BackgroundSoluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer’s disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear.MethodsTo examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH−/−) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH−/− mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches.ResultsWe demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH−/− mice compared with APP/PS1 Tg mice.ConclusionOur results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.

Background-We recently showed that the multidrug resistance related protein-1 (MRP1) is important for the management of oxidative stress in vascular cells. However, the underlying mechanism and the in vivo relevance of these findings remain elusive. We hypothesize that inside-outside transport of leukotriene C 4 (LTC 4 ) via MRP1 is a substantial proatherogenic mechanism in the vasculature. To test this hypothesis, we investigated the effects of MRP1 inhibition and LTC 4 receptor blockade (Cys-LT1 receptor) in vitro and in vivo. Methods and Results-MRP1 is expressed abundantly in vascular smooth muscle cells (VSMCs). Pharmacological inhibition of MRP1 via MK571 reduces angiotensin II-induced reactive oxygen species release by 59% (L012 fluorescence) in VSMCs. The release of reactive oxygen species after angiotensin II stimulation also is inhibited by blockade of the Cys-LT1 receptor with montelukast. Incubation of VSMCs with recombined LTC 4 causes enhanced rates of reactive oxygen species and proliferation in wild-type and MRP1 Ϫ/Ϫ VSMCs. Accordingly, the LTC 4 release in the cell culture supernatant of MRP1 Ϫ/Ϫ VSMCs is significantly decreased compared with wild-type cells. To extend our observations to the in vivo situation, atherosclerosis-prone apolipoprotein E-deficient mice on a high-cholesterol diet were treated with placebo, the MRP1 inhibitor MK571, or the Cys-LT1 receptor inhibitor montelukast for 6 weeks. Treatment with MK571 or montelukast reduced vascular reactive oxygen species production, significantly improved endothelial function, and ameliorated atherosclerotic plaque generation by 52% and 61%, respectively. Conclusions-These findings indicate that MRP1 and LTC 4 exert proatherosclerotic effects and that both MRP1 and LTC 4 are potentially promising targets for atheroprotective therapy. (Circulation. 2008;117:2912-2918.)

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.

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These results suggest that genetic variants in CYP1A2 may be indicators for S-CIT metabolism and that the fast metabolizers may experience more severe adverse reactions in the early stages of S-CIT treatment. Original submitted 27 December 2012; Revision submitted 15 May 2013.

Apigenin, a flavonoid isolated from plants, provides protection against non-alcoholic fatty liver disease. However, the mechanism by which apigenin decreases lipid accumulation in the liver is unclear. In this study, we investigated the molecular mechanism underlying the beneficial effect of apigenin on the hepatic deregulation of lipid metabolism. Oleic acid (OA)-induced lipid accumulation in human hepatoma cells (Huh7 cells) was used as an in vitro model. Western blot analysis was used for evaluating protein expression. Oil red O staining, Nile red staining, and conventional assay kits were used to assess the level of lipids. Immunocytochemistry was performed to observe mitochondrial morphology. Seahorse XF analyzer was used to measure mitochondrial bioenergetics. Treatment with OA induced lipid accumulation in Huh7 cells, which was attenuated by apigenin. Mechanistically, treatment with apigenin increased the expression of autophagy-related proteins including Beclin1, autophagy related gene 5 (ATG5), ATG7, and LC3II, and the formation of autophagolysosomes, leading to an increase in intracellular levels of fatty acids. Inhibition of autophagy by bafilomycin A1 or chloroquine abolished the protection of apigenin in OA-induced lipid accumulation. Apigenin up-regulated the protein expression related to the β-oxidation pathway including acyl-CoA synthetase long chain family member 1, carnitine palmitoyltransferase 1α, acyl-CoA oxidase 1, peroxisome proliferator activated receptor (PPAR) α, and PPARγ coactivator 1-α. Moreover, apigenin increased the mitochondrial network structure and mitochondrial function by increasing the protein expression related to the process of mitochondria fusion and mitochondrial function. Collectively, our findings suggest that apigenin ameliorates hepatic lipid accumulation by activating the autophagy-mitochondrial pathway.