Skip to content
2000
Volume 26, Issue 2
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Objective

Timosaponin AIII, with poorly soluble characteristics, has a potential antidiabetic effect evaluated and . The major problem associated with poorly soluble drugs is very low bioavailability. This study aimed to investigate the metabolic profiles and antidiabetic mechanism of Timosaponin AIII.

Materials and Methods

The metabolic profiles of Timosaponin AIII in intestinal flora were analyzed using LC-MS/MS. Based on mass spectrometry analysis, network pharmacology combined with the GEO database was used to identify potential targets and elucidate the antidiabetic mechanism. Finally, the stability of compound-target complexes was further functionally confirmed by molecular docking.

Results

As a result, 13 metabolites were identified. After the compound-target network, the genes of its metabolites increased by 60 compared to those of Timosaponin AIII. Subsequently, 13 core targets related to antidiabetic efficacy were identified through PPI network analysis. Key genes EGFR, MAPK1, and ICAM1 with strong binding efficiencies with metabolites were identified as crucial targets for the therapeutic effects of Timosaponin AIII. The KEGG analysis indicated that timosaponin AIII combated diabetes through various signaling pathways, including PI3K-Akt, FoxO, and HIF-1 signaling pathways, .

Conclusion

Taken together, this study clarified the mechanism of Timosaponin AIII against diabetes by identifying additional targets and pathways, and the importance of glycosidic structures. Otherwise, we might provide a solid foundation for the development of clinical applications of Timosaponin AIII.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdm/10.2174/0113892002357684250527113902
2025-06-11
2026-01-20

