Zhang Chengxi, Li Xiaoqian, Gao Dan, Zhu Huahe, Wang Shun, Tan Bo, Yang Aidong
School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Center for Traditional Chinese Medicine and Epidemic Disease, Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, People's Republic of China.
J Inflamm Res. 2023 Dec 19;16:6195-6209. doi: 10.2147/JIR.S433840. eCollection 2023.
Tingli Dazao Xiefei Decoction (TDXD) is a Traditional Chinese Medicine (TCM) formula used to treat acute lung injury (ALI). However, the precise mechanism of TDXD in treating ALI remains unclear. We investigated the therapeutic mechanism of TDXD against ALI using a complementary approach combining network pharmacology, molecular docking, and in vitro and in vivo experiments.
Potential drug targets of TDXD and relevant target genes associated with ALI were retrieved from Chinese medicines and disease genes databases. Bioinformatics technology was employed to screen potential active ingredients and core targets. Validation experiments were conducted using a lipopolysaccharide (LPS)-induced ALI mouse (C57BL/6J) model, LPS-induced inflammatory RAW264.7 cells, and molecular docking between active compounds of TDXD and potential targets.
Network pharmacology suggested that the mechanism of TDXD against ALI involved phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) / phosphatase and tensin homolog (PTEN) and Janus kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) pathways. Quercetin, β-sitosterol, kaempferol, isorhamnetin, and L-stepholidine were identified as the main active compounds of TDXD that exerted anti-ALI effects. Molecular docking indicated that these compounds exhibited good binding capabilities (≤ -5kcal/mol) to key targets in PI3K/AKT/PTEN and JAK2/STAT3 signaling pathways. In the animal model, TDXD alleviated injuries and inflammatory responses in lung tissues, accompanied by inhibition of expression of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), STAT3, and Suppressor of Cytokine Signaling 3 (SOCS3) mRNA, and key proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (all P values < 0.05). Cell based experiments showed that TDXD dose-dependently inhibited the expression of essential proteins in PI3K/AKT/PTEN and JAK2/STAT3 pathways (P < 0.05).
This study revealed that the mechanism of TDXD in ALI treatment might involve simultaneous regulation of PI3K/AKT/PTEN and JAK2/STAT3 pathways.
葶苈大枣泻肺汤（TDXD）是一种用于治疗急性肺损伤（ALI）的中药方剂。然而，TDXD治疗ALI的确切机制仍不清楚。我们采用网络药理学、分子对接以及体外和体内实验相结合的补充方法，研究了TDXD抗ALI的治疗机制。
从中药和疾病基因数据库中检索TDXD的潜在药物靶点以及与ALI相关的靶基因。运用生物信息学技术筛选潜在的活性成分和核心靶点。使用脂多糖（LPS）诱导的ALI小鼠（C57BL/6J）模型、LPS诱导的炎性RAW264.7细胞以及TDXD活性化合物与潜在靶点之间的分子对接进行验证实验。
网络药理学表明，TDXD抗ALI的机制涉及磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）/磷酸酶和张力蛋白同源物（PTEN）以及Janus激酶2（JAK2）/信号转导子和转录激活子3（STAT3）通路。槲皮素、β-谷甾醇、山奈酚、异鼠李素和左旋千金藤啶碱被确定为TDXD发挥抗ALI作用的主要活性化合物。分子对接表明，这些化合物对PI3K/AKT/PTEN和JAK2/STAT3信号通路中的关键靶点表现出良好的结合能力（≤ -5kcal/mol）。在动物模型中，TDXD减轻了肺组织的损伤和炎症反应，同时抑制了肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、STAT3和细胞因子信号转导抑制因子3（SOCS3）mRNA的表达，以及PI3K/AKT/PTEN和JAK2/STAT3通路中的关键蛋白（所有P值<0.05）。基于细胞的实验表明，TDXD剂量依赖性地抑制PI3K/AKT/PTEN和JAK2/STAT3通路中必需蛋白的表达（P < 0.05）。
本研究表明，TDXD治疗ALI的机制可能涉及同时调节PI3K/AKT/PTEN和JAK2/STAT3通路。
