Jianhui Liu

Background & objectives: Amyloid β-peptide (Aβ) has been shown to be responsible for senile plaque formation and cell damage in Alzheimer's disease (AD). This study was aimed to explore the role of natural compound icariin on the aggregation and the cytotoxicity of Aβ in vitro. Methods: Thioflavin T (ThT) fluorescence assay and transmission electron microscopy (TEM) imaging were done to determine the influence of icariin on the aggregation of Aβ_1-42 peptide. MTT assay was used to evaluate the protective effect of icariin on Aβ_1-42 induced cytotoxicity in neuroblastoma SH-SY5Y cells. Results: Icariin inhibited Aβ_1-42 aggregation in a dose-dependent manner. Additionally, icariin also prevented the cytotoxicity of Aβ_1-42 in SH-SY5Y cells by decreasing the production of peroxide hydrogen during the aggregation of this peptide. Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ_1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

Type 2 diabetes mellitus is characterized by lack of, or relative deficiency in, insulin productions and insensitivity of target tissues to insulin. Improvement of β-cell functions is a potential strategy for the clinical management of this disease. We reported before that geniposide improved glucose-stimulated insulin secretion with the activation of glucagon-like peptide 1 receptor (GLP-1R) in INS-1 pancreatic β cells, but the cell signaling mechanism of geniposide regulating glucose-stimulated insulin secretion (GSIS) in β cells is so far poorly understood. Effect of LY294002, a specific inhibitor of PI3K, on GSIS in the presence or absence of geniposide in INS-1 cells. In addition, the differential protein expression of geniposide treated INS-1 cells was examined by Western blot. After pretreatment with 10 µM LY294002 for 1 hour, the insulin secretion induced by geniposide was partly abolished in INS-1 cells. After treatment with geniposide, the phosphorylation of PDK1 and Akt473 increased gradually to the maximum at 60 minutes or 120 minutes respectively. Furthermore, geniposide also inhibited the phosphorylation of downstream target GSK3β, and this effect was counteracted by preincubation with LY294002. And the expression of GLUT2 was increased after treatment with different doses geniposide. Geniposide increases insulin secretion in pancreatic β cells in a PI3K dependent mechanism potentially through increased GLUT2 protein levels.

Glucose-stimulated insulin secretion (GSIS) is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM). Although the K_ATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells. Rat INS-1 insulinoma cells were cultured. The content of insulin in the culture medium was measured with ELISA assay. GLP-1R gene in INS-1 cells was knocked down with shRNA interference. The level of GLP-1R protein in INS-1 cells was measured with Western blotting. Geniposide (0.01–100 μmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner. Geniposide (10 μmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose. Blockade of GLP-1R with the GLP-1R antagonist exendin (9–39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 μmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L). Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells.

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Interference with telomerase and telomere maintenance is emerging as an attractive target for antitumor therapies. Ligands stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation of telomeres in tumors. Here, we report that long-term treatment with triethylene tetramine (TETA), at 50 or 100 μM, induced marked cellular senescence phenotypes accompanied by increased time of population doubling of MCF-7 cells. Cyclin-dependent kinase inhibitors, including p53 and p21, were also upregulated in TETA-treated MCF-7 cells. TETA is therefore as novel ligand of G-quadruplex and can induce tumor senescence; it is a promising material for tumor treatment.