  • From This Site

    /content/journals/cdm/10.2174/0113892002357684250527113902
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. CanivellS. GomisR. Diagnosis and classification of autoimmune diabetes mellitus.Autoimmun. Rev.2014134-540340710.1016/j.autrev.2014.01.020 24424179
     [Google Scholar]
  2. PuavilaiG. ChanprasertyotinS. SriphrapradaengA. Diagnostic criteria for diabetes mellitus and other categories of glucose intolerance: 1997 criteria by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ADA), 1998 WHO Consultation criteria, and 1985 WHO criteria.Diabetes Res. Clin. Pract.1999441212610.1016/S0168‑8227(99)00008‑X 10414936
     [Google Scholar]
  3. SunY. TaoQ. WuX. ZhangL. LiuQ. WangL. The utility of exosomes in diagnosis and therapy of diabetes mellitus and associated complications.Front. Endocrinol.20211275658110.3389/fendo.2021.756581 34764939
     [Google Scholar]
  4. DuarteA.A. MohsinS. GolubnitschajaO. Diabetes care in figures: Current pitfalls and future scenario.EPMA J.20189212513110.1007/s13167‑018‑0133‑y 29896313
     [Google Scholar]
  5. TongX.L. DongL. ChenL. ZhenZ. Treatment of diabetes using traditional Chinese medicine: Past, present and future.Am. J. Chin. Med.201240587788610.1142/S0192415X12500656 22928822
     [Google Scholar]
  6. ZhouJ. WangQ. XiangZ. TongQ. PanJ. WanL. ChenJ. Network pharmacology analysis of traditional chinese medicine formula xiao ke yin shui treating type 2 diabetes mellitus.Evid. Based Complement. Alternat. Med.2019201911510.1155/2019/4202563 31583009
     [Google Scholar]
  7. DanyszW. ParsonsC.G. Alzheimer’s disease, β‐amyloid, glutamate, NMDA receptors and memantine – Searching for the connections.Br. J. Pharmacol.2012167232435210.1111/j.1476‑5381.2012.02057.x 22646481
     [Google Scholar]
  8. KimuruM. KimuruI. ChenF-J. combined potentiating effects of byako-ka-ninjin-to, its constituents, rhizomes of anemarrhena asphodeloides, timosaponin A-III, and calcium on pilocarpine-induced salvia secretion in streptozocin-diabetic mice.Biol. Pharm. Bull.199619792693110.1248/bpb.19.926 9004927
     [Google Scholar]
  9. TangY. SunZ. FanM. LiZ. HuangC. Anti-diabetic effects of TongGuanWan, a Chinese traditional herbal formula, in C57BL/KsJ-db/db mice.Planta Med.2012781182310.1055/s‑0031‑1280268 22002851
     [Google Scholar]
  10. PengY. ZhaoL. LinD. LiuY. ZhangM. SongS. Determination of the chemical constituents of the different processed products of Anemarrhena asphodeloides Rhizomes by high‐performance liquid chromatography quadrupole time‐of‐flight mass spectrometry.Biomed. Chromatogr.201630450851910.1002/bmc.3575 26230281
     [Google Scholar]
  11. KimH.S. SongJ.H. YounU.J. HyunJ.W. JeongW.S. LeeM.Y. ChoiH.J. LeeH.K. ChaeS. Inhibition of UVB-induced wrinkle formation and MMP-9 expression by mangiferin isolated from Anemarrhena asphodeloides.Eur. J. Pharmacol.20126891-3384410.1016/j.ejphar.2012.05.050 22683868
     [Google Scholar]
  12. LinY. ZhaoW.R. ShiW.T. ZhangJ. ZhangK.Y. DingQ. ChenX.L. TangJ.Y. ZhouZ.Y. Pharmacological activity, pharmacokinetics, and toxicity of timosaponin AIII, a natural product isolated from Anemarrhena asphodeloides bunge: A review.Front. Pharmacol.20201176410.3389/fphar.2020.00764 32581782
     [Google Scholar]
  13. RenL.X. LuoY.F. LiX. WuY.L. Antidepressant activity of sarsasapogenin from Anemarrhena asphodeloides Bunge (Liliaceae).Pharmazie20076217879 17294820
     [Google Scholar]
  14. WangY. GuoB. ZhangL. Pharmacological functions of chemicals in rhizoma anemarrhenae.Sci. Technol Rev.20102812110115
     [Google Scholar]
  15. DongG.M. YuH. PanL.B. MaS.R. XuH. ZhangZ.W. HanP. FuJ. YangX.Y. KeranmuA. NiuH.T. JiangJ.D. WangY. Biotransformation of timosaponin BII into seven characteristic metabolites by the gut microbiota.Molecules20212613386110.3390/molecules26133861 34202717
     [Google Scholar]
  16. SunY. LiuL. PengY. LiuB. LinD. LiL. SongS. Metabolites characterization of timosaponin AIII in vivo and in vitro by using liquid chromatography-mass spectrometry.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.201599723624310.1016/j.jchromb.2015.06.015 26134298
