Amyloidogenic and Neuroinflammatory Molecular Pathways Are Contrasted Using Menaquinone 4 (MK4) and Reduced Menaquinone 7 (MK7R) in Association with Increased DNA Methylation in SK-N-BE Neuroblastoma Cell Line.

Besides its role in coagulation, vitamin K seems to be involved in various other mechanisms, including inflammation and age-related diseases, also at the level of gene expression. This work examined the roles of two vitamin K2 (menaquinones) vitamers, namely, menaquinone-4 (MK4) and reduced menaquinone-7 (MK7R), as gene modulator compounds, as well as their potential role in the epigenetic regulation of genes involved in amyloidogenesis and neuroinflammation. The SK-N-BE human neuroblastoma cells provided a "first-line" model for screening the neuroinflammatory and neurodegenerative molecular pathways. MK7R, being a new vitamin K form, was first tested in terms of solubilization, uptake and cell viability, together with MK4 as an endogenous control. We assessed the expression of key factors in amyloidogenesis and neuroinflammation, observing that the MK7R treatment was associated with the downregulation of neurodegeneration- (PSEN1 and BACE1) and neuroinflammation- (IL-1ß and IL-6) associated genes, whereas genes retaining protective roles toward amiloidogenesis were upregulated (ADAM10 and ADAM17). By profiling the DNA methylation patterns of genes known to be epigenetically regulated, we observed a correlation between hypermethylation and the downregulation of PSEN1, IL-1ß and IL-6. These results suggest a possible role of MK7R in the treatment of cognitive impairment, giving a possible base for further preclinical experiments in animal models of neurodegenerative disease.

The complex interplay between DNA methylation and miRNAs in gene expression regulation.

The short, non-coding RNAs, also called microRNAs (miRNAs) can bind complementary sequences on cellular mRNAs. The consequence of this binding is generally the degradation of mRNA and the inhibition of its translation. For this reason, miRNAs are included among the epigenetic factors acting as a modulator of gene expression. How miRNAs expression is, in turn, regulated is still the object of active investigation, but DNA methylation, another epigenetic modification, seems to play a central role in this sense. The "one-carbon" metabolism is responsible for the metabolic regulation of trans-methylation reactions and, therefore, DNA methylation. For this reason, to investigate the possible correlations between alterations of the one-carbon metabolism and differential DNA methylation sounds interesting. Moreover, recent evidence indicates that, vice-versa, miRNAs are associated with DNA methylation modulation, in a mutual cross-talk. The present review will discuss the interplay between miRNAs and DNA methylation and its fall-out on gene expression regulation.