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Interferon alpha (IFN-α) therapy is widely used to treat patients with chronic hepatitis B (CHB) but the sustained response rate is low, and the molecular mechanisms for the ineffectiveness of IFN-α treatments are not known. We screened differentially expressed genes between responders (Rs) and nonresponders (NRs) in patients with CHB treated with IFN-α to explore the molecular basis for treatment failure. Expression profiling was performed on percutaneous needle liver biopsy specimens taken before therapy. Gene expression levels were compared between seven patients who did not respond to therapy (NR) and six who did respond (R). Gene ontology category and KEGG pathway were analysed for differentially expressed genes, and the selected differentially expressed genes were confirmed using real-time polymerase chain reaction. We identified 3592 genes whose expression levels differed significantly between all Rs and NRs (P < 0.05); many of these genes are IFN-stimulated genes (ISGs) and immune-related genes. The ISGs were more highly expressed, while immune-related genes were inhibited in NRs before IFN-α treatment. Two ISGs (CEB1 and USP18) that are linked in an IFN inhibitory pathway are highly expressed in NRs, and a potential antiviral gene ISG20 was inhibited in NRs, suggesting a possible rationale for treatment nonresponse. Patients who do or do not respond to IFN have different liver gene expression profiles before IFN-α treatment. Preactivation of the IFN signalling pathway leading to the increased expression of inhibitory ISGs and inhibition of immune response in the pretreatment livers was associated with treatment failure.

Abstract. The rising incidence of type 2 diabetes mellitus (T2DM) is a major public health problem and novel therapeutic strategies are required to prevent and treat T2DM. It has been demonstrated that resveratrol (RSV) may prevent T2DM by targeting Sirtuin type 1 (SIRT1), indicating that SIRT1 may be a novel therapeutic target for T2DM prevention. In the present study, a T2DM rat model was established by administering a high fat diet and streptozotocin (STZ) injections. Measurements of blood glucose and insulin confirmed successful establishment of the T2DM model. RSV was used to treat rats with STZ-induced T2DM and the results indicated that RSV reversed the STZ-induced downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α, SIRT1 and forkhead box protein O 3a. Furthermore, RSV modulated the activity of superoxide dismutase and malondialdehyde, which are associated with oxidative stress. In vitro, cells from the insulinoma cell line clone 1E were pretreated with palmitic acid (PA) to simulate a high fat environment. The results of reverse transcription-quantitative polymerase chain reaction indicated that PA suppressed the expression of SIRT1 in a dose-and time-dependent manner. Furthermore, PA modulated the expression of mitochondrial biogenesis-associated, lipid metabolism-associated and β-cell-associated genes, whereas RSV treatment ameliorated the PA-induced changes in the expression of these genes via SIRT1. The results of the present study suggest that RSV participates in the prevention of T2DM by regulating the expression of mitochondrial genes associated with biogenesis, lipid metabolism and β-cells via SIRT1. The results of the current study provide an insight into the mechanisms by which SIRT1 inhibits T2DM and may be used as a basis for future studies.

Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.

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