Lobetyolin, an anti-AD factor from the diet campanulaceae source, metabolism regulation and target exploration

doi:10.1007/s13659-025-00549-0

Abstract

Abstract: Bioactive compounds from food-compatible medicinal herbs have shown promise as preventive agents against age-related neurodegenerative conditions, particularly Alzheimer's disease (AD). The present work aimed to find Lobetyolin as a new suppressor of Aβ aggregation and its interventions on abnormal metabolism in AD. Aβ-expressing Caenorhabditis elegans (strain CL4176) and wild-type worms were employed to evaluate paralysis onset, lifespan, cerebral Aβ deposition, and intracellular reactive oxygen species (ROS) after Lobetyolin administration. Untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) metabolomics coupled with RNA-seq transcriptomics was carried out to profile systemic metabolic and gene-expression changes. Differential metabolites and transcripts were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and pathway-impact analyses; hub targets were prioritized by integrating enrichment scores with in-silico docking. Lobetyolin (12.5-50 μM) markedly protected C. elegans from Aβ-driven toxicity and oxidative stress. In CL2006 worms, β-amyloid deposits fell by 54.8 ± 9.4%, while paralysis in CL4176 was delayed by 20.9 ± 4.5%. Lifespan increased by up to 18.2% in CL4176 and 25.0% in wild-type N2 worms. Concomitantly, intracellular ROS declined maximally by 28.1 ± 8.9% (N2) and 22.4 ± 3.8% (CL4176). Integrative metabolomic-transcriptomic analyses, validated by RT-qPCR, revealed selective remodeling of glutathione metabolism: gst-38 expression was suppressed, whereas gst-1 was elevated. Lobetyolin confers neuroprotective and geroprotective benefits in vivo, primarily through reprogramming glutathione-centered redox metabolism and selectively modulating glutathione-S-transferases (GST) isoforms. These findings position Lobetyolin as a promising dietary lead compound for AD prevention and healthy aging interventions.

Key words: Lobetyolin, AD prevention, Metabolic intervention, Glutathione metabolism, gst-38, gst-1

摘要： Bioactive compounds from food-compatible medicinal herbs have shown promise as preventive agents against age-related neurodegenerative conditions, particularly Alzheimer's disease (AD). The present work aimed to find Lobetyolin as a new suppressor of Aβ aggregation and its interventions on abnormal metabolism in AD. Aβ-expressing Caenorhabditis elegans (strain CL4176) and wild-type worms were employed to evaluate paralysis onset, lifespan, cerebral Aβ deposition, and intracellular reactive oxygen species (ROS) after Lobetyolin administration. Untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) metabolomics coupled with RNA-seq transcriptomics was carried out to profile systemic metabolic and gene-expression changes. Differential metabolites and transcripts were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and pathway-impact analyses; hub targets were prioritized by integrating enrichment scores with in-silico docking. Lobetyolin (12.5-50 μM) markedly protected C. elegans from Aβ-driven toxicity and oxidative stress. In CL2006 worms, β-amyloid deposits fell by 54.8 ± 9.4%, while paralysis in CL4176 was delayed by 20.9 ± 4.5%. Lifespan increased by up to 18.2% in CL4176 and 25.0% in wild-type N2 worms. Concomitantly, intracellular ROS declined maximally by 28.1 ± 8.9% (N2) and 22.4 ± 3.8% (CL4176). Integrative metabolomic-transcriptomic analyses, validated by RT-qPCR, revealed selective remodeling of glutathione metabolism: gst-38 expression was suppressed, whereas gst-1 was elevated. Lobetyolin confers neuroprotective and geroprotective benefits in vivo, primarily through reprogramming glutathione-centered redox metabolism and selectively modulating glutathione-S-transferases (GST) isoforms. These findings position Lobetyolin as a promising dietary lead compound for AD prevention and healthy aging interventions.

