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Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

ABSTRACT: Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite. In this study, potential synergic mechanism of the herb pair was investigated by utilizing multiple approaches. In silico and in vitro Caco-2?cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein (P-gp), as well as the inhibition effects on P-gp. Additionally, anti-inflammatory activity of aconitine (AC) combined with active ingredients of liquorice, as well as pharmacokinetic patterns of AC after co-administration was investigated. Anti-inflammatory effect of AC (1?mg/kg) in rats was enhanced in combination with bioactive ingredients of liquorice (10?mg/kg). In the meanwhile, the exposure of AC in vivo was altered, in terms of Cmax and AUC. For instance, the Cmax and AUC were increased to 1.9 and 1.3 folds, respectively, when used in combination with liquiritigenin. The in silico study revealed the potential binding mode with outward facing conformation of P-gp. The resulting data obtained from transport of rhodamine-123 (Rh-123) across Caco-2?cell monolayer further indicated that the function of P-gp was inhibited by chemicals in liquorice. The synergic effect was therefore proposed to be attributed to inhibition of P-gp by liquorice since AC has been demonstrated to be the substrate of P-gp. The resuls revealed that potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting function of key efflux transporter P-gp to enhance the exposure of AC in systematic circulation, and further the anti-inflammatory effect, which helps clarify the compatibility rationale of these two herbs.

SUBMITTER: He Y

PROVIDER: S-EPMC7192969 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

He Yufei Y Wei Zihong Z Xie Ying Y Yi Xiulin X Zeng Yong Y Li Yazhuo Y Liu Changxiao C

Journal of pharmaceutical analysis 20190926 2

Wutou-Gancao herb-pair is extensively used to attenuate the toxicity and enhance the efficacy of aconite. In this study, potential synergic mechanism of the herb pair was investigated by utilizing multiple approaches. In silico and in vitro Caco-2 cell models were applied to study the potential binding mode of bioactive ingredients existing in liquorice with P-glycoprotein (P-gp), as well as the inhibition effects on P-gp. Additionally, anti-inflammatory activity of aconitine (AC) combined with ...[more]

PMID: 32373389

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Project description:BackgroundPharmacokinetic interaction is one of the most important indices for the evaluation of the compatibility of herbal medicines. Both Gancao (Glycyrrhizae Radix et Rhizoma) and Huanglian (Coptidis Rhizoma) are commonly used traditional Chinese medicines (TCMs). In this study, the influence of Gancao on the pharmacokinetics of Huanglian was systematically studied by using berberine as a pharmacokinetic marker.MethodsExtracts of the herbal pieces of Huanglian and the herb pair (Huanglian plus Gancao) were prepared with boiling water. The concentration of berberine in the samples was analyzed using liquid chromatography-mass spectrometry. The total amounts of berberine in all extract samples were compared. Comparative pharmacokinetic studies of Huanglian and the herb pair were conducted in ICR mice. In vitro berberine absorption and efflux were studied using mice gut sacs. The equilibrium solubility of berberine in the extracts was determined. The in vitro dissolution of berberine was comparatively studied using a rotating basket method.ResultsGancao significantly reduced berberine exposure in the portal circulation (425.8 ng·h/mL vs. 270.4 ng·h/mL) and the liver (29,500.8 ng·h/mL vs. 15,422.4 ng·h/mL) of the mice. In addition, Gancao decreased the peak concentration (Cmax) of berberine in the portal circulation (104.3 ng·h/mL vs. 76.5 ng·h/mL) and liver (4926.1 ng·h/mL vs. 2642.8 ng·h/mL) of mice. Significant influences of Gancao on the amount of berberine extracted (32% reduction), the solubility of berberine (34.7% compared with the control group), and dissolution (88.7% vs. 66.1% at 15 min in acid buffer and 68% vs. 51.8% at 15 min in phosphate buffer) were also revealed. Comparative pharmacokinetic studies in ICR mice indicated that the formation of sediment was unfavorable in terms of berberine absorption (345.3 ng·h/mL vs. 119.8 ng·h/mL).ConclusionsGancao was able to reduce intestinal absorption and in vivo exposure of berberine in Huanglian via the formation of sediment, which caused reductions in the extracted amount, solubility, and dissolution of berberine.

Project description:BackgroundCoronavirus disease 2019 (COVID-19) keeps spreading globally. Chinese medicine (CM) exerts a critical role for the prevention or therapy of COVID-19 in an integrative and holistic way. However, mining and development of early, efficient, multisite binding CMs that inhibit the cytokine storm are imminent.MethodsThe formulae were extracted retrospectively from clinical records in Hunan Province. Clinical data mining analysis and association rule analysis were employed for mining the high-frequency herbal pairs and groups from formulae. Network pharmacology methods were applied to initially explore the most critical pair's hub targets, active ingredients, and potential mechanisms. The binding power of active ingredients to the hub targets was verified by molecular docking.ResultsEight hundred sixty-two prescriptions were obtained from 320 moderate COVID-19 through the Hunan Provincial Health Commission. Glycyrrhizae Radix et Rhizoma (Gancao) and Pinelliae Rhizoma (Banxia) were used with the highest frequency and support. There were 49 potential genes associated with Gancao-Banxia pair against moderate COVID-19 patients. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that Gancao-Banxia might act via inflammatory response, viral defense, and immune responses signaling pathways. IL-6 and STAT3 were the two most hub targets in the protein-protein interaction (PPI) network. The binding of five active ingredients originated from Gancao-Banxia to IL-6-STAT3 was verified by molecular docking, namely quercetin, coniferin, licochalcone a, Licoagrocarpin and (3S,6S)-3-(benzyl)-6-(4-hydroxybenzyl)piperazine-2,5-quinone, maximizing therapeutic efficacy.ConclusionsThis work provided some potential candidate Chinese medicine formulas for moderate COVID-19. Among them, Gancao-Banxia was considered the most potential herbal pair. Bioinformatic data demonstrated that Gancao-Banxia pair may achieve dual inhibition of IL-6-STAT3 via directly interacting with IL-6 and STAT3, suppressing the IL-6 amplifier. SARS-CoV-2 models will be needed to validate this possibility in the future.

Dataset Information

Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

Publications

Potential synergic mechanism of Wutou-Gancao herb-pair by inhibiting efflux transporter P-glycoprotein.

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