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Hepatitis B [keywords]
- Nuclear import of adenovirus DNA involves direct interaction of hexon with an N-terminal domain of the nucleoporin Nup214. [JOURNAL ARTICLE]
- J Virol 2014 Nov 19.
In this study, we characterized the molecular basis for binding of adenovirus (AdV) to the cytoplasmic face of the nuclear pore complex (NPC), a key step during delivery of the viral genome into the nucleus. We used RNAi to deplete cells of either Nup214 or Nup358, the two major FG repeat nucleoporins localized on the cytoplasmic side of the NPC, and evaluated the impact on hexon binding and AdV infection. The accumulation of purified hexon trimers or partially disassembled AdV at the nuclear envelope (NE) was observed in digitonin permeabilized cells in the absence of cytosolic factors. Both in vitro hexon binding and in vivo nuclear import of the AdV genome were strongly reduced in Nup214-depleted cells but still occurred in Nup358-depleted cells, suggesting that Nup214 is a major binding site of AdV during infection. The expression of an NPC-targeted N-terminal domain of Nup214 in Nup214-depleted cells restored the binding of hexon at the NE and the nuclear import of pVII, indicating that this region is sufficient to allow AdV binding. We further narrowed the binding site to a 137 amino acid segment in N-terminal domain of Nup214. Together, our results have identified a specific region within the N-terminus of Nup214 that acts as a direct NPC binding site for AdV.AdV, which have the largest genome of non-enveloped DNA viruses, are being extensively explored for use in gene therapy, especially in alternative treatments for cancers that are refractory to traditional therapies. In this study, we characterized the molecular basis for binding of AdV to the cytoplasmic face of the NPC, a key step for delivery of the viral genome into the nucleus. Our data indicate that a 137 amino acid region of the nucleoporin Nup214 is a binding site for the major AdV capsid protein hexon, and that this interaction is required for viral DNA import. These findings provide additional insight on how AdV exploits the nuclear transport machinery for infection. The results could promote the development of new strategies for gene transfer, and enhance understanding of the nuclear import of other viral DNA genomes, such as those of papillomavirus or hepatitis B virus that induce specific cancers.
- Anti-hepatitis B Virus Activity of α-DDB-FNCG, a Novel Nucleoside-Biphenyldicarboxylate Compound In Vitro and In Vivo. [JOURNAL ARTICLE]
- J Pharmacol Sci 2014; 126(3):208-215.
A novel codrug, α-DDB-FNCG, was synthesized through coupling of α-biphenyl dimethyl dicarboxylate (α-DDB) and the nucleoside analogue FNCG, via an ester bond. The anti-HBV activity and hepatoprotective effects of this compound were investigated both in vitro and in vivo. In HBV-transfected HepG2.2.15 cell line, the secretion of HBsAg and HBeAg as well as the levels of extracellular and intracellular viral DNA were determined by ELISA and real-time fluorescent quantitative Polymerase Chain Reaction (FQ-PCR), respectively. In DHBV-infected ducks, the viral DNA levels in serum and liver were determined by FQ-PCR. In addition, the levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) in both serum and liver were also examined. The improvement of ducks' livers was evaluated by histopathological analysis. It has been demonstrated that α-DDB-FNCG could suppress the levels of HBV antigens and viral DNA in a time- and dose-dependent manner in the HepG2.2.15 cell line. Furthermore, this codrug could also significantly inhibit the viral DNA replication and reduce the ALT and AST levels in both serum and liver of DHBV-infected ducks, with improved hepatocellular architecture in drug-treated ducks. In short, these results suggest that α-DDB-FNCG could be a promising candidate for further development of new anti-HBV agents with hepatoprotective effects.
- Hepatogastric Fistula following Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma. [JOURNAL ARTICLE]
- Case Rep Gastroenterol 2014 9; 8(3):286-290.
