An integrated strategy for deciphering quality markers of Terminaliae Belliricae Fructus based on a three-dimensional characteristic model

Terminalia bellirica (Gaertn.) Roxb. is an ethnomedicinal plant that has been utilized in Tibetan and traditional Chinese medicine (TCM). Nevertheless, its quality standard officially listed in the Chinese Pharmacopoeia does not include any content determination of the indicator components of Terminaliae Belliricae Fructus, which constrains the effective quality evaluation of medicinal material and related products. In this paper, a three-dimensional “content-pharmacokinetics-pharmacology” network strategy was developed to identify the quality markers (Q-markers) of Terminaliae Belliricae Fructus in terms of “measurability”, “traceability” and “effectiveness”. Chromatographic fingerprint analysis was performed to outline its chemical contour, and identify the differential components of 17 batches of Terminaliae Belliricae Fructus combined with multivariate statistics analysis and UPLC-QTOF-MS analysis. Serum pharmacochemistry analysis was implemented on rats, and 25 prototype components absorbed into the blood were identified. By network pharmacology analysis, a component-disease-target-pathway network was constructed, thus validating the effectiveness of the chemical components of Terminaliae Belliricae Fructus. Afterwards, the above screened candidate components were put into construction of three-dimensional "radar chart". According to the calculated regression area ($RA$) and coefficient of variation ($CV$) values, the potential Q-markers was determined, followed by “specificity” evaluation. Ultimately, ellagic acid (EA), chebulagic acid (CHA), gallic acid (GA), chebulinic acid (CA), corilagin (CO) and chebulanin (CH) were specified as the Q-markers of Terminaliae Belliricae Fructus. Owing to high content, good pharmacokinetic property, high pharmacological activities and specificity. The screened Q-markers could offer a scientific foundation for the quality control of Terminaliae Belliricae Fructus, and the proposed strategy is demonstrated to be reliable and feasible for deciphering Q-markers of TCM.