Xue-Gong Fan

Management of mother-to-child transmission of hepatitis B virus: Propositions and challenges

Chronic hepatitis B virus (HBV) infection due to mother-to-child transmission (MTCT) during perinatal period remains an important global health problem. Despite standard passive-active immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine in neonates, up to 9% of newborns still acquire HBV infection, especially these from hepatitis B e antigen (HBeAg) positive mothers. Management of HBV infection in pregnancy still need to draw careful attention because of some controversial aspects, including the failure of passive-active immunoprophylaxis in a fraction of newborns, the effect and necessity of periodical hepatitis B immunoglobulin (HBIG) injection to the mothers, the safety of antiviral prophylaxis with nucleoside/nucleotide analogs, the benefit of different delivery ways, and the safety of breastfeeding. In this review, we highlight these unsettled issues of preventive strategies in perinatal period, and we further aim to provide an optimal approach to the management of preventing MTCT of HBV infection.

Detection of hepatitis B surface antigen, hepatitis B core antigen, and hepatitis B virus DNA in parotid tissues

OBJECTIVE To examine the presence of hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), and hepatitis B virus (HBV) DNA in parotid tissues from patients with positive serum HBV markers. METHODS HBsAg and HBcAg were examined in parotid biopsy tissues from patients with suspected parotid tumor and positive serum HBV markers by immunocytochemistry, and HBV DNA was detected in parotid tissues by PCR. RESULTS Among the 22 patients with a parotid tumor, only one was pathologically confirmed as a neoplasm; all others were benign. HBsAg and HBcAg were present in parotid cells with positive rates of 45.5% (10/22) and 40.9% (9/22), respectively, with an overall positive rate of 54.5% (12/22). Of the 22 cases with serum markers of HBV infection, seven (31.8%) had both HBsAg and HBcAg in the parotid cells. HBV DNA was present in seven of the 12 samples in which hepatitis B antigen was detected (58.3%). CONCLUSIONS HBV in saliva might originate from the infected salivary glands and the infectious saliva could transmit HBV.

Replication and infectivity of hepatitis B virus in HBV-related glomerulonephritis.

OBJECTIVE To examine the presence of hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), and hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in renal tissues from patients with HBV-related glomerulonephritis. METHODS Renal tissue biopsies taken from patients with HBV-related glomerulonephritis and two control groups were prepared for immunocytochemical detection of HBsAg and HBcAg. HBV cccDNA was examined using a nested PCR. RESULTS Of the 63 HBV-related glomerulonephritis patients studied, HBsAg was present in the renal tissues of 48 (76.2%) and HBcAg in the renal tissues of 27 (42.9%). The HBsAg and HBcAg positive rates in HBV-related glomerulonephritis patients were higher than those of the 20 patients with non-HBV-related glomerulonephritis (p<0.05). However, there was no significant difference when the HBV-related glomerulonephritis patients were compared with 12 patients with renal tuberculosis, renal atrophy, renal calculus, and renal tumor with positive serum HBV markers. In patients with HBV-related glomerulonephritis, there was no significant difference in HBsAg and HBcAg positive rates in renal tissue between patients with and without serum hepatitis B e antigen (HBeAg). By nested PCR, two of five patients with HBV-related glomerulonephritis were positive for HBV cccDNA. CONCLUSION The location and replication of HBV in renal tissue make the kidney a potential reservoir for HBV. HBV cccDNA may be key in the search for anti-HBV drugs.

The FOXM1-ABCC5 axis contributes to paclitaxel resistance in nasopharyngeal carcinoma cells.

