Vascular dementia is the second most common cause of dementia in older people and is characterized by the sudden onset of impairments in thinking skills and behavior, which generally occur following a stroke. Unfortunately, effective therapy for vascular dementia remains inadequate. Erythropoietin (EPO) is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. Recently, a prominent role for EPO has been defined in the nervous system, and there is growing interest in the potential therapeutic use of EPO for neuroprotection. However, whether it is protective from memory impairments and the underlying mechanisms of vascular dementia (VD) remains unknown. In the current study, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could restore impaired memory in 2-vessel occlusion (2VO) rats, a well-established vascular dementia animal model. EPO also rescued impairments in dendritic spines and cholinergic dysfunctions in the hippocampus. Moreover, EPO suppressed the overactivation of GSK-3β in the hippocampus by stimulating the JAK2/STAT5/PI3K/Akt signal pathway. Furthermore, we found that genetic knockdown of the EPO receptor (EPO-R) by shRNA blocks the neuroprotection conferred by EPO on memory in VD. We hypothesized that EPO treatment is able to rescue the memory impairments in VD by stimulating the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway and suggest the potential usage of EPO in the therapy for VD.
WWOX (WW domain-containing oxidoreductase) is known to be an important tumor suppressor in cancer. In this study, we used samples from 201 osteosarcoma patients to investigate the effects of WWOX on angiogenesis and invasion. WWOX levels were negatively correlated with RUNX2 and VEGF levels, but were not correlated with OPN levels. Among the clinicopathological characteristics examined, WWOX was associated only with response to neoadjuvant chemotherapy, and its expression in osteosarcoma tissues was a predictor of disease-free survival. WWOX promoted apoptosis and inhibited invasion and expression of bcl-2, OPN, RUNX2, and VEGF in osteosarcoma cells in vitro. In MG-63 cells, bcl-2 increased VEGF expression, while RUNX2 increased VEGF and OPN expression. Administration of DNA methylation inhibitors increased WWOX expression in MG-63 cells and methylation of WWOX gene promoter CpG island in the osteosarcoma of patients was associated with suppression of WWOX expression. Overexpression of WWOX in osteosarcoma cells inhibited tube formation in co-cultured HUVEC cells, and high WWOX expression was associated with decreased microvessel density (MVD). These results suggest that reduced WWOX expression in osteosarcoma inhibits apoptosis, promotes invasion and increases MVD.
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