Increased DNA binding activity of NF-κB,STAT-3,SMAD3 and AP-1 in acutely damaged liver

AIM: To investigate the role of genes and kinetics of specific transcription factors in liver regeneration, and to analyze the gene expression and the activity of some molecules crucially involved in hepatic regeneration. METHODS: USING gel-shift assay and RT-PCR, transcription factors, such as NF-κB, STAT-3, SMAD3 and AP-1, and gene expression of inducible nitric oxide synthase (iNOS), hepatocyte growth factor (HGF) and c-met were analyzed in an animal model of chemically induced hepatectomy. RESULTS: Gene expression of HGF and its receptor c-met peaked at 3 h and 24 h after acute CCl4 intoxi- cation. iNOS expression was only observed from 6 to 48 h. Transcriptional factor NF-κB had an early activation at 30 min after acute liver damage. STAT-3 peaked 3 h post- intoxication, while AP-1 displayed a peak of activation at 48 h. SMAD3 showed a high activity at all analyzed times. CONCLUSION: TNF-α and IL-6 play a central role in hepatic regeneration. These two molecules are responsible for triggering the cascade of events and switch-on of genes involved in cell proliferation, such as growth factors, kinases and cyclins which are direct participants of cell proliferation.

Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients

BACKGROUND Matrix metalloproteinases(MMPs)participate in the degradation of extracellular matrix compounds,maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver.However,there are few studies on the regulation of liver MMPs in fibrosis progression in humans.AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C(CHC).METHODS A prospective,cross-sectional,multicenter study was conducted.CHC patients were categorized in fibrosis grades through FibroTest®and/or FibroScan®.Serum MMP-2,-7,and-9 were determined by western blot and multiplex suspension array assays.Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests.The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated.Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test,whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays.RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects.MMP-7 distinguished early and advanced stages,with a correlation of 0.32(P<0.001),and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4(area under the receiver operating characteristic,0.705;95%confidence interval:0.605-0.805;P<0.001).Collagenolytic activity was detected at F0 and F1,whereas gelatinase activity was not detected at any fibrosis stage.Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2(P<0.001).CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients,reflecting the impossibility to restrain liver fibrosis progression.MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.

Hepatocellular carcinoma and hepatitis C virus infection in Latin America: epidemiology, diagnosis and treatment

Hepatocellular carcinoma(HCC)is the most common cancer associated with chronic liver disease and cirrhosis.The most common cause of HCC is chronic hepatitis C virus infection and many studies in Europe,Asia and North America have focused on its etiology,epidemiology,diagnostic tools,and therapeutic options.However,little is known about these issues in Latin America.The aim of this review is to address these aspects of HCC in Latin America.The main risk factors associated with developing HCC in this region are:age,concomitant cirrhosis,hepatitis C infection,obesity and hereditary disease such as hemochromatosis.On the other hand,screening tests and diagnostic methods of HCC are mostly serum alpha fetoprotein quantification,liver ultrasound,computed tomography,magnetic resonance,and histopathology.Novel diagnostic methods include gut microbiota analysis and the use of nanotechnology and they continue to be tested.Finally,according to the Barcelona Clinic Liver Cancer,curative treatments used in HCC patients are mainly liver resection,liver transplantation,and local ablation,each with advantages and disadvantages.In conclusion,clear strategies are urgently needed to understand the extent of HCC and related problems in this part of the world.This review provides greater knowledge of HCC for the proper design of preventive programs by taking into consideration specific characteristics of our population.Also,this review allows for an understanding of individualizing treatments according to the patient’s needs.