Hepatitis B virus (HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma (HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNA into the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.

ArrayExpress accession E-MTAB-1795.

RuvBL1 is an AAA+ ATPase whose expression in hepatocellular carcinoma (HCC) correlates with a poor prognosis. In vitro models suggest that targeting RuvBL1 could be an effective strategy against HCC. However, the role of RuvBL1 in the onset and progression of HCC remains unknown. To address this question, we developed a RuvBL1 hep+/− mouse model and evaluated the outcome of DEN-induced liver carcinogenesis up to 12 months of progression. We found that RuvBL1 haploinsufficiency initially delayed the onset of liver cancer, due to a reduced hepatocyte turnover in RuvBL1 hep+/− mice. However, RuvBL1 hep+/− mice eventually developed HCC nodules that, with aging, grew larger than in the control mice. Moreover, RuvBL1 hep+/− mice developed hepatic insulin resistance and impaired glucose homeostasis. We could determine that RuvBL1 regulates insulin signaling through the Akt/mTOR pathway in liver physiology in vivo as well as in normal hepatocytic and HCC cells in vitro. Whole transcriptome analysis of mice livers confirmed the major role of RuvBL1 in the regulation of hepatic glucose metabolism. Finally, RuvBL1 expression was found significantly correlated to glucose metabolism and mTOR signaling by bioinformatic analysis of human HCC sample from the publicly available TGCA database. These data uncover a role of RuvBL1 at the intersection of liver metabolism, hepatocyte proliferation and HCC development, providing a molecular rationale for its overexpression in liver cancer.M.M. and F.Z. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

The establishment of the beneficial interactions between the host and its microbiota is essential for the correct functioning of the organism, since microflora alterations can lead to many diseases. Probiotics improve balanced microbial communities, exerting substantial health-promoting effects. Here we monitored the molecular outcomes, obtained by gut microflora modulation through probiotic treatment, on human urine and serum metabolic profiles, with a metabolomic approach. Twenty-two subjects were enrolled in the study and administered with two different probiotic types, both singularly and in combination, for 8 weeks. Urine and serum samples were collected before and during the supplementation and were analyzed by nuclear magnetic resonance (NMR) spectroscopy and statistical analyses. After eight weeks of treatment, probiotics deeply influence the urinary metabolic profiles of the volunteers, without significantly altering their single phenotypes. Anyway, bacteria supplementation tends to reduce the differences in metabolic phenotypes among individuals. Overall, the effects are recipient-dependent, and in some individuals, robust effects are already well visible after four weeks. Modifications in metabolite levels, attributable to each type of probiotic administration, were also monitored. Metabolomic analysis of biofluids turns out to be a powerful technique to monitor the dynamic interactions between the microflora and the host, and the individual response to probiotic assumption.

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Background: Factors affecting innate immunity and acting as inflammatory regulators, such as the nuclear peroxisome proliferator-activated receptors (PPAR) could be crucial in the pathogenesis of necrotizing enterocolitis (NEC). We hypothesized that the PPARγ agonist pioglitazone (PIO) might be effective in preventing the development of NEC and/or reducing its severity. Methods: We studied preterm rats in which NEC was induced using the hypoxia-hypothermia model. The treatment group (TG; n = 30) received enteral PIO (10 mg/kg/d) for 72 h and the control group (CG; n = 30) did not. Animals were sacrificed 96 h after birth. NEC was diagnosed evaluating histological ileum changes, and mRNA levels of IL-4, IL-12, IL-6, IL-10, INF-γ, and TNF-α cytokines were measured. results: NEC occurrence was higher in the CG (18/30; 60%) than in the TG (5/30; 16.7%) and was more severe. Proinflammatory IL-12 and INF-γ mRNA levels were significantly lower in the TG than in the CG; conversely, the antiinflammatory IL-4 mRNA level was significantly higher in the TG than in the CG. conclusion: Our results demonstrate for the first time that PIO is effective in reducing the incidence and severity of NEC and in decreasing renal injuries in a preterm rat model. n ecrotizing enterocolitis (NEC) is the most common neonatal gastrointestinal complication in preterm infants (1). The prevalence of this disease is about 7% in infants with birth weght from 500 to 1,500 g, with a mortality of 30% in 28 to 36 wk of gestation infants and 40 % in <28-wk infants (2). Moreover, the development of NEC increases the risk of a delay in neurodevelopment, because inflammatory processes occurring in the gut can have a systemic diffusion, affecting other organs such as the brain (3), and, as recently suggested, the kidney (4). The physiopathology of NEC is not completely understood; however it is considered a multifactoral disease including intestinal immaturity, microbial colonization, and hypoxia-ischemia damage as risk factors. Recently, many studies have suggested that the intestinal mucosa and innate immune system play major roles in the pathogenesis of NEC (5). Thus, factors affecting innate immunity and regulating inflammation, such as the nuclear peroxisome proliferatoractivated receptors (PPAR), could be crucial. PPAR are a family of ligand-activated nuclear receptor transcription factors that regulates the function and expression of complex gene networks, especially involved in energy homeostasis and inflammation (6). They consist of three isoforms (α, β, γ), and PPARγ has been shown to induce anti-inflammatory responses inhibiting proinflammatory transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) (7-9). Moreover, PPARγ can promote an antiinflammatory antioxidant response interacting with different enzymatic pathways such as cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) (6). For these reasons, many PPARγ agonists have been implicated in t...

Background & AimsHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although hepatectomy and transplantation have significantly improved survival, there is no effective chemotherapeutic treatment for HCC and its prognosis remains poor. Sustained activation of telomerase is essential for the growth and progression of HCC, suggesting that telomerase is a rational target for HCC therapy. Therefore, we developed a thymidine analogue pro-drug, acycloguanosyl-5′-thymidyltriphosphate (ACV-TP-T), which is specifically activated by telomerase in HCC cells and investigated its anti-tumour efficacy.MethodsFirst, we verified in vitro whether ACV-TP-T was a telomerase substrate. Second, we evaluated proliferation and apoptosis in murine (Hepa1-6) and human (Hep3B, HuH7, HepG2) hepatic cancer cells treated with ACV-TP-T. Next, we tested the in vivo treatment efficacy in HBV transgenic mice that spontaneously develop hepatic tumours, and in a syngeneic orthotopic murine model where HCC cells were implanted directly in the liver.ResultsIn vitro characterization provided direct evidence that the pro-drug was actively metabolized in liver cancer cells by telomerase to release the active form of acyclovir. Alterations in cell cycle and apoptosis were observed following in vitro treatment with ACV-TP-T. In the transgenic and orthotopic mouse models, treatment with ACV-TP-T reduced tumour growth, increased apoptosis, and reduced the proliferation of tumour cells.ConclusionsACV-TP-T is activated by telomerase in HCC cells and releases active acyclovir that reduces proliferation and induces apoptosis in human and murine liver cancer cells. This pro-drug holds a great promise for the treatment of HCC.