Laboratory of Brain and Cognitive Science, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671003, P.R. China.
Yunnan Institute of Materia Medica, Yunnan Province Company Key Laboratory for TCM and Ethnic Drug of New Drug Creation, Kunming, Yunnan 650111, P.R. China.
Mol Med Rep. 2024 Dec;30(6). doi: 10.3892/mmr.2024.13356. Epub 2024 Oct 11.
Alzheimer's disease (AD) is a neurodegenerative disorder that impairs learning and memory, with high rates of mortality. Birch bark has been traditionally used in the treatment of various skin ailments. Betulin (BT) is a key compound of birch bark that exhibits diverse pharmacological benefits and therapeutic potential in AD. However, the therapeutic effects and molecular mechanisms of BT in AD remain unclear. The present study aimed to predict the potential therapeutic targets of BT in the treatment of AD, and to determine the specific underlying molecular mechanisms through network pharmacology analysis and experimental validation. PharmMapper was used to predict the target genes of BT, and four disease databases were searched to screen for AD targets. The intersection targets were identified using the jveen website. Drug‑disease target protein‑protein interaction networks and hub genes were obtained and visualized using the Search Tool for the Retrieval of Interacting Genes/Proteins database and Cytoscape. The Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and AutoDock was used for molecular docking analysis of BT and hub genes. Subsequently, the network‑predicted mechanisms of BT in AD were verified . A total of 495 BT and 1,386 AD targets were identified, and 120 were identified as potential targets of BT in the treatment of AD. The results of the molecular docking analysis revealed a strong binding affinity between BT and the hub genes. In addition, enrichment analyses of GO and KEGG pathways indicated that the neuroprotective effects of BT mainly involved the 'PI3K‑Akt signaling pathway'. The results of experiments demonstrated that pretreatment with BT for 2 h may ameliorate formaldehyde (FA)‑induced cytotoxicity and morphological changes in HT22 cells, and decrease FA‑induced Tau hyperphosphorylation and reactive oxygen species levels. Furthermore, the PI3K/AKT signaling pathway was activated and the expression levels of downstream proteins, namely GSK3β, Bcl‑2 and Bax, were modified following pre‑treatment with BT. Overall, the results of network pharmacology and analyses revealed that BT may reduce FA‑induced AD‑like pathology by modulating the PI3K/AKT signaling pathway, highlighting it as a potential multi‑target drug for the treatment of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，会损害学习和记忆能力，且死亡率较高。白桦树皮传统上被用于治疗各种皮肤疾病。桦木醇（BT）是白桦树皮中的一种关键化合物，具有多种药理学益处和治疗 AD 的潜力。然而，BT 在 AD 中的治疗效果和分子机制尚不清楚。本研究旨在通过网络药理学分析和实验验证来预测 BT 治疗 AD 的潜在治疗靶点，并确定具体的潜在分子机制。使用 PharmMapper 预测 BT 的靶基因，并在四个疾病数据库中筛选 AD 靶点。使用 jveen 网站鉴定交集靶点。使用 Search Tool for the Retrieval of Interacting Genes/Proteins 数据库和 Cytoscape 获取和可视化药物-疾病靶蛋白-蛋白相互作用网络和枢纽基因。使用 Database for Annotation, Visualization and Integrated Discovery 进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析，并使用 AutoDock 进行 BT 和枢纽基因的分子对接分析。随后，验证了 BT 治疗 AD 的网络预测机制。共鉴定出 495 个 BT 和 1386 个 AD 靶标，其中 120 个被鉴定为 BT 治疗 AD 的潜在靶标。分子对接分析结果表明，BT 与枢纽基因之间具有很强的结合亲和力。此外，GO 和 KEGG 通路的富集分析表明，BT 的神经保护作用主要涉及“PI3K-Akt 信号通路”。实验结果表明，BT 预处理 2 小时可改善甲醛（FA）诱导的 HT22 细胞毒性和形态变化，降低 FA 诱导的 Tau 过度磷酸化和活性氧水平。此外，BT 预处理可激活 PI3K/AKT 信号通路，并修饰下游蛋白 GSK3β、Bcl-2 和 Bax 的表达水平。综上所述，网络药理学和分析结果表明，BT 可能通过调节 PI3K/AKT 信号通路减轻 FA 诱导的 AD 样病变，表明其可能成为治疗 AD 的多靶药物。
