Context Tadehaginoside, an active ingredient isolated from Tadehagi triquetrum (Linn.) Ohashi (Leguminosae), exhibited various biological activities. However, the pharmacokinetics and tissue distribution which affect tadehaginoside’s therapeutic actions and application remain elusive.Objective To clarify the metabolism of tadehaginoside in vivo.Materials and methods The pharmacokinetics and tissue distribution of tadehaginoside and its metabolite p-hydroxycinnamic acid (HYD) were investigated using LC-MS/MS. Pharmacokinetic parameters were determined in 10 Sprague-Dawley rats divided into two groups, the intravenous group (5 mg/kg) and the oral group (25 mg/kg). For the tissue-distribution study, 20 rats were intravenously given tadehaginoside (5 mg/kg) before the experiment (n = 4). Biological samples were collected before drug administration (control group) and after drug administration.Results The linearity, accuracy, precision, stability, recovery and matrix effect of the method were well-validated and the results satisfied the requirements of biological sample measurement. Treatment with tadehaginoside via intragastric and intravenous administration, the calculated Cmax in rats was 6.01 ± 2.14 ng/mL and 109.77 ± 4.29 ng/mL, and Tmax was 0.025 ± 0.08 h and 0.08 h, respectively. The results indicated that the quick absorption of tadehaginoside was observed following intravenous administration, and tadehaginoside in plasma of rats with intragastric administration showed relatively low concentration may be due to the formation of its metabolite. Tissue-distribution study indicated that kidney and spleen were the major distribution organs for tadehaginoside in rats and there was no long-term accumulation in most tissues.Discussion and conclusion These results could provide clues for exploring the bioactivity of tadehaginoside based on its pharmacokinetic characteristics.
Aicun Tang,Luying Wei,Jiayi Gao,Zheng Zhang,Bingyu Xia,Xin Li,Qiuyu Lu
To analyze tadehaginoside (TA) for its effect on liver fibrosis and the associated mechanism. Mice with CCl4-mediated liver fibrosis were administered TA treatment for 6 weeks. Histopathological alterations in liver tissues were evaluated, and serum markers of hepatic injury, as well as the hepatic profibrotic gene and protein levels were detected. Transforming growth factor-β1 (TGF-β1) was adopted for inducing LX-2 cells. Following a 24-h TA intervention, we assessed pro-fibrotic gene and protein activation, proliferation and levels of TGF-β1-activated LX-2 cells. miR-155 and FOXO3 expressions were quantified in mice liver tissues and cells. The targeting relation of miR-155 with FOXO3 was verified. After regulating miR-155 and FOXO3 expression, the function of TA in cell activation, proliferation, and collagen accumulation was evaluated. The results indicated that TA treatment markedly alleviated CCl4-mediated mouse liver injury, inhibited collagen fiber deposition, and downregulated the hepatic pro-fibrotic gene and protein levels. Additionally, TA treatment suppressed TGF-β1-induced cell activation and proliferation, thus significantly reducing pro-fibrotic marker levels within cells. Furthermore, treatment with TA down-regulated miR-155 and up-regulated FOXO3 within CCl4-induced liver tissues as well as TGF-β1-induced cells. However, miR-155 overexpression or FOXO3 silencing partially mitigated the inhibition of TA against TGF-β1-mediated activation, proliferation, and fibrosis in cells. In conclusion, TA inhibits the activation of hepatic stellate cell (HSC) via miR-155/FOXO3 axis, thereby exerting its anti-hepatic fibrosis effect.
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