Mangiferin Protects DNase 2 Abundance via Nrf2 Activation to Prevent Cytosolic mtDNA Accumulation during Liver Injury.
Mol Nutr Food Res
; 67(14): e2200885, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37160728
ABSTRACT
SCOPE Mitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage-associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aims to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on deoxyribonuclease 2 (DNase 2) protection from oxidative damage. METHODS AND RESULTS:
Mangiferin administration effectively protects against hepatotoxicity in mice subjected to CCl4 challenge or bile duct ligation (BDL) surgery. Moreover, mangiferin activates nuclear factor erythroid 2-related factor (Nrf2)-antioxidant signaling, reduces cytosolic mtDNA accumulation, and suppresses Toll-like receptor 9 (TLR-9)/myeloid differentiation factor 88 (MyD88)-dependent inflammation in the liver. The study prepares hepatic mtDNA to stimulate hepatocytes, and finds that mangiferin protects DNase 2 protein abundance. mtDNA induces reactive oxygen species (ROS) production to promote DNase 2 protein degradation through oxidative modification, but mangiferin protects DNase 2 protein stability in a Nrf2-dependent manner. In hepatic Nrf2 deficiency mice, the study further confirms that Nrf2 induction is required for mangiferin to clear cytosolic mtDNA and block mtDNA-mediated TLR9/MyD88/nuclear factor kappa-B (NF-κB) inflammatory signaling cascades.CONCLUSION:
These findings provide new insights into the role of mangiferin as a liver protecting agent, and suggest protection of DNase 2 as a novel therapeutic strategy for pharmacological intervention to prevent liver damage.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Fator 2 Relacionado a NF-E2
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article