Mecp2 promotes the anti‐inflammatory effect of alpinetin via epigenetic modification crosstalk

Abstract

In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti‐inflammatory agents, alpinetin has shown promising anti‐inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti‐inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF‐KB family) and p300 (a type of co‐activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti‐inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti‐inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2′s anti‐inflammatory assistance. In conclusion, Mecp2 may augment the anti‐inflammatory effects of alpinetin through epigenetic ‘crosstalk’, highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti‐inflammatory intervention.