An Adequate Supply of Bis(ethylmaltolato)oxidovanadium(IV) Remarkably Reversed the Pathological Hallmarks of Alzheimer's Disease in Triple-Transgenic Middle-Aged Mice.

Alzheimer's disease (AD) is a complex and progressive neurodegenerative disease with impaired synapse, imbalanced mineral metabolism, protein mis-folding and aggregation. Bis(ethylmaltolato)oxidovanadium(IV) (BEOV), an organic bioactive vanadium compound with low toxicity and high bioavailability, has been studied as therapeutic agent against tuberculosis and diabetes. However, its neuroprotective effects have rarely been reported. Therefore, in this study, the potential application of BEOV in intervening AD cognitive dysfunction and neuropathology was evaluated. Both low- and high-dose of BEOV (0.2 mmol/L and 1.0 mmol/L) supplementation for 2 months improved the spatial learning and memory deficits of the triple-transgenic AD (3 × Tg AD) mice and mitigated the loss of synaptic proteins and synaptic dysfunction. By inhibiting the expression of amyloid-ß precursor protein and ß-secretase, and the phosphorylation of tau protein at Ser262, Ser396, Ser404, and Ser202/Thr205 residues, BEOV reduced the amyloid-ß deposition and neurofibrillary tangle formation in AD mouse brains and primarily cultured neurons. Further analysis of the brain ionome revealed that BEOV supplementation could significantly affect the concentrations of a variety of metals, most of which, including several AD risk metals, showed reduced levels, particularly with a high-dose intake. Additionally, the elemental correlation network identified both conserved and specific elemental correlations, implying a highly complex and dynamic crosstalk between vanadium and other elements during long-term BEOV supplementation. Overall, our results suggest that BEOV is effective in AD intervention via both ameliorating the disease related pathology and regulating metal homeostasis.

Transcriptional Regulation of Selenoprotein F by Heat Shock Factor 1 during Selenium Supplementation and Stress Response.

Changes of Selenoprotein F (SELENOF) protein levels have been reported during selenium supplementation, stressful, and pathological conditions. However, the mechanisms of how these external factors regulate SELENOF gene expression are largely unknown. In this study, HEK293T cells were chosen as an in vitro model. The 5'-flanking regions of SELENOF were analyzed for promoter features. Dual-Glo Luciferase assays were used to detect promoter activities. Putative binding sites of Heat Shock Factor 1 (HSF1) were predicted in silico and the associations were further proved by chromatin immunoprecipitation (ChIP) assay. Selenate and tunicamycin (Tm) treatment were used to induce SELENOF up-regulation. The fold changes in SELENOF expression and other relative proteins were analyzed by Q-PCR and western blot. Our results showed that selenate and Tm treatment up-regulated SELENOF at mRNA and protein levels. SELENOF 5'-flanking regions from -818 to -248 were identified as core positive regulatory element regions. Four putative HSF1 binding sites were predicted in regions from -1430 to -248, and six out of seven primers detected positive results in ChIP assay. HSF1 over-expression and heat shock activation increased the promoter activities, and mRNA and protein levels of SELENOF. Over-expression and knockdown of HSF1 showed transcriptional regulation effects on SELENOF during selenate and Tm treatment. In conclusion, HSF1 was discovered as one of the transcription factors that were associated with SELENOF 5'-flanking regions and mediated the up-regulation of SELENOF during selenate and Tm treatment. Our work has provided experimental data for the molecular mechanism of SELENOF gene regulation, as well as uncovered the involvement of HSF1 in selenotranscriptomic for the first time.