Wang XY, Liu F, Wang QT, Li SZ, Ye YZ, Chen T, Cai BC. Rhapontin activates nuclear factor erythroid 2-related factor 2 to ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced gastrointestinal dysfunction in Parkinson's disease mice. World J Gastroenterol 2025; 31(15): 104875 [PMID: 40309229 DOI: 10.3748/wjg.v31.i15.104875]
Corresponding Author of This Article
Ben-Chi Cai, Professor, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou 570100, Hainan Province, China. caibenchi@hainmc.edu.cn
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Neurosciences
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Basic Study
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Wang XY, Liu F, Wang QT, Li SZ, Ye YZ, Chen T, Cai BC. Rhapontin activates nuclear factor erythroid 2-related factor 2 to ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced gastrointestinal dysfunction in Parkinson's disease mice. World J Gastroenterol 2025; 31(15): 104875 [PMID: 40309229 DOI: 10.3748/wjg.v31.i15.104875]
World J Gastroenterol. Apr 21, 2025; 31(15): 104875 Published online Apr 21, 2025. doi: 10.3748/wjg.v31.i15.104875
Rhapontin activates nuclear factor erythroid 2-related factor 2 to ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced gastrointestinal dysfunction in Parkinson's disease mice
Xin-Yu Wang, Fang Liu, Qi-Tong Wang, Shu-Zhu Li, Yu-Zhao Ye, Tao Chen, Ben-Chi Cai
Xin-Yu Wang, Fang Liu, Qi-Tong Wang, Shu-Zhu Li, Yu-Zhao Ye, Tao Chen, Ben-Chi Cai, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou 570100, Hainan Province, China
Co-first authors: Xin-Yu Wang and Fang Liu.
Co-corresponding authors: Tao Chen and Ben-Chi Cai.
Author contributions: Chen T and Cai BC conceptualized and designed the research; Wan XY and Liu F screened patients and acquired clinical data; Wan XY and Liu F collected samples and performed laboratory analysis; Li SZ, Ye YZ, and Wang QT performed data analysis; Wan XY and Cai BC wrote the paper; All the authors have read and approved the final manuscript. Liu F was also responsible for patient screening, enrollment, collection of clinical data. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Both Chen T and Cai BC have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Cai BC applied for and obtained the funds for this research project. Cai BC conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript. Chen T was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, comprehensive literature search. This collaboration between Chen T and Cai BC is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by the Hainan Provincial Natural Science Foundation of China, No. 823MS133 and No. 821QN0979.
Institutional animal care and use committee statement: The animal study protocol was reviewed and approved by the Animal Ethics Committee of Hainan Medical University, No. 2024[148]. All animal procedures were conducted in accordance with the guidelines for the care and use of laboratory animals.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data that support the findings of this study are available from the corresponding author upon reasonable request at caibenchi@hainmc.edu.cn.
Corresponding author: Ben-Chi Cai, Professor, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan Medical University, No. 19 Xiuhua Road, Xiuying District, Haikou 570100, Hainan Province, China. caibenchi@hainmc.edu.cn
Received: January 5, 2025 Revised: February 24, 2025 Accepted: March 24, 2025 Published online: April 21, 2025 Processing time: 103 Days and 21.7 Hours
Abstract
BACKGROUND
Parkinson's disease (PD)-a progressive neurodegenerative disorder-is characterized by motor and gastrointestinal dysfunction. The exploration of novel therapeutic strategies for PD is vital.
AIM
To investigate the potential mechanism of action of rhapontin-a natural compound with known antioxidant and anti-inflammatory properties-in the context of PD.
METHODS
Network pharmacology was used to predict the targets and mechanisms of action of rhapontin in PD. Behavioral tests and tyrosine hydroxylase immunofluorescence analysis were used to assess the effect of rhapontin on symptoms and pathology in MPTP-induced mice. Interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and IL-10 levels in tissues were measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, nuclear factor erythroid 2-related factor 2 (NRF2) activation was confirmed using western blotting.
RESULTS
NRF2 was predicted to be the key transcription factor underlying the therapeutic effects of rhapontin in PD, and its anti-PD action may be associated with its anti-inflammatory and antioxidant properties. Rhapontin ameliorated the loss of dopaminergic neurons and gastrointestinal dysfunction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice by activating NRF2. Additionally, rhapontin treatment significantly decreased pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) in the substantia nigra, striatum, and colon, whereas it increased anti-inflammatory cytokine (IL-10) levels only in the colon, indicating the involvement of gut–brain axis in its neuroprotective potential. Finally, NRF2 was identified as a key transcription factor activated by rhapontin, particularly in the colon.
CONCLUSION
We elucidated the effects of rhapontin in MPTP-induced PD mouse models using a combination of network pharmacology analysis, behavioral assessments, immunofluorescence, ELISA, and Western blotting. Our findings revealed the multifaceted role of rhapontin in ameliorating PD through its anti-inflammatory and antioxidant properties, particularly by activating NRF2, paving the way for future research into targeted therapies for PD.
Core Tip: The specific objectives of this study are to identify key molecular targets of rhapontin, evaluate its impact on gastrointestinal symptoms in Parkinson's disease, and investigate its anti-inflammatory effects mediated by nuclear factor erythroid 2-related factor 2 activation.
