Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays
Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays
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DOI：
10.1016/j.lfs.2019.03.035
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发表时间：
2019-05-01
期刊：
影响因子：
6.1
通讯作者：
Muriel, Pablo
中科院分区：
文献类型：
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作者：
Casas-Grajales, Sael;Ramos-Tovar, Erika;Muriel, Pablo
目的：甜菊糖苷是一种从甜菊叶中提取的二萜类化合物，具有抗氧化、抗纤维化、降糖和抗癌的特性。因此，我们旨在研究甜菊糖甙是否对长期给药硫代乙酰胺（TAA）引起的肝损伤有有益作用，并通过体内、体外和计算机方法探讨其可能的分子机制。主要方法：雄性Wistar大鼠经TAA （200 mg/kg）腹腔灌胃，每周3次诱导肝损伤。大鼠每日两次腹腔注射生理盐水或甜菊糖苷（20 mg/kg）。此外，共培养用脂多糖或乙醇孵育。评估肝损伤、抗氧化和免疫反应。主要发现：长期服用TAA可引起明显的肝损害。此外，TAA上调核因子(NF)- κ B的蛋白表达，通过下调核红细胞因子2 (Nrf2)，增加促炎细胞因子的表达，降低肝脏的抗氧化能力。值得注意的是，甜菊苷的服用阻止了所有这些变化。在体外实验中，当共培养细胞与脂多糖或乙醇孵育时，甜菊糖苷阻止了与肝脏炎症有关的几种基因的上调。利用肿瘤坏死因子受体(TNFR)-1和toll样受体(TLR)-4-MD2进行的计算机实验表明，甜菊苷与TNFR1和TLR4-MD2对接，从而促进对这种促炎介质的拮抗作用。意义：总的来说，这些数据表明甜菊糖苷通过上调Nrf2的抗氧化活性和通过阻断NF-KB信号传导的免疫调节活性来预防肝损伤。
Aims: Stevioside is a diterpenoid obtained from the leaves of Stevia rebaudiana (Bertoni) that exhibits antioxidant, antifibrotic, antiglycemic and anticancer properties. Therefore, we aimed to study whether stevioside has beneficial effects in liver injury induced by long-term thioacetamide (TAA) administration and investigated the possible underlying molecular mechanism using in vivo, in vitro and in silico approaches.Main methods: Liver injury was induced in male Wistar rats by TAA administration (200 mg/kg), intraperitoneally, three times per week. Rats received saline or stevioside (20 mg/kg) twice daily intraperitoneally. In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Liver injury, antioxidant and immunological responses were evaluated.Key findings: Chronic TAA administration induced significant liver damage. In addition, TAA upregulated the protein expression of nuclear factor (NF)-kappa B, thus increasing the expression of proinflammatory cytokines and decreasing the antioxidant capacity of the liver through downregulation of nuclear erythroid factor 2 (Nrf2). Notably, stevioside administration prevented all of these changes. In vitro, stevioside prevented the upregulation of several genes implicated in liver inflammation when cocultured cells were incubated with lipopolysaccharide or ethanol. In silico assays using tumor necrosis factor receptor (TNFR)-1 and Toll-like receptor (TLR)-4-MD2 demonstrated that stevioside docks with TNFR1 and TLR4-MD2, thus promoting an antagonistic action against this proinflammatory mediator.Significance: Collectively, these data suggest that stevioside prevented liver damage through antioxidant activity by upregulating Nrf2 and immunomodulatory activity by blocking NF-KB signaling.