Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in the brain of AßPP transgenic mice.

In addition to its function in calcium and bone metabolism, vitamin D is neuroprotective and important for mitigating inflammation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterized by neuronal loss in many areas of the brain, and the formation of senile (neuritic) plaques, which increase in number and size over time. The goal of this project was to investigate whether vitamin D3 supplementation would affect amyloid plaque formation in amyloid-ß protein precursor (AßPP) transgenic mice that spontaneously develop amyloid plaques within 3-4 months of birth. AßPP mice were fed control, vitamin D3-deficient or vitamin D3-enriched diets for five months, starting immediately after weaning. At the end of the study, the animals were subjected to behavioral studies, sacrificed, and examined for bone changes and brain amyloid load, amyloid-ß (Aß) peptide levels, inflammatory changes, and nerve growth factor (NGF) content. The results obtained indicate that a vitamin D3-enriched diet correlates with a decrease in the number of amyloid plaques, a decrease in Aß peptides, a decrease in inflammation, and an increase in NGF in the brains of AßPP mice. These observations suggest that a vitamin D3-enriched diet may benefit AD patients.

Repressors NFI and NFY participate in organ-specific regulation of von Willebrand factor promoter activity in transgenic mice.

OBJECTIVE: To determine the role of repressors in cell type and organ-specific activation of von Willebrand factor (VWF) promoter sequences -487 to 247 in vivo. METHODS AND RESULTS: Activation patterns of wild-type and mutant VWF promoters (sequences -487 to 247) containing mutations in repressors nuclear factor-I (NFI)- and nuclear factor Y (NFY)-binding sites were analyzed in transgenic mice. Mutation of the NFI-binding site activated the promoter in heart and lung endothelial cells, whereas mutation of the NFY-binding site activated the promoter in kidney vasculature. Immunofluorescence analyses showed that NFIB was predominant in heart and lung endothelial cells, whereas NFIX was predominantly detected in kidney endothelial cell nuclei. By using chromatin immunoprecipitation, we demonstrated that the distal lung-specific enhancer (containing a YY1 site) of the VWF gene is brought in proximity to the NFI binding site. CONCLUSIONS: The NFI and NFY repressors contribute differentially to organ-specific regulation of the VWF promoter, and the organ-specific action of NFI may reflect its organ-specific isoform distribution. In addition, the lung-specific enhancer region of the endogenous VWF gene may inhibit NFI repressor function through chromatin looping, which can approximate the 2 regions.

Identification of Yin Yang 1-interacting partners at -1026C/A in the human iNOS promoter.

Previously we demonstrated the association between human iNOS -1026C/A variant and susceptibility to hypertension, and found that -1026C/A altered the Yin Yang 1 (YY1)-binding pattern. In the current study, we verified that -1026C/A was located in a vital regulatory region of the iNOS promoter, wherein existed a DNA-binding complex composed of YY1, nuclear factor I (NFI) and activator protein-1 (AP-1). We also observed that YY1 bound dominantly to -1026C, and NFI bound dominantly to -1026A. Furthermore, the repressive effect of YY1 was more evident than NFI on the iNOS promoter activity, resulting in a more marked reduction of iNOS expression via YY1/AP-1 than via NFI/AP-1 under the stimulation of cytomix. In conclusion, diverse binding affinities of YY1 and its interacting partners to iNOS -1026C/A resulted in differential promoter activity, and potent inhibition of iNOS expression by YY1/AP-1 complex with -1026C may contribute to an enhanced risk for hypertension.