Ge Cui-Cui, Li Xin-Yu, Qiao Wen-Hao, Cui Can, Wang Ji, Gongpan Pianchou, Wu Sheng-Li, Huang Xiao-Yan, Ma Yun-Bao, Li Da-Hong, Chen Xing-Long, Geng Chang-An
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China; Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.
Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Fitoterapia. 2024 Oct;178:106157. doi: 10.1016/j.fitote.2024.106157. Epub 2024 Aug 3.
The fruits of Alpinia oxyphylla (Alpiniae Oxyphyllae Fructus, AOF) are one of the "Four Famous South Medicines" in China. In this study, beta-site amyloid protein precursor cleaving enzyme 1 (BACE1) was applied to explore the active components in AOF responsible for type 2 diabetes mellitus (T2DM)-related cognitive disorder. As a result, 24 compounds including three unreported ones (1, 3, 4) were isolated from AOF. Compound 1 is an unusual carbon‑carbon linked diarylheptanoid dimer, and compound 4 is the first case of 3,4-seco-eudesmane sesquiterpenoid with a 5/6-bicyclic skeleton. Four diarylheptanoids (3, 5-7), one flavonoid (9) and two sesquiterpenoids (14 and 20) showed BACE1 inhibitory activity, of which the most active 6 was revealed to be a non-competitive and anti-competitive mixed inhibitor. Docking simulation suggested that OH-4' of 6 played important roles in maintaining activity by forming hydrogen bonds with Ser36 and Ile126 residues. Compounds 3, 5, 9 and 20 displayed neuroprotective effects against amyloid β (Aβ)-induced damage in BV2 cells. Mechanism study revealed that compounds 5 and 20 downregulated the expression of BACE1 and upregulated the expression of Lamp2 to exert effects. Thus, the characteristic diarylheptanoids and sesquiterpenoids in AOF had the efficacy to alleviate T2DM-related cognitive disorder by inhibiting BACE1 activity and reversing Aβ-induced neuronal damage.
益智（益智果实）是中国“四大南药”之一。在本研究中，应用β-位点淀粉样前体蛋白裂解酶1（BACE1）来探索益智中与2型糖尿病（T2DM）相关认知障碍有关的活性成分。结果，从益智中分离出24种化合物，包括3种未报道的化合物（1、3、4）。化合物1是一种不寻常的碳-碳连接二芳基庚烷二聚体，化合物4是首例具有5/6双环骨架的3,4-裂桉烷倍半萜。四种二芳基庚烷类化合物（3、5-7）、一种黄酮类化合物（9）和两种倍半萜类化合物（14和20）表现出BACE1抑制活性，其中活性最强的化合物6被发现是一种非竞争性和反竞争性混合抑制剂。对接模拟表明，化合物6的4'-羟基通过与Ser36和Ile126残基形成氢键在维持活性方面发挥重要作用。化合物3、5、9和20对BV2细胞中淀粉样β（Aβ）诱导的损伤具有神经保护作用。机制研究表明，化合物5和20通过下调BACE1的表达和上调Lamp2的表达发挥作用。因此，益智中的特征性二芳基庚烷类化合物和倍半萜类化合物具有通过抑制BACE1活性和逆转Aβ诱导的神经元损伤来缓解T2DM相关认知障碍的功效。
