Gene/Protein Disease Symptom Drug Enzyme Compound
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Recently a new field of immunological research and clinical application of vaccines for therapeutic purposes (vaccine therapy) has been developed for treating several chronic viral infections including chronic hepatitis B virus (HBV) infection. Administration of vaccine containing hepatitis B surface antigen (HBsAg) for 1 year has resulted in negative HBsAg and development of antibody to HBsAg (anti-HBs) in some, but not in all, HBV transgenic mouse (HBV-Tg). In order to develop more potent regimen of vaccine therapy for chronic HBV carrier, we prepared a dendritic cell (DC)-based therapeutic vaccine and evaluated their therapeutic potential in HBV-Tg. DCs were isolated from single cell suspensions of murine spleen cells by collagenase digestion, density centrifugation and depletion of lymphocytes. Spleen DCs were cultured with HBsAg (100 microg) for 24 h to produce HBsAg-pulsed DCs. HBV-Tg expressing HBsAg and HBV DNA in the sera were randomly assigned to receive either HBsAg-pulsed DCs (n = 20) or unpulsed DC (n = 20) or vaccine containing HBsAg (n = 39) or complete Freund's adjuvant (n = 20) or left untreated (n = 20). Only two intraperitoneal injections of HBsAg-pulsed DCs resulted in negative HBsAg and production of anti-HBs in the sera in all HBV-Tg (n = 20). However, administration of un-pulsed DCs (n = 20) or vaccine containing HBsAg (n = 39) or only complete Freund's adjuvant did not induce negative HBsAg or production of anti-HBs in any HBV-Tg within 6 months of therapy commencement. Taken together, this study showed that HBsAg-pulsed DCs represent a highly potent therapeutic vaccine for chronic HBV infection and inspire optimism of using this vaccine in clinical conditions. A clinical trial of HBsAg-pulsed DC in patients with chronic hepatitis B is warranted.
Int J Mol Med 2004 Aug
PMID:Production and efficacy of a dendritic cell-based therapeutic vaccine for murine chronic hepatitis B virus carrierer. 1525 81

Studies show that administration of interferon (IFN)-alpha causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-alpha-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-alpha treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood-brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-alpha treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-alpha-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.
Mol Psychiatry 2005 Jun
PMID:IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. 1549 6

Hepatitis C virus (HCV) induces extrahepatic manifestations such as oral lichen planus (OLP) as well as chronic liver diseases. The treatment of HCV-related chronic liver disease has evolved from the use of a single agent, mainly interferon (IFN), to the combination of IFN and ribavirin. We present a case of erosive OLP, cutaneous lichen planus (CLP), and leukoplakia of the vocal cord in a man with chronic hepatitis C infection treated with IFN and ribavirin. A 65-year-old man suffered from OLP before undergoing combination of IFN and ribavirin therapy for chronic hepatitis C. He was initially treated with IFNbeta (6 million units (MU) /day for 2 weeks), then a combination of IFNalpha-2b (6 MU/day for 2 weeks and 3 times a week for 14 weeks) and ribavirin (400-600 mg/day). The OLP lesion was not aggravated by application of steroids during the 7 weeks after the treatment, but after 18 weeks, the combination of IFN and ribavirin was stopped because of aggravation of the OLP. Elevated aminotransferase levels returned to normal during the therapy. But 7 weeks after discontinuation, aminotransferase levels rose to 10 times the normal range. Five months after discontinuation, the papules of CLP appeared. Eight months after discontinuation, the OLP erosion had gradually reduced, but some erosion remained. Aminotransferase levels were decreased, but serum HCV RNA had not disappeared. Caution should be exercised when IFN or ribavirin therapy is given to chronic hepatitis C patients with prior erosive OLP.
Int J Mol Med 2005 Feb
PMID:Exacerbation of oral erosive lichen planus by combination of interferon and ribavirin therapy for chronic hepatitis C. 1564 37

