Search Results (7)

In this study, we detected 12 duck and 11 goose flocks that were positive for duck hepatitis B virus (DHBV) using polymerase chain reaction and isolated 23 strains between 2020 and 2022 in China. The complete genomes of goose strains E200801 and E210501 shared the highest identity (99.9%), whereas those of strains Y220217 and E210526 shared the lowest identity (91.39%). The phylogenetic tree constructed based on the genome sequences of these strains and reference strains was classified into three major clusters: the Chinese branch DHBV-I, the Chinese branch DHBV-II, and the Western branch DHBV-III. Furthermore, the duck-origin strain Y200122 was clustered into a separate branch and was predicted to be a recombinant strain derived from DHBV-M32990 (belonging to the Chinese branch DHBV-I) and Y220201 (belonging to the Chinese branch DHBV-II). Additionally, preS protein analysis of the 23 DHBV strains revealed extensive mutation sites, almost half of which were of duck origin. All goose-origin DHBV contained the mutation site G133E, which is related to increased viral pathogenicity. These data are expected to promote further research on the epidemiology and evolution of DHBV. Continuing DHBV surveillance in poultry will enhance the understanding of the evolution of HBV. Full article

In cancer, antigen-presenting cells (APC), including dendritic cells (DCs), take up and process proteins to mount adaptive antitumor immune responses. This often happens in the context of inflamed cancer, where reactive oxygen species (ROS) are ubiquitous to modify proteins. However, the inflammatory consequences of oxidized protein uptake in DCs are understudied. To this end, we investigated human monocyte-derived cell surface marker expression and cytokine release profiles when exposed to oxidized and native proteins. Seventeen proteins were analyzed, including viral proteins (e.g., CMV and HBV), inflammation-related proteins (e.g., HO1 and HMGB1), matrix proteins (e.g., Vim and Coll), and vastly in the laboratory used proteins (e.g., BSA and Ova). The multifaceted nature of inflammation-associated ROS was mimicked using gas plasma technology, generating reactive species cocktails for protein oxidation. Fourteen oxidized proteins led to elevated surface marker expression levels of CD25, CD40, CD80, CD86, and MHC-II as well as strongly modified release of IL6, IL8, IL10, IL12, IL23, MCP-1, and TNFα compared to their native counterparts. Especially IL8, heme oxygenase 2, and vimentin oxidation gave pronounced effects. Furthermore, protein kinase phospho-array studies in monocyte-derived cells pulsed with native vs. oxidized IL8 and insulin showed enhanced AKT and RSK2 phosphorylation. In summary, our data provide for the first time an overview of the functional consequences of oxidized protein uptake by human monocyte-derived cells and could therefore be a starting point for exploiting such principle in anticancer therapy in the future. Full article

Some infants born to hepatitis B surface antigen (HBsAg)-positive mothers, especially born to hepatitis B e antigen (HBeAg)-positive mothers, can still be infected with hepatitis B virus (HBV) through mother-to-child transmission (MTCT) of HBV and develop chronic HBV infection. At present, the virological factors affecting HBV MTCT are still unclear. In this study, we found that the mutation rates of amino acids in the HBV X region were high, and there were obvious differences between the immunoprophylaxis success group and the immunoprophylaxis failure group of HBeAg-positive mothers. Specifically, the mutation rate of HBx 128–133 deletion (x128–133del) or corresponding nucleotide 1755–1772 deletion (nt1755–1772del) in the immunoprophylaxis success group was significantly higher than that in the immunoprophylaxis failure group. Furthermore, we found that x128–133del could weaken HBV replication by reducing the level of the HBx protein due to the increased proteasome-dependent degradation of HBx protein, and the transcriptional activity of HBV core promoter (CP)/enhancer II (ENII) due to the attenuated binding capacity of hepatocyte nuclear factor 4α (HNF4α) to HBV CP/ENII. This study suggests that x128–133del may contribute to immunoprophylaxis success, which may be helpful in clarifying the virological mechanism affecting HBV MTCT and formulating an optimal immunization strategy for children born to HBeAg-positive mothers. Full article

Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in Escherichia coli at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance. Full article

Hepatitis B virus (HBV) replication is controlled by four promoters (preS1, preS2, Cp, and Xp) and two enhancers (EnhI and EnhII). EnhII stimulates Cp activity to regulate the transcriptions of precore, core, polymerase, and pregenomic RNAs, and therefore, EnhII/Cp is essential for the regulation of HBV replication. This study revealed a distinct mechanism underlying the suppression of EnhII/Cp activation and HBV replication. On the one hand, the sex determining region Y box2 (SOX2), a transcription factor, is induced by HBV. On the other hand, SOX2, in turn, represses the expression levels of HBV RNAs, HBV core-associated DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg), thereby playing an inhibitory role during HBV replication. Further studies indicated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation. With the deletion of the high mobility group (HMG) domain, SOX2 loses the ability to repress EnhII/Cp activation, viral RNA transcription, HBV core-associated DNA replication, HBsAg and HBeAg production, as well as fails to enter the nucleus, demonstrating that the HMG domain is required for the SOX2-mediated repression of HBV replication. Moreover, SOX2 represses HBsAg and HBeAg secretion in BALB/c mice sera, and attenuates HBV 3.5 kb RNA transcription and hepatitis B virus core protein (HBc) production in the liver tissues, demonstrating that SOX2 suppresses HBV replication in mice. Furthermore, the results revealed that the HMG domain was required for SOX2-mediated repression of HBV replication in the mice. Taken together, the above facts indicate that SOX2 acts as a new host restriction factor to repress HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation through the HMG domain. Full article

Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively. Full article

Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC. Full article