Background and objectives Alzheimer’s disease (AD) is a common geriatric disease with a complex pathogenesis and challenging treatment options. Wuling capsule is a single herbal formula mainly composed of Xylaria nigripes powder, which has sedative and neuroprotective effects on the central nervous system. This study aimed to explore various potential pathways and targets of Wuling capsules for the treatment of AD.
Methods The anti-AD mechanism of Wuling capsule was systematically analyzed by integrating multiple databases and using network pharmacology. The active ingredients of Wuling capsules were screened through the Pubchem website, the SwissADME database, and a literature search. The related targets of AD were then screened in the GeneCards database. Using Cytoscape software and STRING, the disease-drug-target interaction network and the protein-protein interaction network were visualized, and topological analysis revealed the differences in the effects of different types of compounds.
Results Fifty-four compounds and 284 targets were screened by network pharmacology. The main active ingredients included quercetin, xylaric acid A-D, lysine, gamma-aminobutyric acid, glutamic acid, other amino acids, trace elements, guanosine, adenosine, etc. The targets in the network cover inflammation, oxidative stress, modulation of chemical synaptic transmission, and other related proteins, including protein kinase B, tumor necrosis factor-alpha, and tumor suppressor p53. The enrichment analysis results showed that these pathways include the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase, and tumor necrosis factor-alpha signaling pathways. We also explored five potential protein functional modules.
Conclusions This study revealed the multi-target and multi-pathway effects of the drug-ingredient-target-disease network through network pharmacology. This systematic screening strategy provides a new concept and theoretical basis for the treatment of AD with Wuling capsules.
Acknowledgments
None.
Funding
This research was funded by a grant from the National Natural Science Foundation of China (No. 81973786).
Conflict of interest
The authors declare that they have no conflicts of interest.
Author contributions
Study concept and design (TM); analysis and interpretation of data, figure preparation, and writing of the manuscript text (HNY, GHH); acquisition of data (HNY, GHH, MJS); critical revision of the manuscript for important intellectual content and procure-ment of funding (TM). All authors reviewed the manuscript and approved the version to be published.
Data availability
The datasets used or analyzed during the present study are avail-able from the corresponding author upon reasonable request.
| [1] |
Peineau S, Rabiant K, Pierrefiche O, Potier B. Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease. Pharmacol Res 2018; 130:385-401. doi: 10.1016/j.phrs.2018.01.018,PMID:29425728.
|
| [2] |
Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention. J Prev Alzheimers Dis 2021; 8(3):313-321. doi:10.14283/jpad.2021.15,PMID:34101789.
|
| [3] |
Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunis-sen CE, et al. Alzheimer’s disease. The Lancet 2021;397(10284):1577-1590. doi:10.1016/s0140-6736(20)32205-4, PMID:33667416.
|
| [4] |
Gong QF, Wu SH, Tan NH, Chen ZH. Study on compounds with anti-oxidant and antitumor activity from fermental mycelium of Xylaria nigripes. Food Sci Technol 2008; 33(12):28-31. doi:10.13684/j.cnki.spkj.2008.12.067.
|
| [5] |
He XD, Zhang LS, Chen JF, Hu XY, Chen W. Effects of Wuling Myceli-aon Seizure Development and Memory Impairment Induced by Pen-tylenetetrazole Kindling Epilepsy in Rats Chin Pharm J 2010; 45(16):1238-1242. (in Chinese).
|
| [6] |
Yang N, Hao W, Liu Y, Ji C, Zuo P. Behavioral studies on the anxiolytic effects of Xylaria nigripes Chinese Journal of Ethnomedi-cine and Ethnopharmacy 2010; 19(5):27-28,30. doi:10.3969/j.issn.1007-8517.2010.05.019. (in Chinese).
|
| [7] |
Zou XD, Zhang ZZ, Cheng YG, Li ZC, Wang H, Hu ZW. Effect of Wuling Capsule on cognitive function of mice Chin J Clin Pharma-col 2018; 20:2421-2423. doi:10.13699/j.cnki.1001-6821.2018.20.008. (in Chinese).
|
| [8] |
Souza FN, Oliveira NKS, de Lima HB, Silva AG, Cruz RAS, Oliveira FR, et al. Therapeutic Potential of Quercetin in the Treatment of Alzhei-mer’s Disease: In Silico, In Vitro and In Vivo Approach. Applied Sci-ences 2025; 15(19):10340. doi:10.3390/app151910340.
|
| [9] |
Jarrell JT, Gao L, Cohen DS, Huang X. Network Medicine for Alzheimer’s Disease and Traditional Chinese Medicine. Molecules 2018; 23(5):1143. doi:10.3390/molecules23051143,PMID:29751596.
|
| [10] |
Wang H, Zou XD, Yang QQ, Zhang YL, Guo DJ. Effect of Wu-Ling Powder therapy on cognition, Aβ1-42 and p-Tau expression in APP-swe /PS1dE9 double transgenic AD mice Chin J General Practice 2019; 17(8):1279-1281,1395. doi:10.16766/j.cnki.issn.1674-4152.000921. (in Chinese).
