Gene/Protein Disease Symptom Drug Enzyme Compound
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Infection with hepatitis C virus (HCV) is a major cause of chronic liver disease. Hepatic fibrosis may develop in subjects with chronic HCV infection, culminating in cirrhosis and an increased risk of hepatocellular carcinoma. The rate of development of fibrosis varies substantially between individuals; while it is influenced by a number of demographic and environmental factors, these account for only a small proportion of the variability. There are no clinical markers or tests that predict the rate of fibrosis progression in an individual subject. Thus, there has been increasing interest in the influence of host genetic factors on the rate of disease progression, and whether a genetic signature can be developed to reliably identify individuals at risk of severe disease. Numerous case-control, candidate gene, allele-association studies have examined the relationship between host single nucleotide polymorphisms or other genetic mutations and fibrosis in patients with chronic HCV infection. However, these studies have generally been irreproducible and disappointing. As seen with genetic studies for other diseases, small study cohorts and poor study design have contributed to limited meaningful findings. The successful determination of genetic signatures for fibrosis progression in chronic HCV will require multicenter collaborations using genome-wide association studies, with large, phenotypically well-defined sample sets. While these studies will require a significant financial commitment, a successful outcome offers the potential for personalized therapy and better patient management.
Mol Diagn Ther 2008
PMID:Recognition of genetic factors influencing the progression of hepatitis C : potential for personalized therapy. 1865 17

Chronic liver disease (CLD) is a cause of morbidity and mortality worldwide, due to haemodynamic and metabolic complications of liver cirrhosis. During CLD the extracellular matrix undergoes a process of remodelling, leading to new collagen formation and deposition. Tissue remodelling is regulated by fine molecular mechanisms, involving proteases, inhibitors and growth factors. The major role in matrix degradation is played by matrix metalloproteinases (MMPs), a class of zinc and calcium-dependent enzymes, and their tissue inhibitors (TIMPs). Along with the progress in diagnostic techniques, leading to more precise and less invasive methods, the concept of monitoring has gained importance for the clinical management of CLD. At the present state of our knowledge, liver biopsy still represents an essential procedure for staging liver disease. However, despite its importance, liver biopsy presents some limitations: the risk of a disease underestimation is the most significant one, as hepatic lesions are often irregularly located within the liver. Parallel to the limitations of liver biopsy, clinical needs for an early identification of progressive fibrosis require additional non-invasive techniques to be developed. In this review we discuss the major problems concerning this important clinical necessity. Moreover, we focus on the role of MMPs and TIMPs in the pathogenesis of CLD, as well as their possible use as non-invasive serum markers for inflammation and fibrosis in this pathology.
Int J Mol Med 2009 Aug
PMID:Matrix metalloproteinases and their inhibitors as markers of inflammation and fibrosis in chronic liver disease (Review). 1957 87

Erythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism in which decreased activity of ferrochelatase (FECH) leads to accumulation of protoporphyrin IX (PP IX) in red blood cells, plasma, liver, and bile, and increased PP IX excretion in feces. Clinically, EPP is characterized by photosensitivity that begins in early childhood and includes burning, swelling, itching, and painful erythema in sun-exposed areas. Chronic liver disease is an important complication in a minority of EPP patients, and in some cases liver transplantation has been performed. So far, about 110 different mutations and several polymorphisms have been characterized in the human FECH gene. The relationship between mutations, polymorphisms, and porphyria development in Argentinean patients was investigated. This is the first genetic study carried out in the Argentinean population. In five Argentinean EPP families we detected three novel mutations: a deletion (451delT) producing a stop codon located 18 codons downstream from the mutation and two splicing mutations: IVS1-2A>G leading to exon 2 skipping and IVS4-2A>G, which causes the loss of the first 48 bp of exon 5. We also found two previously described mutations: C343T and 400delA, which produce stop codons. All patients had an FECH activity 25% of normal and also had the polymorphisms -251A>G in the promoter region and IVS1-23 C>T and IVS3-48 T>C. Our findings provide supporting evidence for the concept that the inheritance of the low expression allele IVS3-48C in trans with a mutation in the FECH gene is necessary for EPP to become clinically manifest.
Mol Med
PMID:Novel null-allele mutations and genotype-phenotype correlation in Argentinean patients with erythropoietic protoporphyria. 1969 96

