Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a systematic comparison of three modules that enhance expression from retroviral gene transfer vectors at a posttranscriptional level: (i) splice signals (SS) that create an intron in the 5' untranslated region; (ii) constitutive RNA transport elements (CTE), originally discovered in D-type retroviruses; and (iii) the posttranscriptional regulatory element of woodchuck hepatitis virus (WPRE). Here we show that enhancement of expression depends not only on the specific element, but also on the gene of interest, implying context-dependent activity of the RNA elements. Interestingly, different results were obtained for genes that normally require or do not require such control elements. Expression of the HIV-1 gag-protease gene, which normally depends on the viral export factor Rev, was strongly enhanced by an oligomeric CTE, while WPRE had only a marginal effect. On the other hand, both CTE and WPRE compensated for the lack of an intron in the expression of human beta-globin. In this case, the strongest stimulation of RNA production was observed when functional SS were combined with the WPRE. Both CTE and, in particular, WPRE also enhanced expression of cDNAs that do not normally require any such element (green fluorescent protein, human multidrug resistance-1). In this study, functional SS and WPRE acted in an additive manner, resulting in a 10-fold higher level of expression. Our results indicate that the described modules act on different levels of RNA processing, transport, and translation and that the correct choice of a posttranscriptional enhancer configuration depends on the type of cDNA to be expressed.
Mol Ther 2000 Nov
PMID:Context dependence of different modules for posttranscriptional enhancement of gene expression from retroviral vectors. 1108 17

Accumulated data indicate that current generation lentiviral vectors, which generally utilize an internal human cytomegalovirus (CMV) immediate early region enhancer-promoter to transcribe the gene of interest, are not yet optimized for efficient expression in human hematopoietic stem/progenitor cells (HSPCs). As a first step toward this goal, we constructed self-inactivating derivatives of the HIV-1-based transfer vector pHR' containing the enhanced green fluorescent protein (GFP) gene as reporter and the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). GFP expression was driven by a variety of strong viral and cellular promoters, including the murine stem cell virus (MSCV) long terminal repeat (LTR), a Gibbon ape leukemia virus (GALV) LTR, the human elongation factor 1alpha (EF1alpha) promoter, the composite CAG promoter (consisting of the CMV immediate early enhancer and the chicken beta-actin promoter), and the human phosphoglycerate kinase 1 (PGK) promoter. In contrast to results obtained in human embryonic kidney 293T cells and fibrosarcoma HT1080 cells, in which the CMV promoter expressed GFP at the highest levels, significantly higher levels of GFP expression (3- to 5-fold) were achieved with the MSCV LTR, the EF1alpha promoter, and the CAG promoter in the human HSPC line KG1a. Removal of the WPRE indicated that it stimulated GFP expression from all of the vectors in KG1a cells (up to 3-fold), although it only marginally improved the performance of the intron-containing EF1alpha and CAG promoters (<1.5-fold stimulation). The vectors using the MSCV LTR, the GALV LTR, and the PGK promoter were the most efficient at transducing primary human CD34+ cord blood progenitors under the conditions employed. High-level GFP expression in the NOD/SCID xenograft model was demonstrated with the pHR' derivative bearing the MSCV LTR. These new lentiviral vector backbones provide a basis for the rational design of improved delivery vehicles for human HSPC gene transfer applications.
Mol Ther 2000 Nov
PMID:Lentiviral vectors for enhanced gene expression in human hematopoietic cells. 1108 19

JunD is the most broadly expressed member of the Jun family and the AP-1 transcription factor complex. Primary fibroblasts lacking JunD displayed p53-dependent growth arrest, upregulated p19(Arf) expression, and premature senescence. In contrast, immortalized cell lines lacking JunD showed increased proliferation and higher cyclinD1 levels. These properties are reminiscent of the effects of oncogenic Ras expression on primary and established cell cultures. Furthermore, JunD(-/-) fibroblasts exhibited increased p53-dependent apoptosis upon ultraviolet irradiation and were sensitive to the cytotoxic effects of TNF-alpha. The antiapoptotic role of JunD was confirmed using an in vivo model of TNF-mediated hepatitis. We propose that JunD protects cells from senescence, or apoptotic responses to stress stimuli, by acting as a modulator of the signaling pathways that link Ras to p53.
Mol Cell 2000 Nov
PMID:JunD protects cells from p53-dependent senescence and apoptosis. 1110 50

Hepatitis delta virus (HDV) encodes a single polypeptide called hepatitis delta antigen (DAg). Dimerization of DAg is required for viral replication. The structure of the dimerization region, residues 12 to 60, consists of an anti-parallel coiled coil [Zuccola et al., Structure, 6(1998)821]. Multiple Copy Simultaneous Searches (MCSS) of the hydrophobic core region formed by the bend in the helix of one monomer of this structure were carried out for many diverse functional groups. Six critical interaction sites were identified. The Protein Data Bank was searched for backbone templates to use in the subsequent design process by matching to these sites. A 14 residue helix expected to bind to the D-isomer of the target structure was selected as the template. Over 200,000 mutant sequences of this peptide were generated based on the MCSS results. A secondary structure prediction algorithm was used to screen all sequences. and in general only those that were predicted to be highly helical were retained. Approximately 100 of these 14-mers were model built as D-peptides and docked with the L-isomer of the target monomer. Based on calculated interaction energies, predicted helicity, and intrahelical salt bridge patterns, a small number of peptides were selected as the most promising candidates. The ligand design approach presented here is the computational analogue of mirror image phage display. The results have been used to characterize the interactions responsible for formation of this model anti-parallel coiled coil and to suggest potential ligands to disrupt it.
J Comput Aided Mol Des 2000 Nov
PMID:Computational design of D-peptide inhibitors of hepatitis delta antigen dimerization. 1113 65

