Glycolysis is a typical conduit for energy metabolism in pancreatic cancer (PC) due to the hypoxic microenviroment. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis. The aim of the present study was to explore the mechanism of interactions between hypoxia, HIF-1/2α and LDHA, and the function of LDHA on PC cells by analyzing 244 PC and paratumor specimens. It was found that LDHA was over-expressed and related to tumor stages. The result of in vitro study demonstrated that hypoxia induced LDHA expression. To explore the relationship between HIF and LDHA, chromatin immunoprecipitation assay and luciferase assay were performed. The result showed that HIF-1/2α bound to LDHA at 89bp under the hypoxic condition. Furthermore, knockdown of endogenous HIF-1α and HIF-2α decreased the LDHA expression even in the hypoxic condition, which was accompanied with a significant decrease in lactate production and glucose utilization (p < 0.01). Immunofluorescence in the 244 specimens showed that HIF-1/2α was over-expressed and associated with LDHA over-expression (p < 0.0001). Forced expression of LDHA promoted the growth and migration of PC cells, while knocking down the expression of LDHA inhibited the cell growth and migration markedly. In summary, the present study proved that HIF1/2α could activate LDHA expression in human PC cells, and high expression of LDHA promoted the growth and migration of PC cells.

D-galactose causes aging acceleration in different animal models but the mechanism is unclear. In the present study, we investigated the effects of D-galactose on lifespan and oxidative stress biomarkers in the fruit fly (Drosophila melanogaster) and housefly (Musca domestica). D-galactose was added to drinking water (20 mg/ml) for housefly and to culture medium (6.5%) for fruit fly from 24 h after emergence. Oxidative stress was estimated by measuring the activity of Cu-Zn-superoxide dismutase (SOD) and the levels of lipid peroxidation products, namely malondialdehyde (MDA) and lipofuscin in housefly brain (male) and in fruit fly (male and female). D-galactose caused a significant decrease in mean lifespan (by 12.6% of male and 15.9% of female) and maximum lifespan (by 12.9% of male and 17.1% of female) in fruit fly, and also a significant decrease in mean lifespan (by 27.1% of male, 19.8% of female) and maximum lifespan (by 27.1% of male, 21.9% of female) in housefly. MDA and lipofuscin increased with age in fruit fly and in housefly brains while change of the SOD activity showed a biphasic shape with age. D-galactose caused a significant increase in MDA and lipofuscin and decrease in SOD activity in the age-matched fruit flies and houseflies. These data indicate that D-galactose shortens the lifespan of the two different fly species and that the life shortening effect is associated with an increase in oxidative stress.

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.