Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF‐κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation

Abstract

Stevia has been shown to prevent oxidative stress and inflammation in carbon tetrachloride-induced cirrhosis models. This study aimed to investigate the ability of an aqueous extract of stevia (AES) to prevent thioacetamide (TAA)-induced cirrhosis in rats and to explore its mechanism of action. Liver cirrhosis was established by administering TAA (200 mg/kg by i.p. injections three times a week for 10 weeks); AES was administered (100 mg/kg by gavage daily) during the TAA treatment. Liver damage and fibrosis were evaluated, and the profibrotic pathways were analyzed by western blotting and immunohistochemistry. TAA increased nuclear factor kappa B (NF-κB) and pro-inflammatory cytokine production, as well as the malondialdehyde and 4hydroxynonenal levels, whereas the glutathione/glutathione disulfide and nuclear factor-E2-related factor 2 (Nrf2) levels were decreased. Moreover, TAA increased collagen production, hepatic stellate cell (HSC) activation, and expression of profibrogenic mediators. TAA-treated rats that had been exposed to Mn2+ exhibited altered striatal dopamine turnover, indicating hepatic encephalopathy. AES partially or completely prevented all of these effects. AES showed antioxidant, anti-inflammatory, and antifibrotic properties, probably because of its capacity to induce Nrf2 expression, reduce NF-κB expression, and block several profibrogenic signaling pathways, subsequently inhibiting HSC activation and preventing fibrosis and dopamine turnover.

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

“…During chronic liver injury, activation of quiescent HSCs is a necessary step to promote the expression of ECM proteins, which ultimately leads to fibrosis. In this regard, our present results indicate that one of the beneficial mechanisms of Reb A in inhibiting the development of fibrosis is the prevention of HSC activation; this observation is consistent with our previous observations that stevia leaves prevent experimental cirrhosis and modulate profibrogenic pathways mainly by blocking HSCs (Ramos‐Tovar, Buendia‐Montaño, et al, ; Ramos‐Tovar, Flores‐Beltrán, et al, ). The present results showed that Reb A exerted an antifibrogenic effect when coadministered with the profibrogenic agent TAA, maintaining the deposition of collagen in the liver parenchyma.…”

“…Several studies have demonstrated the pharmacological properties of Stevia rebaudiana Bertoni as a hepatoprotector and mainly as an antifibrotic agent (Ramos‐Tovar, Buendia‐Montaño, et al, ; Ramos‐Tovar, Flores‐Beltrán, et al, ; Ramos‐Tovar, Hernández‐Aquino, et al, ). However, few studies have been performed to evaluate the related pharmacological effects of its secondary compounds, such as Reb A (Holvoet et al, ; Wang et al, ).…”

“…Stevia leaves and isolated stevioside have been shown to display immunomodulatory activity, mainly by downregulating NF‐κB and proinflammatory cytokines (Latha, Chaudhary, & Ray, ; Potočnjak et al, ; Ramos‐Tovar, Flores‐Beltrán, et al, ); however, Reb A has thus far not been studied as an anti‐inflammatory drug. Herein, we demonstrated that Reb A downregulates NF‐κB in experimental fibrosis, thus blocking the expression of proinflammatory cytokines such as IL‐6 and TNF‐α, which also participate in the profibrogenic response.…”

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

“…Stevioside has been shown to be able to reduce oxidative stress and inflammation by several mechanism of actions. Ramos-Tovar et al (2018a) revealed that stevia extract (100 mg/kg) and stevioside (100 mg/kg) can prevent oxidative damage Table 4. Anti-inflammation activity of stevioside and related compounds (N.S., not stated; N.R., not relevant; TPA, 12-Otetradecanoylphorbol-13-acetate; ID 50 , half maximum inhibitory dose; LPS, lipopolysaccharides; qRT-PCR, quantitative real-time PCR; MPO, Myeloperoxidase; ELISA, enzyme-linked immunosorbent assay; IHC, Immunohistochemistry; Nrf2, nuclear factor (erythroid-derived 2)-like 2; TAA, thioacetamide).…”

“…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.…”