Self-cleavage of the genomic and antigenomic ribozymes from hepatitis delta virus (HDV) requires divalent cation for optimal activity. Recently, the HDV genomic ribozyme has been shown to be active in NaCl in the absence of added divalent metal ion at low pH (apparent pKa 5.7). However, we find that the antigenomic ribozyme is 100 to 1000-fold less active under similar conditions. With deletion of a three-nucleotide sequence (C41-A42-A43) unique to the genomic ribozyme, the rate constant for cleavage decreased substantially, while activity of the antigenomic ribozyme was enhanced by introducing a CAA sequence. From the crystal structure, it has been proposed that C41 in this sequence is protonated. To investigate a possible connection between activity at low pH and protonation of C41, mutations were made that were predicted to either eliminate protonation or alter the nature of the tertiary interaction upon protonation. In the absence of added Mg2+, these mutations reduced activity and eliminated the observed pH-rate dependence. Thermal denaturation studies revealed a pH-sensitive structural feature in the genomic ribozyme, while unfolding of the mutant ribozymes was pH-independent. We propose that, in the absence of added Mg2+, protonation of C41 contributes to enhanced activity of the HDV genomic ribozyme at low pH.
J Mol Biol 2001 Feb 02
PMID:A pH-sensitive RNA tertiary interaction affects self-cleavage activity of the HDV ribozymes in the absence of added divalent metal ion. 1116 13

Anorexia that develops in chronic hepatitis is associated with cytokine expression in the brain. Treatment of mice with concanavalin A (12.5 mg/kg, i.v.) elevated the plasma alanine aminotransferase activity at 8.5 h after treatment. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta mRNA expression was induced at 6 and 24 h after concanavalin A treatment in both the liver and brain. Treatment of mice with concanavalin A reduced the body weight at 24 h after treatment and this decreased body weight was accompanied by a decreased food intake. Glycyrrhizin (200 mg/kg, i.p.) inhibited the concanavalin A-induced elevation of plasma alanine aminotransferase activity, however, it did not inhibit the concanavalin A-induced decreased body weight. The present results indicate that treatment of mice with concanavalin A caused the development of anorexia and that this anorexia might develop independently of the induction of hepatitis.
Int J Mol Med 2001 Feb
PMID:Development of anorexia in concanavalin A-induced hepatitis in mice. 1117 20

The effects of imperatorin and its synthetic derivative, Y355, on anti-Fas antibody-induced mice hepatitis were studied. Pretreatment of mice by intraperitoneal administration of imperatorine or Y355 at 30 mg/kg inhibited more than 80% of the anti-Fas antibody (150 microg/kg, i.v.)-induced elevation of plasma alanine aminotransferase activity. Furthermore, oral administration of imperatorin or Y355 at 100 mg/kg also had an inhibitory effect on anti-Fas antibody-induced hepatitis. Both compounds inhibited anti-Fas antibody (250 microg/kg)-induced caspase-1 and caspase-3 activities. The present results showed the inhibition of anti-Fas antibody-induced hepatitis by imperatorin and Y355, which might be a result of inhibition of caspase activities.
Int J Mol Med 2001 Feb
PMID:Inhibition of anti-Fas antibody-induced mice hepatitis by furocoumarin derivatives. 1117 22

Molsidomine is effective in reducing portal hypertension in cirrhosis, but its effect on hepatitis is not known. In the present study, the effect of molsidomine on hepatitis was examined using mouse concanavalin A (Con A)-induced hepatitis and mouse anti-Fas antibody-induced hepatitis. Treatment of mice with Con A caused elevation of plasma alanine aminotransferase (ALT) at 8 and 24 h (n=4). Pretreatment of mice with molsidomine (3, 10, 30 and 100 mg/kg, i.p.) prevented Con A-induced hepatitis. Treatment of mice with anti-Fas antibody (150 microg/kg, i.v.) caused elevation of plasma ALT at 3.5 h. Pretreatment mice with molsidomine (10 mg/kg, i.p.) showed only 47% inhibition of anti-Fas antibody caused elevation of plasma ALT. The present results showed effectiveness of molsidomine in preventing Con A-induced mice hepatitis.
Int J Mol Med 2001 Mar
PMID:Prevention of concanavalin A-induced mice hepatitis by molsidomine. 1117 12

Efficient inhibition of human immunodeficiency virus-1 (HIV-1) replication with intracellularly expressed antiviral genes would be an important step toward clinical gene therapy for HIV-1 disease. Enzo Biochem is investigating and developing antisense genes as a potential gene therapy approach against a variety of conditions including acquired immunodeficiency syndrome (AIDS), cancer and hepatitis. The subsidiary of Enzo Biochem, Enzo Therapeutics, utilized its StealthVector technology and initiated phase I trials in July 1998 [291511,307156]. StealthVector, which is comprised of independent antisense sequences directed against two functional HIV-1 regions, is involved in regulation of gene expression soon after HIV infection, transactivation response (TAR) and tat/rev. StealthVector localizes primarily in the cell nucleus, where it could be most effective in inhibiting viral growth.
Curr Opin Mol Ther 1999 Oct
PMID:Technology evaluation: StealthVector (HIV) Enzo. 1124 72

Hepatitis virus infection occurs in close to a billion people worldwide at some point in their lifetimes. Hepatitis B and C viruses together account for infections in half a billion people and are considered the most carcinogenic of any known biological agent. The diagnostic approaches to detect hepatitis viruses are discussed.
Mol Biotechnol 2000 Nov
PMID:Approaches of the diagnosis of hepatitis viruses. 1125 11


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