Hepatogastric fistula (HGF) formation following transcatheter arterial chemoembolization (TACE) leads to increased morbidity and mortality. A 51-year-old Caucasian male with chronic hepatitis B virus-associated cirrhosis and unresectable hepatocellular carcinoma (HCC) presented to the Interventional Radiology Unit for TACE to achieve tumor necrosis. Following the procedure, the patient was admitted with symptoms of fever, epigastric and right upper quadrant pain secondary to the development of an abscess. The abscess was drained; however, an exceedingly rare HGF resulted that was favored to represent a direct invasion of HCC. HGF, the rare complication following TACE, leads to grave consequences and vigilant monitoring, for the development of this entity is recommended to reduce patient mortality. We present a case and literature review of HGF development following TACE for HCC.
- Association of Polymorphism in MicroRNA 604 with Susceptibility to Persistent Hepatitis B Virus Infection and Development of Hepatocellular Carcinoma. [JOURNAL ARTICLE]
- J Korean Med Sci 2014 Nov; 29(11):1523-1527.
MicroRNA polymorphisms may be associated with carcinogenesis or immunopathogenesis of infection. We evaluated whether the mircoRNA-604 (miR-604) polymorphism can affect the persistence of hepatitis B virus (HBV) infection, and the development to hepatocellular carcinoma (HCC) in patients with chronic HBV infection. A total of 1,439 subjects, who have either past or present HBV infection, were enrolled and divided into four groups (spontaneous recovery, chronic HBV carrier without cirrhosis, liver cirrhosis and HCC). We genotyped the precursor miR-604 genome region polymorphism. The CC genotype of miR-604 rs2368392 was most frequently observed and T allele frequency was 0.326 in all study subjects. The HBV persistence after infection was higher in those subjects with miR-604 T allele (P=0.05 in a co-dominant and dominant model), which implied that the patients with miR-604 T allele may have a higher risk for HBV chronicity. In contrast, there was a higher rate of the miR-604 T allele in the chronic carrier without HCC patients, compared to those of the HCC patients (P=0.03 in a co-dominant model, P=0.02 in a recessive model). The T allele at miR-604 rs2368392 may be a risk allele for the chronicity of HBV infection, but may be a protective allele for the progression to HCC in chronic HBV carriers.
- Enhanced Levels of Interleukin-8 Are Associated with Hepatitis B Virus Infection and Resistance to Interferon-Alpha Therapy. [JOURNAL ARTICLE]
- Int J Mol Sci 2014; 15(11):21286-21298.
The objective of this study was to analyze the expression levels of IL-8 in serum and liver tissues from patients with chronic hepatitis B (CHB) infection and to investigate whether IL-8 may antagonize interferon-alpha (IFN-α) antiviral activity against HBV. IL-8 expression in serum was determined by enzyme linked immunosorbent assay (ELISA), and fluorescence-based quantitative real-time PCR (RT-qPCR) was used to measure IL-8 mRNA in peripheral blood mononuclear cells (PBMCs) in patients with CHB. IL-8 protein expression was detected in liver biopsy tissues by immunohistochemistry. In addition, the differences in serum IL-8 and PBMCs mRNA levels were also observed in patients with different anti-viral responses to IFN-α. Compared to normal controls, serum IL-8 protein and mRNA levels were increased in CHB patients, IL-8 levels were positively correlated with the severity of liver inflammation/fibrosis. Moreover, serum IL-8 protein and mRNA levels were positively correlated with serum alanine aminotransferase (ALT) level and negatively correlated with serum prealbumin (PA) level. IL-8 expression was mainly located in portal area of liver tissues and was increased with the severity of liver inflammation and fibrosis stage. The expression serum and mRNA levels of IL-8 in the CHB patients with a complete response to IFN-α are significantly lower than that of the patients with non-response to IFN-α treatment. It is suggested that IL-8 might play important roles in the pathogenesis of CHB. Moreover, interferon resistance may be related to the up-regulation of IL-8 expression in the patients did not respond to IFN-α treatment.
- [Private companies: an opportunity for hepatitis B virus (HBV) prevention and care in Ivory Coast in the wake of HIV/AIDS?] [JOURNAL ARTICLE]
- Bull Soc Pathol Exot 2014 Nov 18.
