Exploratory study of sea buckthorn enhancing QiangGuYin efficacy by inhibiting CKIP-1 and Notum activating the Wnt/β-catenin signaling pathway and analysis of active ingredients by molecular docking

Yi-Feng Yuan; Shen Wang; Hang Zhou; Bin-Bin Tang; Yang Liu; Hai Huang; Cai-Jian He; Tian-Peng Chen; Mou-Hao Fang; Bo-Cheng Liang; Ying-De-Long Mao; Feng-Qin Qie; Kang Liu; Xiao-Lin Shi

doi:10.3389/fphar.2022.994995

Exploratory study of sea buckthorn enhancing QiangGuYin efficacy by inhibiting CKIP-1 and Notum activating the Wnt/β-catenin signaling pathway and analysis of active ingredients by molecular docking

Front Pharmacol. 2022 Oct 11:13:994995. doi: 10.3389/fphar.2022.994995. eCollection 2022.

Authors

Yi-Feng Yuan¹, Shen Wang¹, Hang Zhou¹, Bin-Bin Tang^{1

2}, Yang Liu¹, Hai Huang¹, Cai-Jian He¹, Tian-Peng Chen¹, Mou-Hao Fang¹, Bo-Cheng Liang², Ying-De-Long Mao², Feng-Qin Qie³, Kang Liu², Xiao-Lin Shi²

Affiliations

¹ The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
² The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital of Zhejiang Province), Hangzhou, China.
³ Yushi Health Research Institute, Tokyo, Japan.

Abstract

Background: Sea buckthorn (SBT) is a traditional Chinese medicine (TCM), rich in calcium, phosphorus, and vitamins, which can potentially prevent and treat osteoporosis. However, no research has been conducted to confirm these hypotheses. QiangGuYin (QGY) is a TCM compound used to treat osteoporosis. There is a need to investigate whether SBT enhances QGY efficacy. Objectives: The aim of this study was to explore whether SBT enhances QGY efficacy by inhibiting CKIP-1 and Notum expression through the Wnt/β-catenin pathway. The study also aimed to explore the active components of SBT. Methods: Experimental animals were divided into control, model, QGY, SBT, SBT + Eucommia ulmoides (EU), and SBT + QGY groups. After treatment, bone morphometric parameters, such as estrogen, PINP, and S-CTX levels, and Notum, CKIP-1, and β-catenin expression were examined. Screening of SBT active components was conducted by molecular docking to obtain small molecules that bind Notum and CKIP-1. Results: The results showed that all the drug groups could elevate the estrogen, PINP, and S-CTX levels, improve femoral bone morphometric parameters, inhibit Notum and CKIP-1 expression, and promote β-catenin expression. The effect of SBT + EU and SBT + QGY was superior to the others. Molecular docking identified that SBT contains seven small molecules (folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin) with potential effects on CKIP-1 and Notum. Conclusion: SBT improves bone morphometric performance in PMOP rats by inhibiting CKIP-1 and Notum expression, increasing estrogen levels, and activating the Wnt/β-catenin signaling pathway. Furthermore, SBT enhances the properties of QGY. Folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin are the most likely active ingredients of SBT. These results provide insight into the pharmacological mechanisms of SBT in treating osteoporosis.

Keywords: CKIP-1; Notum; QiangGuYin; Wnt/β-catenin signaling pathway; molecular docking; postmenopausal osteoporosis; sea buckthorn.