Li Wei-Jie, Zhang Yan-Qiong, Zhou Shu-Fan, Xia Cong-Min, Wang Ping, Wu Zhuo-Yun, Qu Yang, Zhou Chun-Ling, Xu Hai-Yu
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences Beijing 100700, China.
Liaoning Good Nurse Pharmaceutical (Group) Co., Ltd. Hengren 117201, China.
Zhongguo Zhong Yao Za Zhi. 2024 Jul;49(14):3924-3935. doi: 10.19540/j.cnki.cjcmm.20240408.501.
The clinical advantage staging and underlying mechanisms of Wangbi Tablets against knee osteoarthritis(KOA) were studied based on the "disease-formula" interaction network. Firstly, the clinical symptoms and related genes corresponding to Wangbi Tablets and KOA in the acute, remission, and recovery phases were collected from clinical guidelines/consensus and SoFDA database, and the putative targets of Wangbi Tablets were obtained from ETCM 2.0. Then, Jaccard similarity and cosine similarity were employed to assess the similarities of clinical symptoms, genes, and enriched pathways between Wangbi Tablets and KOA in different phases. The "disease-formula" interaction network of the drug targets and disease genes was constructed, and the key targets were screened by topological feature calculation. KEGG and Reactome database were used for the functional enrichment of the key targets, on the basis of which the functional characteristics of Wangbi Tablets against KOA in the acute, remission, and recovery phases were predicted. Finally, the SW1353 cells exposed to lipopolysaccharide were used to decipher the mechanism of Wangbi Tablets against KOA. The results showed that 92/3 921, 138/3 708, 139/3 800, and 196/3 946 clinical symptoms and the related genes corresponded to KOA in the acute, remission, and recovery phases and Wangbi Tablets were collected from SoFDA, and 260 putative targets of Wangbi Tablets were obtained from ETCM 2.0. Wangbi Tablets had highest similarity of clinical symptoms, genes, and enriched pathways with KOA in the remission phase and the secondary highest similarity with KOA in the recovery phase. The key targets of Wangbi Tablets mainly participated in the regulation of immunity-inflammation imbalance and exerted pain-relieving and bone-protecting effects to alleviate symptoms such as knee joint pain, joint swelling, soreness, fatigue, and dysfunction. Intriguingly, the key targets of Wangbi Tablets possessed antioxidant effects during KOA in the acute and remission phases, while they maintained material and energy metabolism homeostasis and protected vessels during KOA in the recovery phase. The cell experiment indicated that Wangbi Tablets down-regulated the expression of interleukin(IL)-6, IL-1β, tumor necrosis factor-α(TNF-α), and Bcl-2-associated X protein(Bax)/B-cell lymphoma 2(Bcl-2) via regulating the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt) signaling pathway. The findings lay a theoretical foundation for further clarifying the clinical advantage stage and precise clinical application of Wangbi Tablets in treating KOA.
基于“病证方”相互作用网络研究尪痹片治疗膝骨关节炎（KOA）的临床优势分期及潜在机制。首先，从临床指南/共识及国家食品药品监督管理总局数据库收集尪痹片和KOA在急性期、缓解期及恢复期的临床症状及相关基因，从中药系统药理学数据库与分析平台（ETCM 2.0）获取尪痹片的潜在作用靶点。然后，采用杰卡德相似性和余弦相似性评估尪痹片与不同阶段KOA的临床症状、基因及富集通路的相似性。构建药物靶点与疾病基因的“病证方”相互作用网络，通过拓扑特征计算筛选关键靶点。利用京都基因与基因组百科全书（KEGG）和Reactome数据库对关键靶点进行功能富集，在此基础上预测尪痹片在急性期、缓解期及恢复期治疗KOA的功能特性。最后，用脂多糖处理的SW1353细胞解析尪痹片治疗KOA的机制。结果显示，从国家食品药品监督管理总局数据库收集到KOA在急性期、缓解期及恢复期与尪痹片对应的临床症状及相关基因分别为92/3921、138/3708、139/3800及196/3946条，从ETCM 2.0获取尪痹片260个潜在作用靶点。尪痹片与KOA在缓解期的临床症状、基因及富集通路相似性最高，与恢复期KOA的相似性次之。尪痹片的关键靶点主要参与免疫炎症失衡的调控，发挥止痛和保护骨质的作用，以缓解膝关节疼痛、关节肿胀、酸痛、乏力及功能障碍等症状。有趣的是，尪痹片的关键靶点在KOA急性期和缓解期具有抗氧化作用，而在恢复期维持物质和能量代谢稳态并保护血管。细胞实验表明，尪痹片通过调节磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（Akt）信号通路下调白细胞介素（IL）-6、IL-1β、肿瘤坏死因子-α（TNF-α）及Bcl-2相关X蛋白（Bax）/B细胞淋巴瘤2（Bcl-2）的表达。这些研究结果为进一步阐明尪痹片治疗KOA的临床优势分期及精准临床应用奠定了理论基础。
