Insights into the impact of hepatitis B virus on hepatic stellate cell activation.

During chronic hepatitis B virus (HBV) infection, hepatic fibrosis is a serious pathological condition caused by virus-induced liver damage. The activation of hepatic stellate cells (HSCs) is a central event in the occurrence and progression of liver fibrosis. Although accumulating evidence has shown that HBV directly stimulates HSC activation, whether the virus infects and replicates in HSCs remains controversial. Inflammation is one of the obvious characteristics of chronic HBV infection, and it has been demonstrated that persistent inflammation has a predominant role in triggering and maintaining liver fibrosis. In particular, the regulation of HSC activation by HBV-related hepatocytes via various inflammatory modulators, including TGF-ß and CTGF, in a paracrine manner has been reported. In addition to these inflammation-related molecules, several inflammatory cells are essential for the progression of HBV-associated liver fibrosis. Monocytes, macrophages, Th17 cells, NK cells, as well as NKT cells, participate in the modulation of HBV-related liver fibrosis by interacting with HSCs. This review summarizes current findings on the effects of HBV and the relevant molecular mechanisms involved in HSC activation. Because HSC activation is essential for liver fibrosis, targeting HSCs is an attractive therapeutic strategy to prevent and reverse hepatic fibrosis induced by HBV infection. Video abstract.

Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis.

Glutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin-proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.

Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis.

PURPOSE: As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC. METHODS: Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC. RESULTS: We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells. CONCLUSIONS: These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.

Revealing the contribution of GbPR10.5D1 to resistance against Verticillium dahliae and its regulation for structural defense and immune signaling.

As an important family of pathogenesis-related (PR) proteins, the functional diversification and roles of PR10s in biotic stress have been well documented. However, the molecular basis of PR10s in plant defense responses against pathogens remains to be further understood. In the present study, we analyzed the phylogenetic relationship and function of a novel PR10 named GbPR10.5D1 in Sea-Island (or Pima or Egyptian) cotton (Gossypium barbadense L.), which has been identified as a Verticillium dahliae Kleb.-induced protein in a previous proteomics study. Phylogenetic analysis revealed that GbPR10.5D1, located on chromosome 2, is a unique member of GbPR10. The expression of GbPR10.5D1 was preferably in the root and induced upon V. dahliae infection. GbPR10.5D1 proteins were distributed in both nucleus and cytoplasm. GbPR10.5D1-virus-induced gene-silencing (VIGS) cotton plants were more susceptible to infection by V. dahliae, whereas overexpression (OE) of GbPR10.5D1 in cotton enhanced the resistance. By comparative transcriptome analysis between GbPR10.5D1-OE and wild-type (WT) plants and quantitative real-time polymerase chain reaction (qRT-PCR) verification, we found transcriptional activation of genes involved in cutin, suberine, and wax biosynthesis and mitogen-activated protein kinase (MAPK) signaling under normal conditions. Upon pathogen infection, defense signaling, fatty acid degradation, and glycerolipid metabolism were specifically activated in GbPR10.5D1-OE plants; biological processes (BPs), including glycolysis and gluconeogenesis, DNA replication, and cell wall organization, were specifically repressed in WT plants. Collectively, we proposed that GbPR10.5D1 possibly mediated lipid metabolism pathway to strengthen structural defense and activate defense signaling, which largely released the repression of cell growth caused by V. dahliae infection.

Spraying sorbitol-chelated calcium affected foliar calcium absorption and promoted the yield of peanut (Arachis hypogaea L.).

The prevalent use of foliar calcium fertilizers in peanut production is inorganic, but calcium absorbed from the foliar has poor availability. Sorbitol-chelated calcium is a novel organic foliar calcium fertilizer that has rarely been studied for application in peanut production. To explore whether calcium absorption and peanut yields can be affected by foliar application of sorbitol-chelated calcium, this study conducted two field experiments using Virginia peanut (Huayu-22) in 2020 and 2021. The five spray treatments included: deionized water (CK), sorbitol (Sor), calcium nitrate (CaN), a mixture of sorbitol and calcium nitrate (SN), and sorbitol-chelated calcium (SC). The yield of peanuts treated with sorbitol-chelated calcium was increased by 12.31-16.63%, 10.22-11.83%, 6.31-9.69%, and 4.18-6.99% compared to the CK, Sor, CaN, and SN treatments, respectively. Sorbitol-chelated calcium had the lowest contact angle due to the wetting effect of sorbitol, which promoted calcium absorption by leaves. Sorbitol-chelated calcium improved the leaf calcium concentration by 13.12-19.32% and kernel calcium concentration by 6.49-8.15% compared to the CK treatment. Foliar fertilization increased the calcium concentration of each subcellular fraction of leaves and changed the distribution of calcium in mesophyll cells. This change was directly observed by transmission electron microscopy. Additionally, spraying sorbitol alone obtained similar effects to spraying calcium nitrate alone, indicating that the benefits of sorbitol itself were not negligible. The results of the principal component and correlation analysis showed that the increase in calcium concentrations and the change in calcium distribution improved the pod traits of the peanut, thus affecting the peanut yield. The above results showed that from the perspective of calcium absorption and distribution, sorbitol-chelated calcium is a more effective foliar calcium fortifier for peanuts and effectively improves peanut yields.