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Paeonol Inhibits the MAPK Signaling Pathway by Targeting SIRT1 in AGE-Induced HUVECs Injury
Dingkun Liu1, Hongrui Gao1, Xiaochun Wu1
1School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
Combinatorial Chemistry & High Throughput Screening
|March 28, 2025
Summary
Paeonol effectively reduces diabetic endothelial injury by targeting the SIRT1-MAPK pathway. This natural compound shows promise in treating diabetes-related vascular complications.
Area of Science:
- Endocrinology
- Molecular Biology
- Pharmacology
Background:
- Diabetes-induced chronic hyperglycemia causes endothelial injury via oxidative stress.
- Paeonol is investigated for its potential to mitigate this damage by reducing oxidative stress.
- This study explores paeonol's effects on diabetic endothelial dysfunction and its underlying mechanisms.
Purpose of the Study:
- To investigate the protective effects of paeonol against advanced glycation end product (AGE)-induced endothelial injury.
- To elucidate the molecular mechanisms by which paeonol exerts its protective effects.
- To identify key molecular targets and signaling pathways involved in paeonol's action.
Main Methods:
- Developed a novel human umbilical vein endothelial cell (HUVEC) model using AGEs.
- Utilized network analysis to identify paeonol's molecular targets.
- Validated key targets using polymerase chain reaction (PCR), western blot, and immunofluorescence staining.
- Employed small interfering RNA (siRNA) to confirm SIRT1's role in AGEs-induced injury.
Main Results:
- Detected twelve paeonol metabolites in vivo.
- Paeonol significantly reduced levels of AGEs, Col IV, ET-1, E-selectin, FN, hs-CRP, ICAM-1, MMP2, and sVCAM-1.
- Network analysis highlighted the mitogen-activated protein kinase (MAPK) signaling pathway.
- Paeonol increased SIRT1 and ERK expression while decreasing p38MAPK expression in a dose-dependent manner.
Conclusions:
- Paeonol inhibits p38 and ERK activation within the MAPK signaling pathway.
- SIRT1 is crucial for paeonol's suppressive effect on the MAPK pathway, as demonstrated by compromised efficacy after SIRT1 silencing.
- SIRT1 holds therapeutic potential for diabetic endothelial impairment and associated cardiovascular risks.
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