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)

Cancer gene therapy has been of great challenge in achieving maximal high levels of specificity and more rational efficiency in target cancer cell. We herein developed a novel approach for cancer-specific gene therapy using both transcriptional and translational targeting regulation. We integrated the tumor-specific gene promoter of hTERT, the 5'UTR of bFGF-2, the enhancer of woodchuck hepatitis virus post-transcriptional regulatory element (WRE), and/or the 3'UTR of the human EGFR into two major chimeric gene regulators. We found that chimeric gene regulator I (hTERT_5'UTR...WRE_BGHpolyA) enhanced the specificity of expression in hepatocellular carcinoma (HCC) cells up to 300% in total due to increases at both the transcriptional and translational levels but only 120-200% enhancement at the transcriptional level and 120-180% enhancement at the translational level. In addition, chimeric gene regulator II (hTERT_5'UTR...WRE_3'UTR_BGHpolyA) improved the specificity to 550% and also highly strengthened the stability of the mRNA. In vitro cytotoxicity assays demonstrated that HCC cell growth was inhibited by HSV-1 TK expression under the control of both chimeric regulators, with a relative cell viability of approximately 80% for 2 days and approximately 85% for 4 days after transfection, respectively. These observations represent a new approach for highly tumor-specific gene expression and also provide insights into application to cancer gene therapy.
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PMID:Development of chimeric gene regulators for cancer-specific gene therapy with both transcriptional and translational targeting. 2010 58

The transcription and replication of the severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is regulated by specific viral genome sequences within 5'- and 3'-untranslated regions (5'-UTR and 3'-UTR). Here we report the solution structure of 5'-UTR derived stem-loop 2 (SL2) of SARS-CoV determined by NMR spectroscopy. The highly conserved pentaloop of SL2 is stacked on 5-bp stem and adopts a canonical CUYG tetraloop fold with the 3' nucleotide (U51) flipped out of the stack. The significance of this structure in the context of a previous mutagenesis analysis of SL2 function in replication of the related group 2 coronavirus, mouse hepatitis virus, is discussed.
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PMID:The solution structure of coronaviral stem-loop 2 (SL2) reveals a canonical CUYG tetraloop fold. 2138 73

Duck hepatitis virus (DHV-1) is a worldwide distributed picornavirus that causes acute and fatal disease in young ducklings. Recently, the complete genome of DHV-1 has been determined and comparative sequence analysis has shown that possesses the typical picornavirus organization but exhibits several unique features. For the first time, we provide evidence that the 626-nucleotide-long 5'-UTR of the DHV-1 genome contains an internal ribosome entry site (IRES) element that functions efficiently both in vitro and in mammalian cells. The prediction of the secondary structure of the DHV-1 IRES shows significant similarity to the hepatitis C virus (HCV) IRES. Moreover, similarly to HCV IRES, DHV-1 IRES can direct translation initiation in the absence of a functional eIF4F complex. We also demonstrate that the activity of the DHV-1 IRES is modulated by a viral coding sequence located downstream of the DHV-1 5'-UTR, which enhances DHV-1 IRES activity both in vitro and in vivo. Furthermore, mutational analysis of the predicted pseudo-knot structures at the 3'-end of the putative DHV-1 IRES supported the presence of conserved domains II and III and, as it has been previously described for other picornaviruses, these structures are essential for keeping the normal internal initiation of translation of DHV-1.
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PMID:The duck hepatitis virus 5'-UTR possesses HCV-like IRES activity that is independent of eIF4F complex and modulated by downstream coding sequences. 2145 Jan 10

The 5' 140 nucleotides of the mouse hepatitis virus (MHV) 5' untranslated region (5'UTR) are predicted to contain three secondary structures, stem-loop 1 (SL1), SL2, and SL4. SL1 and SL2 are required for subgenomic RNA synthesis. The current study focuses on SL4, which contains two base-paired regions, SL4a and SL4b. A series of reverse genetic experiments show that SL4a is not required to be base paired. Neither the structure, the sequence, nor the putative 8-amino-acid open reading frame (ORF) in SL4b is required for viral replication. Viruses containing separate deletions of SL4a and SL4b are viable. However, deletion of SL4 is lethal, and genomes carrying this deletion are defective in directing subgenomic RNA synthesis. Deletion of (131)ACA(133) just 3' to SL4 has a profound impact on viral replication. Viruses carrying the (131)ACA(133) deletion were heterogeneous in plaque size. We isolated three viruses with second-site mutations in the 5'UTR which compensated for decreased plaque sizes, delayed growth kinetics, and lower titers associated with the (131)ACA(133) deletion. The second-site mutations are predicted to change either the spacing between SL1 and SL2 or that between SL2 and SL4 or to destabilize the proximal portion of SL4a in our model. A mutant constructed by replacing SL4 with a shorter sequence-unrelated stem-loop was viable. These results suggest that the proposed SL4 in the MHV 5'UTR functions in part as a spacer element that orients SL1, SL2, and the transcriptional regulatory sequence (TRS), and this spacer function may play an important role in directing subgenomic RNA synthesis.
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PMID:Mouse hepatitis virus stem-loop 4 functions as a spacer element required to drive subgenomic RNA synthesis. 2171 2