     [Google Scholar]
  17. CardonaF. Andrés-LacuevaC. TulipaniS. TinahonesF.J. Queipo-OrtuñoM.I. Benefits of polyphenols on gut microbiota and implications in human health.J. Nutr. Biochem.20132481415142210.1016/j.jnutbio.2013.05.001 23849454
     [Google Scholar]
  18. FengW. AoH. PengC. YanD. Gut microbiota, a new frontier to understand traditional Chinese medicines.Pharmacol. Res.201914217619110.1016/j.phrs.2019.02.024 30818043
     [Google Scholar]
  19. ZhaoY. ZhongX. YanJ. SunC. ZhaoX. WangX. Potential roles of gut microbes in biotransformation of natural products: An overview.Front. Microbiol.20221395637810.3389/fmicb.2022.956378 36246222
     [Google Scholar]
  20. JiaY. FuZ. LiZ. HuP. XueR. ChenM. XiangT. HuangC. In-vivo and in-vitro metabolism study of timosaponin B-II using HPLC-ESI-MS n.Chromatographia20157817-181175118410.1007/s10337‑015‑2927‑6
     [Google Scholar]
  21. LiT. ZhangM. TanZ. MiaoJ. HeY. ZhangA. OuM. HuangD. WuF. WangX. Rapid characterization of the constituents in Jigucao capsule using ultra high performance liquid chromatography with quadrupole time‐of‐flight mass spectrometry.J. Sep. Sci.202245367769610.1002/jssc.202100664 34822724
     [Google Scholar]
  22. ZhangX. ChenY. FengX. LiL. SongK. SunY. ZhangG. ZhangL. A comprehensive study of celastrol metabolism in vivo and in vitro using ultra‐high‐performance liquid chromatography coupled with hybrid triple quadrupole time‐of‐flight mass spectrometry.J. Sep. Sci.20224561222123910.1002/jssc.202100807 35080126
     [Google Scholar]
  23. DongW. YangK.X. HeX.F. LiT.Z. ChenJ.J. New eudesmanolides from Artemisia verlotorum and their potential targets of hepatocellular carcinoma by network pharmacology.Fitoterapia202316710549110.1016/j.fitote.2023.105491 37001826
     [Google Scholar]
  24. TianX. WeiJ. YangM. NiuY. LiuM. DuY. JinY. An integrated strategy to reveal the potential anti‐asthma mechanism of peimine by metabolite profiling, network pharmacology, and molecular docking.J. Sep. Sci.202245152819283210.1002/jssc.202200128 35638750
     [Google Scholar]
  25. ZengL. YangK. Exploring the pharmacological mechanism of Yanghe Decoction on HER2-positive breast cancer by a network pharmacology approach.J. Ethnopharmacol.2017199688510.1016/j.jep.2017.01.045 28130113
     [Google Scholar]
  26. YuH. ChenJ. XuX. LiY. ZhaoH. FangY. LiX. ZhouW. WangW. WangY. A systematic prediction of multiple drug-target interactions from chemical, genomic, and pharmacological data.PLoS One201275e3760810.1371/journal.pone.0037608 22666371
     [Google Scholar]
  27. EdgarR. DomrachevM. LashA.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.Nucleic Acids Res.200230120721010.1093/nar/30.1.207 11752295
     [Google Scholar]
  28. WuZ. ZhuZ. FuL. Integrating GEO, network pharmacology, and in vitro assays to explore the pharmacological mechanism of Bruceae Fructus against laryngeal cancer.Naunyn Schmiedebergs Arch. Pharmacol.202439764165418110.1007/s00210‑023‑02869‑9 38032489
     [Google Scholar]
  29. FerreiraL. Dos SantosR. OlivaG. AndricopuloA. Molecular docking and structure-based drug design strategies.Molecules2015207133841342110.3390/molecules200713384 26205061
     [Google Scholar]
  30. SaikiaS. BordoloiM. Molecular docking: Challenges, advances and its use in drug discovery perspective.Curr. Drug Targets201920550152110.2174/1389450119666181022153016 30360733
     [Google Scholar]
  31. SongW. ZhengW. ZhangT. LiuS.C. YuL.Y. MaB.P. Metabolism of saponins from traditional Chinese medicines: A review.Yao Xue Xue Bao2018201016091619
     [Google Scholar]
  32. ZhouZ. LiC. ChenL. YangY. YinW. LiuB. Biotransformation of natural saponins.Zhongguo Shiyan Fangjixue Zazhi20192516173192
     [Google Scholar]
  33. WangN. XuP. WangX. YaoW. WangB. WuY. ShouD. Timosaponin AIII attenuates inflammatory injury in AGEs-induced osteoblast and alloxan-induced diabetic osteoporosis zebrafish by modulating the RAGE/MAPK signaling pathways.Phytomedicine20207515324710.1016/j.phymed.2020.153247 32502823
