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comment to 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 We are delighted to have read the article titled "Rhapontin activates nuclear factor erythroid 2-related factor 2 to ameliorate 1-methyl-4-phenyl-1,2,3,6-tetrahydr- opyridine-induced gastrointestinal dysfunction in Parkinson's disease mice" authored by Xin-Yu Wang’s team in the World Journal of Gastroenterology. Parkinson’s disease (PD) is a multicentric neurodegenerative disorder characterized by the accumulation and aggregation of alfa-synuclein (α-syn) in the substantia nigra in the central nervous system (CNS) and in other neural structures(1). It is the second most common and the most rapidly rising neurodegenerative disease in the world(2). While the exact causes behind the increasing incidence and prevalence of PD remain unclear, contributing factors may include longer life expectancy, declining smoking rates, and exposure to environmental pollutants and toxins(3). Among the earliest manifestations of PD are gastrointestinal (GI) symptoms, which often precede the onset of motor impairments. GI dysfunction in PD is closely linked to the gut-brain axis, reflecting the bidirectional communication between the CNS and the GI tract in both health and disease (4). However, there are still limitations in the research on the relationship between PD and GI dysfunction, and the specific molecular mechanism has not been fully elucidated. In this study, the findings of Xin-Yu Wang’s team provide valuable insights and innovative approaches for PD treatment. This paper represents the first systematic demonstration that rhapontin alleviates gut-brain axis dysfunction in PD by activating colonic NRF2, thereby offering a novel therapeutic target for the disease. By integrating network pharmacology predictions with experimental validation, this study enhances its scientific robustness and credibility. Furthermore, a key discovery of this study is that the anti-inflammatory effects of rhapontin are predominantly localized to the intestinal tract rather than being mediated through the brain-derived NRF2 pathway. This provides experimental evidence supporting the "enteric pathology hypothesis" of PD (5). Overall, these findings present critical theoretical support for rhapontin as a promising therapeutic agent for GI dysfunction in PD. However, we have several exploratory comments regarding certain aspects of the study. First, extensive research has established the critical role of the gut-brain axis in mediating GI dysfunction associated with PD through interconnected pathophysiological mechanisms. For example, gut microbiota dysbiosis can compromise intestinal barrier integrity, leading to a "leaky gut" phenomenon. This allows lipopolysaccharides (LPS) to trigger immune cell activation and the release of pro-inflammatory cytokines, which contribute to systemic inflammation and increased blood-brain barrier (BBB) permeability. Consequently, peripheral inflammatory signals can spread to the CNS, and after that, pathological α-syn will aggregate in the dorsal motor nucleus of the vagus nerve (DMV) and the substantia nigra. The levels of pathological α-syn also increase mitochondrial fragmentation in the DMV, ultimately leading to PD pathophysiology (6). Pathogenic α-syn may spread from the gut to the brain, leading to the degeneration of the nigrostriatal dopaminergic system, thus increasing the risk of developing PD (7, 8). Supporting this, animal studies have shown that fecal microbiota transplantation from PD patients induces α-syn aggregation and dopaminergic neuron loss (9). Additionally, gut microbiota also can regulate neurotransmitter homeostasis by modulating dopamine (DA) and serotonin production, while short-chain fatty acids (SCFAs) help mitigate intestinal inflammation, reduce oxidative stress, and enhance BBB integrity to protect DA neurons(6, 10-12). One of the characteristics of PD is the progressive loss of DA neurons in the substantia nigra pars compacta (13). Lastly, dysbiotic gut microbiome (dysbiome) can impair mitochondrial energy metabolism, trigger the TLR4/NF-κB pathway, and exacerbate oxidative stress, ultimately leading to the degeneration of nigral dopaminergic neurons (6). Collectively, these mechanisms form a core network through which the gut-brain axis contributes to PD pathogenesis. In this study, only studied the effect between rhapontin and the gastrointestinal dysfunction caused by PD, without systematically combining the gut-brain axis with PD for research. Additionally, although gut microbiota play a pivotal role in the gut-brain axis of PD, the study does not evaluate the influence of rhapontin on microbiota composition