Analysis of the R2 retrotransposons from multiple silkmoth and fruitfly species have revealed three segments that contain conserved RNA secondary structures. These conserved structures play important roles in the propagation of the R2 element, including R2 RNA processing and transposon integration into the host genome as well as a likely role in translation. Two of the structured regions comprise protein binding sites: one is located in the 3' UTR and the other is in the 5' UTR close to the putative start of the R2 open reading frame (ORF). The 3' structure was deduced from chemical mapping and sequence comparison. The 5' structure was determined using a combination of chemical mapping, oligonucleotide binding, NMR and sequence analysis and contains an unusual pseudoknot structure. The third structure occurs at the 5' end of the R2 RNA and is responsible for self-cleavage of the 5' end of the element from a 28S ribosomal RNA co-transcript. A structure for this fragment was proposed based on motif searching and sequence comparison. There is remarkable similarity in sequence and structure to the hepatitis delta virus (HDV) ribozyme. Seed alignments for the 5' structure and the R2 ribozyme, containing representative sequences and consensus structures, have been submitted to the Rfam database.
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PMID:The R2 retrotransposon RNA families. 2173 71

Sequence analysis of duck hepatitis virus type 1 (DHV-1) led to its classification as the only member of a new genus, Avihepatovirus, of the family Picornaviridae, and so was renamed duck hepatitis A virus (DHAV). The 5' untranslated region (5' UTR) plays an important role in translation initiation and RNA synthesis of the picornavirus. Here, we provide evidence that the 651-nucleotide (nt)-long 5' UTR of DHAV genome contains an internal ribosome entry site (IRES) element that functions efficiently in vitro and within BHK cells. Comparative sequence analysis showed that the 3' part of the DHAV 5' UTR is similar to the porcine teschovirus 1 (PTV-1) IRES in sequence and predicted secondary structure. Further mutational analyses of the predicted domain IIId, domain IIIe, and pseudoknot structure at the 3' end of the DHAV IRES support our predicted secondary structure. However, unlike the case for the PTV-1 IRES element, analysis of various deletion mutants demonstrated that the optimally functional DHAV IRES element with a size of approximately 420 nt is larger than that of PTV-1 and contains other peripheral domains (Id and Ie) that do not exist within the type IV IRES elements. The domain Ie, however, could be removed without significant loss of activity. Surprisingly, like the hepatitis A virus (HAV) IRES element, the activity of DHAV IRES could be eliminated by expression of enterovirus 2A protease. These findings indicate that the DHAV IRES shares common features with type IV picornavirus IRES elements, whereas it exhibits significant differences from type IV IRESs. Therefore, we propose that DHAV possesses a distinct type IV IRES element of picornavirus.
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PMID:Duck Hepatitis A virus possesses a distinct type IV internal ribosome entry site element of picornavirus. 2209 Jan 6

