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

Recently, a novel virus, tentatively designated GB virus (GBV-C) was identified in patients with hepatitis. The frequency of this novel virus infection was therefore investigated in 58 patients with chronic hepatitis B virus (HBV) infection and in 74 patients with chronic hepatitis C virus (HCV) infection who had received orthotopic liver transplantation (OLT) because of decompensated liver cirrhosis. Before OLT, GBV-C sequences were found by reverse transcription nested polymerase chain reaction with primers derived from the helicase-like region in six (10%) of the HBV- and in six (8%) of the HCV-infected patients. Specificity of the polymerase chain reaction products was confirmed in eight of them by direct sequencing. Pretransplant GBV-6 viremia was associated with posttransplant viremia in 75% of patients. The comparison of GBV-C nucleotide and amino acid sequences within the helicase-like region revealed that pre- and posttransplant sequences differed only in 0-7 nucleotide exchanges, and with the exception of one, all of them were silent mutations. After OLT, 29% of the HBV- infected and 12% of the HCV-infected patients became GBV-C positive,indicating a high rate of "de novo" GBV-C infection. By correlating the GBV-C status with the frequency of the occurrence of graft hepatitis in both groups of patients, it became evident that posttransplant GBV-C viremia did not increase the risk for this clinical condition. However, we found a significantly higher percentage of hepatocellular carcinoma in patients with pre-OLT GBV-C/HCV coinfection compared with patients with HCV infection alone (5/6 vs. 16/68;P<0.01).
 ...
PMID:GB virus C infection in patients with chronic hepatitis B and C before and after liver transplantation. 882 65

Infection with putative non-A to E hepatitis virus, designated GB virus C (GBV-C), was surveyed in 286 patients with chronic liver disease in Japan. RNA of GBV-C was detected, by reverse-transcription polymerase chain reaction with nested primers from the 5'-noncoding region, in 19 patients (6.6%) at a frequency higher (P < 0.001) than in three of 275 (1.1%) normal controls. It was detected in three of 83 (4%) patients with hepatitis B virus infection, 15 of 188 (8%) patients with hepatitis C virus infection, and one of 12 (8%) patients without evidence of ongoing infection with hepatitis B or C virus. GBV-C RNA was detected in nine of 186 (5%) patients with chronic hepatitis aged 51.2 +/- 13.3 years, six of 64 (9%) with liver cirrhosis aged 62.9 +/- 11.4 years, and four of 36 (11%) with hepatocellular carcinoma aged 62.0 +/- 11.1 years. Nucleotide sequences of 100 base pairs in the helicase region of GBV-C isolates from the 19 patients varied up to 21%, while sequences of 33 deduced amino acids were conserved and differed only by up to 6%. These results indicate that infection with GBV-C in patients with non-B, non-C chronic liver disease would not be frequent, although the sensitivity of the detection method could be improved. Coinfection of GBV-C with hepatitis B or C virus, as well as the duration of infection, might accelerate the progression of chronic liver disease.
 ...
PMID:Infection with GB virus C in patients with chronic liver disease. 913 80

Hepatitis C virus (HCV) infection is a major health problem that leads to cirrhosis and hepatocellular carcinoma in a substantial number of infected individuals, estimated to be 100-200 million worldwide. Unfortunately, immunotherapy or other effective treatments for HCV infection are not yet available, and interferon administration has limited efficacy. Different approaches to HCV therapy are being explored, and these include inhibition of the viral proteinase, helicase, and RNA-dependent RNA polymerase and development of a vaccine. Here we present the design of selective inhibitors with nanomolar potencies of HCV NS3 proteinase based on eglin c. These eglin c mutants were generated by reshaping the inhibitor active site-binding loop, and the results emphasize the role played by residues P5-P4' in enzyme recognition. In addition, alanine scanning experiments provide evidence that the N terminus of eglin c also contributes to NS3 binding. These eglin inhibitors offer a unique tool for accurately assessing the requirements for effective inhibition of the enzymatic activity of NS3 and at the same time can be considered lead compounds for the identification of other NS3 inhibitors in targeted design efforts.
 ...
PMID:Design of selective eglin inhibitors of HCV NS3 proteinase. 970 81