In the 1990s, defenders of "aids exceptionnalism" have promised that the inequities caused by HIV/AIDS could provide leverage in the care of other health issues later. Fifteen years later, this argument can be rethought at the light of the current context of hepatitis B virus (HBV) in Ivory Coast. In fact, in this country, the challenges caused by HBVecho those of HIV/AIDS fifteen years ago: high prevalence (8-10%), ignorance of the disease, and high cost of care. To this end, this article compares the role of private companies in the fights against HIV/AIDS in the 2000s and its role in the fight against HBV today. Although some private firms played a critical role in the promotion of universal access to ART, today, they are one of the few places where HBV screening, vaccination and treatment are offered in the country. HIV/AIDS opened the door for private companies to address other diseases through their health care systems. However, many challenges still need to be met: the absence of qualitative ongoing training for health professionals, illness representations and the costs of treatments, which are all related to the lack of international and national collective action. In Ivory Coast, at the early stage of the HIV/AIDS epidemic, national authorities took up the leadership in the fight against AIDS in West Africa, by developing extraverted strategies (Xth ICASA's organization, Unaids initiative hosting). The exceptional international mobilization and the creation of innovative funding mechanisms [International Therapeutic Solidarity Fund (ITSF), Global Fund (GM), and President's Emergency Plan for AIDS Relief (PEPFAR)] have facilitated easy access to ARV. Although 380 million people are infected by chronic HBV in the world, even so, international and national collective actions are fledgling and remained weak. Moreover, private firms have represented leverage for testing, treatment, and the provision of universal access to medication in the context of the HIV/AIDS epidemic in Ivory Coast, as relayed by other public and private actors. In the HBV context, private companies can only be a vector for the development of a two tier healthcare system. Therefore, the lack of a strong international commitment prevents public and private local initiatives to generalize HBV prevention and treatment.
- In vitro Immunomodulatory Activity of Oxymatrine on Toll-Like Receptor 9 Signal Pathway in Chronic Hepatitis B. [JOURNAL ARTICLE]
- Am J Chin Med 2014 Nov 19.:1-12.
Oxymatrine, extracted from the herb Sophora alopecuraides L., was investigated to determine its anti-HBV immunomodulatory mechanism in vitro. Human peripheral lymphocytes were isolated from heparinized whole blood from 48 chronic hepatitis B (CHB) patients. The lymphocytes from each patient were divided into two groups according to pretreatment or no pretreatment with Oxymatrine in vitro. We examined the changes of expression and function of the toll-like receptor 9 (TLR9) signal transduction pathway in the peripheral lymphocytes with different treatment methods and investigated the synergism of Oxymatrine and the TLR9 ligand on antiviral cytokine secretions in vitro. The data showed Oxymatrine could induce antiviral cytokine secretions directly from the peripheral lymphocytes. For the TLR9 signal pathway, Oxymatrine not only augmented the expressions of TLR9 signal transduction molecules, but also activated the TLR9 signal function. This study has clearly demonstrated that TLR9 ligand could stimulate peripheral lymphocytes that have been pretreated with Oxymatrine. Furthermore, the quantity of antiviral cytokines secreted by the pretreated lymphocytes was greater than that of those without pretreatment. The interaction between the Oxymatrine and the TLR9 ligand appears to be synergistic. This study suggests Oxymatrine could be a strong immunomodulator, influence TLR9 signaling transduction, and synergistically improve the immune efficacy of the TLR9 ligand against CHB.
- BAsE-Seq: a method for obtaining long viral haplotypes from short sequence reads. [JOURNAL ARTICLE]
- Genome Biol 2014 Nov 19; 15(11):517.
We present a method for obtaining long haplotypes, of over 3 kb in length, using a short-read sequencer, Barcode-directed Assembly for Extra-long Sequences (BAsE-Seq). BAsE-Seq relies on transposing a template-specific barcode onto random segments of the template molecule and assembling the barcoded short reads into complete haplotypes. We applied BAsE-Seq on mixed clones of Hepatitis B virus and accurately identified haplotypes occurring at frequencies greater than or equal to 0.4%, with >99.9% specificity. Applying BAsE-Seq to a clinical sample, we obtained over 9,000 viral haplotypes, which provided an unprecedented view of Hepatitis B virus population structure during chronic infection. BAsE-Seq is readily applicable for monitoring quasispecies evolution in viral diseases.