Gandouling induces GSK3β promoter methylation to improve cognitive impairment in Wilson's disease.

Autor: Tian L; The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, China; Key Laboratory of Xin'an Medicine Ministry of Education, Hefei, Anhui, 230031, China., Wu M; Wannan Medical College, Wuhu, 241000, China., Zhao C; The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, China., Wen Y; The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, China., Chen J; The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, China., Dong T; The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, China; Key Laboratory of Xin'an Medicine Ministry of Education, Hefei, Anhui, 230031, China. Electronic address: dongting@ahtcm.edu.cn.
Jazyk: angličtina
Zdroj: Journal of ethnopharmacology [J Ethnopharmacol] 2024 Nov 15; Vol. 334, pp. 118493. Date of Electronic Publication: 2024 Jun 24.
DOI: 10.1016/j.jep.2024.118493
Abstrakt: Ethnopharmacologic Significance: Cognitive impairment is a serious clinical manifestation of Wilson's disease (WD) in the nervous system. Gandouling (GDL) is a hospital preparation of the First Affiliated Hospital of Anhui University of Chinese Medicine. Previous studies have found that GDL has an ameliorative effect on cognitive impairment in WD.
Aim of the Study: We aimed to explore the molecular-level regulatory mechanisms underlying cognitive impairment in WD, and provide evidence supporting GDL as a promising candidate drug for the treatment of cognitive impairment in WD. We found that GSK3β was significantly up-regulated in the brain tissue of C3He-Atp7Btx-J/J (tx-j) mice in the WD gene mutant model, and the monomer components of GDL could combine well with GSK3β. Therefore, in this work, we used Behavioral tests, Hematoxylin and eosin (H&E), Nissl and Terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling(TUNEL) staining, Ultrastructural morphological observation by Transmission electron microscopy (TEM), bisulfite sequencing (BSP), Quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, immunofluorescence, network pharmacology, molecular docking, and related methods to study the effects of GDL in tx-j mice and HT22 cell to clarify the effect of GDL on cognitive impairment in WD.
Results: In this study, MWM, NOR, H&E, Nissl TUNEL and TEM results showed that GDL could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the HT22 cell experiment, the CCK-8 method showed that GDL increased the viability of copper-overloaded cell models. The study found that GSK3β may be a target of GDL for the treatment of WD cognitive impairment through network pharmacology. Western blot and qRT-PCR results confirmed that GDL significantly increased the expression of proteins and mRNA in DNMT1, Nrf2, and HO-1. BSP showed that GSK3β promoter methylation was lower in the Model group than in the control group, and the promoter methylation of GSK3β was further reduced after intraperitoneal injection with decitabine, and GDL could ameliorate this pathology.
Conclusion: GDL demonstrates a protective role by inducing GSK3β promoter methylatio, regulating the GSK3β/Nrf2 signaling pathway in WD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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