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      Diosgenin is an exogenous activator of 1,25D 3-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice

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          Abstract

          The aim of this study was to investigate the effects and the mechanism of diosgenin, a famous plant-derived steroidal sapogenin, on memory deficits in Alzheimer's disease (AD) model mice. Diosgenin-treated 5XFAD mice exhibited significantly improved performance of object recognition memory. Diosgenin treatment significantly reduced amyloid plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Degenerated axons and presynaptic terminals that were only observed in regions closely associated with amyloid plaques were significantly reduced by diosgenin treatment. The 1,25D 3-membrane-associated, rapid response steroid-binding protein (1,25D 3-MARRS) was shown to be a target of diosgenin. 1,25D 3-MARRS knockdown completely inhibited diosgenin-induced axonal growth in cortical neurons. Treatment with a neutralizing antibody against 1,25D 3-MARRS diminished the axonal regeneration effect of diosgenin in Aβ(1–42)-induced axonal atrophy. This is the first study to demonstrate that the exogenous stimulator diosgenin activates the 1,25D 3-MARRS pathway, which may be a very critical signaling target for anti-AD therapy.

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          Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements

          Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol−1. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol−1. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol−1. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries. Figure Calculated structure of the complex ion [Ta6Cl12]2+ (footnote): Reference value in parenthesis Electronic supplementary material The online version of this article (doi:10.1007/s00894-007-0233-4) contains supplementary material, which is available to authorized users.
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            Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.

            Despite a growing body of evidence that Vitamin D is involved in mammalian brain functioning, there has been a lack of direct evidence about its role in the human brain. This paper reports, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. The receptor and the enzyme were found in both neurons and glial cells in a regional and layer-specific pattern. The VDR was restricted to the nucleus whilst 1alpha-OHase was distributed throughout the cytoplasm. The distribution of the VDR in human brain was strikingly similar to that reported in rodents. Many regions contained equivalent amounts of both the VDR and 1alpha-OHase, however the macrocellular cells within the nucleus basalis of Meynert (NBM) and the Purkinje cells in the cerebellum expressed 1alpha-OHase in the absence of VDR. The strongest immunohistochemical staining for both the receptor and enzyme was in the hypothalamus and in the large (presumably dopaminergic) neurons within the substantia nigra. The observed distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids. The widespread distribution of 1alpha-OHase and the VDR suggests that Vitamin D may have autocrine/paracrine properties in the human brain.
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              Target identification using drug affinity responsive target stability (DARTS).

              Identifying the molecular targets for the beneficial or detrimental effects of small-molecule drugs is an important and currently unmet challenge. We have developed a method, drug affinity responsive target stability (DARTS), which takes advantage of a reduction in the protease susceptibility of the target protein upon drug binding. DARTS is universally applicable because it requires no modification of the drug and is independent of the mechanism of drug action. We demonstrate use of DARTS to identify known small-molecule-protein interactions and to reveal the eukaryotic translation initiation machinery as a molecular target for the longevity-enhancing plant natural product resveratrol. We envisage that DARTS will also be useful in global mapping of protein-metabolite interaction networks and in label-free screening of unlimited varieties of compounds for development as molecular imaging agents.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                26 July 2012
                2012
                : 2
                : 535
                Affiliations
                [1 ]simpleDivision of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama , 2630 Sugitani, Toyama 930-0194, Japan
                [2 ]simpleDivision of International Cooperative Research, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama , 2630 Sugitani, Toyama 930-0194, Japan
                [3 ]simpleDepartment of Nutrition, Dietetics, and Food Sciences, Utah State University , Logan, Utah 84322, USA
                Author notes
                Article
                srep00535
                10.1038/srep00535
                3405293
                22837815
                3f2e60df-2bed-4656-b1e0-445b57d03281
                Copyright © 2012, Macmillan Publishers Limited. All rights reserved

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareALike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 22 May 2012
                : 09 July 2012
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