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Objectives: Arctigenin (ATG) is a natural product with a variety of biological activity, which can improve the pathological changes of Alzheimer's disease (AD) model mice through multiple mechanisms. This study aims to further elucidate the potential mechanism by which ATG improves memory impairment in AD mice. Methods: Here, we used pR5 mice as an experimental model, and ATG was administered continuously for 90 days. Novel object recognition, Y-maze, and Morris water maze were used to evaluate the therapeutic effect of ATG on memory impairment in AD mice. Immunohistochemical and immunofluorescence analyses were used to evaluate the effects of ATG on tau hyperphosphorylation and neuroinflammation, respectively. Finally, proteomics techniques were used to explore the possible mechanism of ATG. Key findings: ATG significantly improved memory impairment in pR5 mice and inhibited tau phosphorylation in the hippocampus and neuroinflammation in the cortex. According to the proteomic analysis, the altered cognitive function of ATG was associated with the proteins of the tricarboxylic acid cycle and the electron transport chain. Conclusion: These results suggest that ATG is a potential therapeutic agent for diseases related to aberrant energy metabolism that can treat AD by improving mitochondrial function. [ABSTRACT FROM AUTHOR]

Dermatomyositis ( DM) is a polygenic disorder characterized by inflammation of skeletal muscle and skin. To date, the exact etiopathogenesis of DM remains elusive. To explore the genetic basis of DM, we conducted genome-wide genotyping analysis of 127 patients and 1566 healthy controls by Illumina Human OmniZhongHua-8 BeadChips in the Chinese Han population. We investigated whether the three SNP (, and ) at 6p21.32 in the HLA- DPB1 gene were significantly associated with DM ( P < 5 × 10−8) and identified two susceptibility loci at 7q34 ( PIP, , P = 7.45 × 10−7, odds ratio [ OR] = 2.71) and 10q24.2 ( CPN1, , P = 9.04 × 10−7, OR = 4.39) with suggestive evidence. We imputed 6674 classical human leukocyte antigen ( HLA) alleles, amino acids and SNP from the discovery dataset, and stepwise analysis revealed that HLA- DPB1*17 in class II HLA genes were significantly associated with DM susceptibility. This study represents the first genome-wide association study ( GWAS) of DM in the Chinese Han population. For the first time, HLA- DPB1 was found to be associated with DM in this population. Moreover, we identified two novel suggestive susceptibility loci ( PIP and CPN1) and confirmed four previously reported genes ( DMB, DQA1, DQB1 and DRB1) having potential associations with DM in the Chinese Han population. Our GWAS results in this population should provide important information regarding the genetic etiopathogenesis of DM and facilitate the development of new therapies for the treatment of DM and the prevention of DM progression. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether modified acidic fibroblast growth factor (MaFGF) can protect NRK52E cell against apoptotic death induced by actinomycin D (Act D) and the effect of MaFGF on PI3K/Akt signaling pathway. Methods: NRK52E cell apoptotic death was measured by several methods including cell morphologic observation, Hoechst 33342 staining and flow cytometry. In addition, the levels of phosphorylated-Akt protein were analyzed by Western blotting method. Results: The results showed that 0.75 mg/L Act D-treated NRK52E cell for 20 h was the optimal conditions for establishing NRK52E cell apoptotic model. Different doses of MaFGF (0.01, 0.03, 0.1, 0.3 and 1.0 mg/L) decreased apoptotic rate but enhanced the expression of phosphorylated Akt protein. However, MaFGF's protection against Act D-induced apoptosis was significantly (p < 0.05) prevented when NRK52E cells were exposed to wortmannin. Conclusion: These results reveal that MaFGF can reduce the level of ActD-induced apoptotic cell death in 20 h, and the protective mechanism of MaFGF may be associated with the activation of PI3K/Akt signaling pathway by up-regulation of expression of phosphorylated Akt protein. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia and beta-amyloid (Abeta) overproduction are critical etiological and pathological factors in Alzheimer disease, respectively; however, the intrinsic link between them is still missing. Here, we found that Abeta levels increased and amyloid precursor protein (APP) levels simultaneously decreased in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine. Concurrently, both the mRNA and protein levels of presenilin-1, a component of gamma-secretase, were elevated, whereas the expression levels of beta-secretase and presenilin-2 were not altered. We also observed that levels of phosphorylated APP at threonine-668, a crucial site facilitating the amyloidogenic cleavage of APP, increased in rats with hyperhomocysteinemia, although the phosphorylation per se did not increase the binding capacity of pT668-APP to the secretases. The enhanced phosphorylation of APP in these rats was not relevant to either c-Jun N-terminal kinase or cyclin-dependent kinase-5. A prominent spatial memory deficit was detected in rats with hyperhomocysteinemia. Simultaneous supplementation of folate and vitamin-B12 attenuated the hyperhomocysteinemia-induced abnormal processing of APP and improved memory. Our data revealed that hyperhomocysteinemia could increase Abeta production through the enhanced expression of gamma-secretase and APP phosphorylation, causing memory deficits that could be rescued by folate and vitamin-B12 treatment in these rats. It is suggested that hyperhomocysteinemia may serve as an upstream factor for increased Abeta production as seen in patients with Alzheimer disease.