Cell Nuclear Antigen-positive Hepatocytes Research Articles

Exendin-4 improves hepatocyte injury by decreasing proliferation through blocking NGF/TrkA in diabetic mice

The hepatocytes express nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A (TrkA). However, the link between NGF/TrkA system and hepatocyte proliferation in diabetic animals and the effects of exendin-4, a glucagon like peptide-1 (GLP-1) receptor agonist, on this system are not known. BALB/c male mice were divided into four groups. The first group was given citrate buffer only, the second group was administered exendin-4 alone, the third group received streptozotocin (STZ), and the fourth group was given both STZ and exendin-4. Exendin-4 (3 μg/kg) was administered by subcutaneous injection daily for 30 days after the animals were rendered diabetic by administration of STZ (200 mg/kg). With treatment of exendin-4 to the diabetic mice the following results were noted (i) NGF, TrkA and proliferating cell nuclear antigen positive hepatocytes were decreased; (ii) p75 neurotrophin receptor and caspase-3 positive hepatocyte could not be detected; (iii) liver alanine transaminase and aspartate transaminase activities, lipid peroxidation, protein carbonyl and myeloperoxidase levels were decreased; (iv) liver catalase, superoxide dismutase, glutathione peroxidase activities and glutathione levels were increased. These data suggest that exendin-4 might exerts its anti-proliferative action through blocking NGF/TrkA system and stimulating oxidative defense system in liver of diabetic mice.

Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis‐promoted hepatocarcinogenesis in rats

Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) promoted diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in a rat model. Using this model, we investigated the efficacy of an equivalent dosage of dietary LY from either a pure compound or a tomato extract (TE) against NASH-promoted hepatocarcinogenesis. Six groups of rats were injected with DEN and then fed either Lieber-DeCarli control diet or HFD with or without LY or TE for 6 weeks. Results showed that both LY and TE supplementations significantly decreased the number of altered hepatic foci expressing the placental form of glutathione S-transferase in the livers of HFD-fed rats. This was associated with significantly lower proliferating cell nuclear antigen positive hepatocytes and cyclinD1 protein, as well as decreased activation of extracellular signal-regulated kinase and nuclear NF-kappaB. Although both LY and TE supplementations reduced HFD-induced lipid peroxidation in the livers, we observed significantly decreased cytochrome P450 2E1, inflammatory foci and mRNA expression of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-12) in the HFD+TE fed group but increased nuclear NF-E2-related factor-2 and heme oxygenase-1 proteins in the HFD+LY fed group, relative to HFD feeding alone. These data indicate that LY and TE can inhibit NASH-promoted hepatocarcinogenesis mainly as a result of reduced oxidative stress, which could be fulfilled through different mechanisms.

Enhancement of Hepatocellular Proliferative Activity of Kojic Acid in Mice by a Simultaneous Administration of Ascorbic Acid

To examine the tumor modification activity of kojic acid (KA) by sodium ascorbic acid (AA), 5-week-old male ICR mice were administered intraperitoneally with N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after the initiation treatment, animals were fed basal diet containing 0 (Group 1: DEN alone) or 3% KA (Group 3: DEN+KA), drinking water containing 5,000 ppm AA (Group 2: DEN+AA) or 3% KA and 5,000 ppm AA (Group 4: DEN+KA+AA) for 6 weeks. One week after the administration of KA and/or AA, all mice were subjected to two-thirds partial hepatectomy. At the end of the experimental period, all surviving mice were sacrificed and removed the liver. The liver weights of the Groups 3 and 4 were significantly increased, and the number of proliferating cell nuclear antigen positive hepatocytes and the gene expressions of Ccnc, Ccnd1, Ercc and Cyp7a1 were significantly increased in the Group 4, as compared to the Group 1. These results of the present study suggest that AA enhances the hepatocellular proliferative activity of KA in mice.

The overexpression of proliferating cell nuclear antigen in biliary cirrhosis in the rat and its relationship with epidermal growth factor receptor

Chronic bile duct obstruction in the rat leads to biliary cirrhosis but maintained hepatocellular mass. We have previously demonstrated translocation of epidermal growth factor receptor to nuclei. It remained unclear, however, whether this was due to hepatocyte proliferation and/or altered handling of epidermal growth factor receptor. Therefore, in the present investigation we stereologically estimated expression of proliferating cell nuclear antigen, a marker of the S phase of the cell cycle at 1, 2, 3, 7, 14, 21 and 28 days after bile duct ligation. Proliferating cell nuclear antigen positive hepatocytes averaged 2.1±3.6% in sham-operated control animals. This increased to 20.7±6.4, 26.8±18.7, 31.3±23.9, 42.3±16.6 and 24.7±28.0%, 3, 7, 14, 21 and 28 days after bile duct ligation, respectively ( p<0.005 by ANOVA). This was correlated with the number of epidermal growth factor receptor positive nuclei (r s=0.737) and inversely with the maximal binding capacity of epidermal growth factor to a crude plasma membrane fraction (r s=0.697) reported previously. We conclude that bile duct ligation in the rat induces a significant hepatocellular proliferation as assessed by proliferating cell nuclear antigen expression and that this process could, at least in part, be related to increased nuclear expression of the epidermal growth factor receptor.