Stevia prevents experimental cirrhosis by reducing hepatic myofibroblasts and modulating molecular profibrotic pathways

Abstract

Aim The aims of the present study were to investigate the capacity of stevia leaves to prevent experimental cirrhosis induced by chronic administration of carbon tetrachloride (CCl4) in rats and to explore the action mechanism involved. Methods Liver cirrhosis was established by CCl4 treatment (400 mg/kg i.p. three times a week for 12 weeks); stevia powder was administered (100 mg/kg by gavage daily) during the CCl4 treatment. Serum markers of liver damage and hydroxyproline were evaluated and histopathological analyses were carried out. The profibrotic pathways were analyzed by western blot and immunohistochemistry. Results We found for the first time that stevia cotreatment prevented the elevation of serum markers of necrosis and cholestasis and the occurrence of liver fibrosis. It is worth noting that stevia downregulated several profibrogenic pathways, including the reduction of hepatic myofibroblasts and decreased matrix metalloproteinase (MMP)2 and MMP13 expression, thereby blocking the liberation of transforming growth factor‐β from the extracellular matrix. Notably, stevia reduced the phosphorylation of pSmad3L, the most profibrogenic and mitogenic Smad, by inhibiting the activation of c‐Jun N‐terminal kinase and extracellular signal‐regulated kinase. Interestingly, Smad7, an important antifibrotic molecule, was upregulated by stevia treatment in cirrhotic rats. These multitarget mechanisms led to the prevention of experimental cirrhosis. Conclusions Because stevia possesses a reasonable safety profile, our results indicate that it could be useful in the clinical setting to treat chronic liver diseases.

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, ).…”

“…Moreover, stevioside inhibits the phosphorylation of p38, extracellular signaling kinase and c‐Jun kinase (Fengyang et al, ). Interestingly, the MAPK pathway participates in the profibrogenic response through the noncanonical Smad pathway by phosphorylating Smad3 in the linker domain (Hernández‐Aquino et al, ; Ramos‐Tovar, Buendia‐Montaño, et al, ). In this scenario, it is reasonable to propose that Reb A, similar to stevioside, may protect the liver by exerting the immunomodulatory and antifibrogenic effects, downregulating the NF‐κB pathway and modulating the MAPK pathway.…”

Stevioside inhibits experimental fibrosis by down‐regulating profibrotic Smad pathways and blocking hepatic stellate cell activation

“…Previously, we found that stevia leaves powder inhibited chronic liver damage induced by CCl 4 administration by reducing hepatic myofibroblasts and modulating some molecular profibrotic pathways . Herein, we found that SVT, a diterpenoid present in stevia leaves, inhibited liver cirrhosis induced by TAA in rats by modulating MMPs, inhibiting the activation of HSCs, down‐regulating TGF‐β1 and the canonical and non‐canonical Smad pathways.…”

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].…”