Paclitaxel is clinically used as a first-line chemotherapeutic regimen for several cancer types, including head and neck cancers. However, acquired drug resistance results in the failure of therapy, metastasis and relapse. The drug efflux mediated by ATP-binding cassette (ABC) transporters and the survival signals activated by forkhead box (FOX) molecules are critical in the development of paclitaxel drug resistance. Whether FOX molecules promote paclitaxel resistance through drug efflux remains unknown. In this study, we developed several types of paclitaxel-resistant (TR) nasopharyngeal carcinoma (NPC) cells. These TR NPC cells acquired cancer stem cell (CSC) phenotypes and underwent epithelial to mesenchymal transition (EMT), and developed multidrug resistance. TR cells exhibited stronger drug efflux than parental NPC cells, leading to the reduction of intracellular drug concentrations and drug insensitivity. After screening the gene expression of ABC transporters and FOX molecules, we found that FOXM1 and ABCC5 were consistently overexpressed in the TR NPC cells and in patient tumor tissues. Further studies demonstrated that FOXM1 regulated abcc5 gene transcription by binding to the FHK consensus motifs at the promoter. The depletion of FOXM1 or ABCC5 with siRNA significantly blocked drug efflux and increased the intracellular concentrations of paclitaxel, thereby promoting paclitaxel-induced cell death. Siomycin A, a FOXM1 inhibitor, significantly enhanced in vitro cell killing by paclitaxel in drug-resistant NPC cells. This study is the first to identify the roles of FOXM1 in drug efflux and paclitaxel resistance by regulating the gene transcription of abcc5, one of the ABC transporters. Small molecular inhibitors of FOXM1 or ABCC5 have the potential to overcome paclitaxel chemoresistance in NPC patients.

Hepatitis B virus X protein inhibits apoptosis by modulating endoplasmic reticulum stress response

Chronic Hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC) worldwide. Hepatitis B virus X protein (HBx) is encoded by one of the four open reading frames of HBV, and is well known as an important coactivator for HBV replication and HBV-associated hepatocellular carcinogenesis. However, its role in keeping cells from apoptosis to promote HCC proliferation remains controversial. Here, we used HBx expressing HCC cells as a model, to investigate the mechanism of HBx-mediated cellular response to endoplasmic reticulum (ER) stress. We found that HBx protein was localized in ER lumen and interacted with GRP78 directly. This interaction resulted in suppression of eIF2α phosphorylation, inhibited expression of ATF4/CHOP/Bcl-2, and reduced cleavage of poly ADP-ribose polymerase (PARP) and level of γH2AX, thus preventing HCC cells from cell death and negatively regulating DNA repair. This study reveals a novel mechanism of the HBx-mediated oncogenesis and provides a basis for potential HBx-targeted therapeutic intervention of HCC.

SPAG5 promotes proliferation and suppresses apoptosis in bladder urothelial carcinoma by upregulating Wnt3 via activating the AKT/mTOR pathway and predicts poorer survival

Sperm-associated antigen 5 (SPAG5) is involved in various biological processes. However, the roles of SPAG5 in bladder urothelial carcinoma (BUC) are unknown. This study showed that upregulation of SPAG5 was detected frequently in primary BUC tissues, and was associated with significantly worse survival among the 112 patients that underwent radical cystectomy (RC). Up and downregulating the expression of SPAG5 enhanced or inhibited, respectively, the proliferation of BUC cells in vitro and in vivo, and suppressed or enhanced, respectively, apoptosis in vitro and in vivo. Moreover, SPAG5 increased the resistance of BUC cells to chemotherapy-induced apoptosis. Mechanistic investigations showed that SPAG5 promotes proliferation and suppresses apoptosis in BUC at least partially via upregulating Wnt3 through activating the AKT/mTOR signaling pathway. The importance of the SPAG5/AKT-mTOR/Wnt3 axis identified in BUC cell models was confirmed via immunohistochemical analysis of a cohort of human BUC specimens that underwent RC. Collectively, our data suggested that in patients with BUC who underwent RC, high SPAG5 expression is associated with poor survival. In addition, targeting SPAG5 might represent a novel therapeutic strategy to improve the survival of patients with BUC.

The Association between Helicobacter pylori Infection and Chronic Hepatitis C: A Meta-Analysis and Trial Sequential Analysis

Purpose. Helicobacter pylori is a common gastric disease-inducing pathogen. Although an increasing number of recent studies have shown that H. pylori is a risk factor for liver disease, the potential association between H. pylori infection and chronic hepatitis C still remains controversial. The aim of our meta-analysis was to evaluate a potential association between H. pylori infection and chronic hepatitis C. Methods. We searched the PubMed, Embase, CNKI, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases between January 1, 1994, and May 1, 2015. Results. This study included a total of 1449 patients with chronic hepatitis C and 2377 control cases. The prevalence of H. pylori was significantly higher in patients with chronic hepatitis C than in those without chronic hepatitis C. The pooled odds ratio was 2.93. In a subgroup analysis, the odds ratios were 4.48 for hepatitis C virus- (HCV-) related cirrhosis and 5.45 for hepatocellular carcinoma. Conclusion. Our study found a strong association between H. pylori and chronic hepatitis C, particularly during the HCV progression stage; thus, we recommend active screening for H. pylori in patients with chronic hepatitis C.

