Feng Peng

HBx down-regulated Gld2 plays a critical role in HBV-related dysregulation of miR-122.

miR-122 is a liver-rich-specific microRNA that plays an important role in hepatic gene expression via post-transcription regulation, and it is potentially associated with the development of hepatocellular carcinoma. It has been confirmed that miR-122 is down-regulated during HBV infection; however, how HBV affects miR-122 is still debated. One research provided evidence that HBx could reduce the miR-122 transcription level, but the other insisted that HBV had no significant effect on miR-122 transcription level but reduce miR-122 level via binding and sequestering endogenous miR-122. It is determinate that Gld2 could increase the specific miRNA stabilization by monoadenylation which was a post-transcription regulation. In this study, we aimed to investigate the mechanism of HBV-induced reduction of miR-122 and examine whether Gld2 is involved in it. According to the results of a microRNA microarray, we found miR-122 was the most down-regulated microRNA in HepG2.2.15 compared to HepG2. As revealed by qRT-PCR and western blotting analyses, both miR-122 and Gld2 levels were reduced in hepatic cell lines with expression of HBV or HBx but not other proteins of HBV, and over-expression of Gld2 could abolish the effect of HBV and HBx on the miR-122 level. Whats more, both HBV and HBx have no significant effect on pre-miR-122 levels. And the dual-luciferase assay implicated that HBx could reduce the Gld2 promoter activity but had no significant effect on miR-122 promoter activity. In conclusion, HBx is a critical protein derived from HBV, which regulates miR-122 via down-regulating Gld2.

Hepatitis C virus NS5A drives a PTEN‐PI3K/Akt feedback loop to support cell survival

Decreased levels of phosphatase and tensin homologue (PTEN) are associated with hepatocellular carcinoma (HCC) pathogenesis and poor prognosis in hepatitis C virus (HCV)‐infected HCC patients. The molecular processes governing the reduction in PTEN and outcome of PTEN dysfunction in hepatocytes are poorly understood.

HBx promotes cell proliferation by disturbing the cross-talk between miR-181a and PTEN.

Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the mechanism is still needed to be elucidated. In this study, we explored the relationship between HBx and microRNA and their roles in hepato-carcinogenesis. Firstly, by global microarray-based microRNA profiling and qRT-PCR, we found miR-181a was strongly up-regulated in HepG2.2.15 cells (HBV positive) and pHBV1.3-expressing HepG2 cells, and HBx played a major role in it. Secondly, reduced PTEN protein expression in the presence of HBx was aslo mediated by miR-181a, and in the Luciferase reporter system, miR-181a inhibited the PTEN translation by binding the PTEN 3′-untranslated-region (UTR), and PTEN protein was decreased when epigenetic expression of miR-181a and rescued by knocking down miR-181a. Finally, HBx interrupted the balance between apoptosis and proliferation, which contributed to the development of hepatocellular carcinoma, was also related to the interaction of miR-181a and PTEN. Taken together, we presented here a novel cross-talk between miR-181a and PTEN which was raised by HBx, and this shined a new line in HBV-related hepato-carcinogenesis.

Clinical features in different age groups of patients with autoimmune hepatitis

The Chinese population are at an increased risk of autoimmune hepatitis (AIH). The aims of this study were to determine the demographic and clinical features of AIH in China. A total of 83 patients with AIH diagnosed by the revised scoring system were re-analyzed, and the clinical presentations among the different ages were compared. The patients were classified according to age at presentation. AIH occurred in patients aged ≤30 years (9.6%), 31–39 years (10.8%), 40–49 years (16.9%), 50–59 years (31.3%) and ≥60 years (31.3%). There were no differences in the form of the clinical presentation, concurrent autoimmune diseases, cirrhosis distribution and autoantibodies among the groups. However, patients aged ≥60 years presented with higher levels of alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GT) compared with patients aged ≤30 years (P=0.034, P=0.043, respectively), and patients aged 31–39 years had a significantly lower immunoglobulin G (IgG) level compared with those aged 50–59 years (P=0.049) and those aged ≥60 years (P=0.012). By contrast, patients aged ≤30 years had a significantly higher total bilirubin (TBIL) level compared with those aged 31–39 years (P=0.007), 50–59 years (P=0.002) and ≥60 years (P=0.013). A substantial portion of patients with AIH were aged >60 years, indicating a poor liver-associated outcome under current management strategies. Elderly patients appeared to be more asymptomatic compared with the younger patients.