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease, and is commonly observed in patients with obesity or type 2 diabetes. The pathogenesis of hepatic fibrosis is clinically important to the outcome of NAFLD, however, is not well understood. Since dietary habits are often considered to be responsible for NAFLD, we used a synthetic diet rich in disaccharides (12.1% calorie sucrose and lactose), which can be considered for human consumption. We examined the long-term (24 weeks) effect of this diet on the liver of Zucker (fa/fa) rats. The synthetic diet-fed Zucker (fa/fa) rats showed hepatic fibrosis during the development of NAFLD with no apparent infiltration of inflammatory cells. They showed significantly elevated hepatic mRNA levels of proinflammatory and profibrogenic cytokines. These findings suggest that excess long-term feeding of a diet similar to the synthetic diet used in our study leads to hepatic fibrosis during the development of NAFLD in patients with obesity or type 2 diabetes. Our results were different from NAFLD accompanied by infiltration of inflammatory cells. However, they also suggest that long-term feeding of this synthetic diet to Zucker (fa/fa) rats is useful for studying the hepatic fibrogenesis during the pathogenesis of NAFLD.
Int J Mol Med 2010 Feb
PMID:Long-term feeding of a synthetic diet rich in disaccharides induces hepatic fibrosis in nonalcoholic fatty liver disease in Zucker rats. 2004 26

Xanthohumol (XN) is a major prenylated chalcone found in hops, which is used to add bitterness and flavor to beer. In this study, we first investigated the effects of XN on hepatocytes and hepatic stellate cells (HSC), the central mediators of liver fibrogenesis. XN inhibited the activation of primary human HSC and induced apoptosis in activated HSC in vitro in a dose dependent manner (0-20 microM). In contrast, XN doses as high as 50 microM did not impair viability of primary human hepatocytes. However, in both cell types XN inhibited activation of the transcription factor NFkappaB and expression of NFkappaB dependent proinflammatory genes. In vivo, feeding of XN reduced hepatic inflammation and expression of profibrogenic genes in a murine model of non-alcoholic steatohepatitis. These data indicate that XN has the potential as functional nutrient for the prevention or treatment of non-alcoholic steatohepatitis or other chronic liver disease.
Mol Nutr Food Res 2010 Jul
PMID:Xanthohumol, a chalcon derived from hops, inhibits hepatic inflammation and fibrosis. 2008 58

In recent years, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing. The aim of this study was to compare the liver function and the background factors of HCC patients with hepatitis C virus (HCV) infection by generation and to examine the characteristics of this disease in the elderly. A total of 1096 patients (776 men and 320 women) diagnosed with HCV-related HCC at our institution from 1995 to 2006 were divided into 4 groups as follows: D group, 75 years of age or older; C group, 65-74 years of age; B group, 55-64 years of age; A group, 54 years of age or younger, and the liver function and other clinical characteristics were compared among these 4 groups. The average age at initial diagnosis of HCV-related HCC was 66.9 years of age. The A, B, C and D groups were comprised of 87, 363, 514 and 132 patients, respectively. The rate of Child-Pugh class A patients in the D group was significantly higher than that of the other groups (P<0.05). The average levels of ALT, TB and PT-INR in the D group were significantly lower than the levels in the other groups (P<0.05). The average Alb level in the D group was significantly higher than that in the other groups (P<0.05). In conclusion, we found that HCV-related HCC in the elderly occurred against a background of chronic liver disease with mild inflammation and fibrosis.
Int J Mol Med 2010 Aug
PMID:HCC develops even in the early stage of chronic liver disease in elderly patients with HCV infection. 2059 5

