increased expression of tumor necrosis factor-alpha, cytochrome 2E1 and cyclooxygenase-2, enhanced activation of c-jun N-terminal kinase and signal transducer activator of transcription 3, and chronic hepatocyte proliferation was also observed. No such effects were observed when alpha-LA was added to a choline-supplemented diet. In conclusion, administration of alpha-LA in conditions associated with hepatic damage aggravates liver injury and stimulates the development of pre-neoplastic lesions; the results also suggest caution in its use in the presence of chronic liver injury.
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PMID:Alpha-lipoic acid promotes the growth of rat hepatic pre-neoplastic lesions in the choline-deficient model. 1789 35

Hepatitis C virus (HCV) induces inflammatory signals leading to progressive liver damage. The mechanism of HCV involvement in the host's innate immune responses has not been well characterized and little is known about the molecular mechanisms by which immune cells recognize HCV. In this work we studied Toll-like receptor (TLR) 2 and TLR4, in chronic HCV infection, as recently detected important components of the innate immunity in humans, as microbial recognition receptors. The study involved 30 HCV patients; 15 with chronic hepatitis (group I) and 15 with liver cirrhosis (group II), in addition to 10 healthy controls (group III). mRNA expression of TLR2 and TLR4 in peripheral blood mononuclear cells (PBMCs) was examined using reverse transcriptase PCR. This was carried out in relation to quantitative analysis of HCV-RNA by Real time-PCR and serum tumor necrosis factor-alpha (TNF-alpha) estimation by ELISA. Significant correlation was found, in HCV patients, between the viral load and TLR2 (r = 0.704; p < 0.01 in group I & r = 0.629; p <0.05 in group II) and TLR4 (r = 0.549; p < 0.05 in group I & r = 0.596; p < 0.05 in group II) and between TLR2 and TLR4 (r = 0.814; p < 0.001 in group I & r = 699 p < 0.01 in group II). Over expression of TLR2 and TLR4 was detected in chronic hepatitis patients as compared to controls (p < 0.001). In cirrhotic patients down regulation of TLR4 mRNA expression was found when compared to group I chronic hepatitis (p < 0.001), while TLR2 showed steady over expression. A positive correlation was also detected between TLR2 expression and TNF-alpha in HCV patients (r = 0.571; p < 0.05 in group I & r = 0.723; p < 0.01 in group II), while a weak relationship was found between TLR4 and TNF-alpha in cirrhotic patients. (r = 0.359; p > 0.05). TLR2 correlated significantly with the hepatic necroinflammatory activity grade (r = 0.629; p < 0.05 in group I & r 0.502; p < 0.05 in group II), while TLR4 correlated with the fibrosis stage (r = 0.682; p < 0.01). On the other hand no correlation could be detected between TLR2 and TLR4 and the child's grade in cirrhotic patients. It is concluded that TLR2 and TLR4 may play a vital role in HCV recognition, initiation and progression of HCV induced liver diseases. Lager scale studies as well as advanced molecular researches on immune-modulation of TLRs are recommended. This may have the way to a new therapeutic tool for HCV.
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PMID:Significance of toll-like receptors 2 and 4 mRNA expression in chronic hepatitis C virus infection. 1797 58

Tissue factor (TF) is one of the proteins that participate in hemostatic and inflammatory processes. Activated monocytes present in the liver increase expression of TF, and while accumulating in the organ they can intensify inflammation. The aim of the present study was to evaluate the expression of TF on monocytes in advanced liver cirrhosis with regard to other activation markers. The flow cytometric analysis of TF (CD142), CD14, adhesive molecules CD11b and CD11c, costimulatory molecules CD40, CD80 and CD86, and HLA-DR on monocytes was carried out in 45 patients with postalcoholic liver cirrhosis (Child Pugh B, 20 patients; Child Pugh C, 25 patients) and in 25 healthy persons. The positive correlation between monocytic TF expression and monocyte [soluble CD14 (sCD14), CD11b, monocyte aggregates] activation, the expression of costimulatory molecules on monocytes (CD40, CD80), blood platelet (soluble P-selectin, microplatelets) activation, the level of tumor necrosis factor-alpha, biochemical parameters of liver damage (alanine aminotransferase, aspartate aminotransferase, alkaline phosphate, gamma-glutamyltransferase, and bilirubin) as well as coagulation disorders were observed in the study. In conclusion, the study revealed that the activation of monocytes and blood platelets is accompanied by the elevation of monocytic TF expression in advanced liver cirrhosis. The monocytic TF is a significant link connecting clotting processes and inflammatory and immunological phenomena in liver cirrhosis.
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PMID:Increase in expression of monocytic tissue factor (CD142) with monocytes and blood platelet activation in liver cirrhosis. 1798 14

