Mechanistic exploration of licorice reconciling Medicine:Huangqi Guizhi Wuwu decoction and Shaoyao Gancao decoction compatibility as an example

Ethnopharmacological relevance: Glycyrrhiza uralensis Fisch. (GU) is a pivotal botanical in traditional Chinese medicine (TCM), because of its ability to reconcile various herbs, and its crucial role in numerous formulas. Huanggui Shaogan decoction (HSGD) is an empirical formula, developed by Huangqi Guizhi Wuwu decoction (HGD) and Shaoyao Gancao decoction (SGD), and prepared by adding GU to HGD. However, the mechanisms of GU reconciling medicine remain incompletely characterized. Aim of the study: This study aimed to explain mechanisms of GU reconciling medicine based on the differences of components, pharmacological efficacy, and the existence of the components. Methods: Differential components between HSGD and HGD were systematically identified using LC-MS/MS coupled with chemometric analysis. The existence states and binding affinities of these differential components were further characterized via ultrafiltration separation. The therapeutic potential of HSGD was validated in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). Results: Twenty-two differential chemical components between HSGD and HGD were identified, including flavonoids, saponins, gingerol, and monoglycoside. The transmittance of flavonoids and gingerols increased in HSGD. However, the transmittance of astragalus saponins decreased, which may be due to micelle association and the increase in molecular clusters. HSGD could enhance the mechanical pain threshold, alleviate cold nociceptive hypersensitivity, relieve dorsal root ganglia neuron injury, and decrease the expression of nerve growth factor, 5-hydroxytryptamine, substance P, and calcitonin gene-related peptide better. The differential correlation analysis revealed the relationship between differential components and pharmacological indicators. The above results indicated that different herbs combinations had a greater impact on the dissolution and molecular state of the components of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. Conclusion: The study highlights the solubilizing effect of GU within HSGD, and it also improves the efficacy of the treatment of OIPN, which underpins its compatibility rationality. It provided an inspiration for the study of other TCM formulas.