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. Here we attempt to further our understanding of the biological context of protein interactions in HCV pathogenesis, by investigating interactions between HCV proteins Core and NS4B and human host proteins. Using the yeast two-hybrid (Y2H) membrane protein system, eleven human host proteins interacting with Core and 45 interacting with NS4B were identified, most of which are novel. These interactions were used to infer overall protein interaction maps linking the viral proteins with components of the host cellular networks. Core and NS4B proteins contribute to highly compact interaction networks that may enable the virus to respond rapidly to host physiological responses to HCV infection. Analysis of the interaction networks highlighted enriched biological pathways likely influenced in HCV infection. Inspection of individual interactions offered further insights into the possible mechanisms that permit HCV to evade the host immune response and appropriate host metabolic machinery. Follow-up cellular assays with cell lines infected with HCV genotype 1b and 2a strains validated Core interacting proteins ENO1 and SLC25A5 and host protein PXN as novel regulators of HCV replication and viral production. ENO1 siRNA knockdown was found to inhibit HCV replication in both the HCV genotypes and viral RNA release in genotype 2a. PXN siRNA inhibition was observed to inhibit replication specifically in genotype 1b but not in genotype 2a, while SLC25A5 siRNA facilitated a minor increase in the viral RNA release in genotype 2a. Thus, our analysis can provide potential targets for more effective anti-HCV therapeutic intervention.
Mol Biosyst 2010 Dec
PMID:Network based analysis of hepatitis C virus core and NS4B protein interactions. 2095 6

Among the different processes occurring during the evolution of liver disease, fibrosis has a predominant role. Liver fibrosis mechanisms are fairly constant irrespective of the underlying etiology. Cirrhosis is the end-stage of this reaction. Metabolic profiles, which are affected by many physiological and pathological processes, may provide further insight into the metabolic consequences of this severe liver disease. The aim of this study was to demonstrate the applicability of 1H high resolution magic angle spinning (HR-MAS) NMR spectroscopy in the biochemical profile determination of human liver needle biopsy samples for the characterization of metabolic alterations related to the severity of liver disease. We recorded and analyzed HR-MAS spectra of 68 liver tissue samples obtained by needle biopsy from patients with chronic liver disease. Multivariate analysis was applied to these data to obtain discrimination patterns and to reveal relevant metabolites. The metabolic characterization of liver tissue from needle biopsies by HR-MAS NMR spectroscopy provided differential patterns for cirrhotic and non-cirrhotic chronic liver disease tissue. Metabolites closely related to the liver metabolism such as some fatty acids, glucose and amino acids show differences between the two groups. Phospholipid precursors, which have been previously correlated with hepatic lesions also show differences. Furthermore, the correlation between histologically assessed liver disease stages and the levels of the most discriminative metabolites show that liver dysfunction is present at the initial stages of chronic hepatic lesions. Overall, this work suggests that the additional information obtained by NMR metabolomics applied to needle biopsies of human liver may be useful for assessing metabolic alterations and liver dysfunction in chronic liver disease.
Int J Mol Med 2011 Jan
PMID:Metabolic profile of chronic liver disease by NMR spectroscopy of human biopsies. 2107 94

The understanding of the cellular and molecular mechanisms of the fibrotic wound-healing response of the liver has made dramatic progress in the past 20 years. Hepatic stellate cells (HSCs), which after liver injury proliferate and transdifferentiate to myofibroblasts, have emerged as the primary source of the fibrotic response, even though other fibrogenic cells may also contribute to the production of extracellular matrix (ECM). Advances in the understanding of HSC regulation include apoptotic signaling, angiogenic signaling, and responses to oxidative stress. The ECM has emerged not only as a structural scaffold, but also as a dynamic and interactive matrix regulating stellate cell activation. Additionally, the innate immune system and immune signaling, as well as a broadening understanding of the transcriptional regulation including microRNAs and epigenetic events offer potential therapeutic targets. Unraveling genetic determinants related to mechanisms of hepatic fibrogenesis promise individualized therapy or prevention. Hepatic fibrosis and cirrhosis have emerged as treatable and potentially reversible consequence of chronic liver disease.
Prog Mol Biol Transl Sci 2010
PMID:Fibrosis in the liver: acute protection and chronic disease. 2107 33

The hepatitis viruses, named A-E, cause acute and chronic liver disease depending on the virus. Laboratory-based diagnosis relies on the detection of specific markers of infection for each virus, through the use of appropriate serological tests. In recent years, molecular tests that rely on the amplification of viral nucleic acids have also been employed, not only in confirming active viral replication but also in monitoring antiviral treatment efficacy. Some of these tests that are currently in use in routine diagnostic laboratories are outlined in this chapter.
Methods Mol Biol 2011
PMID:The detection of hepatitis viruses. 2111 97


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