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Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aβ1-42 aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of 4-month-old APP/PS1 mice, but also significantly reduced the more severe deficits developed in the 9-month-old APP/PS1 mice in terms of spatial learning, reference memory, short-term recognition and spatial working memory. The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated 9-month-old APP/PS1 mice with increased expression of synaptic marker proteins. Evidence from atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA significantly reduces Aβ1-42 aggregation both in vitro and in vivo. Further, pre-incubating GA with oligomeric Aβ1-42 reduced Aβ1-42-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of Aβ1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and e-amino group of Lys16 is also critical for the disruption of Aβ1-42 S-shaped triple-β-motif and toxicity. Together, these studies demonstrated that GA can be further developed as a drug to treat AD through disrupting the formation of Aβ1-42 aggregation.

Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory.

Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aβ

Gastric carcinoma (GC) is the most common primary malignancy of the digestive tract, with increasing incidence in many countries. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess inhibition of HepG2 cell proliferation by 2'-hydroxyflavanone. The STAT3 pathway was performed. 2'-hydroxyflavanone reduced inhibitory effects on MGC-803 cell proliferation. 2'-hydroxyflavanone exhibited the highest inhibition rate. Treatment of MGC-803 cells with 400, 200, and 100 μg/ml 2'-hydroxyflavanone resulted in 88.9±0.7%, 81.2±0.5%, 68.4±0.5% decrease in cell viability, respectively, indicating an IC50 of 9.3 μg/ml. The 100 μg/ml 2'-hydroxyflavanone can significantly inhibit the STAT3 pathway activation. 2'-hydroxyflavanone inhibits MGC-803 cell proliferation by inhibiting STAT3 pathway activation. This extract is therefore a potential drug candidate for treatment of liver cancer.

Background. A precise understanding of immunological mechanisms is needed to prevent transplant vasculopathy. Methods. The developing process of transplant vasculopathy was investigated by retransplanting rat cardiac allografts and measuring the expressions of 21 different genes inside the retransplanted allografts under nonimmunosuppressive conditions. Results. Significant transplant vasculopathy developed if WKY hearts were grafted to LEW and retransplanted to WKY 5 days after the initial grafting, but it did not in allografts retransplanted 3 days after the initial grafting. The disease did not progress in retransplanted isografts or if nude rats were used as the initial recipients. However, the development of transplant vasculopathy was not affected by changing the second recipients to the Fl progeny of donor x recipient or to nude animals. Among the expressions of 21 different genes observed in allografts at 1, 14, 30, or 60 days after retransplantation, those of T-cell activation-related genes, such as interferon-γ and Fas ligand, showed the earliest and the most dramatic difference between 3- and 5-day-retransplanted allografts whereas macrophage/ monocyte activation-related genes showed little difference. Furthermore, reverse transcription-polymerase chain reaction analyses of allografts retransplanted to nude animal indicated that T cells of the initial recipient origin survive and remain activated even 60 days after retransplantation. Conclusions. The T-cell response occurring between 3 and 5 days after grafting was identified as the critical parameter to the disease progression. Once allo-reactive T cells enter a graft, they may be able to survive a long period and promote chronic rejection.

A doubly salient brushless high voltage DC power system, that is composed of a 12/8 pole electromagnetic doubly salient (EMDS) generator and a diode bridge rectifier, is developed in this paper. The operational principle of voltage regulating system under sudden load changes is analyzed, and the effect of the filter capacitance of tri-phase rectifying bridge on dynamic characteristics for the EMDS brushless DC generator system is also discussed here. In order to improve further the dynamic characteristic further, the PI algorithm which includes load-current forward compensating (LCFC) control is developed. Then, the proposed LCFC method was compared with traditional PI. The experimental results verify the theoretical analysis. The voltage change is reduced during loading and unloading transient processes. The developed control scheme can be extended to the other digital voltage regulation systems of DC generators

Purpose. We studied the gene expression in rat cardiac allografts retransplanted into (donor × recipient) F1 animals to identify unknown or unexpected genes whose expression might contribute to the progression of transplant vasculopathy. Methods. Gene expression was first studied using a mRNA differential display, then it was further investigated using quantitative reverse transcription–polymerase chain reaction and immunohistochemistry. Results. We found that the rat immunoglobulin kappa chain gene was preferentially induced in retransplanted cardiac allografts in which transplant vasculopathy was developing. The diseased vessels in the same allografts were heavily infiltrated with CD45R-positive B cells. The expression of two genes related to B-cell responses, B-lymphocyte chemoattractant, and CD40 ligand, showed a similar time course to that of the immunoglobulin kappa chain gene. We observed a heavy deposit of both IgM and IgG on the pathological neointima late in the development of transplant vasculopathy (i.e., 30 days after retransplantation) that was absent from the allografts immediately after retransplantation. Conclusion. During the development of transplant vasculopathy in a (donor × recipient) F1 environment, B cells were selectively recruited into the allografts and stimulated; meanwhile, antibodies against the pathological neointima were formed. These antibodies may be involved in the pathogenesis of transplant vasculopathy.

Background: Chemokine systems probably play a role in transplant vasculopathy; however, a comprehensive study of the expression of chemokines and their receptors in this disease has not been performed. Methods: The expression of all the rat chemokines and chemokine receptor genes for which the nucleotide sequences are known were quantitatively monitored using the fluorescence-based real-time reverse-transcriptase polymerase chain reaction technique, and selected cytokine–receptor pairs were determined using immunohistochemical staining. The analysis covered the whole time course of transplant vasculopathy in 2 different graft models (cardiac and aortic grafts) with 4 different strain combinations of rats. Results: Among the 13 receptor genes examined, the CXCR3, CCR5, and CCR2 genes and those of their corresponding ligands were selectively and strongly induced in grafts that develop transplant vasculopathy. The expression patterns of the receptors were similar in both cardiac and aortic allografts, although their induction and their absolute levels of expression were amplified several fold in the grafted aorta compared with heart grafts. The genes were induced before morphologic changes became apparent and expression was sustained during the whole period of neointimal formation. Interestingly, immunohistochemical staining for CXCR3 showed a unique pattern of expression: we found weak expression on cells in the outer layer of the neointima and adventitia and found the strongest staining in the innermost layer of the neointima. Conclusions: This study suggested diagnostic as well as potential functional roles of the chemokine–receptor pairs IP10-CXCR3, RANTES-CCR5, and MCP1-CCR2 in rat models of transplant vasculopathy.