Insights into the Hippocampus Proteomics Reveal Epigenetic Properties of Walnut-Derived Peptides in a Low-Grade Neuroinflammation Model

Epigenetic mechanisms that dysregulate gene expressions may play a significant role in the development of neurological disorders. However, whether peptides can modulate epigenetic mechanisms remains elusive. This work aimed to investigate the impact of pretreatment with walnut-derived peptides─WHP and YVLLPSPK─on DNA methylation in a low-grade neuroinflammation model. The enriched KEGG pathways included oxidative phosphorylation, riboflavin metabolism, ribosome, and pyrimidine metabolism, which are associated with methylation modification by oral administration of YVLLPSPK in mice with scopolamine-induced cognitive deficits. Furthermore, when THP-1 cells (human acute monocytic leukemia cell line) were exposed to lipopolysaccharide (LPS)-induced inflammation responses, both WHP and YVLLPSPK markedly inhibited the level of Il-6 to 2.05 ± 0.76 and 1.29 ± 0.19 (p < 0.05) and also declined the mRNA expression of Mcp-1 to 1.64 ± 0.02 and 3.29 ± 1.21 (p < 0.01), respectively. Meanwhile, YVLLPSPK decreased the activities of DNA methyltransferases (DNMTs) to 1.03 ± 0.02 and 1.20 ± 0.31 (p < 0.05) based on Dnmt3b and Tet2, respectively. The results indicated that YVLLPSPK modulated DNA methylation in embryonic and neural precursor cells in creating new methylation patterns. Further trials are needed to assess the mechanisms underlying DNA methylation changes through peptides in the pathophysiology of neurological disorders.