关键词: Lobetyolin, AD prevention, Metabolic intervention, Glutathione metabolism, gst-38, gst-1

Wen Huang, Yihan Liu, Haixin Jiang, Dongxue Guo, Yi Song, Junqi Wang, Luqi Li, Qiang Zhang. Lobetyolin, an anti-AD factor from the diet campanulaceae source, metabolism regulation and target exploration[J]. Natural Products and Bioprospecting, 2025, 15(6): 64-64.

References

[1] Zheng S. Protective effect of Polygonatum sibiricum polysaccharide on D-galactose-induced aging rats model. Sci Rep. 2020;10:2246. https://doi.org/10.1038/s41598-020-59055-7.
[2] Gur?u F, Baldoni S, Prattichizzo F, Espinosa E, Amenta F, Procopio AD, et al. Anti-senescence compounds: a potential nutraceutical approach to healthy aging. Ageing Res Rev. 2018;46:14-31. https://doi.org/10.1016/j.arr.2018.05.001.
[3] Best L, Dost T, Esser D, Flor S, Gamarra AM, Haase M, et al. Metabolic modelling reveals the aging-associated decline of host-microbiome metabolic interactions in mice. Nat Microbiol. 2025;10:973-91. https://doi.org/10.1038/s41564-025-01959-z.
[4] Culley G, Henriques A, Hardy D, Wojcinski A, Chabert A, El Waly B, et al. Amyloid-beta peptide toxicity in the aged brain is a one-way journey into Alzheimer’s disease. Front Aging Neurosci. 2025. https://doi.org/10.3389/fnagi.2025.1569181.
[5] Chen Y, Onken B, Chen H, Xiao S, Liu X, Driscoll M, et al. Mechanism of longevity extension of Caenorhabditis elegans induced by pentagalloyl glucose isolated from Eucalyptus leaves. J Agric Food Chem. 2014;62:3422-31. https://doi.org/10.1021/jf500210p.
[6] Wang C, An J, Bai Y, Li H, Chen H, Ou D, et al. Tris(1,3-dichloro-2-propyl) phosphate accelerated the aging process induced by the 4-hydroxynon-2-enal response to reactive oxidative species in Caenorhabditis elegans. Environ Pollut. 2019;246:904-13. https://doi.org/10.1016/j.envpol.2018.12.082.
[7] Song X, Sun Y, Wang Z, Su Y, Wang Y, Wang X. Exendin-4 alleviates β-amyloid peptide toxicity via DAF-16 in a caenorhabditis elegans model of Alzheimer’s disease. Front Aging Neurosci. 2022;14:955113. https://doi.org/10.3389/fnagi.2022.955113.
[8] Markaki M, Tavernarakis N. Caenorhabditis elegans as a model system for human diseases. Curr Opin Biotechnol. 2020;63:118-25. https://doi.org/10.1016/j.copbio.2019.12.011.
[9] Long NP, Kang JS, Kim HM. Caenorhabditis elegans: a model organism in the toxicity assessment of environmental pollutants. Environ Sci Pollut Res Int. 2023;30:39273-87. https://doi.org/10.1007/s11356-023-25675-5.
[10] Zhang X, Kang X, Du L, Zhang L, Huang Y, Wang J, et al. Tanshinone IIA loaded chitosan nanoparticles decrease toxicity of β-amyloid peptide in a Caenorhabditis elegans model of Alzheimer’s disease. Free Radic Biol Med. 2022;193:81-94. https://doi.org/10.1016/j.freeradbiomed.2022.09.030.
[11] Sánchez-Martínez JD, Cifuentes A, Valdés A. Omics approaches to investigate the neuroprotective capacity of a Citrus sinensis (sweet orange) extract in a Caenorhabditis elegans Alzheimer’s model. Food Res Int. 2023;172:113128. https://doi.org/10.1016/j.foodres.2023.113128.
[12] Fan WY, Fan XX, Xie YJ, Yan XD, Tao MX, Zhao SL, et al. Research progress on the anti-aging effects and mechanisms of polysaccharides from chinese herbal medicine. Food Med Homol. 2025. https://doi.org/10.26599/FMH.2026.9420108.
