Curcumin downregulates Smad pathways and reduces hepatic stellate cells activation in experimental fibrosis

Introduction and Objectives: Curcumin, a polyphenol, is a natural compound that has been widely studied as a hepatoprotector; however, only a few studies have examined its ability to reduce fibrosis in previously established cirrhosis. The objective of this study was to investigate whether curcumin could reduce carbon tetrachloride (CCl4)-induced fibrosis and if so, to determine the action mechanisms involved in the reduction process.Materials and Methods: CCl4 was administered to male Wistar rats (400 mg/kg, three times a week, i. p.) for 12 weeks; curcumin (100 mg/kg body weight twice per day, p. o.) was administered from week 9-12 of CCl4 treatment. Biochemical markers of hepatic injury and oxidative stress were evaluated. Hematoxylin and eosin, Masson's trichrome stains, transmission electron microscopy; immunohistochemistry, and zymography assays were carried out. Moreover, Smad3 and alpha-SMA mRNA and protein levels were studied. Western blotting by TGF-alpha, CTGF, Col-I, MMP-13, NF-kappa B, IL-1, IL-10, Smad7, pSmad3, and pJNK proteins was developed.Results and Conclusions: Curcumin reduced liver damage, oxidative stress, fibrosis, and restored normal activity of MMP-9 and MMP-2. Besides, curcumin restored NF-kappa B, IL-1, IL-10, TGF-beta, CTGF, Col-I, MMP-13, and Smad7 protein levels. On the other hand, curcumin decreased JNK and Smad3 phosphorylation. Furthermore, curcumin treatment decreased alpha-SMA and Smad3 protein and mRNA levels. Curcumin normalized GSH, and NF-kappa B, JNK-Smad3, and TGF-beta-Smad3 pathways, leading to a decrement in activated hepatic stellate cells, thereby producing its antifibrotic effects. (C) 2020 Fundacion Clinica Medica Sur, A.C. Published by Elsevier Espana, S.L.U.