TFP5 attenuates cyclin-dependent kinase 5-mediated islet ß-cell damage in diabetes.

Islet ß-cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin-dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet ß-cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo. CDK5 was upregulated under high glucose conditions in vivo and in vitro, which resulted in inflammation, oxidative stress, and apoptosis of islet ß-cells, thereby decreasing insulin secretion. However, TFP5 treatment inhibited the overexpression of CDK5; reduced the inflammatory response, oxidative stress, and apoptosis of islet ß cells; and restored insulin secretion. In conclusion, CDK5 is involved in islet ß-cell damage under high glucose conditions, and TFP5 may represent a promising candidate for the development of treatments for T2DM.

Dextran Sulfate Inhibits Angiogenesis and Invasion of Gastric Cancer by Interfering with M2-type Macrophages Polarization.

PURPOSE: To explore the effect of dextran sulfate (DS) on the angiogenesis, invasion, and migration of gastric cancer cells by interfering with the polarization of M2-type macrophages. METHODS: The infiltration of M2-type macrophages and microvascular density in gastric cancer and paracancerous tissues were analyzed using immunohistochemistry and immunofluorescence. The effects of DS on M2-type macrophages and the angiogenesis in metastatic tumors were investigated in the nude mice intraperitoneal metastasis model using immunohistochemistry and western blot. The differentiation and polarization of macrophages, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization of macrophages, immunocytochemistry, western blot, ELISA, and transwell migration assay were used to evaluate the effect of DS on the polarization and recruitment capacity of macrophages. Immunocytofluorescence, tube formation assay, transwell invasion assay, wound healing assay, and western blot were used to investigate the effect of DS on the angiogenesis, invasion, and migration-promoting phenotype of M2- type macrophage in a co-culture system of macrophages and gastric cancer cells. RESULTS: The infiltration of M2-type macrophages and the microvascular density were highly expressed and positively correlated in the human gastric cancer tissue. DS can significantly inhibit the intraperitoneal metastases of gastric cancer in nude mice, and reduce the infiltration of M2-type macrophages and the angiogenesis in intraperitoneal metastatic tumors. Moreover, DS can prevent the polarization of M0-type macrophages to M2 type, reduce the expression of M2-type macrophage markers (CD206, CD163, IL-10, and Arg-1), down-regulate the IL-6-STAT3 pathway, and inhibit the recruitment capability of M2-type macrophages. Finally, the co-culture experiment showed that DS significantly reduced the enhancing effects of M2-type macrophages on the angiogenesis, invasion, and migration of gastric cancer cells, as well as down-regulated the related expressions of proteins (VEGF, N-cadherin, MMP-2 and Vimentin) in gastric cancer cells. CONCLUSION: DS can reduce the infiltration of M2-type macrophages and the microvascular density in intraperitoneal metastases of gastric cancer in nude mice, and inhibit the angiogenesis, invasion, and migration of gastric cancer cells by interfering with the polarization of M2-type macrophages through repression of the IL-6/STAT3 signaling pathway.

Nrf2/HO-1 Axis Regulates the Angiogenesis of Gastric Cancer via Targeting VEGF.

PURPOSE: Gastric cancer (GC) is one of the most fatal digestive tumors worldwide. Abnormal activation or accumulation of the nuclear factor-erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) axis is a malignant event in numerous solid tumors. However, its involvement in angiogenesis of GC remains unknown. This study investigated the role of the Nrf2/HO-1 axis in angiogenesis of GC. METHODS: The expression of Nrf2, HO-1, and vascular endothelial growth factor (VEGF) in BGC-823 cells under hypoxia was analyzed using immunocytochemistry, immunofluorescence, Western blotting, and quantitative polymerase chain reaction. The effects of brusatol (Nrf2 inhibitor) and tert-butylhydroquinone (Nrf2 inducer) on these factors and angiogenesis were examined using immunofluorescence, Western blotting, quantitative polymerase chain reaction, and tube formation assay. Moreover, immunohistochemistry and Western blotting were used to determine these factors and microvessel density in tumor and normal tissues of tumor-bearing and tumor-free mice, respectively. Immunohistochemistry and Western blotting were employed to examine these factors and microvessel density in human paracancerous tissues, well-differentiated GC, and poorly differentiated GC. The correlations between Nrf2, HO-1, and VEGF gene expression in 375 patients with GC from The Cancer Genome Atlas cohort were analyzed. RESULTS: The expression of Nrf2, HO-1, and VEGF was increased in hypoxic BGC-823 cells (P<0.05). Although brusatol decreased their expression and angiogenesis (P<0.05), tert-butylhydroquinone had the opposite effect (P<0.05). Moreover, the expression of Nrf2, HO-1, and VEGF, and microvessel density in tumor tissues was higher than that recorded in normal tissues of nude mice (P<0.05). Similarly, these parameters were low in paracancerous tissues, but high in GC tissues (P<0.05). Also, they were weak in well-differentiated GC, but strong in poorly differentiated GC (P<0.05). In addition, there was a significant correlation between Nrf2, HO-1, and VEGF (P<0.05). CONCLUSION: The Nrf2/HO-1 axis may regulate the angiogenesis of GC via targeting VEGF. These findings provide a promising biomarker and potential treatment target for GC.