RESEARCH ARTICLE Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF‐κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation Erika Ramos‐Tovar 1 | Rosa E. Flores‐Beltrán 1 | Silvia Galindo‐Gómez 2 | Eunice Vera‐Aguilar 3 | Araceli Diaz‐Ruiz 4 | Sergio Montes 4 | Javier Camacho 3 | Víctor Tsutsumi 2 | Pablo Muriel 1 1 Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav‐IPN, Mexico City, Mexico 2 Department of Infectomics and Molecular Pathogenesis, Cinvestav‐IPN, Mexico City, Mexico 3 Department of Pharmacology, Cinvestav‐ IPN, Mexico City, Mexico 4 Department of Neurochemistry, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez” , Mexico City, Mexico Correspondence Pablo Muriel, PhD, Laboratory of Experimental Hepatology, Department of Pharmacology, Cinvestav‐IPN, Av. Instituto Politécnico Nacional 2508, Apartado Postal 14‐740, Mexico City 07000, Mexico. Email: pmuriel@cinvestav.mx Funding information National Council of Science and Technology, Grant/Award Numbers: 253037 and 380833 Stevia has been shown to prevent oxidative stress and inflammation in carbon tetra- chloride‐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 admin- istering 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 4‐ hydroxynonenal levels, whereas the glutathione/glutathione disulfide and nuclear factor‐E2‐related factor 2 (Nrf2) levels were decreased. Moreover, TAA increased col- lagen 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, subse- quently inhibiting HSC activation and preventing fibrosis and dopamine turnover. KEYWORDS anti‐inflammatory, antioxidant, encephalopathy, fibrosis, liver, stevia 1 | INTRODUCTION Liver cirrhosis is the final common pathological pathway of liver dam- age arising from a wide variety of chronic liver diseases. The most common causes of cirrhosis include alcohol abuse, chronic hepatitis C or B virus infections, and nonalcoholic fatty liver disease (Muriel, 2017). Perhaps one of the most important features of cirrhosis is fibrosis, which is a dynamic process characterized by the net accumu- lation of extracellular matrix (ECM; Higashi, Friedman, & Hoshida, 2017). The central driver of hepatic fibrosis is the activation of hepatic stellate cells (HSCs) into profibrogenic myofibroblasts that produce exacerbated amounts of ECM (Tsuchida & Friedman, 2017). It is now well recognized that the signaling pathway of transforming growth factor beta (TGF‐β) plays a crucial role in the progression of hepatic fibrosis (Tsuchida & Friedman, 2017). Moreover, expression of con- nective tissue growth factor (CTGF), a potent fibrogenic cytokine that is predominantly present in HSCs, is highly upregulated in fibrogenesis (Tsuchida & Friedman, 2017) and contributes to ECM production; additionally, CTGF regulates several cellular responses, including pro- liferation, migration, adhesion, and survival of HSCs (Novo & Parola, Received: 15 May 2018 Revised: 1 August 2018 Accepted: 23 August 2018 DOI: 10.1002/ptr.6197 Phytotherapy Research. 2018;1–9. © 2018 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/ptr 1