ERK1/2-HNF4α axis is involved in epigallocatechin-3-gallate inhibition of HBV replication.

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, exhibits diverse biological activities. Previous studies show that EGCG could effectively suppress HBV gene expression and replication, but the role of EGCG in HBV replication and its underlying mechanisms, especially the signaling pathways involved, remain unclear. In this study we investigated the mechanisms underlying EGCG inhibition on HBV replication with a focus on the signaling pathways. We showed that EGCG (12.5-50 µM) dose-dependently inhibited HBV gene expression and replication in HepG2.2.15 cells. Similar results were observed in HBV mice receiving EGCG (25 mg· kg-1· d-1, ip) for 5 days. In HepG2.2.15 cells, we showed that EGCG (12.5-50 µM) significantly activate ERK1/2 MAPK signaling, slightly activate p38 MAPK and JAK2/STAT3 signaling, while had no significant effect on the activation of JNK MAPK, PI3K/AKT/mTOR and NF-κB signaling. By using specific inhibitors of these signaling pathways, we demonstrated that ERK1/2 signaling pathway, but not other signaling pathways, was involved in EGCG-mediated inhibition of HBV transcription and replication. Furthermore, we showed that EGCG treatment dose-dependently decreased the expression of hepatocyte nuclear factor 4α (HNF4α) both at the mRNA and protein levels, which could be reversed by pretreatment with the ERK1/2 inhibitor PD98059 (20 µM). Moreover, we revealed that EGCG treatment dose-dependently inhibited the activity of HBV core promoter and the following HBV replication. In summary, our results demonstrate that EGCG inhibits HBV gene expression and replication, which involves ERK1/2-mediated downregulation of HNF4α.These data reveal a novel mechanism for EGCG to inhibit HBV gene expression and replication.

Stable solar-driven oxidation of water by semiconducting photoanodes protected by transparent catalytic nickel oxide films.

Reactively sputtered nickel oxide (NiOx) films provide transparent, antireflective, electrically conductive, chemically stable coatings that also are highly active electrocatalysts for the oxidation of water to O2(g). These NiOx coatings provide protective layers on a variety of technologically important semiconducting photoanodes, including textured crystalline Si passivated by amorphous silicon, crystalline n-type cadmium telluride, and hydrogenated amorphous silicon. Under anodic operation in 1.0 M aqueous potassium hydroxide (pH 14) in the presence of simulated sunlight, the NiOx films stabilized all of these self-passivating, high-efficiency semiconducting photoelectrodes for >100 h of sustained, quantitative solar-driven oxidation of water to O2(g).

Portal vein tumor thrombosis in hepatocellular carcinoma: molecular mechanism and therapy.

Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future.

Development of a prognostic score for recommended transarterial chemoembolization candidates with spontaneous rupture of hepatocellular carcinoma.

Background: Although transarterial chemoembolization (TACE) has been widely used for treating the spontaneous rupture of hepatocellular carcinoma (HCC), no existing model exists for predicting survival. The aim of this study was thus to develop and validate a nomogram for estimating the prognosis in patients with ruptured HCC upon undergoing TACE treatment. Methods: This study included 55 patients with spontaneously ruptured HCC who underwent TACE treatment between January 2015 and April 2019. The diagnosis of spontaneous HCC rupture was based on the disruption of the peritumoral liver capsule with surrounding fluid in the perihepatic region. The prognostic nomogram was constructed using the independent predictors assessed by the multivariate Cox proportional hazards model. Results: The median overall survival (OS) was 6.4 months, with 6-month and 1-year survival rates of 52.7% and 41.8%, respectively. In the univariate analysis, the size of the largest tumor, total bilirubin (TBIL) levels, and aspartate aminotransferase (AST) levels were associated with the OS of patients. Multivariate analysis suggested that TBIL levels (HR =0.358, P=0.036) and diameter of the largest tumor (HR =1.012, P=0.044) were independent prognostic factors for predicting the OS. Based on these variables, we developed and validated a nomogram for the risk stratification of HCC rupture after TACE treatment for individual patients. According to the nomogram risk assessment, we were able to evaluate the approximate 1- and 2-year survival rates based on patients' tumor diameter and TBIL level after TACE treatment of ruptured HCC. The concordance index for the OS prediction was 0.748 (95% CI: 0.691-0.805). This newly developed nomogram represents an intuitive tool for predicting the OS of patients with ruptured HCC. Conclusions: This study indicated that TBIL levels and diameter of the largest tumor were independent prognostic factors for predicting the OS of ruptured HCC. This study may help maximize favorable TACE treatment outcomes.

Neutrophils: Driving inflammation during the development of hepatocellular carcinoma.

The relationship between immune and inflammatory responses in hepatocellular carcinoma (HCC) has garnered significant interest. In the peripheral blood and tumour microenvironment (TME), neutrophils, which are innate immune cells, crucially respond to various inflammatory factors, leading to tumour progression. To some extent, they affect the clinical treatment strategy and survival among HCC patients. A high circulating neutrophil-to-lymphocyte ratio is a reliable factor that can be used to predict poor outcomes in HCC patients. However, the mechanisms underlying the protumoural effects of circulating neutrophils remain poorly understood. Besides, the distinct role and function of neutrophils at the site of HCC remain relatively unclear, which is partially attributed to their substantial heterogeneity compared with other immune cells. In this review, we firstly discuss the current information available, detailing distinct subsets, functional phenotypes, and the impact of circulating and tumour-infiltrating neutrophils on tumourigenesis in HCC. Furthermore, we describe recent pre-clinical and clinical studies concerning neutrophils for evaluating the feasibility of targeting diverse protumoural aspects to improve therapeutic efficacy, thus paving the way for neutrophil-based treatment, especially in combination with immunotherapy.