|
| [11] |
Jen CI, Su CH, Lu MK, Lai MN, Ng LT. Synergistic anti-inflammatory effects of different polysaccharide components from Xylaria ni-gripes. J Food Biochem 2021; 45(4):e13694. doi:10.1111/jfbc.13694,PMID:33687093.
|
| [12] |
Ko HJ, Song A, Lai MN, Ng LT. Immunomodulatory properties of Xy-laria nigripes in peritoneal macrophage cells of Balb/c mice. J Eth-nopharmacol 2011; 138(3):762-768. doi:10.1016/j.jep.2011.10.022,PMID:22044578.
|
| [13] |
Li J, Li LQ, Long HP, Liu J, Jiang YP, Xue Y, et al. Xylarinaps A-E, five pairs of naphthalenone derivatives with neuroprotective activities from Xy-laria nigripes. Phytochemistry 2021;186:112729. doi:10.1016/j.phyto-chem.2021.112729,PMID:33721798.
|
| [14] |
Fu YZ, Tong JF, Di LL, Zhang J, Liu XH. Clinical Observation of Wuling Capsules Combined with Oxiracetam in the Treatment of Alzhei-mer’s Disease China Pharmaceuticals 2021;(4):69-71. doi:10.3969/j.issn.1006-4931.2021.04.019. (in Chinese).
|
| [15] |
Zu G, Sun K, Li L, Zu X, Han T, Huang H. Mechanism of quercetin therapeutic targets for Alzheimer disease and type 2 diabetes mel-litus. Sci Rep 2021; 11(1):22959. doi:10.1038/s41598-021-02248-5,PMID:34824300.
|
| [16] |
Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK. Neuroprotective Ef-fects of Quercetin in Alzheimer’s Disease. Biomolecules 2019; 10(1):59. doi:10.3390/biom10010059,PMID:31905923.
|
| [17] |
Paula PC, Angelica Maria SG, Luis CH, Gloria Patricia CG. Preventive Ef-fect of Quercetin in a Triple Transgenic Alzheimer's Disease Mice Mod-el. Molecules 2019; 24(12):2287. doi:10.3390/molecules24122287.PMID:31226738.
|
| [18] |
Dash UC, Swain SK, Kanhar S, Banjare P, Roy PP, Dandapat J, et al. The modulatory role of prime identified compounds in Geophila repens in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer’s disease via attenuation of cholinesterase, beta-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation. J Ethnopharmacol 2022;282:114637. doi:10.1016/j.jep.2021.114637,PMID:34534598.
|
| [19] |
Li HL, Zhang SY, Ren YS, Zhou JC, Zhou YX, Huang WZ, et al. Identifi-cation of ellagic acid and urolithins as natural inhibitors of Abeta25-35- induced neurotoxicity and the mechanism predication using network pharmacology analysis and molecular docking. Front Nutr 2022;9:966276. doi:10.3389/fnut.2022.966276,PMID:35983489.
|
| [20] |
Ramadan WS, Alkarim S. Ellagic Acid Modulates the Amyloid Precursor Protein Gene via Superoxide Dismutase Regulation in the Entorhinal Cortex in an Experimental Alzheimer’s Model. Cells 2021; 10(12):3511. doi:10.3390/cells10123511,PMID:34944019.
|
| [21] |
Chaitanya GV, Steven AJ, Babu PP. PARP-1 cleavage fragments: signa-tures of cell-death proteases in neurodegeneration. Cell Commun Sig-nal 2010; 8:31. doi:10.1186/1478-811X-8-31,PMID:21176168.
|
| [22] |
Khan A, Ali T, Rehman SU, Khan MS, Alam SI, Ikram M, et al. Neuro-protective Effect of Quercetin Against the Detrimental Effects of LPS in the Adult Mouse Brain. Front Pharmacol 2018;9:1383. doi:10.3389/fphar.2018.01383,PMID:30618732.
|
| [23] |
Kiasalari Z, Heydarifard R, Khalili M, Afshin-Majd S, Baluchnejadmoja-rad T, Zahedi E, et al. Ellagic acid ameliorates learning and memory def-icits in a rat model of Alzheimer’s disease: an exploration of underlying mechanisms. Psychopharmacology (Berl) 2017; 234(12):1841-1852. doi:10.1007/s00213-017-4589-6,PMID:28303372.
|
| [24] |
Rojanathammanee L, Puig KL, Combs CK. Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and micro-glial activation in vitro and in a transgenic mouse model of Alzheimer disease. J Nutr 2013; 143(5):597-605. doi:10.3945/jn.112.169516,PMID:23468550.
|
| [25] |
Devi KP, Shanmuganathan B, Manayi A, Nabavi SF, Nabavi SM. Molecu-lar and Therapeutic Targets of Genistein in Alzheimer’s Disease. Mol Neurobiol 2017; 54(9):7028-7041. doi:10.1007/s12035-016-0215-6,PMID:27796744.