Hepatitis C virus (HCV) is a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. To study the effects of HCV protein expression on host cells, we established conditional expression of the full-length open reading frame (ORF) of an infectious cDNA clone of HCV (genotype 1a, H77 strain) in the nontransformed human hepatocyte line cell HH4 using the ecdysone receptor regulatory system. Treatment with the ecdysone analog ponasterone-A induced tightly regulated and dose-dependent full-length HCV ORF expression and properly processed HCV proteins. HCV Core, NS3, and NS5A colocalized in perinuclear regions and associated with the early endosomal protein EEA1. HCV ORF expression caused marked growth inhibition, increased intracellular reactive oxygen species, up-regulation of glutamate-l-cysteine ligase activity, increased glutathione level, and activation of nuclear factor kappaB. Although it was not directly cytotoxic, HCV ORF expression sensitized HH4 cells to Fas at certain concentrations but not to tumor necrosis factor-related apoptosis-inducing ligand. HCV ORF expression in HH4 cells up-regulated genes involved in innate immune response/inflammation and oxidative stress responses and down-regulated cell growth-related genes. Expression of HCV ORF in host cells may contribute to HCV pathogenesis by producing oxidative stress and increasing the expression of genes related to the innate immune response and inflammation.
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PMID:Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame. 1799 16

Spontaneous bacterial peritonitis (SBP) occurs as a direct consequence of bacteria entering ascitic fluid (AF) from the intestinal lumen trough in several ways, including the hematogenous and mesenteric lymph nodes route. There are few studies on the cytokine profile of ascitic-derived mononuclear cells of patients with SBP, particularly on granzyme B (GZB). The aim of the present study was to verify whether patients with SBP have GZB-positive cells, whether they are increased in patients with aseptic ascites, and their trend after antibiotic treatment. We enrolled 36 consecutive patients (24 males and 12 females) with SBP on histologically-proven hepatitis C virus cirrhosis (group A) and 20 patients (11 males and nine females with ascites, but without evidences of SBP (group B). The diagnosis of SBP was made according to the following criteria: positive colture in AF or blood (at least two cultures) and neutrophils in AF (>250 mL polymorphonuclear leukocytes). For these patients we used ELISpot to assay GZB production on purified mononuclear cells in ascitesand peripheral blood, coupled with tumor necrosis factor-alpha tested using ELISA. A non-parametric statistical analysis was used to assess significant differences and correlations. We found positive culture in all of the patients with SBP (80% Escherichia coli; 20% Enterococcus faecium). Furthermore, the patients in group A had a higher number of GZB spot-forming colonies than the patients in group B (P < 0.001). GZB-positive cells were lower in the peripheral blood than those found in the AF of patients with SBP, while no differences were found between blood and AF in group B. Furthermore, after antibiotic treatment, GZB was reduced in the patients with SBP (P < 0.05). In conclusion, GZB may be an important mediator of the immune response towards bacteria in AF and could be used as a diagnostic tool.
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PMID:Increase of granzyme B-positive cells in ascitic fluid of patients with spontaneous bacterial peritonitis. 1802 Dec 32

Studies suggest that cytokines have a role in the biology of depression. In this study, we evaluated depression and cytokine levels in patients with and without chronic hepatitis C (HCV) to better assess how chronic infection alters cytokines levels and may contribute to depressive symptomotology. Twenty-three adults with (n=16) and without (n=7) HCV were recruited through the Portland VA Medical Center. Research participants were excluded for current substance abuse, psychotic disorder, liver cirrhosis, or interferon (IFN) therapy. Participants completed the Beck Depression Inventory-II (BDI-II) and a blood draw to evaluate plasma cytokine levels [i.e., interleukin (IL)-1beta, IL-10 and tumor necrosis factor (TNF)-alpha]. t-Tests were performed to compare cytokine levels in patients with or without HCV. HCV patients showed higher TNF-alpha values compared to patients without HCV (group means=7.94 vs. 3.41pg/mL, respectively, p=0.047). There were no significant differences between the groups for the other cytokines assessed. In patients with HCV, TNF-alpha and IL-1beta levels (but not IL-10) were correlated with BDI-II scores [r=0.594, p=0.020 and r=0.489, p=0.055 (trend), respectively]. Taken together, these results show an association between severity of depressive symptoms and expression of pro-inflammatory cytokines in patients with HCV. Future studies should investigate how inflammatory mediators play a role in the expression of specific depressive symptoms in patients with chronic infection. Patients with HCV represent an interesting model to examine this relationship.
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PMID:Depressive symptoms in patients with chronic hepatitis C are correlated with elevated plasma levels of interleukin-1beta and tumor necrosis factor-alpha. 1806 7