In the present study the hepatitis G virus (HGV) infection and its pathogenic significance in patients of cirrhosis were assessed using reverse transcription plus nested polymerase chain reaction (RT-PCR). Serum samples were collected from a total of 50 patients of histologically proven non-alcoholic cirrhosis and from a control group consisting of 50 healthy voluntary blood donors. HGV RNA was detected by RT-PCR using primer sequences located in the conserved NS3 helicase region of HGV genome. Serological evaluation for markers of chronic infection with HBV (HBsAg, IgG anti-HBc, HBeAg) and HCV (anti-HCV) was carried out using commercially available kits. HBV DNA and HCV RNA were also tested by PCR in those samples that were found to be non-B, non-C by serological assays. Serological evidence of exposure to HBV was found in 31 (62%) and to HCV in 15 (30%) patients. HGV RNA was detected in 6 (12%) cirrhosis patients and in 2 (4%) healthy blood donors but the difference between the two groups was not statistically significant. Of the 6 HGV positive patients, 2 were coinfected with HBV, 1 with HCV, while the remaining 3 belonged to non-B, non-C category. No significant difference was observed in the clinical and biochemical profiles of HGV-positive and HGV-negative patients except that a history of blood transfusion was significantly (P < 0.005) more common in the former. The findings indicate that the HGV infection is commonly observed in both cirrhosis patients as well as healthy blood donors. A significant association of the virus with blood transfusion is indicative of a parenteral route of transmission. The observations of this study also suggest that the pathogenic role of HGV in the causation of liver disease may be insignificant.
 ...
PMID:Hepatitis G virus (HGV) infection & its pathogenic significance in patients of cirrhosis. 1057 52

The family Flaviviridae contains three genera: Hepacivirus, Flavivirus, and Pestivirus. Worldwide, more than 170 million people are chronically infected with Hepatitis C virus and are at risk of developing cirrhosis and/or liver cancer. In addition, infections with arthropod-borne flaviviruses (such as dengue fever, Japanese encephalitis, tick-borne encephalitis, St. Louis encephalitis, Murray Valley encephalitis, West Nile, and yellow fever viruses) are emerging throughout the world. The pestiviruses have a serious impact on livestock. Unfortunately, no specific antiviral therapy is available for the treatment or the prevention of infections with members of the Flaviviridae. Ongoing research has identified possible targets for inhibition, including binding of the virus to the cell, uptake of the virus into the cell, the internal ribosome entry site of hepaciviruses and pestiviruses, the capping mechanism of flaviviruses, the viral proteases, the viral RNA-dependent RNA polymerase, and the viral helicase. In light of recent developments, the prevalence of infections caused by these viruses, the disease spectrum, and the impact of infections, different strategies that could be pursued to specifically inhibit viral targets and animal models that are available to study the pathogenesis and antiviral strategies are reviewed.
 ...
PMID:Perspectives for the treatment of infections with Flaviviridae. 1062 92

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. It is estimated that about 170 million people are chronically infected with HCV. Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma and HCV-related end-stage liver disease is, in many countries, the first cause of liver transplantation. HCV infection is characterized by its propensity to chronicity. Because of its high genetic variability, HCV has the capability to escape the immune response of the host. HCV is not directly cytopathic and liver lesions are mainly related to immune-mediated mechanisms, which are characterized by a predominant type 1 helper cell response. Co-factors influencing the outcome of the disease including age, gender and alcohol consumption are poorly understood and other factors such as immunologic and genetic factors may play an important role. Recent studies have shown that the combination therapy with alpha interferon and ribavirin induces a sustained virological response in about 40% of patients with chronic hepatitis C. The sustained response rates are mainly dependent on the viral genotype (roughly 60% in genotype non-1 and 30% in genotype 1). Reliable diagnostic tools are now available and useful for detecting HCV infection, to quantify viral load and to determine the viral type. The assessment of the viral quasispecies and the characterization of viral sequences might be clinically relevant but standardized and simple techniques are needed. The lack of animal models and of in vitro culture systems hampers the understanding of the pathogenesis of chronic hepatitis C and the development of new antivirals. New therapeutic schedules with higher and/or daily doses of alpha interferon do not seem to improve the efficacy greatly. The conjugation with polyethylene glycol (PEG) improved the pharmacodynamics and the efficacy of alpha interferon. Emerging new therapies include inhibitors of viral enzymes (protease, helicase and polymerase), cytokines (IL-12 and IL-10), antisense oligonucleotides and ribozymes. The first candidate compounds should be available in the next few years. The development of an effective vaccine remains the most difficult and pressing challenge. Because of the high protein variability of HCV, protective vaccines could be extremely difficult to produce and therapeutic vaccines seem more realistic. Considerable progress has been made in the field of HCV since its discovery 10 years ago but a major effort needs to be made in the next decade to control HCV-related liver disease.
 ...
PMID:Pathogenesis, diagnosis and management of hepatitis C. 1072 98

