[Mechanism of Ding-Zhi-Xiao-Wan on sphingolipid metabolism disorders in Alzheimer's disease based on network pharmacology, molecular docking, and animal experiments].

Exploring the mechanism of Ding-Zhi-Xiao-Wan(DZXW) on disorders of sphingolipid metabolism in Alzheimer's disease(AD) through network pharmacology, molecular docking and animal experiments. The chemical constituents of DZXW were obtained via the TCMSP, with target prediction conducted using the SwissTargetPrediction database; the GeneCards database was consulted to identify targets associated with AD and sphingolipid metabolism disorders. The intersecting targets from these three databases underwent GO and KEGG enrichment analyses. Cytoscape was employed to construct networks and screen core components and targets for molecular docking validation. Animal experiments employed AD model mice, utilising the water maze, ELISA, qPCR, LC-MS, and Western blot to evaluate the effects of DZXW on behavioural, oxidative stress, inflammatory, apoptotic, and sphingolipid metabolism-related indicators. Network pharmacology identified 51 common targets, with enrichment analysis indicating their involvement in multiple pathways including signal transduction, apoptosis, and the phosphatidylinositol 3kinase/protein kinase B(PI3K/Akt) pathway. Molecular docking revealed that multiple components within DZXW(such as cerevisterol and isorhamnetin) interacted with targets including caspase 3(CASP3), mitogen-activated protein kinase 14(MAPK14), estrogen receptor 1(ESR1), and silent information regulator factor 2 related enzyme 1(SIRT1), with SIRT1 being particularly crucial. Animal studies indicate that DZXW enhances learning and memory capacity in AD mice, reduces ceramide levels, and inhibits oxidation factors [4-hydroxynonenal(4-HNE), 8-hydroxy-2'-deoxyguanosine(8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)] and inflammatory factors [tumour necrosis factor-α(TNF-α), interleukin(IL)-1β], downregulates CASP3, MAPK14, sphingomyelin phosphodiesterase 1-3(SMPD1-3), B cell chronic lymphocytic leukaemia/lymphoma-2(Bcl-2)-associated X protein(Bax), and increases IL-10, ESR1, mammalian target of rapamycin(mTOR), SIRT1, PI3K phosphorylation, Akt phosphorylation, and Bcl-2. In conclusion, DZXW may improve sphingolipid metabolism disorders in AD by inhibiting neuronal apoptosis and mitigating oxidative and inflammatory responses through the SIRT1/PI3K/Akt pathway.