Notch1 Has an Important Role in ß-Cell Mass Determination and Development of Diabetes.

BACKGROUND: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). METHODS: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and ß-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. RESULTS: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and ß-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. CONCLUSION: Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and ß-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in ß-cell mass determination and diabetes.

Induction of apoptosis and the regulation of ErbB signaling by laminarin in HT-29 human colon cancer cells.

Laminarin, found in marine brown algae, is used as a carbohydrate reserve for phytoplankton; however, it is also used in traditional Chinese medicine, and has been shown to have several biological activities, including anticancer activities. In this study, we examined the mechanisms through which laminarin from Laminaria digitata induces apoptosis in HT-29 colon cancer cells, as well as the involvement of the ErbB signaling pathway. Cell viability assay revealed that laminarin induced cell death in a dose-dependent manner. Cell cycle analysis revealed that laminarin increased the percentage of cells in the sub-G1 and G2-M phase. Western blot analysis demonstrated that laminarin inhibited the heregulin-stimulated phosphorylation of ErbB2. A decrease in cellular proliferation was also observed; this was found to be dependent on ErbB, which activates c-Jun N-terminal kinase. These findings demonstrate the important role of the epidermal growth factor receptor in colon cancer tumorigenesis, and suggest the potential of laminarin as a bio-functional food with anticancer effects on human colon cancer.

Induction of apoptosis by laminarin, regulating the insulin-like growth factor-IR signaling pathways in HT-29 human colon cells.

In recent years, algae have been highlighted as potential sources of anticancer agents. Laminarin is a molecule found in marine brown algae that has potentially beneficial biological activities. However, these activities have not been investigated. In the present study, we examined the effects of laminarin on HT-29 cells and analyzed its effect on the insulin-like growth factor (IGF-IR) signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays revealed that laminarin induced cell death in a dose-dependent manner. Western blotting showed that laminarin decreased mitogen-activated protein kinases (MAPK) and ERK phosphorylation. Decreased proliferation depended on IGF-IR, which was associated with the downregulation of MAPK/ERK. These results are important for understanding the roles of IGF-IR in colon cancer cell tumorigenesis, and suggest that laminarin shows activity against human colon cancer.