A major cause of liver cirrhosis and hepatocarcinoma is chronic infection by hepatitis C virus. Ethanol consumption is the most significant environmental factor that exacerbates the progression of chronic hepatitis C to liver cirrhosis and hepatocarcinoma, perhaps due to increased cytokine secretion together with increased lipid peroxidation. In this study, we compare the intensity of lipid peroxidation (estimated as malondialdehyde (MDA) serum levels), the antioxidant status, (measured as glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities in red blood cells), and levels of cytokines derived from Th1 cells (such as interferon gamma (IFNG)), Th2 cells (such as interleukin (IL)-4), Th3 cells (such as transforming growth factor beta (TGF-beta)), and IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in patients affected by chronic hepatitis C virus infection, 26 drinkers of alcohol and 40 nondrinkers of alcohol. Patients showed significantly higher TNF-alpha (Z = 4.92, P < 0.001), IL-8 (Z = 4.95, P < 0.001), IFNG (Z = 2.81, P = 0.005), TGF-beta (t = 2.12, P = 0.037), MDA (Z = 5, P < 0.001), but lower IL-6 (Z = 3.61, P < 0.001) and GPX (F = 4.30, P < 0.05) than controls, whereas no differences were observed regarding IL-4 (Z = 0.35, P = 0.72), GPX and SOD activities. Alcoholics showed significantly higher TNF-alpha, but lower IL-4, MDA, and GPX, than nonalcoholics. TNF-alpha was significantly related to albumin and prothrombin activity, whereas TGF-beta was significantly related to MDA levels. Thus, cytokine secretion is altered in HCV infection. This alteration mainly consists of a stimulation of Th1 cytokines and an inhibition--or at least, no stimulation--of Th2 cytokines; these changes are especially marked among alcoholics with HCV infection, and are accompanied by raised TGF-beta.
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PMID:Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection. 1821 80

Alcohol is a well-known risk factor for liver damage and is one of the major causes of liver disease worldwide. Chronic intake of alcohol, over a certain limit, inevitably leads to hepatic steatosis. If the injury persists, steatosis with concomitant tumor necrosis factor-alpha and other cytokines, progresses to steatohepatitis, fibrosis and finally cirrhosis. Among the multiple factors involved in the process of alcohol-induced liver injury, a crucial role is played by oxidative stress. Several mechanisms during ethanol metabolism result in reactive oxygen species (ROS) production. Although the main site of ethanol metabolism is hepatocytes, other mechanisms are involved in alcohol-induced liver injury. Specifically, in the ROS production activity, an important role is played by the NADPH oxidase complex. NADPH oxidase is expressed in hepatocytes, hepatic stellate cells and Kupffer cells in the liver. Studying NADPH oxidase gives new insights into alcohol-induced liver damage and provides new direction for future therapeutic strategies.
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PMID:Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. 1833 75

Chronic consumption of ethanol induces hepatic steatosis and inflammation, which can eventually lead to more severe liver injury, characterized by fibrosis and cirrhosis. Recruitment of neutrophils to the liver, as well as activation of Kupffer cells, mediates the inflammatory responses observed after chronic ethanol exposure. Kupffer cells, the resident macrophages of the liver, are critical to the onset of ethanol-induced liver injury. Activation of Kupffer cells leads to an increased production of proinflammatory cytokines, such as tumor necrosis factor-alpha and also reactive oxygen species, a process mediated in part by changes in lipopolysaccharide-induced TLR4-dependent signal transduction. The isolation and culture of Kupffer cells is an important technique with which one can elucidate the mechanisms that contribute to alcoholic liver injury.
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PMID:Isolation of Kupffer cells from rats fed chronic ethanol. 1836 21


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