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Aims Increasing nicotinamide adenine dinucleotide (NAD+) by Nicotinamide riboside (NR) provides protective benefits in multiple disorders. However, the role of NR on liver fibrosis is unclear. We performed in vivo and in vitro experiments to test the hepatic protective effects of NR against liver fibrosis and the underlying mechanisms. Materials and methods Mice were injected with CCl4 to establish liver fibrosis model. NR was given by gavage to explore the hepatic protection of NR. LX-2 cells were given a TGF-β stimulation ± NR, the activation of LX-2 cells and the acetylation of Smads were analyzed. To further confirm the role of Sirt1 on the protective pathway of NR, we knockdown Sirt1 in LX-2 cells. Key findings We found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-β, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway. Significance NR protected mice against liver fibrosis induced by CCl4. NR suppressed activation of hepatic stellate cells induced by TGF-β. NR protects liver fibrosis via increasing the activity of Sirt1 and decreasing the expression of P300, resulting in the deacetylation of Smads in stellate cells.

Switching aerobic respiration to anaerobic glycolysis of cancer cells plays an important role in development and progression of acquired resistance. Since vitamin C enabled the inhibition of glycolysis of cancer cells, and erlotinib-resistant sub-line of HCC827 (ER6 cells) switched its metabolic features to higher glycolysis for survival, we hypothesize that vitamin C is able to inhibit glycolysis of ER6 cells. In this study, we found that both reduced vitamin C and oxidized vitamin C (DHA) could selectively suppress the viability of ER6 cells. DHA was efficient in inhibiting glycolysis and leading to energy crisis, which could be one mechanism for overcoming drug resistance to erlotinib of ER6 cells. Our data suggest that applying DHA could be a novel treatment strategy for NSCLC with acquired resistance to targeted therapy.

Aim Cyanidin-3-O-β-glucoside (Cy-3-G) the most abundant monomer of anthocyanins has multiple protective effects on many diseases. To date, whether Cy-3-G could regulate the function of brown adipose tissue (BAT) is still unclear and whether this regulation could influence the secretion of adipokines from BAT to prevent non-alcoholic fatty liver disease (NAFLD) indirectly remains to be explored. In this study we investigated the effect of Cy-3-G on BAT and the potential role of Cy-3-G to prevent fatty liver through regulating the secretion of BAT. Methods Male C57BL/6 J mice were fed with a high fat high cholesterol (HFC) diet with or without 200 mg/kg B.W Cy-3-G for 8 weeks. In in vitro experiments, the differentiated brown adipocytes (BAC) and C3H10T1/2 clone8 cells were treated with 0.2 mM palmitate with or without Cy-3-G for 72 or 96 h. Then the culture media of C3H10T1/2 clone8 cells were collected for measuring the adipokines secretion by immunoblot assay and were applied to culture HepG2 cells or LO2 cells for 24 h. Lipid accumulation in HepG2 cells or LO2 cells were evaluated by oil red O staining. Results Here we found that Cy-3-G regulated the activation of BAT and the expression of adipokines in BAT which were disrupted by HFC diet and alleviated diet induced fatty liver in mice. In in vitro experiments, Cy-3-G inhibited the release of adipokines including extracellular nicotinamide phosphoribosyltransferase (eNAMPT) and fibroblast growth factor 21 (FGF21) from differentiated C3H10T1/2 clone8 cells induced by palmitate, which was accompanied by a reduction of lipid accumulation in HepG2 cells and LO2 cells cultured by the corresponding collected media of C3H10T1/2 clone8 cells. Conclusions These results indicate that Cy-3-G can regulate the thermogenic and secretory functions of BAT. Furthermore, our data suggest that the protective effect of Cy-3-G on hepatic lipid accumulation is probably via regulating the secretion of adipokines from BAT.

Cyanidin-3-O-β-glucoside (Cy-3-G) has protective properties in many diseases. Whether Cy-3-G has protective effects on alcohol induced liver injuries remains uncertain. In our study, mice were fed with a high fat high cholesterol diet (HFC) plus ethanol for 12 weeks. Cy-3-G supplementation reversed the liver damage induced by alcohol. In vitro studies, Cy-3-G restored the intracellular energy status of LX-2 cells and inhibited the activation of LX-2 cells induced by ethanol plus palmitate. The protective effect of Cy-3-G is via the increase of AMPK phosphorylation and autophagy. In conclusion, Cy-3-G ameliorated chronic alcoholic liver injuries, possibly by improving energy metabolic status. Specifically, liver fibrosis was protected by Cy-3-G via inhibiting the activation of stellate cells, which was mediated partially by AMPK/autophagy signaling pathway.

Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy.

Increasing nicotinamide adenine dinucleotide (NADMice were injected with CClWe found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-β, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway.NR protected mice against liver fibrosis induced by CCl

Nonalcoholic fatty liver disease has become a social health challenge of global concern. The term nonalcoholic steatohepatitis (NASH) is a more severe condition than simple steatosis and distinguishing NASH from nonalcoholic fatty liver disease is particularly important. Liver biopsy remains a gold standard in diagnosing NASH. Meanwhile, radiological techniques such as ultrasonography and MRI are also applied widely. However, the invasive and expensive examination is not suitable for screening, and there is a great need for reliable and appropriate biomarkers to screen patients for NASH. Based on the current studies of blood-based novel biomarkers, we attempt to summarize the latest findings on biomarkers for NASH, including blood biomarkers encompassing proteins, lipids and miRNAs; the correlation between extracellular vesicles and NASH; and treatment strategies for NASH.