Therapy of different manifestations of HCV infection is discussed--after 12 years of the discovery of HCV. In acute hepatitis C the antiviral treatment of the early phase is debated, but if 3 months after the onset the HCV viremia persists, interferon (IFN) therapy may be recommended. Asymptomatic HCV carriers with normal alanine aminotransferase (ALT) do not need antivirals. However, their serum ALT, GGT, gammaglobulin values and liver ultrasound findings should be monitored, to disclose an underlying liver disease, and biopsy is considered, if suspicion of hepatitis raises. In patients with chronic hepatitis C biopsy is mandatory, it may prove mild, moderate or severe histological activity (HAI). Moderate or severe active hepatitis C (> 2 x normal ALT, HAI > 7) should be treated. In the first period of the antiviral treatment for HCV, a standard IFN monotherapy (3 x 3 MU s.c. IFN weekly for 6-12 months) has been used, which resulted in 15-20% sustained response (SR) rate. In the second half of nineties, combination of IFN with an oral nucleoside analogue ribavirin increased the SR to 30-30%, by means of decrease in relapse rate. Recently, pegylated IFN (PEG-IFN) in combination with ribavirin can lead to 60% SR. (Genotype HCV1 patients may show SR of about 40%, HCV 2.3 ones about 80%, respectively). Compensated HCV cirrhosis patients may also be treated with this type of combination, which can possibly inhibit progression. Decompensated cirrhosis needs liver transplantation. In the prevention of HCV infection, screening of blood donors, viral inactivation of blood products, disposable needles and education of risk populations are of basic importance, HCV vaccination, however is not on the horizon yet. Thus, antiviral treatment remains of great significance. Searches for new therapeutic modalities, such as multiple antiviral combinations (e.g amantadin + ribavirin + IFN), protease- and helicase inhibitors, ribozymes and cytokines may result further advances.
 ...
PMID:[Hepatitis C virus infection--after 12 years. Advances in the management of chronic hepatitis C]. 1250 75

Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. HCV has a positive-strand RNA genome of about 9.4 kb in size, which serves as a template for replication and for translation of a polyprotein of about 3,000 amino acids. The polyprotein is cleaved co- and posttranslationally by cellular and viral proteases into at least 10 different mature proteins. One of these proteins, nonstructural protein 3 (NS3), has serine protease and NTPase/RNA helicase activity. Arginine 467 in the helicase domain of NS3 (arginine 1493 in the polyprotein) can be methylated by protein arginine methyltransferase 1 (PRMT1). Here we report that the methylation of NS3 inhibits the enzymatic activity of the helicase. Furthermore, we found that PRMT1 activity itself is regulated by protein phosphatase 2A (PP2A). PP2A inhibits PRMT1 enzymatic activity and therefore increases the helicase activity of NS3. This is important, because we found an increased expression of PP2A in cell lines with inducible HCV protein expression, in transgenic mice expressing HCV proteins in hepatocytes, and in liver biopsy samples from patients with chronic hepatitis C. Interestingly, up-regulation of PP2A not only modulates the enzymatic activity of an important viral protein, NS3 helicase, but also interferes with the cellular defense against viruses by inhibiting interferon-induced signaling through signal transducer and activator of transcription 1 (STAT1). We conclude that up-regulation of PP2A might be crucial for the efficient replication of HCV and propose PP2A as a potential target for anti-HCV treatment strategies.
 ...
PMID:Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1. 1630 5

Hepatitis C virus (HCV) is considered one of the most dangerous pathogens since about 3% of the world population is HCV-infected and the virus is a major cause of hepatitis, cirrhosis, and liver carcinoma. A need for a more efficient therapy prompted us to investigate new class of compounds, such as tropolone derivatives that possess antiviral, antibacterial, and antifungal activities. To synthesize bromo- and morpholinomethyl-analogues of tropolone, the previously reported methods were modified. The influence of new derivatives on the activity of the helicase and NTP-ase of HCV was investigated. The most potent inhibitory effect in the fluorometric helicase assay was exerted by 3,7-dibromo-5-morpholinomethyltropolone, for which the IC50 value was at low micromolar range. All the morpholino-derivatives had inhibitory activities higher than those of the non-modified analogues. Low toxicity in a yeast-based toxicity assay indicates that these compounds could be further modified to develop potent inhibitors of the HCV helicase and of viral replication.
 ...
PMID:Searching for a new anti-HCV therapy: synthesis and properties of tropolone derivatives. 1643 39

Infection by the hepatitis C virus (HCV) is a major public health problem, with more than 170 million people infected throughout the world. The infection prevalence, with small regional differences, is estimated in 1-3% of the global population. HCV is the most frequent cause of chronic liver disease and 20-30% of patients develop cirrhosis with a risk of hepatocellular carcinoma. Nowadays, pegylated interferon-a (PEG-IFN) in combination with ribavirin, a nucleoside analogue, is the current treatment for chronic hepatitis C (CHC), with less adverse effects and better compliance. Dosage and duration depend on some factors as weight, genotype, viral load and a rapid virological response presented by the patient. One of the most relevant aspects in the treatment of CHC is how to manage the group of non-responder or relapser patients to previous treatments. As such, a substantial proportion of patients had already been unsuccessfully treated with interferon-based therapies and these patients claim for an optimal therapeutic option. The future treatment of CHC walk along through the association of two or three drugs, including nucleoside/nucleotide analogues, higher PEG-IFN initial dosages (induction) or longer treatments duration, or combination of helicase and protease inhibitors.
 ...
PMID:Treatment regimens for patients with chronic hepatitis C. 1831 92


1 2 3 Next >>