Sael Casas-Grajales1, Erika Ramos-Tovar1, Esmeralda Chávez-Estrada2, Diana Alvarez-Suarez1, Erika Hernández-Aquino1, Karina Reyes-Gordillo3, Carlos M Cerda-García-Rojas2, Javier Camacho1, Víctor Tsutsumi4, M Raj Lakshman3, Pablo Muriel5. 1. Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico. 2. Department of Chemistry, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico. 3. Department of Biochemistry and Molecular Biology, School of Medicine and Health Science, The George Washington University Medical Center, 2300 I St NW, Washington, DC 20052, United States of America; Lipid Research Laboratory, VA Medical Center, 50 Irving St, Washington, DC 20422, United States of America. 4. Department of Infectomics and Molecular Pathogenesis, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico. 5. Department of Pharmacology, Cinvestav-IPN, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, 07360, Apartado Postal 14-740, Mexico City, Mexico. Electronic address: pmuriel@cinvestav.mx.
Abstract
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)-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. SIGNIFICANCE: Collectively, these data suggest that stevioside prevented liver damage through antioxidant activity by upregulating Nrf2 and immunomodulatory activity by blocking NF-κB signaling.
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)-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. SIGNIFICANCE: Collectively, these data suggest that stevioside prevented liver damage through antioxidant activity by upregulating Nrf2 and immunomodulatory activity by blocking NF-κB signaling.
Authors: P H Carter; P A Scherle; J K Muckelbauer; M E Voss; R Q Liu; L A Thompson; A J Tebben; K A Solomon; Y C Lo; Z Li; P Strzemienski; G Yang; N Falahatpisheh; M Xu; Z Wu; N A Farrow; K Ramnarayan; J Wang; D Rideout; V Yalamoori; P Domaille; D J Underwood; J M Trzaskos; S M Friedman; R C Newton; C P Decicco; J A Muckelbauer Journal: Proc Natl Acad Sci U S A Date: 2001-10-09 Impact factor: 11.205