Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico.
Department of Chemistry, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico.
Life Sci. 2019 May 1;224:187-196. doi: 10.1016/j.lfs.2019.03.035. Epub 2019 Mar 16.
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.
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.
Chronic TAA administration induced significant liver damage. In addition, TAA upregulated the protein expression of nuclear factor (NF)-κB, 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.
Collectively, these data suggest that stevioside prevented liver damage through antioxidant activity by upregulating Nrf2 and immunomodulatory activity by blocking NF-κB signaling.
甜菊苷是从甜叶菊（Bertoni）的叶子中提取的二萜类化合物，具有抗氧化、抗纤维化、降血糖和抗癌作用。因此，我们旨在研究甜菊苷是否对长期硫代乙酰胺（TAA）给药引起的肝损伤有有益作用，并使用体内、体外和计算方法研究其可能的潜在分子机制。
通过 TAA（200mg/kg）腹腔内三次/周给药诱导雄性 Wistar 大鼠肝损伤。大鼠每天两次腹腔内给予生理盐水或甜菊苷（20mg/kg）。此外，将共培养物与脂多糖或乙醇孵育。评估肝损伤、抗氧化和免疫反应。
慢性 TAA 给药诱导明显的肝损伤。此外，TAA 上调核因子（NF）-κB 的蛋白表达，从而通过下调核红细胞因子 2（Nrf2）增加促炎细胞因子的表达并降低肝脏的抗氧化能力。值得注意的是，甜菊苷给药可预防所有这些变化。在体外，当共培养细胞用脂多糖或乙醇孵育时，甜菊苷可防止几种与肝炎症相关的基因上调。使用肿瘤坏死因子受体（TNFR）-1 和 Toll 样受体（TLR）-4-MD2 的计算分析表明，甜菊苷与 TNFR1 和 TLR4-MD2 结合，从而对这种促炎介质发挥拮抗作用。
总之，这些数据表明，甜菊苷通过上调 Nrf2 发挥抗氧化活性，通过阻断 NF-κB 信号发挥免疫调节活性，从而预防肝损伤。