     [Google Scholar]
  34. XueX. HuJ. Research methods and applications in network pharmacology.J. Pharm. Pract.20153305401405
     [Google Scholar]
  35. PoornimaP. KumarJ.D. ZhaoQ. BlunderM. EfferthT. Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature.Pharmacol. Res.201611129030210.1016/j.phrs.2016.06.018 27329331
     [Google Scholar]
  36. ZhaoL. ZhangH. LiN. ChenJ. XuH. WangY. LiangQ. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula.J. Ethnopharmacol.202330911630610.1016/j.jep.2023.116306 36858276
     [Google Scholar]
  37. GuoH. WuH. LiZ. The pathogenesis of diabetes.Int. J. Mol. Sci.2023248697810.3390/ijms24086978 37108143
     [Google Scholar]
  38. XuZ. ZhaoY. ZhongP. WangJ. WengQ. QianY. HanJ. ZouC. LiangG. EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress.Oncotarget2017820326553266710.18632/oncotarget.15948 28427241
     [Google Scholar]
  39. RieussetJ. The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update.Cell Death Dis.20189338810.1038/s41419‑018‑0416‑1 29523782
     [Google Scholar]
  40. LiuS. HanS. WangC. ChenH. XuQ. FengS. WangY. YaoJ. ZhouQ. TangX. LinL. HuL. DavidsonA.J. YangB. YeC. YangF. MaoJ. TongC. ChenJ. JiangH. MAPK1 mediates MAM disruption and mitochondrial dysfunction in diabetic kidney disease via the PACS-2-dependent mechanism.Int. J. Biol. Sci.202420256958410.7150/ijbs.89291 38169625
     [Google Scholar]
  41. GuH.F. MaJ. GuK.T. BrismarK. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy.Front. Endocrinol. (Lausanne)2013317910.3389/fendo.2012.00179 23346076
     [Google Scholar]
  42. LiZ. ShangguanZ. LiuY. WangJ. LiX. YangS. LiuS. Puerarin protects pancreatic β-cell survival via PI3K/Akt signaling pathway.J. Mol. Endocrinol.2014531717910.1530/JME‑13‑0302 24827001
     [Google Scholar]
  43. SadiG. PektaşM.B. KocaH.B. TosunM. KocaT. Resveratrol improves hepatic insulin signaling and reduces the inflammatory response in streptozotocin-induced diabetes.Gene2015570221322010.1016/j.gene.2015.06.019 26071184
     [Google Scholar]
  44. CatrinaS.B. OkamotoK. PereiraT. BrismarK. PoellingerL. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function.Diabetes200453123226323210.2337/diabetes.53.12.3226 15561954
     [Google Scholar]
  45. BentoC.F. PereiraP. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes.Diabetologia20115481946195610.1007/s00125‑011‑2191‑8 21614571
     [Google Scholar]
  46. CatrinaS.B. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia.J. Mol. Med.201492101025103410.1007/s00109‑014‑1166‑x 25027070
     [Google Scholar]
  47. KanekoK. LinH.Y. FuY. SahaP.K. De la Puente-GomezA.B. XuY. OhinataK. ChenP. MorozovA. FukudaM. Rap1 in the VMH regulates glucose homeostasis.JCI Insight2021611e14254510.1172/jci.insight.142545 33974562
     [Google Scholar]
  48. CalissiG. LamE.W.F. LinkW. Therapeutic strategies targeting FOXO transcription factors.Nat. Rev. Drug Discov.2021201213810.1038/s41573‑020‑0088‑2 33173189
     [Google Scholar]
  49. GuL. DingX. WangY. GuM. ZhangJ. YanS. LiN. SongZ. YinJ. LuL. PengY. Spexin alleviates insulin resistance and inhibits hepatic gluconeogenesis via the FoxO1/PGC-1α pathway in high-fat-diet-induced rats and insulin resistant cells.Int. J. Biol. Sci.201915132815282910.7150/ijbs.31781 31853220
     [Google Scholar]
/content/journals/cdm/10.2174/0113892002357684250527113902
Loading
A Gut Microbial Transformation-Integrated Network Pharmacology Approach to Elucidate the Therapeutic Mechanisms of Timosaponin AIII in Diabetes
Current Drug Metabolism 26, 121 (2025); https://doi.org/10.2174/0113892002357684250527113902
/content/journals/cdm/10.2174/0113892002357684250527113902
/content/journals/cdm/10.2174/0113892002357684250527113902
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): Biotransformations; diabetes; metabolism; molecular docking; network pharmacology; timosaponin AIII

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test