The let-7 microRNA (miRNA) plays important roles in human liver development and diseases such as hepatocellular carcinoma, liver fibrosis and hepatitis wherein oxidative stress accelerates the progression of these diseases. To date, the role of the let-7 miRNA family in modulation of heme oxygenase 1 (HMOX1), a key cytoprotective enzyme, remains unknown. Our aims were to determine whether let-7 miRNA directly regulates Bach1, a transcriptional repressor of the HMOX1 gene, and whether indirect up-regulation of HMOX1 by let-7 miRNA attenuates oxidant injury in human hepatocytes. The effects of let-7 miRNA on Bach1 and HMOX1 gene expression in Huh-7 and HepG2 cells were determined by real-time qRT-PCR, Western blot, and luciferase reporter assays. Dual luciferase reporter assays revealed that let-7b, let-7c, or miR-98 significantly decreased Bach1 3'-untranslated region (3'-UTR)-dependent luciferase activity but not mutant Bach1 3'-UTR-dependent luciferase activity, whereas mutant let-7 miRNA containing base complementarity with mutant Bach1 3'-UTR restored its effect on mutant reporter activity. let-7b, let-7c, or miR-98 down-regulated Bach1 protein levels by 50-70%, and subsequently up-regulated HMOX1 gene expression by 3-4 fold, compared with non-specific controls. Furthermore, Huh-7 cells transfected with let-7b, let-7c or miR-98 mimic showed increased resistance against oxidant injury induced by tert-butyl-hydroperoxide (tBuOOH), whereas the protection was abrogated by over-expression of Bach1. In conclusion, let-7 miRNA directly acts on the 3'-UTR of Bach1 and negatively regulates expression of this protein, and thereby up-regulates HMOX1 gene expression. Over-expression of the let-7 miRNA family members may represent a novel approach to protecting human hepatocytes from oxidant injury.
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PMID:The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes. 2269 95

Two complete duck hepatitis virus type 1 (DHV-1) genomes, strain SY5 and its chicken embryos passage descendent vaccine strain ZJ-A, were compared and analyzed in order to identify possible sites of attenuation. Of the 205 nucleotide changes, 22 resulted in sense mutations, 174 produced nonsense mutations. Besides, there are 7 consistent nucleotides substitutions in 5'UTR and 2 in 3'UTR. Three of these 22 sense mutations resided in VP0, 6 exists in VP1, one exists in VP3, 3 exists in 2A2, 3 exists in 2C, one was detected in 3B and 5 was in 3D. These results suggested that VP0, VP1, 3D, and 5'/3'UTR may contribute to the attenuation of DHV-1 in chicken/duck/embryos. The results provide a genetic basis for future manipulation of a DHV-1 infectious clone.
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PMID:Complete genome comparison of duck hepatitis virus type 1 parental and attenuated strains. 2272 99

RNA possesses great potential for expanding the toolbox currently available to synthetic biologists. Here, the modulation of the Hepatitis Delta Virus ribozyme's activity with a series of rationally designed aptamers and effector RNA oligonucleotides is described. The ribozyme was initially fused with an 18-nucleotide hairpin structure that abolished its self-cleaving activity. The binding of a 14-mer oligonucleotide to the hairpin rescued the self-cleavage in a concentration-dependent manner. This modified ribozyme was inserted into the 5' UTR of a reporter gene, and the resulting construct was used to demonstrate that it is possible to modulate the ribozyme activity in cellulo with the oligonucleotide. Subsequently, ribozymes possessing specialized aptamers respecting other logic gates were also successfully designed and found to be functional in vitro. To our knowledge, this is the first example of HDV ribozyme regulation by oligonucleotides, as well as the first allosteric regulation of HDV ribozyme in mammalian cells.
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PMID:Programming a highly structured ribozyme into complex allostery using RNA oligonucleotides. 2295 Aug 75

Coxsackievirus B (CVB) is a significant pathogen of neonatal diseases with severe systemic involvement and high mortality. Hence, it is essential to develop a CVB-induced acute systemic disease model on newborn mouse and study the injury at the onset phase. In this work, a clinical strain of CVB3, Nancy, and its variant strain, Macocy, were adopted in 24 hour old neonates by oral infection. The pathological changes in the heart, liver and lung tissues were analyzed by pathology assays. In situ end labeling assay for programmed cell death was carried out for liver tissues. The data on fatality and infection rates and pathology scores were analyzed statistically. The genomic sequences of the two strains were aligned. The model represented the manifest clinical syndromes of hepatitis, pneumonia and myocardial injury at the onset phase, in which massive numbers of hepatocytes had undergone programmed cell death. Statistical and pathological analysis indicated that the myocardial injury was mild, whereas the liver and lung were more severe. The fatality rate, infection and pathology of the two CVB strains were the same. Therefore, two nucleotide mutations in the 5' UTR and four amino acid mutations in polyprotein, which did not alter virulence, were shown. By peroral CVB infection of neonatal mice, we developed an acute systemic disease model for studying visceral pathology and systemic disease. At the onset of acute neonatal systemic disease, the hepatitis and pneumonia may be the dominant reason of death, as the injury of liver and lung is more severe than that of heart.
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PMID:Visceral pathology of acute systemic injury in newborn mice on the onset of Coxsackie virus infection. 2469 8


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