[13] Wang D, Li X, Miao Y, Zhang Q. Profiling chemobiological connection between natural product and target space based on systematic analysis. Int J Mol Sci. 2023;24:11265. https://doi.org/10.3390/ijms241411265.
[14] Liu Y, Zhang X, Wang Y, Wang J, Wei H, Zhang C, et al. Cyclocodon lancifolius fruit prolongs the lifespan of Caenorhabditis elegans via antioxidation and regulation of purine metabolism. Food Funct. 2024;15:3353-64. https://doi.org/10.1039/d3fo02931j.
[15] Guan Y, Du Z, Gao N, Cao Y, Wang X, Scott P, et al. Stereochemistry and amyloid inhibition: asymmetric triplex metallohelices enantioselectively bind to Aβ peptide. Sci Adv. 2018;4:eaao6718. https://doi.org/10.1126/sciadv.aao6718.
[16] Zhi D, Wang D, Yang W, Duan Z, Zhu S, Dong J, et al. Dianxianning improved amyloid β-induced pathological characteristics partially through DAF-2/DAF-16 insulin like pathway in transgenic C. elegans. Sci Rep. 2017;7:11408. https://doi.org/10.1038/s41598-017-11628-9.
[17] Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, et al. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006;26:13102-13. https://doi.org/10.1523/JNEUROSCI.3448-06.2006.
[18] Zhang Z-P, Bai X, Cui W-B, Chen X-H, Liu X, Zhi D-J, et al. Diterpenoid caesalmin c delays Aβ-induced paralysis symptoms via the DAF-16 pathway in Caenorhabditis elegans. Int J Mol Sci. 2022;23:6871. https://doi.org/10.3390/ijms23126871.
[19] Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nat. 2000;408:239-47. https://doi.org/10.1038/35041687.
[20] Ni S-H, OuYang X-L, Liu X, Lin J-H, Li Y, Sun S-N, et al. A molecular phenotypic screen reveals that Lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting Osteopontin. Phytomedicine. 2022;107:154412. https://doi.org/10.1016/j.phymed.2022.154412.
[21] Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20:148-60. https://doi.org/10.1038/s41583-019-0132-6.
[22] Birla H, Minocha T, Kumar G, Misra A, Singh SK. Role of oxidative stress and metal toxicity in the progression of Alzheimer’s disease. Curr Neuropharmacol. 2020;18:552-62. https://doi.org/10.2174/1570159X18666200122122512.
[23] Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26:9057-68. https://doi.org/10.1523/JNEUROSCI.1469-06.2006.
[24] Polimanti R, Piacentini S, Porreca F, Fuciarelli M. Glutathione s-transferase omega class (GSTO) polymorphisms in a sample from Rome (central Italy). Ann Hum Biol. 2010;37:585-92. https://doi.org/10.3109/03014460903508520.
[25] Maurya PK, Rizvi SI. Age-dependent changes in Glutathione-S-Transferase: correlation with total plasma antioxidant potential and red cell intracellular glutathione. Ind J Clin Biochem. 2010;25:398-400. https://doi.org/10.1007/s12291-010-0047-5.
[26] Cheng L, Zhai H, Du J, Zhang G, Shi G. Lobetyolin inhibits cell proliferation and induces cell apoptosis by downregulating ASCT2 in gastric cancer. Cytotechnology. 2023;75:435-48. https://doi.org/10.1007/s10616-023-00588-w.
[27] Wang J, Liu X, Wei W, Yang J, Li Q, Chu S, et al. Regulation of oxygen-glucose deprivation/reperfusion-induced inflammatory responses and M1-M2 phenotype switch of BV2 microglia by lobetyolin. Metab Brain Dis. 2023;38:2627-44. https://doi.org/10.1007/s11011-023-01292-6.
