Objective: To understand the relationship between AOX1, IRF4 gene methylation status in peripheral blood leukocyte DNA, as well as its interaction with environmental factors, and the risk of breast cancer. Methods: A case-control study was conducted among 401 breast cancer patients and 555 cancer-free controls selected from 2010 to 2014. Methylation sensitive-high resolution melting curve analysis was used to detect the methylation status of AOX1 and IRF4. The multiplication interaction effect between genes' methylation and environmental factors on the risk of breast cancer was analyzed by using unconditional logistic regression, and Excel software was used to analyze the additive interaction effect. Results: Individuals without AOX1 methylation had a 1.37-fold (95%CI: 1.02-1.84) higher breast cancer risk compared to individuals with AOX1 methylation. AOX1 methylation interacted with fungi intake (OR=2.06, 95%CI: 1.12-3.79) and physical activity (OR=2.18, 95%CI: 1.16-4.09) synergistically, on the risk for breast cancer, but no additive interaction effects were observed. Non-methylation of IRF4 could increase the risk for breast cancer, with statistical significance (OR=1.71, 95%CI: 0.99-7.43). Neither multiplication nor additive interactions were observed between IRF4 methylation and environmental factors. Conclusion: Non-methylation of AOX1 and IRF4 were a risk factors for breast cancer.
Aldehyde Oxidase/genetics* ; Breast Neoplasms/genetics* ; Case-Control Studies ; DNA Methylation/genetics* ; Female ; Genetic Predisposition to Disease ; Humans ; Interferon Regulatory Factors/genetics* ; Leukocytes/metabolism*

OBJECTIVETo study the protective effect of epalrestat against endothelial cell injuries induced by high glucose.

METHODSHuman umbilical vein endothelial cells were pretreated with epalrestat (0.1 µmol/L) for 30 min followed by exposure to high glucose for 8 h. NO concentration in the cell culture supernatant was assayed using chemiluminescence method following the exposure. Real-time PCR and Western blotting were used to detect eNOS mRNA and protein expression levels and the protein expressions of AR gene (the target gene of epalrestat) and NOX4 (the upstream gene of NO).

RESULTSCompared with mannitol treatment, an 8-h exposure to high glucose caused significantly decreased NO levels and eNOS mRNA and protein expression in the vascular endothelial cells (P<0.05). Pretreatment with epalrestat prior to high glucose exposure resulted in elevated eNOS mRNA and protein expression levels and NO up-regulation in the cell culture as compared with the glucose exposure alone group (P<0.05), causing also decreased expression of AR and NOX4 in the cells.

CONCLUSIONSHigh glucose can induce endothelial cell damage characterized by a lowered level of NO secretion. Epalrestat can protect the endothelial cells against high glucose-induced injury by inhibiting the expression of AR and NOX4.

Aldehyde Reductase ; antagonists & inhibitors ; Cells, Cultured ; Endothelium, Vascular ; drug effects ; metabolism ; Enzyme Inhibitors ; pharmacology ; Glucose ; adverse effects ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; Humans ; NADPH Oxidase 4 ; NADPH Oxidases ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; RNA, Messenger ; genetics ; Rhodanine ; analogs & derivatives ; pharmacology ; Thiazolidines ; pharmacology