Bax Inhibitor-1 down-regulation in the progression of chronic liver diseases

<p>Abstract</p> <p>Background</p> <p>Bax inhibitor-1 (BI-1) is an evolutionary conserved endoplasmic reticulum protein that, when overexpressed in mammalian cells, suppresses the apoptosis induced by Bax, a pro-apoptotic member of the Bcl-2 family. The aims of this study were: (1) to clarify the role of intrinsic anti- and pro-apoptotic mediators, evaluating Bax and BI-1 mRNA and protein expressions in liver tissues from patients with different degrees of liver damage; (2) to determine whether HCV and HBV infections modulate said expression.</p> <p>Methods</p> <p>We examined 62 patients: 39 with chronic hepatitis (CH) (31 HCV-related and 8 HBV-related); 7 with cirrhosis (6 HCV-related and 1 HBV-related); 13 with hepatocellular carcinoma (HCC) [7 in viral cirrhosis (6 HCV- and 1 HBV-related), 6 in non-viral cirrhosis]; and 3 controls. Bax and BI-1 mRNAs were quantified by real-time PCR, and BI-1 protein expression by Western blot.</p> <p>Results</p> <p>CH tissues expressed significantly higher BI-1 mRNA levels than cirrhotic tissues surrounding HCC (P < 0.0001) or HCC (P < 0.0001). Significantly higher Bax transcripts were observed in HCV-genotype-1-related than in HCV-genotype-3-related CH (P = 0.033). A positive correlation emerged between BI-1 and Bax transcripts in CH tissues, even when HCV-related CH and HCV-genotype-1-related CH were considered alone (P = 0.0007, P = 0.0005 and P = 0.0017, respectively).</p> <p>Conclusions</p> <p>BI-1 expression is down-regulated as liver damage progresses. The high BI-1 mRNAs levels observed in early liver disease may protect virus-infected cells against apoptosis, while their progressive downregulation may facilitate hepatocellular carcinogenesis. HCV genotype seems to have a relevant role in Bax transcript expression.</p

Fas/FasL system, IL-1 beta expression and apoptosis in chronic HBV and HCV liver disease

Abstract: The Fas/Fas-ligand (FasL) system is an important death signal pathway in the liver. An enhanced local inflammatory response prompted by FasL expression, which contributes to neutrophil recruitment and interleukin-1 beta (IL-1 beta) release, seems to be crucial to chronic liver damage, persistence of viral infections, and probably initiation and/or promotion of HCC. In order to evaluate the expression of Fas, FasL, and IL-1 beta in different stages of human liver disease and to determine whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infections modulate their expression, also in relation to apoptosis, we examined 87 liver samples obtained from patients with: chronic hepatitis (CH) (n.42), cirrhosis (n.9) and hepatocellular carcinoma (HCC) (n.16) and corresponding peritumoural tissues (n.16); histologically-normal liver (n.4) as controls. Fas, FasL and IL-1 beta mRNA were quantified using reverse transcriptase-polymerase chain reaction. The apoptotic index was evaluated by TUNEL analysis. Our data showed a progressive Fas/FasL increase from CH to cirrhosis followed by a decline from the latter to HCC. In histological sections apoptosis was detected in HCC. A significant difference emerged between HCV and HBV-related disease for IL-1 beta expression only in CH. A significant positive correlation between IL-1 beta and FasL in HCV-related disease (P = 0.014) and an inverse correlation between IL-1 beta and Fas in HBV-related disease (P = 0.021) were observed. The different pattern of IL-1 beta, Fas and FasL expression found in HCV- and HBV-mediated liver disease, points to a different modulation of immune response B and C virus induced, while the decline in Fas/FasL expression in HCC may be related to defence mechanisms adopted by HCC cells against the immune system

Oxidative damage, pro-inflammatory cytokines, TGF-alpha and c-myc in chronic HCV-related hepatitis and cirrhosis.

Abstract: Aim: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-alpha and c-myc. Methods: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TNF-alpha, IL-1 beta, TGF-alpha and c-myc in liver specimens was detected by semiquantitative comparative RT-PCR. Results: TNF-alpha levels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1 beta was higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-alpha and staging (P=0.05) and between IL-1 beta levels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-alpha expression and HCV genotype (P=0.02). Conclusion: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-alpha levels. As HCV-related liver damage progresses, TNF-alpha levels drop while IL-1 beta and c-myc levels increase, which may be relevant to liver carcinogenesis

Oxidative Stress and Inducible Nitric Oxide Synthase Induction in Carcinogenesis

Background: Chronic inflammation is linked to an increased risk of cancer. The molecular mechanisms underlying this correlation have been long investigated and it is well known that the inflammatory cells recruited in the inflamed tissues release chemical mediators, in particular reactive oxygen species (ROS). With respect to digestive systems, ROS have been implicated in a number of pathologies, including Helicobacter pylori-related gastritis, Barrett's esophagus, inflammatory disease of the lower gastrointestinal tract, alcoholic liver disease and several other types of toxic and virus-mediated liver injury. ROS levels within cells and tissues are controlled by numerous antioxidant defense mechanisms, but in inflammation, ROS overproduction exceeds defenses and damage intracellular macromolecules, including nucleic acids, with formation of potentially mutagenic and carcinogenic DNA adducts. Aims: This paper summarizes our own experience investigating the link between inflammation, ROS production and oxidative DNA damage as well as the impact of the above events on cytokine and growth factor release, oncogene activation, telomere instability and microRNA in H. pylori-related gastritis, Barrett's esophagus and, in particular, hepatitis C virus-related liver disease. The paper also describes, at least in part, the complex scenario involving nitric oxide production and its impact in some gastrointestinal diseases, as well as a number of other molecular and biochemical changes related to ROS production and inflammation. Conclusions: The paper falls obviously short of being an exhaustive summary of our understanding, but the data reported are intended as a stimulus to broaden the knowledge on the topic, also in view of the possible therapeutic implications of any advance obtained