Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Differential gene expression profiles of hepatocellular carcinomas associated or not with viral infection

Chronic hepatitis B (HBV) and C (HCV) virus infections are the most important factors associated with hepatocellular carcinoma (HCC), but tumor prognosis remains poor due to the lack of diagnostic biomarkers. In order to identify novel diagnostic markers and therapeutic targets, the gene expression profile associated with viral and non-viral HCC was assessed in 9 tumor samples by oligo-microarrays. The differentially expressed genes were examined using a z-score and KEGG pathway for the search of ontological biological processes. We selected a non-redundant set of 15 genes with the lowest P value for clustering samples into three groups using the non-supervised algorithm k-means. Fisher’s linear discriminant analysis was then applied in an exhaustive search of trios of genes that could be used to build classifiers for class distinction. Different transcriptional levels of genes were identified in HCC of different etiologies and from different HCC samples. When comparing HBV-HCC vs HCV-HCC, HBV-HCC/HCV-HCC vs non-viral (NV)-HCC, HBC-HCC vs NV-HCC, and HCV-HCC vs NV-HCC of the 58 non-redundant differentially expressed genes, only 6 genes (IKBKâ, CREBBP, WNT10B, PRDX6, ITGAV, and IFNAR1) were found to be associated with hepatic carcinogenesis. By combining trios, classifiers could be generated, which correctly classified 100 percent of the samples. This expression profiling may provide a useful tool for research into the pathophysiology of HCC. A detailed understanding of how these distinct genes are involved in molecular pathways is of fundamental importance to the development of effective HCC chemoprevention and treatment.

Reduction of pancreatic enzyme content and mortality in experimental acute pancreatitis in rats

A previous report has shwon that undernutrition reduces the mortality of acute experimental pancreatitis probably by decreasing pancreatic enzyme content of the pancreas without any harmful effect on the organ. The aim of the present study was to assess the effect of acute reduction of pancreatic enzyme content on the outcome of acute pancreatitis. Two groups of males Wistar rats weighing 230-250 g were studied: group I, 12-h fasted animals, and group II, add libitum-fed animals who received cerulein at the inframaximal dose (0.2 µg kg-1h-1) for 2 h. Cerulein adminsitration resulted in the reduction of the pancreatic contents of chymotrypsinogen (71 percent), trypsinogen (55 percent), proelastase (60 percent), amylase (62 percent) and cathepsin B (45 percent) (P<0.05). However, no significant reduction in pancreatic phospholipase content was observed. Acute pancreatitis wass induced in group I after 12-h fasting and in group II at the end of cerulein infusion by retrograde injection of 0.5 ml of 2.5 percent Na+ taurocholate into the pancreatic duct. Ascites volume and the degree of histologically observed lesions were similar in both groups, but 72-h mortality was 56 percent in the control group (10/18) and 23 percent (5/22) in the cerulein group (P<0.05). We speculate that the reduction of pancreatic enzyme content may exert its beneficial effect in acute pancreatitis by decreasing the quantity of pancreatic enzymes reaching the circulation and consequently their pathogenic effects