[28] Hou Y-Y, Qi S-M, Leng J, Shen Q, Tang S, Zhang J-T, et al. Lobetyolin, a Q-marker isolated from Radix Platycodi, exerts protective effects on cisplatin-induced cytotoxicity in HEK293 cells. J Nat Med. 2023;77:721-34. https://doi.org/10.1007/s11418-023-01714-w.
[29] Zhao F, Fan L, Yang J, Yang M, Zhang C, Wang F, et al. Heterologous expression of BACE1 and its interaction with Codonopsis pilosula polysaccharides and lobetyolin. Int J Biol Macromol. 2024;277:133440. https://doi.org/10.1016/j.ijbiomac.2024.133440.
[30] Dumlu MU, Gurkan E, Tuzlaci E. Chemical composition and antioxidant activity of Campanula alliariifolia. Nat Prod Res. 2008;22:477-82. https://doi.org/10.1080/14786410701640429.
[31] Chen JJ, Thiyagarajah M, Song J, Chen C, Herrmann N, Gallagher D, et al. Altered central and blood glutathione in Alzheimer’s disease and mild cognitive impairment: a meta-analysis. Alzheimers Res Ther. 2022;14:23. https://doi.org/10.1186/s13195-022-00961-5.
[32] Xiang J, Tian S, Wang S, Liu Y, Li H, Peng B. Pyruvate abundance confounds aminoglycoside killing of multidrug-resistant bacteria via glutathione metabolism. Res. 2024;7:0554. https://doi.org/10.34133/research.0554.
[33] Xiang X, Wang X, Jin S, Hu J, Wu Y, Li Y, et al. Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer’s disease induced by Aβ1-42 through inhibiting RhoA/ROCK2 pathway. Prog Neuropsychopharmacol Biol Psychiatry. 2022;112:110423. https://doi.org/10.1016/j.pnpbp.2021.110423.
[34] Bailly C. Anticancer properties of Lobetyolin, an essential component of Radix Codonopsis (Dangshen). Nat Prod Bioprospect. 2021;11:143-53. https://doi.org/10.1007/s13659-020-00283-9.
[35] Ishimaru K, Yonemitsu H, Shimomura K. Lobetyolin and lobetyol from hairy root culture of Lobelia inflata. Phytochemistry. 1991;30:2255-7. https://doi.org/10.1016/0031-9422(91)83624-t.
[36] Tang Z, Zhao Z, Chen S, Lin W, Wang Q, Shen N, et al. Dragon fruit-kiwi fermented beverage: in vitro digestion, untargeted metabolome analysis and anti-aging activity in Caenorhabditis elegans. Front Nutr. 2022;9:1052818. https://doi.org/10.3389/fnut.2022.1052818.
[37] DanQing L, YuJie G, ChengPeng Z, HongZhi D, Yi H, BiSheng H, et al. N-butanol extract of Hedyotis diffusa protects transgenic Caenorhabditis elegans from Aβ-induced toxicity. Phytother Res. 2021;35:1048-61. https://doi.org/10.1002/ptr.6871.
[38] Zhang A-N, Huang C, Yan L, Liu X, Wang F, Zhang Z, et al. Metabolic regulation and antihyperglycemic properties of diet-derived PGG through transcriptomic and metabolomic profiling. Food Funct. 2023;14:5620-30. https://doi.org/10.1039/d3fo00997a.
[39] Liu Y, Deng Y, Wang F, Liu X, Wang J, Xiao J, et al. A new mechanism for ginsenoside Rb1 to promote glucose uptake, regulating riboflavin metabolism and redox homeostasis. Metabolites. 2022;12:1011. https://doi.org/10.3390/metabo12111011.
[40] Pang Z, Xu L, Viau C, Lu Y, Salavati R, Basu N, et al. Metaboanalystr 4.0: a unified LC-MS workflow for global metabolomics. Nat Commun. 2024;15:3675. https://doi.org/10.1038/s41467-024-48009-6.
[41] Picart-Armada S, Fernández-Albert F, Vinaixa M, Yanes O, Perera-Lluna A. FELLA: an R package to enrich metabolomics data. BMC Bioinform. 2018;19:538. https://doi.org/10.1186/s12859-018-2487-5.