The activities and mechanisms of intestinal microbiota metabolites of TCM herbal ingredients could be illustrated by a strategy integrating spectrum-effects, network pharmacology, metabolomics and molecular docking analysis: Platycodin D as an example

Article

Author: Zhang, Xin-Yu ; Peng, Yi-Ming ; Zhang, Ting ; Huang, Hui-Lian ; Zhong, Yuan-Han ; Zhong, Guo-Yue ; Liang, Jian ; He, Jun-Wei ; Zeng, Jin-Xiang ; Qin, Qian ; Zhang, Shou-Wen ; Wang, Yu-Jie ; Liu, Fang-Yuan

BACKGROUNDThe intestinal microbiota plays a key role in understanding the mechanism of traditional Chinese medicine (TCM), as it could transform the herbal ingredients to metabolites with higher bioavailability and activity comparing to their prototypes. Nevertheless, the study of the activity and mechanism of microbiota metabolites reported by the published literature still lacks viable ways. Hence a new strategy is proposed to solve this issue.PURPOSEA new strategy to study the activity and mechanism of intestinal microbiota metabolites of TCM herbal ingredients by integrating spectrum-effect relationship, network pharmacology, metabolomics analysis and molecular docking together was developed and proposed.METHODPlatycodin D (PD) and its microbiota metabolites with antitussive and expectorant effect were selected as an example for demonstration. First, the PD and its microbiota metabolites with important contribution to antitussive and/or expectorant effects were screened through spectrum-effect relationship analysis. Second, network pharmacology and metabolomics analysis were integrated to identify the upstream key targets of PD and its microbiota metabolites as well as the downstream endogenous metabolites. Finally, the active forms of PD were further confirmed by molecular docking.RESULTSResults showed that PD was an active ingredient with antitussive and/or expectorant effects, and the active forms of PD were its microbiota metabolites: 3-O-β-d-glucopyranosyl platycodigenin, 3-O-β-d-glucopyranosyl isoplatycodigenin, 7‑hydroxyl-3-O-β-d-glucopyranosyl platycodigenin, platycodigenin and isoplatycodigenin. In addition, those microbiota metabolites could bind the key targets of PAH, PLA2G2A, ALOX5, CYP2C9 and CYP2D6 to exert antitussive effects by regulating four metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Similarly, they could also bind the key targets of PLA2G1B, ALOX5, CYP2C9 and CYP2D6 to exert expectorant effect by regulating two pathways of glycerophospholipid metabolism and linoleic acid metabolism.CONCLUSIONThe proposed strategy paves a new way for the illustration of the activities and mechanisms of TCM herbal ingredients, which is very important to reconcile the conundrums of TCM herbal ingredients with low oral bioavailability but high activity.

01 Nov 2022·Applied Biochemistry and Biotechnology

Synchronous Investigation of the Mechanism and Substance Basis of Tripterygium Glycosides Tablets on Anti-rheumatoid Arthritis and Hepatotoxicity

Article

Author: Gao, Yanhua ; Su, Suwen ; Qian, Qi ; Ge, Jiachen ; Mou, Feifei ; Xun, Ge ; Zhang, Huaxing ; Wang, Qiao ; Wang, Xu

