Zhu Jing, Huang Yiming, Ye Chao, Deng Xiaoxia, Zou Yuxuan, Yuan En, Chen Qi
Research Center for Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, People's Republic of China.
School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People's Republic of China.
J Inflamm Res. 2024 Dec 29;17:11757-11787. doi: 10.2147/JIR.S489691. eCollection 2024.
The main objective of this study was to elucidate the effector material basis of Cimicifugae Rhizoma (CR) for the treatment of acute pneumonia (AP) and to explore the potential mechanisms underlying the anti-AP effects of these active components in a lipopolysaccharide (LPS)-induced inflammation model of lung epithelial cells.
Chemical components were identified using ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry (UPLC-TOF-MS), and a CR component library was subsequently established based on a combination of databases and available literature. Bioinformatics techniques were used to construct "component-target" and "protein-protein interaction (PPI)" networks, and the potential active components and core targets screened according to degree value, followed by molecular docking and in vitro experiments for verification. Inflammation was induced in normal human lung epithelial cells using lipopolysaccharide (LPS) to mimic the occurrence of AP.
In total, 122 CR components were identified. The therapeutic effects of potential active components against AP were associated with 147 targets involving 165 signaling pathways. Molecular docking experiments revealed the strong affinity of N-cis- feruloyltyramine, ferulic acid, cimifugin, and isoferulic acid for core AP-associated targets. In vitro cellular experiments showed that the above compounds and CR alcoholic extracts inhibited the expression of inflammatory factors in the following order: isoferulic acid > cimifugin > CR alcoholic extract > N-cis-feruloyltyramine > ferulic acid.
N-cis- feruloyltyramine, ferulic acid, cimifugin, and isoferulic acid were the effector components of CR with activity against AP. These compounds potentially co-regulate the IL-6/JAK/STAT3 and TLR4/IL-1β-IRAK pathways through the inhibition of cytokines such as IL-6, TNF-α, and IL-1β, and downregulation of P-STAT3, TLR4, PIK3CA, and NF-κB involved in TLR4/IL-1β-IRAK/NF-κB and PI3K-Akt signaling pathways to exert therapeutic effects on AP.
本研究的主要目的是阐明升麻治疗急性肺炎（AP）的效应物质基础，并在脂多糖（LPS）诱导的肺上皮细胞炎症模型中探索这些活性成分抗AP作用的潜在机制。
采用超高效液相色谱-四极杆-飞行时间串联质谱（UPLC-TOF-MS）鉴定化学成分，随后基于数据库和现有文献建立升麻成分库。利用生物信息学技术构建“成分-靶点”和“蛋白质-蛋白质相互作用（PPI）”网络，并根据度值筛选潜在的活性成分和核心靶点，随后进行分子对接和体外实验验证。用脂多糖（LPS）诱导正常人肺上皮细胞发生炎症以模拟AP的发生。
共鉴定出122种升麻成分。潜在活性成分对AP的治疗作用与涉及165条信号通路的147个靶点相关。分子对接实验表明，N-顺式阿魏酰酪胺、阿魏酸、升麻苷和异阿魏酸与AP相关核心靶点具有较强亲和力。体外细胞实验表明，上述化合物和升麻醇提物对炎症因子表达的抑制作用顺序为：异阿魏酸＞升麻苷＞升麻醇提物＞N-顺式阿魏酰酪胺＞阿魏酸。
N-顺式阿魏酰酪胺、阿魏酸、升麻苷和异阿魏酸是升麻抗AP的效应成分。这些化合物可能通过抑制白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）等细胞因子，并下调参与Toll样受体4（TLR4）/IL-1β/白细胞介素-1受体相关激酶（IRAK）/核因子-κB（NF-κB）和磷脂酰肌醇-3激酶（PI3K）-蛋白激酶B（Akt）信号通路的磷酸化信号转导和转录激活因子3（P-STAT3）、TLR4、磷脂酰肌醇-3激酶催化亚基α（PIK3CA）和NF-κB，共同调节IL-6/Janus激酶（JAK）/STAT3和TLR4/IL-1β-IRAK通路，从而对AP发挥治疗作用。
