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Alzheimer's disease (AD) is the leading cause of late-onset dementia, and there exists an unmet medical need for effective treatments for AD. The accumulation of neurotoxic amyloid-b (Ab) plaques contributes to the pathophysiology of AD. EPHX2 encoding soluble epoxide hydrolase (sEH)-a key enzyme for epoxyeicosatrienoic acid (EET) signaling that is mainly expressed in lysosomes of astrocytes in the adult brain-is cosited at a locus associated with AD, but it is unclear whether and how it contributes to the pathophysiology of AD. In this report, we show that the pharmacologic inhibition of sEH with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) or the genetic deletion of Ephx2 reduces Ab deposition in the brains of both male and female familial Alzheimer's disease (53FAD) model mice. The inhibition of sEH with TPPU or the genetic deletion of Ephx2 alleviated cognitive deficits and prevented astrocyte reactivation in the brains of 6-monthold male 53FAD mice. 14,15-EET levels in the brains of these mice were also increased by sEH inhibition. In cultured adult astrocytes treated with TPPU or 14,15-EET, astrocyte Ab clearance was increased through enhanced lysosomal biogenesis. Infusion of 14,15-EET into the hippocampus of 53FAD mice prevented the aggregation of Ab. Notably, a higher concentration of 14,15-EET (200 ng/ml) infusion into the hippocampus reversed Ab deposition in the brains of 6-month-old male 53FAD mice. These results indicate that EET signaling, especially 14,15-EET, plays a key role in the pathophysiology of AD, and that targeting this pathway is a potential therapeutic strategy for the treatment of AD.

BackgroundThe prognostic value of Ki-67 expression in colorectal cancer patients was controversial. Therefore, this meta analysis was conducted to ascertain the prognostic value of Ki-67 expression in colorectal cancer patients.MethodsThe electronic databases, including EMBASE, PubMed, Cochrane Library and Web of Knowledge database, were searched from January 1970 to July 2017. The pooled hazard ratios and 95% confidence intervals were calculated to evaluate the prognostic value of Ki-67 expression for colorectal cancer patients.ResultsTotally 34 eligible studies and 6180 colorectal cancer patients were included in the present meta analysis. The pooled hazard ratios were 1.54(95% CI 1.17–2.02, P = 0.005) for overall survival and 1.43(1.12–1.83, P = 0.008) for disease free survival in univariate analysis. After adjustment of other prognostic factors, the pooled HR was 1.50(95% CI 1.02–2.22, P = 0.03) for overall survival in multivariate analysis.ConclusionThe present meta analysis demonstrated that high Ki-67 expression is significantly correlated with poor overall survival and disease free survival, indicating that high Ki-67 expression may serve as a valuable predictive method for poor prognosis of colorectal cancer patients.