We analyzed lipids in liver diseases by agarose gel electrophoresis, and differential staining and simultaneous analysis of the cholesterol (Chol) and triglyceride (TG) fractions. Liver diseases were classified into chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and metastatic liver cancer, and each fraction was compared among these diseases. Atypical patterns that were unclassifiable according to the WHO classification of hyperlipidemia phenotypes were classified, and their clinical importance was evaluated. With progression of the pathologic conditions of CH, LC, and HCC, the T-Chol level, each Chol fraction, and the TG fraction decreased while the LDL-TG fraction increased. Metastatic liver cancer showed a lower HDL-fraction level but higher levels of the other parameters than HCC. When the subjects were classified into survivors and patients who died, the HDL fraction level in HCC and metastatic liver cancer, and the LDL level in LC and metastatic liver cancer differed between survivors and patients who died. Phenotypes of hyperlipidemia also differed among diseases, and atypical patterns were frequently observed in patients who died. There were 6 atypical patterns, of which 4 (slow alpha HDL, abnormal LDL, Lp-X, and Lp-Y) were associated with liver diseases. Slow alpha HDL appeared during slight bile stagnation and was accompanied by increases in the apo E level and the HDL particle size. Abnormal LDL appeared with severe liver dysfunction; a TG peak appeared at the position of LDL, and the HDL and VLDL fractions were negligible. Lp-X was a Chol-rich band, occurring on the cathode side of LDL in the presence of marked bile stagnation such as that in obstructive jaundice, and was accompanied by appearance of abnormal LDL. Lp-Y was similar to Lp-X in terms of mobility and associated diseases but contained Chol and TG. Abnormal LDL, Lp-X, and Lp-Y were often observed in patients with poor outcomes. Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful.
Int J Mol Med 2005 Apr
PMID:Clinical significance of abnormal lipoprotein patterns in liver diseases. 1575 28

Hepatitis C virus (HCV) infection is a major world-wide health problem causing chronic hepatitis, liver cirrhosis and primary liver cancer. The high frequency of treatment failure points to the need for more specific, less toxic and more active antiviral therapies for HCV. The HCV NS3 is currently regarded as a prime target for anti-viral drugs, thus specific inhibitors of its activity are of utmost importance. Here, we report the development of a novel bacterial genetic screen for inhibitors of NS3 catalysis and its application for the isolation of single-chain antibody-inhibitors. Our screen is based on the concerted co-expression of a reporter gene, of recombinant NS3 protease and of fusion-stabilized single-chain antibodies (scFvs) in Escherichia coli. The reporter system had been constructed by inserting a short peptide corresponding to the NS5A/B cleavage site of NS3 into a permissive site of the enzyme beta-galactosidase. The resulting engineered lacZ gene, coding for an NS3-cleavable beta-galactosidase, is carried on a low copy plasmid that also carried the NS3 protease-coding sequence. The resultant beta-galactosidase enzyme is active, conferring a Lac+ phenotype (blue colonies on indicator 5-bromo-4-chloro-3-indolyl beta-D-galactoside (X-gal) plates), while induction of NS3 expression results in loss of beta-galactosidase activity (transparent colonies on X-gal plates). The identification of inhibitors, as shown here by isolating NS3-inhibiting single-chain antibodies, expressed from a compatible high copy number plasmid, is based on the appearance of blue colonies (NS3 inhibited) on the background of colorless colonies (NS3 active). Our source of inhibitory scFvs was an scFv library that we prepared from spleens of NS3-immunized mice and subjected to limited affinity selection. Once isolated, the inhibitors were validated as genuine and specific NS3 binders by an enzyme-linked immunosorbent assay and as bone fide NS3 serine protease inhibitors by an in vitro catalysis assay. We further show that upon expression as cytoplasmic intracellular antibodies (intrabodies) in NS3-expressing mammalian cells, three of the scFvs inhibit NS3-mediated cell proliferation. Although applied here for the isolation of antibody-based inhibitors, our genetic screen should be applicable for the identification of candidate inhibitors from other sources.
J Mol Biol 2005 Apr 15
PMID:HCV NS3 serine protease-neutralizing single-chain antibodies isolated by a novel genetic screen. 1578 58

Mitochondrial DNA (mtDNA) polymerase gamma (Polg) is a heterodimeric enzyme containing a Pol I-like catalytic core (PolgA) and an accessory subunit. Mutations in POLGA, affecting the stability of mtDNA, have been identified in several human pathologies such as progressive external ophthalmoplegia and Alpers' syndrome. Extensive literature shows mitochondrial toxicity effects nucleoside analogue reverse transcriptase inhibitors used in the treatment of HIV and chronic hepatitis B as a consequence of an inhibitory effect on Polg. We have previously shown that mice with an error-prone version of PolgA accumulate higher levels of somatic mtDNA mutations resulting in a premature aging phenotype. In the present paper, we demonstrate PolgA deficiency in mouse embryos causes an early developmental arrest between embryonic days 7.5 and 8.5 associated with severe mtDNA depletion. Heterozygous knockout mice have half the wild-type levels of PolgA transcripts and a slight reduction in mtDNA levels but develop normally. Surprisingly, amounts of PolgA transcripts in heterozygous knockout mice are increased in response to artificially elevated mtDNA copy number, revealing a possible regulatory link between mtDNA maintenance and PolgA expression. Our results show that Polg indeed is the only DNA polymerase capable of maintaining mtDNA in mammalian mitochondria. In addition, presence of Polg is absolutely essential for the organogenesis during mammalian embryonic development.
Hum Mol Genet 2005 Jul 01
PMID:Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. 1588 83