|
| [26] |
Guo J, Yang G, He Y, Xu H, Fan H, An J, et al. Involvement of alpha-7nAChR in the Protective Effects of Genistein Against beta-Amyloid-In-duced Oxidative Stress in Neurons via a PI3K/Akt/Nrf2 Pathway-Relat-ed Mechanism. Cell Mol Neurobiol 2021; 41(2):377-393. doi:10.1007/s10571-020-01009-8,PMID:33215356.
|
| [27] |
Ma WW, Hou CC, Zhou X, Yu HL, Xi YD, Ding J, et al. Genistein allevi-ates the mitochondria-targeted DNA damage induced by beta-amyloid peptides 25-35 in C6 glioma cells. Neurochem Res 2013; 38(7):1315-1323. doi:10.1007/s11064-013-1019-y,PMID:23519932.
|
| [28] |
Valles SL, Dolz-Gaiton P, Gambini J, Borras C, Lloret A, Pallardo FV, et al. Estradiol or genistein prevent Alzheimer’s disease-associated inflam-mation correlating with an increase PPAR gamma expression in cul-tured astrocytes. Brain Res 2010; 1312:138-144. doi:10.1016/j.brain-res.2009.11.044,PMID:19948157.
|
| [29] |
Chen CF, Su CH, Lai MN, Ng LT. Differences in water soluble non-di-gestible polysaccharides and anti-inflammatory activities of fruit-ing bodies from two cultivated Xylaria nigripes strains. Int J Biol Macromol 2018; 116:728-734. doi:10.1016/j.ijbiomac.2018.05.047,PMID:29763701.
|
| [30] |
Wei S, Wang YF, Li H, Liu Y. Effects of Wuling Capsule on PI3K/Akt/mTOR pathway and neurotransmitters in hippocampus of post-stroke depression rats Chin J Modern Med 2021;(14):47-51. doi:10.3969/j.issn.1005-8982.2021.14.009. (in Chinese).
|
| [31] |
Zheng J, Xie Y, Ren L, Qi L, Wu L, Pan X, et al. GLP-1 improves the sup-portive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease. Mol Metab 2021;47:101180. doi:10.1016/j.molmet.2021.101180, PMID:33556642.
|
| [32] |
Reddy PH, Oliver DM. Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease. Cells 2019; 8(5):488. doi:10.3390/cells8050488,PMID:31121890.
|
| [33] |
Rather MA, Khan A, Alshahrani S, Rashid H, Qadri M, Rashid S, et al. Inflammation and Alzheimer's Disease: Mechanisms and Therapeutic Implications by Natural Products. Mediators Inflamm 2021; 2021:9982954. doi:10.1155/2021/9982954.PMID:3438130.
|
| [34] |
Zeng P, Su HF, Ye CY, Qiu SW, Tian Q. Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer’s Disease From the Perspective of Pathophysiological Processes. Front Pharmacol 2021;12:806984. doi:10.3389/fphar.2021.806984,PMID:34975502.
|
| [35] |
Zheng X, Lin W, Jiang Y, Lu K, Wei W, Huo Q, et al. Electroacupunc-ture ameliorates beta-amyloid pathology and cognitive impairment in Alzheimer disease via a novel mechanism involving activation of TFEB (transcription factor EB). Autophagy 2021; 17(11):3833-3847. doi:10.1080/15548627.2021.1886720,PMID:33622188.
|
| [36] |
Wang Y, Lin Y, Wang L, Zhan H, Luo X, Zeng Y, et al. TREM2 amelio-rates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice. Aging (Albany NY) 2020; 12(20):20862-20879. doi:10.18632/aging.104104,PMID:33065553.
|
| [37] |
Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS, et al. IL-1beta, IL-6, TNF- alpha and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis. Sci Rep 2018; 8(1):12050. doi:10.1038/s41598-018-30487-6,PMID:30104698.
|
| [38] |
Liu M, Xu Z, Wang L, Zhang L, Liu Y, Cao J, et al. Cottonseed oil allevi-ates ischemic stroke injury by inhibiting the inflammatory activation of microglia and astrocyte. J Neuroinflammation 2020; 17(1):270. doi:10.1186/s12974-020-01946-7,PMID:32917229.
|
| [39] |
Zhou Z, Gao S, Li Y, Peng R, Zheng Z, Wei W, et al. VEGI Improves Out-comes in the Early Phase of Experimental Traumatic Brain Injury. Neu-roscience 2020; 438:60-69. doi:10.1016/j.neuroscience.2020.04.042,PMID:32380270.
|
| [40] |
Rangaraju S, Dammer EB, Raza SA, Rathakrishnan P, Xiao H, Gao T, et al. Identification and therapeutic modulation of a pro-inflammatory sub-set of disease-associated-microglia in Alzheimer’s disease. Mol Neuro-degener 2018; 13(1):24. doi:10.1186/s13024-018-0254-8,PMID:29784049.
|
| [41] |
Bouter Y, Kacprowski T, Rossler F, Jensen LR, Kuss AW, Bayer TA. miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice. Front Neurosci 2020;14:580524. doi:10.3389/fnins.2020.580524,PMID:33013313.
|
PDF
