Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of beta-amyloid peptides (A beta) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma A beta and a decrease in brain A beta monomer after 7 d, indicating increased transport of A beta from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the A beta-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain A beta levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain A beta. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain A beta, indicating that increase in liver LRP and sLRP occurring independent of A beta concentration could result in clearance of A beta. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for A beta clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.

Vertical uplift resistance of two horizontal strip anchors with common vertical axis

With an application of the upper bound finite element limit analysis, the vertical pullout capacity of a group of two horizontal strip plate anchors, with the common vertical axis and placed in a cohesive-frictional soil, has been computed. The variation of the uplift factors Fc, Fq and Fy, due to the contributions of soil cohesion, surcharge pressure and unit weight, respectively, has been evaluated for different combinations of S/B and H/B. As compared to single isolated anchor, the group of two anchors generates significantly greater magnitude of Fc for Φ ≤ 20° especially with greater values of H/B and under fully bonded anchor-soil interface condition. The factor Fc attains almost the maximum value when the upper anchor plate is placed midway between ground surface and the lower anchor plate. The factors Fq and Fy, on the other hand, for a group of two anchors are found to remain almost equal to that of a single isolated anchor as long as the levels of the lower plate in the group and the single isolated anchor are kept the same.