Helicobacter pylori infection may increase the risk of progression of chronic hepatitis B disease among the Chinese population: a meta-analysis

OBJECTIVES Helicobacter pylori is a bacterium that infects over 50% of the human population worldwide. An increasing number of studies have demonstrated that H. pylori may cause liver diseases, and the underlying relationship between H. pylori infection and chronic hepatitis B has attracted much attention. This study aimed to examine the association between H. pylori infection and the progression of chronic hepatitis B in the Chinese population. METHODS A search was performed of the PubMed/MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, as well as the Chinese databases, China National Knowledge Infrastructure and Wanfang Data, for studies published between January 1, 1994 and November 1, 2015. RESULTS In total, 2977 patients were included in the chronic hepatitis B group, while 1668 participants were included in the healthy control group. The prevalence of H. pylori among patients with chronic hepatitis B was significantly higher than that among those without chronic hepatitis B. The pooled odds ratio was 3.17. In the subgroup analysis, the odds ratio was 4.28 for hepatitis B virus (HBV)-related cirrhosis and 6.02 for hepatocellular carcinoma. CONCLUSION These results indicate a strong relationship between H. pylori and chronic hepatitis B, particularly during HBV progression.

Crosstalk between hepatitis B virus X and high‐mobility group box 1 facilitates autophagy in hepatocytes

Hepatitis B virus (HBV) X (HBx) protein is a pivotal regulator of HBV‐triggered autophagy. However, the role of HBx‐induced epigenetic changes in autophagy remains largely unknown. The cytoplasmic (Cyt) high‐mobility group box 1 (HMGB1) has been identified as a positive regulator of autophagy, and its Cyt translocation is closely associated with its acetylation status. Here, we evaluated the function of HMGB1 in HBx‐mediated autophagy and its association with histone deacetylase (HDAC). Using cell lines with enforced expression of HBx, we demonstrated that HBx upregulated the expression of HMGB1 and promoted its Cyt translocation by acetylation to facilitate autophagy. We further identified the underlying mechanism by which decreased nuclear HDAC activity and expression levels contribute to the HBx‐promoted hyperacetylation and subsequent translocation of HMGB1. We also identified the HDAC1 isoform as a critical factor in regulating this phenomenon. In addition, HBx bound to HMGB1 in the cytoplasm, which triggered autophagy in hepatocytes. Pharmacological inhibition of HMGB1 Cyt translocation with ethyl pyruvate prevented HBx‐induced autophagy. These results demonstrate a novel function of acetylated HMGB1 in HBx‐mediated autophagy in hepatocytes.

The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis

Background and aim Besides regulating lipid metabolism, statins have garnered considerable interest because of their antiviral and antineoplastic properties. The potential benefit of statins using in chronic hepatitis C (CHC) patients is not well described. This meta-analysis was carried out to quantitatively assess the efficacy of statins in improving the therapeutic effect and prognosis of patients with CHC. Patients and methods We searched electronic databases for relevant studies comparing the course of benefit in CHC patients with statins versus without statins. Risk estimates were pooled to assess the association of statins use with sustained virological response and the prognosis of CHC patients. Results Twenty-three studies fulfilled the inclusion criteria. Meta-analysis of 16 homogeneous studies showed that the sustained virological response rate increased by 31% [relative risk (RR)=1.31; 95% confidence interval (CI): 1.23–1.39] in 12 791 CHC patients with statins as an adjuvant under the general antiviral therapy compared with those without this adjuvant therapy. Moreover, meta-analysis of seven studies suggested that statins was beneficial on several specific poor outcomes of CHC patients (RR=0.49; 95% CI: 0.42–0.56). CHC patients with statin use were found to be inversely associated with a 55% reduced risk of hepatocellular carcinoma (RR=0.45; 95% CI: 0.36–0.57) and 53% reduced risk of cirrhosis (RR=0.47; 95% CI: 0.33–0.67) as well as 44% reduced risk of mortality (RR=0.56; 95% CI: 0.46–0.69). However, significant heterogeneity and publication bias were present in some of our analyses. Conclusion Beneficial effects of statins use were found in the therapy and the prognosis of CHC patients. Further prospective studies are still needed to confirm these benefits.