The long-term usefulness of interferon-alpha (IFN-alpha) in chronic hepatitis B remains controversial. To investigate the long-term efficacy of IFN-alpha therapy in chronic hepatitis B, 62 Japanese patients, including 27 patients treated with IFN-alpha (IFN group) and 35 patients without antiviral therapy matched by age and sex as controls (control group), were followed up for 2-14 years. At entry, the serum alanine aminotransferase (ALT) level in the IFN group was significantly higher than that in the control group (238.6+/-250.1 vs. 142.3+/-152.1 IU/l, P < 0.05). The prevalence of genotype C was 89%, with no difference between the two groups (93 vs. 86%). There was no significant difference in the presence of the precore mutation or the dual core promoter mutations between the IFN and control groups (37 vs. 46%, 74 vs. 66%). After long-term follow-up, the rate of sustained HBeAg seroconversion was comparable in the two groups (33 vs. 31%). Normalization of serum ALT level was seen in 44% of the IFN group and 51% of the control group, with no difference. There was also no difference in the percentage of cases with loss of serum HBV-DNA by PCR assay between the two groups (33 vs. 29%). During follow-up, two patients of the control group and three patients of the IFN group developed cirrhosis, and one of the IFN- treated patients progressed to hepatocellular carcinoma. The results of this long-term follow-up study showed that no benefit of IFN-alpha treatment was detectable during long-term follow-up in Japanese patients with chronic hepatitis B.
Int J Mol Med 2005 Aug
PMID:Long-term follow-up of Japanese patients with chronic hepatitis B treated with interferon-alpha. 1601 62

Hepatitis C virus is an RNA virus that is associated with chronic infection in the majority of people infected. Chronic infection with hepatitis C virus is the cause of significant morbidity and mortality worldwide and is associated with a large spectrum of liver disease including cirrhosis and hepatocellular carcinoma. End-stage liver disease due to chronic hepatitis C virus infection is currently the leading indication for liver transplantation in the USA. Hepatitis C virus genotyping of viral isolates circulating in the blood during chronic infection has become an important part of hepatitis C virus monitoring in chronically infected patients, and is useful as a prognostic indicator and to direct duration of therapy. This review will summarize information on hepatitis C genotyping, describe the limitations of current commercially available methods, give information on more recently developed methods, and provide a look to the future in terms of where advances in hepatitis C virus genotyping assays need to be made.
Expert Rev Mol Diagn 2005 Jul
PMID:Molecular methods of hepatitis C genotyping. 1601 69

Beta-catenin is upregulated in many human cancers and considered to be an oncogene. Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies, and individuals who are chronic hepatitis B virus (HBV) carriers have a greater than 100-fold increased relative risk of developing HCC. Here we report a mechanism by which HBV-X protein (HBX) upregulates beta-catenin. Erk, which is activated by HBX, associates with GSK-3beta through a docking motif ((291)FKFP) of GSK-3beta and phosphorylates GSK-3beta at the (43)Thr residue, which primes GSK-3beta for its subsequent phosphorylation at Ser9 by p90RSK, resulting in inactivation of GSK-3beta and upregulation of beta-catenin. This pathway is a general signal, as it was also observed in cell lines in which Erk-primed inactivation of GSK-3beta was regulated by IGF-1, TGF-beta, and receptor tyrosine kinase HER2, and is further supported by immunohistochemical staining in different human tumors, including cancers of the liver, breast, kidney, and stomach.
Mol Cell 2005 Jul 22
PMID:Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. 1603 86

The results of the microscopic examinations on 23 paired liver biopsies of patients affected by the chronic hepatitis C, were realized successively before and after treatment by interferon alpha during six months. They showed a particular interest in the use of the antibody Anticore. The other antibody Anti C100-3-clone Tordji 32, was partially associated with the Anticore to improve its total number of positive responses by interchanging the loss of 3 wrong positive numbers (-) of the same patients from the Anticore, against earnings of 3 wrong negative numbers (+) for the same patients from the Anti C100-3-clone 32. This operation led to 70% of sensitivity. The results were submitted to mathematical verification and allowed to look for the maximum of the predictive probabilities. As for the other antibody Anti C100-3-Tordji-clone 22, it only used as a witness for some positive values. Moreover, this work brought a practical implementation to solve the problem concerning the indeterminate responses. Elsewhere, it appeared plausible for the Anticore to advance beyond its value, if the improvement of its conditions of realization were requiring. That hope was reasonable since it was yielded from the results of the predictive equations of the likelihood ratios by the logistic regression method which built two mathematical models to comparison for confirmation.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 02
PMID:Immunohistochemical hepatocytes nuclear test for the evaluation of responses to treatment of the chronic hepatitis C by interferon alpha. 1617 71


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