or function (14-16). It remains unclear whether rhapontin indirectly activates NRF2 or reduces inflammation by modulating specific microbial populations. Future studies could explore this by employing approaches such as 16S rRNA sequencing or metagenomics to assess changes in fecal microbiota composition, alongside quantifying microbiota-derived metabolites. Such investigations would provide deeper insights into the gut-brain axis dynamics and further elucidate rhapontin’s mechanisms of action. Secondly, rhapontin is a stilbenoid glucoside compound, found in medicinal plant of rhubarb rhizomes. Research into the anti-inflammatory mechanisms of rhapontin has revealed its multi-pathway synergistic effects. For example, in LPS-induced endothelial cell inflammation models, rhapontin effectively suppresses nitric oxide (NO) and TNF-α production while downregulating the expression of Inducible Nitric Oxide Synthase (iNOS), Cyclooxygenase-2 (COX-2), and NADPH Oxidase - related genes (NOX-related genes). These effects are primarily achieved by inhibiting the activation of key proteins in the Nuclear Factor-kappa B (NF-κB) and Mitogen - Activated Protein Kinase (MAPK) signaling pathways(17). In terms of antioxidant regulation, rhapontin activates the NRF2 signaling pathway, which reduces Tumor Necrosis Factor-alpha (TNF-α) and Matrix Metalloproteinase-2 (MMP-2) levels in diabetic retinopathy models, while enhancing the expression of Interleukin – 10 (IL-10) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and inhibiting NF-κB nuclear translocation(18). Its anti-fibrotic properties are mediated through dual mechanisms: activating Adenosine Monophosphate - Activated Protein Kinase (AMPK) and inhibiting the Transforming Growth Factor – beta (TGF-β)/Smad pathway, which helps reverse abnormal extracellular matrix deposition and prevents the progression of pulmonary fibrosis(19). Additionally, rhapontin has been shown to improve colonic epithelial barrier function via Sirtuin 1 (SIRT1) signaling activation(20). Together, these findings systematically highlight rhapontin's integrative therapeutic effects through coordinated modulation of NF-κB/MAPK, AMPK/TGF-β/Smad, and SIRT1 signaling networks, addressing inflammation, oxidative stress, and fibrosis. The current study demonstrated that rhapontin effectively reduces inflammation by decreasing the levels of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, while also activating the NRF2 signaling pathway to improve gastrointestinal function. However, the study did not explore rhapontin's potential role in preventing the progression of pulmonary fibrosis through AMPK activation and inhibition of the TGF-β/Smad pathway, nor did it investigate its effects on improving colonic epithelial barrier function via activation of the SIRT1 signaling pathway. Additionally, while network pharmacology was used to predict shared targets between PD and rhapontin, and the top 10 key targets were identified using a protein-protein interaction (PPI) network, the relationship between these targets and NRF2 remains poorly defined. Moreover, the study lacks detailed mechanistic insights into the specific signaling pathways associated with NRF2, including its upstream and downstream regulatory mechanisms—an area that requires further investigation. The article also does not clearly explain how NRF2 was identified as a key target. o address these research gaps, future studies could employ techniques such as Western blotting (WB) and co-immunoprecipitation (Co-IP) to validate the protein-protein interactions between rhapontin's potential targets and NRF2. Additionally, methods such as quantitative real-time polymerase chain reaction (qPCR) or RNA sequencing could be used to analyze downstream gene expression regulated by NRF2. These approaches would provide a more comprehensive understanding of the molecular mechanisms underlying rhapontin's anti-inflammatory effects, offering deeper insights into its therapeutic potential for PD. In evaluating the experimental section of this study, some points warrant further discussion. First, regarding the presentation of the results: Figure 2A does not clearly label which specific experimental group each result corresponds to, making interpretation challenging. Additionally, the WB image in Figure 5A lacks clarity and does not exhibit an obvious trend in the results, which may hinder the ability to draw definitive conclusions. Second, concerning the experimental methods: the study utilized only two approaches—the open field test and the pole-climbing test—to assess the motor abilities of mice. While these methods provide useful insight, they may be insufficient for a comprehensive evaluation of motor behavior in PD. Incorporating additional behavioral experiments, such as the Morris water maze, eight-arm radial maze, and elevated plus maze, could allow for a more thorough assessment of motor and cognitive functions in the mouse model (21). In summary, Wang XY’s team has conducted pioneering research, offering significant insights into the therapeutic potential of rhapontin for GI dysfunction in PD. This work is highly commendable, and we look forward to the authors addressing the aforementioned concerns in future studies through more detailed experimental design and exploration. Such efforts would further enhance the robustness and comprehensiveness of their findings. 1. Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW Neuropathology and molecular diagnosis of Synucleinopathies. Mol Neurodegener. 2021;16(1):83. 2. delete Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(11):939-53. 3. Bloem BR, Okun MS, Klein C Parkinson's disease. Lancet. 2021;397(10291):2284-303. 4. Gao V, Crawford CV, Burré J The Gut-Brain Axis in Parkinson's Disease. Cold Spring Harb Perspect Med. 2025;15(1). 5. Safarpour D, Sharzehi K, Pfeiffer RF Gastrointestinal Dysfunction in Parkinson's Disease. Drugs. 2022;82(2):169-97. 6. Munoz-Pinto MF, Candeias E, Melo-Marques I, Esteves AR, Maranha A, Magalhães JD, Carneiro DR, Sant'Anna M, Pereira-Santos AR, Abreu AE, Nunes-Costa D, Alarico S, Tiago I, Morgadinho A, Lemos J, Figueiredo PN, Januário C, Empadinhas N, Cardoso SM Gut-first Parkinson's disease is encoded by gut dysbiome. Mol Neurodegener. 2024;19(1):78. 7. Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S, Lee JH, Kim WR, Kook M, Foss CA, Shen C, Lee H, Kulkarni S, Pasricha PJ, Lee G, Pomper MG, Dawson VL, Dawson TM, Ko HS Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. Neuron. 2019;103(4):627-41.e7. 8. Van Den Berge N, Ferreira N, Gram H, Mikkelsen TW, Alstrup AKO, Casadei N, Tsung-Pin P, Riess O, Nyengaard JR, Tamgüney G, Jensen PH, Borghammer P Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol. 2019;138(4):535-50. 9. Tan AH, Lim SY, Lang AE The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic. Nat Rev Neurol. 2022;18(8):476-95. 10. Du J, Zhang P, Tan Y, Gao C, Liu J, Huang M, Li H, Shen X, Huang P, Chen S Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD). Mov Disord. 2024;39(8):1397-402. 11. Nishiwaki H, Hamaguchi T, Ito M, Ishida T, Maeda T, Kashihara K, Tsuboi Y, Ueyama J, Shimamura T, Mori H, Kurokawa K, Katsuno M, Hirayama M, Ohno K Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson's Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder. mSystems. 2020;5(6). 12. Wang Q, Luo Y, Ray Chaudhuri K, Reynolds R, Tan EK, Pettersson S The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options. Brain. 2021;144(9):2571-93. 13. Tolosa E, Garrido A, Scholz SW, Poewe W Challenges in the diagnosis of Parkinson's disease. Lancet Neurol. 2021;20(5):385-97. 14. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016;167(6):1469-80.e12. 15. Zhao Z, Ning J, Bao XQ, Shang M, Ma J, Li G, Zhang D Fecal microbiota transplantation protects rotenone-induced Parkinson's disease mice via suppressing inflammation mediated by the lipopolysaccharide-TLR4 signaling pathway through the microbiota-gut-brain axis. Microbiome. 2021;9(1):226. 16. Metta V, Leta V, Mrudula KR, Prashanth LK, Goyal V, Borgohain R, Chung-Faye G, Chaudhuri KR Gastrointestinal dysfunction in Parkinson's disease: molecular pathology and implications of gut microbiome, probiotics, and fecal microbiota transplantation. J Neurol. 2022;269(3):1154-63. 17. Li R, Chinnathambi A, Alharbi SA, Shair OHM, Veeraraghavan VP, Surapaneni KM, Rengarajan T Anti-inflammatory effects of rhaponticin on LPS-induced human endothelial cells through inhibition of MAPK/NF-κβ signaling pathways. J Biochem Mol Toxicol. 2021;35(5):e22733. 18. Shi Q, Cheng Y, Dong X, Zhang M, Pei C, Zhang M Effects of rhaponticin on retinal oxidative stress and inflammation in diabetes through NRF2/HO-1/NF-κB signalling. J Biochem Mol Toxicol. 2020;34(11):e22568. 19. Tao L, Cao J, Wei W, Xie H, Zhang M, Zhang C Protective role of rhapontin in experimental pulmonary fibrosis in vitro and in vivo. Int Immunopharmacol. 2017;47:38-46. 20. Wei W, Wang L, Zhou K, Xie H, Zhang M, Zhang C Rhapontin ameliorates colonic epithelial dysfunction in experimental colitis through SIRT1 signaling. Int Immunopharmacol. 2017;42:185-94. 21. Tuersong T, Wu QF, Chen Y, Shan Li P, Yong YX, Shataer M, Shataer S, Ma LY, Yang XL Integrated network pharmacology, metabolomics, and microbiome studies to reveal the therapeutic effects of Anacyclus pyrethrum in PD-MCI mice. Phytomedicine. 2025;142:156729.

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