Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays

• Published in: Life sciences (1973) 2019-05, Vol.224, p.187-196
• Main Authors: Casas-Grajales, Sael, Ramos-Tovar, Erika, Chávez-Estrada, Esmeralda, Alvarez-Suarez, Diana, Hernández-Aquino, Erika, Reyes-Gordillo, Karina, Cerda-García-Rojas, Carlos M., Camacho, Javier, Tsutsumi, Víctor, Lakshman, M. Raj, Muriel, Pablo
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antioxidants; Antioxidants - pharmacology; Chemical and Drug Induced Liver Injury - drug therapy; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Cocultures; Computer Simulation; Cytokines; Damage assessment; Damage prevention; Diterpenes, Kaurane - pharmacology; Docking; Docks; Ethanol; Glucosides - pharmacology; Hepatocytes; Immune system; Immunologic Factors - pharmacology; Immunology; Immunomodulation; Immunomodulatory; In Vitro Techniques; In vivo methods and tests; Inflammation; Injuries; Lipopolysaccharides; Liver; Male; NF-κB protein; Nrf2; Oxidative Stress - drug effects; Proteins; Rats; Rats, Wistar; Rodents; Signal Transduction - drug effects; Stevioside; Sweetening Agents - pharmacology; TAA; Thioacetamide; Thioacetamide - toxicity; TLR4 protein; Toll-like receptors; Tumor necrosis factor receptors
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.03.035

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. [Display omitted]