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 1,25D3-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS) was shown to be a target of diosgenin. 1,25D3-MARRS knockdown completely inhibited diosgenin-induced axonal growth in cortical neurons. Treatment with a neutralizing antibody against 1,25D3-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 1,25D3-MARRS pathway, which may be a very critical signaling target for anti-AD therapy.

We used a ribozyme loss-of-function approach to demonstrate that the protein product of a cDNA encoding a multifunctional membrane-associated protein binds the seco-steroid 1,25(OH)2D3 and transduces its stimulatory effects on phosphate uptake. These results are paralleled by studies in which the ability of the hormone to stimulate phosphate uptake in isolated chick intestinal epithelial cells is abolished by preincubation with Ab099 directed against the amino terminus of the protein. We now report the complete sequence of the cloned chicken cDNA for the 1,25D3-MARRS (membrane-associated, rapid-response steroid-binding) protein and reveal it to be identical to the multifunctional protein ERp57. Functional studies showed that active ribozyme, but not a scrambled control, decreased specific membrane-associated 1,25(OH)2D3 binding, but did not affect binding to the nuclear receptor for 1,25(OH)2D3. Seco-steroid-dependent stimulation of protein kinase C activity was diminished as 1,25D3-MARRS protein levels were reduced in the presence of the ribozyme, as judged by Western blot analyses. Phosphate uptake in isolated cells is an index of intestinal phosphate transport that occurs during growth and maturation. Whereas cells and perfused duodena robustly responded to 1,25(OH)2D3 in preparations from young birds, older animals no longer responded with stimulated phosphate uptake or transport. The age-related decline was accompanied by a decrease in 1,25D3-MARRS mRNA that was apparent up to 1 year of age. Together, these studies functionally link phosphate transport in the chick duodenum with the 1,25D3-MARRS protein and point to a previously uncharacterized role for this multifunctional protein class.

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As immune defects in amyloid-β (Aβ) phagocytosis and degradation underlie Aβ deposition and inflammation in Alzheimer’s disease (AD) brain, better understanding of the relation between Aβ phagocytosis and inflammation could lead to promising preventive strategies. We tested two immune modulators in peripheral blood mononuclear cells (PBMCs) of AD patients and controls: 1α,25(OH)2-vitamin D3 (1,25D3) and resolvin D1 (RvD1). Both 1,25D3 and RvD1 improved phagocytosis of FAM-Aβ by AD macrophages and inhibited fibrillar Aβ-induced apoptosis. The action of 1,25D3 depended on the nuclear vitamin D and the protein disulfide isomerase A3 receptors, whereas RvD1 required the chemokine receptor, GPR32. The activities of 1,25D3 and RvD1 commonly required intracellular calcium, MEK1/2, PKA, and PI3K signaling; however, the effect of RvD1 was more sensitive to pertussis toxin. In this case study, the AD patients: a) showed significant transcriptional up regulation of IL1RN, ITGB2, and NFκB; and b) revealed two distinct groups when compared to controls: group 1 decreased and group 2 increased transcription of TLRs, IL-1, IL1R1 and chemokines. In the PBMCs/macrophages of both groups, soluble Aβ (sAβ) increased the transcription/secretion of cytokines (e.g., IL1 and IL6) and chemokines (e.g., CCLs and CXCLs) and 1,25D3/RvD1 reversed most of the sAβ effects. However, they both further increased the expression of IL1 in the group 1, sβ-treated cells. We conclude that in vitro, 1,25D3 and RvD1 rebalance inflammation to promote Aβ phagocytosis, and suggest that low vitamin D3 and docosahexaenoic acid intake and/or poor anabolic production of 1,25D3/RvD1 in PBMCs could contribute to AD onset/pathology.

Calcium is an essential ion in all organisms and participates in a variety of structural and functional roles. Calcium (re)absorption occurs in epithelia, including the intestine, kidney, mammary glands, placenta, and gills of fish. Its transport is regulated by a complex array of processes that are mediated by hormonal, developmental, and physiological factors involving the gastrointestinal tract, bone, kidney, and the parathyroids. Here we review the calcium transport mechanisms-paracellular, which is energy independent, and transcellular, which is energy dependent-primarily focusing on the intestine. We provide a new perspective on the facilitated diffusion and vesicular transport models to account for the emerging concepts on transcellular calcium transport. Finally, we discuss how 1,25(OH)2D3 and parathyroid hormone regulate calcium transport.

ERp57/GRp58 is a thiol-protein disulphide oxidoreductase and has been studied in many clinically relevant systems, both as a chaperone protein and as a membrane receptor for the steroid hormone, 1,25(OH)2D3. Our laboratory investigates phenomena associated with rapid, membrane-initiated signaling by steroid hormones synthesized from vitamin D (cholecalciferol). We have recently reported that the cell surface receptor for the metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which we have termed the 1,25D3-MARRS (Membrane Associated, Rapid Response Steroid binding) receptor, is in fact identical to ERp57/GRp58. Here we review the dynamic role ERp57/GRp58/1,25D3-MARRS receptor plays in a variety of cellular processes. Starting with its structure at the DNA and protein levels, we review the available literature about its role as a chaperone protein, in immune function through the assembly of MHC class I molecules, DNA binding, and its function as the 1,25D3-MARRS receptor. Finally, we present the role it may play in relation to important disease states. While ERp57/GR58/1,25D3-MARRS receptor is a pivotal protein in many cell functions, it has yet to be determined whether-and to what extent-these phenomena are regulated by the vitamin D endocrine system. However, 1,25(OH)2D3 is involved in differentiation of certain cancer cells and in muscle function, and ERp57/1,25D3-MARRS protein has been reported to be involved in such processes. Thus, medicinal chemistry aimed at the 1,25D3-MARRS receptor in lymphocytes, cancer cells, bone, intestinal epithelia, and kidney may add to the current therapeutic regimens for various disease states.

The effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3) on calcium transport was studied in vascularly perfused duodena of normal, vitamin D-replete chicks. Addition of 130 pM 1,25(OH)2D3 to the perfusate resulted in a significant increase in 45Ca transport from the lumen to the vascular effluent within 14 min; the transport rate rose to 140% of levels in comparable preparations exposed for 40 min to vehicle. No effects of 1,25(OH)2D3 were noted on the back flux or transfer of 45Ca from the vascular effluent to the lumen. Vascular perfusion with 100 microM colchicine, an antimicrotubular agent, abolished the rapid lumen-to-vascular effluent effect of 1,25(OH)2D3 on 45Ca transport, relative to preparations exposed to the secosteroid and 100 microM lumicolchicine, (a light inactivated analog of colchicine). Colchicine did not, however, alter basal 45Ca transport rates. Addition of 130 pM 1,25(OH)2D3 to the lumenal compartment of normal chicks or vascular perfusion of duodena from vitamin D-deficient birds failed to increase 45Ca transport above control levels. Perfusion of duodena from normal chicks with 650 pM 1,25(OH)2D3 further increased calcium transport to 170% of levels observed in preparations treated with 130 pM steroid, and 210% of levels in controls. Although 15 nM vitamin D3 had no effect, in one series of experiments 125 nM 25-hydroxyvitamin D3 elicited vascular calcium levels that were 185% of controls at 40 min. These results suggest that 1,25(OH)2D3 can act in vitamin D-replete animals to produce rapid unidirectional calcium transport responses (through unknown mechanisms), as well as by interaction with intestinal nuclear receptors in D-deficient animals to promote induction of protein(s) that support long acting calcium transport responses.