Tripterygium Glycosides Tablets (TGT) has shown obvious anti-rheumatoid arthritis (RA) effects accompanied by hepatotoxicity. Despite that many studies looked at TGT's anti-RA or hepatotoxic mechanism and substance basis, the results were still insufficient. Furthermore, the anti-RA and hepatotoxicity investigations of TGT were undertaken separately, neglecting the relationship between efficacy and toxicity. Herein, an integrated approach combining metabolomics, network pharmacology, serum pharmacochemistry, and molecular docking was adopted to elucidate the mechanism and substance basis of Tripterygium Glycosides Tablets (TGT) on anti-rheumatoid arthritis and hepatotoxicity simultaneously. The results showed that 33 components in TGT were absorbed into rat serum. Two toxic targets (PRKCA, FASN), three effective targets (PLA2G10, PTGES, PLA2G1B), and four effective and toxic targets (PTGS1, PTGS2, PLA2G2A, ALOX5) were obtained by metabolomics combined with network analysis and network pharmacology. A component-target-RA-hepatotoxicity network was constructed and five hepatotoxic components (1-desacetylwilforgine, wilfordconine, wilforgine, wilformine, wilfornine D), eight effective-toxic components (14-oxo-19-(4 → 3) abeo-abieta-3,8,12-tetraen-19,18-olide, 7-oxo-18(4 → 3) abeo-abieta-3,8,11,13-tetraen-18-oic acid, hypoglaulide, triptotriterpenic acid A, wilforol F, wilforlide B, triptoquinone B, wilforlide A); and 23 non-effective and non-toxic components were acquired and validated by molecular docking. In addition, our research revealed that glycerophospholipid metabolism and ether lipid metabolism were correlated to both hepatotoxicity and anti-RA of TGT. While in sphingolipid metabolism, ceramidases regulated ceramide-sphingosine and phytoceramide-phytosphingosine reaction were found to be correlated to hepatotoxicity, sphinganine-1-phosphate lyase (SPL) regulated sphingosine 1-phosphate (S1P)-phosphoethanolamine and sphinganine 1-phosphate-phosphoethanolamine were found to be attributed to anti-RA effects.

01 Mar 2019·Biomedicine & PharmacotherapyQ2 · MEDICINE

The modulatory properties of Si Jun Zi Tang enhancing anticancer of gefitinib by an integrating approach

Q2 · MEDICINE

Article

Author: Wang, Ruilin ; Zhou, Xiao Wei ; Qi, Shuya ; Niu, Ming ; Li, RuiSheng ; Li, Chunyu ; Li, Guohui ; Chen, Wei ; Shi, Yafei ; Zhang, Mingyu ; Dong, Bin

Lung cancer remains the leading cause of cancer death worldwide, and the current therapy seems to have reached a plateau due to toxicities and acquired resistance. Therefore, exploration of novel therapeutic avenues may be useful. Si Jun Zi Tang (SJZ), a four-herb Chinese medicine formula first described approximately one thousand years, is often prescribed for cancer patients as a complementary therapy. However, whether SJZ benefits cancer patients as well as the main active constituents and its regulatory mechanism in combination with anticancer drugs remains unknown. Here, we investigated the anti-lung cancer potency and underlying mechanisms of the combination of gefitinib plus SJZ in mice with Lewis lung carcinoma (LLC), using histopathology and an integrated strategy of metabolomics and network pharmacology. The results showed that SJZ significantly enhanced gefitinib suppressing tumor growth and inhibiting LLC metastasis in LLC-bearing mice. Furthermore, 9 potential metabolomics biomarkers that differentially expressed in the SJZ/gefitinib group compared to the SJZ group or gefitinib group were identified by untargeted metabolomics, mainly involved three pathways: tricarboxylic acid cycle, tyrosine and tryptophan biosynthesis metabolism and linoleic acid metabolism. Five active ingredients, kaempferol, ginsenoside Rf, caprylic acid, lauric acid and naringenin, acted directly on 9 targets and regulated 4 out of 9 metabolites. Our results indicated that SJZ enhanced the anti-lung cancer effects of gefitinib via the key targets ABCG2, ABCC1, ABAT, GSR, CYP1A2, ALOX5, CYP3A4, PLA2G1B and PLA2G2A and the key metabolites 2-oxoglutarate, taurocholic acid, oxidized glutathione and linoleic acid. This work illustrated the modulatory properties of SJZ, which enhanced the anticancer effects of gefitinib, using metabolomics and network pharmacology analyses, and provided insights into underlying the mechanism the active ingredients of SJZfor the treatment of lung cancer in combination with gefitinib.

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