Artesunate, an anti-malarial drug, has a potential to inhibit HCV replication.

Hepatitis C virus (HCV) infection is a major global health issue. Although the search for HCV treatments has resulted in great achievements, the current treatment methods have limitations, and new methods and drugs for hepatitis C treatment are still required. The aim of the present study was to investigate the effects of artesunate (ART) on HCV replication and compared these effects with those of ribavirin (RBV) and interferon-2b (IFN). The study was performed in HCV-infection cell models (JFH1-infected Huh7.5.1 and OR6 cell lines). Our results showed that the antimalarial drug ART inhibited HCV replicon replication in a dose- and time-dependent manner at a concentration that had no effect on the proliferation of exponentially growing host cells, and the inhibitory effect on HCV replication was stronger than RBV but weaker than IFN, as determined by qPCR, luciferase assays, and Western blot analysis. Furthermore, the combination of ART and IFN resulted in a greater inhibition of HCV replication. These findings demonstrated that ART had an inhibitive effect on HCV replication and may be a novel supplemental co-therapy with IFN and RBV for HCV and as an alternative strategy to combat resistance mechanisms that have emerged in the presence of DAA agents.

Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells

The HBx protein of hepatitis B virus (HBV) is widely recognized to be a critical oncoprotein contributing to the development of HBV-related hepatocellular carcinoma (HCC). In addition, cationic amino acid transporter 1 (CAT-1) gene is a target of miR-122. In this study, we found that CAT-1 protein levels were higher in HBV-related HCC carcinomatous tissues than in para-cancerous tumor tissues, and that CAT-1 promoted HCC cell growth, proliferation, and metastasis. Moreover, HBx-induced decreases in Gld2 and miR-122 levels that contributed to the upregulation of CAT-1 in HCC. These results indicate that a Gld2/miR-122/CAT-1 pathway regulated by HBx likely participates in HBV-related hepatocellular carcinogenesis.The HBx protein of hepatitis B virus (HBV) is widely recognized to be a critical oncoprotein contributing to the development of HBV-related hepatocellular carcinoma (HCC). In addition, cationic amino acid transporter 1 (CAT-1) gene is a target of miR-122. In this study, we found that CAT-1 protein levels were higher in HBV-related HCC carcinomatous tissues than in para-cancerous tumor tissues, and that CAT-1 promoted HCC cell growth, proliferation, and metastasis. Moreover, HBx-induced decreases in Gld2 and miR-122 levels that contributed to the upregulation of CAT-1 in HCC. These results indicate that a Gld2/miR-122/CAT-1 pathway regulated by HBx likely participates in HBV-related hepatocellular carcinogenesis.

HIV Vpr protein upregulates microRNA-122 expression and stimulates hepatitis C virus replication

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection is characterized by higher serum HCV RNA loads compared with HCV mono-infection. However, the relationship between HIV and HCV replication remains to be clarified. HIV Vpr has been shown to play an essential role in HIV replication. In this study, we aimed to explore the role of Vpr in HCV replication and pathogenesis. We therefore used the genotype 2a full-length HCV strain JFH1 infection system and the genotype 1b full-length HCV replicon OR6 cell line to analyse the effects of Vpr on HCV replication. We found that Vpr promoted HCV 5′ UTR activity, HCV RNA replication and HCV protein expression in two HCV infection cell models. Additionally, lymphocyte-produced Vpr significantly induced HCV 5′ UTR activity and HCV replication in hepatocytes. We also found that Vpr upregulated the expression of miR-122 by stimulating its promoter activity. Furthermore, an miR-122 inhibitor suppressed the Vpr-mediated enhancement of both HCV 5′ UTR activity and HCV replication. In summary, our results revealed that the Vpr-upregulated expression of miR-122 is closely related to the stimulation of HCV 5′ UTR activity and HCV replication by Vpr, providing new evidence for how HIV interacts with HCV during HIV/HCV co-infection.

