Screening effective-component compatibility from Jinshui Chenfei formula for silicosis treatment by...

The unclear chemical composition and mechanisms of action pose challenges for new drug development and quality control of traditional Chinese medicine (TCM) formulas. To address this, the concept of effective-component compatibility (ECC) was proposed to represent drug combination with equivalent efficacy to TCM formulas, along with clear composition and dosage. However, previous strategies for screening ECC have often overlooked the synergistic effects of its components.

This study proposed a strategy integrating serum pharmacochemistry and feedback system control (FSC) to identify synergistic combinations as ECC of TCM formulas. The strategy was applied to identify the ECC of Jinshui Chenfei formula (JCF) for silicosis treatment.

A chemical library of JCF was constructed using ultra-high-performance liquid chromatography-quadrupole extractive orbitrap mass spectrometry (UHPLC-Q-Extractive Orbitrap MS). The library was then used to identify absorbed prototype compounds of JCF, and the serum levels of its main components were analyzed. Based on the primary absorbed prototypes, FSC was employed to screen the most effective synergistic combinations from JCF for inhibiting LPS- and IL-4-induced macrophage polarization. The pharmacological effects of ECC-JCF were further validated using a silica-induced silicosis mouse model, and its synergistic mechanisms were investigated through transcriptomics and molecular dynamic simulations.

A total of 437 compounds were identified in JCF, with 203 absorbed prototypes detected following oral administration. After three rounds of FSC iterative screening, a synergistic combination of isoliquiritin (180 μg/ml/0.43 mM), glycyrrhizic acid (180 μg/ml/0.22 mM), and gallic acid (3.75 μg/ml/0.02 mM) significantly inhibited the expression of TNF-α, IL-1β, IL-6, CD206, and Arg-1 mRNA in mouse alveolar macrophages. This combination also protected lung tissues from alveolar collapse, inflammatory cell infiltration, fibroblast proliferation, and fibrous nodule formation. In addition, the combination improved alveolitis and fibrosis scores in silicosis mice, outperforming both the original JCF formula and the sum of individual components. The synergistic effects of these compounds may regulate targets in inflammation and fibrosis formation pathways.

This study identified an ECC of JCF with a well-defined composition and mechanism of action, facilitating the future development of JCF as a new drug. Compared with traditional ECC screening methods, this strategy reduces experimental workload while accounting for synergistic effects.