Wuzi Yanzong Pill improves Parkinson's disease via miR-146a-5p/USP3/NF-κB axis.
Wuzi Yanzong Pill improves Parkinson's disease via miR-146a-5p/USP3/NF-κB axis.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Jinzhong, CN · Author affiliation
The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine/Research Center of Neurobiology, Shanxi University of Chinese Medicine, 030619 Jinzhong, China.Location evidence
Taiyuan, CN · Author affiliation
The First Affiliated Hospital, Shanxi University of Chinese Medicine, Taiyuan, 030024, China.Location evidence
Huashan, CN · Author affiliation
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200025, China.Location evidence
Shanghai, CN · Author affiliation
Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200025, China.Location evidence
A plain-language reading has not been prepared for this paper yet.
Original abstract
BACKGROUND AND PURPOSE: Neuroinflammation, characterized by dysregulated activation of microglia, is a hallmark of Parkinson's disease (PD). Nevertheless, therapeutic strategies aimed at the mechanism of inflammation resolution remain limited. STUDY DESIGN AND METHODS: This study integrated PD clinical cohorts, MPTP-induced and miR-146a-induced mouse models, as well as LPS-stimulated and miR-146a-activated cell models. Combined with omics analysis, behavioral detection and molecular biology experiments, we systematically evaluated the anti-inflammatory protective effects of Wuzi Yanzong Pills (WYP). The active plant metabolites of WYP were identified using a combination of UHPLC-Q-Exactive-MS/MS, AP-SMALDI Orbitrap MSI, and pharmacokinetic analysis. RESULTS: In PD patients, WYP significantly improved motor dysfunction, inhibited pro-inflammatory cytokines, and elevated neurotransmitter levels. Exosomal miRNA sequencing analysis indicated that miR-146a-5p may serve as a biomarker for PD and is positively correlated with disease severity. Animal experiments further showed that WYP improved motor symptoms and neuroinflammation in MPTP- and miR-146a-induced PD mice models. A dual-luciferase reporter assay confirmed ubiquitin specific peptidase 3 (USP3) as a direct target gene of miR-146a-5p. In an LPS-activated BV2 microglial cell model, WYP intervention reduced the content of miR-146a-5p in cell-derived exosomes and mitigated their pro-inflammatory damaging effects on neuronal cells. Component analysis revealed that 16 plant metabolites in WYP can enter the bloodstream, among which 11 can cross into the brain. Notably, geniposidic acid, hyperoside, kaempferol, protocatechuic acid, and schisandrol A significantly suppressed the expression of pro-inflammatory factors in BV2 cells, suggesting that they may be the main active components underlying the anti-inflammatory effects of WYP. CONCLUSION: WYP improves PD by regulating the miR-146a-5p/USP3/NF-κB pathway. Meanwhile, the active plant metabolites of WYP have been identified. These findings provide experimental evidence for WYP as a potential therapeutic agent for PD.