Diagnosis and management of fulminant Wilson’s disease: a single center’s experience

BackgroundMedical therapy is rarely effective in patients with fulminant Wilson’s disease (FWD). Liver transplantation is limited by the lack of donor liver in most patients with FWD at the time of diagnosis. New Wilson’s index, model for end-stage liver disease (MELD) and Child-Pugh score are useful tools for decision-making of liver transplantation; however, none of them is an independent decisive tool. It is worthwhile to explore a more effective and practical therapeutic strategy and reevaluate the prediction systems for patients with FWD.MethodsNine patients with FWD associated with hemolytic crisis and fulminant hepatic failure (FHF) were investigated. The clinical presentation, prognostic score and medical therapies of the patients were analyzed.ResultsIn 7 of the 9 patients with FWD who received the comprehensive therapy of corticosteroid, copper-chelating agent (dimercaptopropansulfonate sodium) and therapeutic plasma exchange (TPE), 6 patients recovered from FHF. The remaining one had been improved through the comprehensive therapy but died of septicemia 51 days later. Two patients with spontaneous bacterial peritonitis (SBP) died from liver failure in three or five hospital days without plasma exchange or chelating therapy. All of the 9 patients with FWD presented with acute hepatic failure, severe jaundice and mild to severe hemolytic anemia. No marked difference in the incidence of severe hemolytic anemia was detected between the survival and deceased groups. However, the incidence and the degree of hepatic encephalopathy (HE) in the non-survival group were higher than those in the survival group. Unlike the deceased group, the survival group had no complications induced by bacterial infection. Compared to new Wilson’s index, Child-Pugh score and MELD score, the variation of prothrombin activity (PTA) between the survival and deceased groups was more evident.ConclusionFor patients with FWD, the episode of severe hepatic encephalopathy or/and spontaneous bacterial peritonitis indicates worse prognosis, and PTA is a recommendable predictor. An emergent liver transplantation should be considered for patients whose PTA is below 20%, or for those with severe HE or/and SBP. The comprehensive therapy of corticosteroid, copper-chelating agent and TPE is effective for patients without SBP and whose PTA is higher than 20%.

Genotype distribution of hepatitis C virus in 952 cases from 2014 to 2016 in Hunan Province, China

Introduction Few large-scale investigations on genotype (GT) distribution of hepatitis C virus (HCV) in Hunan Province, China, are reported. Material and methods We recruited all of the 952 patients in the census register of Hunan Province who were first diagnosed with HCV infection in the Second Xiangya Hospital, Central South University in 2014–2016. HCV genotypes were surveyed. The genotype distribution pattern was compared with those of the neighboring regions in China. Results Among the 952 patients, genotype 1 (GT1) (69.9%) was the most common HCV genotype, followed by GT6 (19.0%), GT3 (8.4%), and GT2 (2.6%). GT4 and GT5 were not found. One case had mixed infection of GT3 and GT6. Predominance of GT1 HCV was more evident in the patients aged ≥ 40 years than in those aged < 40 years (79.5% vs. 47.9%, χ2 = 95.993, p < 0.001). HCV genotype distribution had gender difference (χ2 = 44.695, p < 0.001), with GT3 and GT6 more prevalent in males than in females (36.2% vs. 18.2%, χ2 = 39.088, p < 0.001) while GT1 more prevalent in females than in males (80.1% vs. 60.3%, χ2 = 44.276, p < 0.001). Though Hunan Province is located in central China, its HCV genotype priority was similar with the change trend in south and southwest China, while distinguished from those of other regions, in particular from the neighboring central province, Hubei Province. Conclusions HCV GT1 was the most predominant HCV genotype in Hunan Province, and GT6 and GT3 accounted for a significant percentage, especially in young patients. The HCV distribution pattern was more similar to those of the regions in south China.