Rebaudioside A administration prevents experimental liver fibrosis: an in vivo and in vitro study of the mechanisms of action involved

Abstract

Rebaudioside A (Reb A) is a diterpenoid isolated from the leaves of Stevia rebaudiana (Bertoni) that has been shown to possess pharmacological activity, including antiinflammatory and antioxidant properties. However, the ability of Reb A to prevent liver injury has not been evaluated. Therefore, we aimed to study the potential of Reb A (20 mg/kg; two times daily intraperitoneally) to prevent liver injury induced by thioacetamide (TAA) administration (200 mg/kg; three times per week intraperitoneally). In addition, cocultures were incubated with either lipopolysaccharide or ethanol. Antifibrotic, antioxidant and immunological responses were evaluated.Chronic TAA administration produced considerable liver damage and distorted the liver parenchyma with the presence of prominent thick bands of collagen. In addition, TAA upregulated the expression of α-smooth muscle actin, transforming growth factor-β1, metalloproteinases 9, 2 and 13, and nuclear factor kappaB and downregulated nuclear erythroid factor 2. Reb A administration prevented all of these changes.In cocultured cells, Reb A prevented the upregulation of genes implicated in fibrotic and inflammatory processes when cells were exposed to ethanol and lipopolysaccharide. Altogether, our results suggest that Reb A prevents liver damage by blocking oxidative processes via upregulation of nuclear erythroid factor 2, exerts immunomodulatory effects by downregulating the nuclear factor-κB system and acts as an antifibrotic agent by maintaining collagen content.

‘Sweeter’ than its name: anti-inflammatory activities of Stevia rebaudiana

“…by activating nuclear factor erythroid 2-related factor 2 (Nrf2) response, an important transcription factor that can avert inflammation. Similar findings were reported by a recent study by Casas-Grajales in 2019, in which they demonstrated that rebaudioside A preserved expression of Nrf2 as well as downregulated/prevented the expression of pro-inflammatory pathway and genes such as NF-κB, TGF-β1, Smad7 and MMP-13 protein (Casas-Grajales et al 2019a, 2019b.…”

“…It has been speculated that the activators of Nrf2 can hinder IKK/IκB phosphorylation and p65 NF-κB subunit nuclear translocation, and then preventing NF-κB signaling pathway. Based on the proposed theory, stevioside may possibly prevent inflammation (a) via direct actions on NF-κB signaling pathway which then inhibiting the production of pro-inflammatory cytokines, and/or (b) via activating Nrf2 antioxidant response which then inhibits NF-κB signaling pathway (Bunprajun et al 2012;Yingkun et al 2013;Garcia-Arroyo et al 2016;Ramos-Tovar et al 2018a, 2018bCasas-Grajales et al 2019a, 2019b.…”

Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver

“…Several studies have been performed to investigate the effects of various antioxidants on different models of liver damage and have shown the causative role of ROS in the profibrogenic process. In models of bile duct ligation-, CCl 4 -, and thioacetamide chronic intoxication-induced fibrosis in rodents and in vitro studies, several compounds with direct or indirect antioxidant activity have been shown to prevent or reverse the accumulation of extracellular matrix (ECM) proteins (fibrotic tissue) within the hepatic parenchyma or the production of profibrogenic genes or proteins [59][60][61][62][63][64][65][66][67][68][69][70][71][72]. One of the most studied phytodrugs with important antioxidant properties is silibinin, the main active constituent of silymarin [73].…”

Drinking Non-nutritive Sweetness Solution of Sodium Saccharin or Rebaudioside a for Guinea Pigs: Influence on Histologic Change and Expression of Sweet Taste Receptors in Testis and Epididymis

“…Numerous studies suggested that high-intensity sodium saccharin contributed adverse biological, even toxicological, effects on reproductive systems (19,(32)(33)(34)(35). Conversely, a certain intensity of rebaudioside A represented positive biological functions (36)(37)(38). A study showed that natural sweeteners exerted their sweet taste by specifically binding to sweet taste receptors (39).…”