It has been reported that epithelial-mesenchymal transition (EMT) mediates multiple physiological and pathological processes. However, the occurrence and the pathogenic role of high glucose-induced EMT in retinal pigment epithelial cells (RPE cells) is unknown. The aim of this study was to examine the effects of high glucose on EMT in RPE cells. Cultured RPE cells were exposed to 25 mM D-glucose. A vector encoding the Snail gene and siRNA targeting Snail (Snail siRNA) were transfected into the cells to induce the overexpression or silencing of Snail, respectively. AKT and extracellular signal-regulated kinase (ERK) inhibitors were used to block the activation of AKT and ERK, respectively. The levels of EMT markers, fibrogenic factors, phosphorylated ERK and phosphorylated AKT were determined by western blot analysis and immunofluorescence staining. Cell migration was evaluated by wound healing assay. Our results revealed that high glucose elevated the expression of the key EMT transcriptional factor, Snail, and that of other mesenchymal makers, and promoted cell migration. Moreover, the overexpression of Snail elevated the levels of fibronectin and connective tissue growth factor (CTGF), whereas the silencing of Snail decreased the expression of fibronectin and CTGF induced by high glucose in the cells. Mechanistically, the AKT inhibitor (AKT inhibitor IV) and ERK inhibitor (U0126) significantly decreased the expression of Snail, as well as the levels of fibronectin and CTGF which were induced by high glucose. On the whole, and to the best of our knowedge, the present study is the first to demonstrate the upregulation of mesenchymal markers in RPE cells induced by high glucose, and suggest that mesenchymal transition may be involved in the pathological processes of retinal diseases.

Gastric cancer is one of the most malignant tumor types, and its metastasis is a notable cause of mortality. Among the methods of tumor metastasis, lymphatic metastasis is the predominant one in gastric cancer. A previous study reported that the plasma oxidized low-density lipoprotein (oxLDL) is the risk factor associated with the development of tumors in patients with abnormal lipid metabolism, but the influence of plasma oxLDL in the lymphatic metastasis of gastric cancer remains unclear. In the present study, the concentration of plasma oxLDL from patients with gastric cancer was detected with an ELISA kit, and the lymphatic vessel density in gastric cancer tissues was determined by D2-40 staining. The correlation analysis of oxLDL concentration and lymphatic vessel density demonstrated that plasma oxLDL was positively correlated with lymphatic metastasis in patients with gastric cancer. Subsequently, the popliteal lymph node metastasis animal experiment with nude mice confirmed that oxLDL could promote the lymphatic metastasis of gastric cancer. Following this, the western blotting and ELISA data demonstrated that oxLDL promoted the expression and secretion of vascular endothelia growth factor (VEGF)-C in gastric cancer cell lines. Finally, blocking the lectin-like oxLDL-1 (LOX-1) receptor, a specific receptor for oxLDL, and the nuclear factor (NF)-κB signaling pathway following oxLDL (50 µg/ml) treatment in HGC-27 cells revealed that oxLDL could activate the NF-κB signaling pathway mediated by LOX-1, with subsequent upregulation of VEGF-C expression, and secretion in and from gastric cancer cells, and finally that it could promote the lymphatic metastasis of gastric cancer. These data indicate the association between the plasma oxLDL and the lymphatic metastasis of gastric cancer, and indicate that oxLDL elimination may be a potential therapeutic target for the prevention and intervention of early lymph node metastasis in gastric cancer.

Background:The voltage-dependent anion channel 1 (VDAC1) is identified as a receptor of human plasminogen kringle 5 (K5), but the role and mechanisms of VDAC1 in K5-induced endothelial cell (EC) apoptosis remain elusive. Results: K5 up-regulates VDAC1 through a AKT-GSK3␤ pathway. Conclusion: A positive feedback loop of "VDAC1-AKT-GSK3␤-VDAC1" mediates K5-induced EC apoptosis. Significance: This finding provides new perspectives on the mechanisms of K5-induced apoptosis.

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