Network pharmacology-based mechanism analysis of dauricine on the alleviating Aβ-induced neurotoxicity in Caenorhabditis elegans

文献类型： 外文期刊

第一作者： Zhang, Ranran

作者： Zhang, Ranran;Jia, Dongsheng;Xie, Xiaoliang;Zhang, Ju;Zhang, Ranran;Huang, Xiaoyan;Zhou, Chunling;Zhang, Qian;Zhang, Ju

作者机构：

关键词： Dauricine; Alzheimer's disease; Network pharmacology; Caenorhabditis elegans; Autophagy-lysosome

期刊名称：BMC COMPLEMENTARY MEDICINE AND THERAPIES （ 影响因子：3.4； 五年影响因子：3.8 ）

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年卷期： 2024 年 24 卷 1 期

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收录情况： SCI

摘要： Background Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, exhibits promising anti-Alzheimer's disease (AD) effects, but its underlying mechanisms remain inadequately investigated. This paper aims to identify potential targets and molecular mechanisms of DAU in AD treatment. Methods Network pharmacology and molecular docking simulation method were used to screen and focus core targets. Various transgenic Caenorhabditis elegans models were chosen to validate the anti-AD efficacy and mechanism of DAU. Results There are 66 potential DAU-AD target intersections identified from 100 DAU and 3036 AD-related targets. Subsequent protein-protein interaction (PPI) network analysis identified 16 core targets of DAU for anti-AD. PIK3CA, AKT1 and mTOR were predicted to be the central targets with the best connectivity through the analysis of "compound-target-biological process-pathway network". Molecular docking revealed strong binding affinities between DAU and PIK3CA, AKT1, and mTOR. In vivo experiments demonstrated that DAU effectively reduced paralysis in AD nematodes caused by A beta aggregation toxicity, downregulated expression of PIK3CA, AKT1, and mTOR homologues (age-1, akt-1, let-363), and upregulated expression of autophagy genes and the marker protein LGG-1. Simultaneously, DAU increased lysosomal content and enhanced degradation of the autophagy-related substrate protein P62. Thioflavin T (Th-T) staining experiment revealed that DAU decreased A beta accumulation in AD nematodes. Further experiments also confirmed DAU's protein scavenging activity in polyglutamine (polyQ) aggregation nematodes. Conclusion Collectively, the mechanism of DAU against AD may be related to the activation of the autophagy-lysosomal protein clearance pathway, which contributes to the decrease of A beta aggregation and the restoration of protein homeostasis.

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