Article Publish Status: FREE
Abstract Title:

Naringenin prevents experimental liver fibrosis by blocking TGFβ-Smad3 and JNK-Smad3 pathways.

Abstract Source:

World J Gastroenterol. 2017 Jun 28 ;23(24):4354-4368. PMID: 28706418

Abstract Author(s):

Erika Hernández-Aquino, Natanael Zarco, Sael Casas-Grajales, Erika Ramos-Tovar, Rosa E Flores-Beltrán, Jonathan Arauz, Mineko Shibayama, Liliana Favari, Víctor Tsutsumi, José Segovia, Pablo Muriel

Article Affiliation:

Erika Hernández-Aquino


AIM: To study the molecular mechanisms involved in the hepatoprotective effects of naringenin (NAR) on carbon tetrachloride (CCl)-induced liver fibrosis.

METHODS: Thirty-two male Wistar rats (120-150 g) were randomly divided into four groups: (1) a control group (= 8) that received 0.7% carboxy methyl-cellulose (NAR vehicle) 1 mL/daily p.o.; (2) a CClgroup (= 8) that received 400 mg of CCl/kg body weight i.p. 3 times a week for 8 wk; (3) a CCl+ NAR (= 8) group that received 400 mg of CCl/kg body weight i.p. 3 times a week for 8 wk and 100 mg of NAR/kg body weight daily for 8 wk p.o.; and (4) an NAR group (= 8) that received 100 mg of NAR/kg body weight daily for 8 wk p.o. After the experimental period, animals were sacrificed under ketamine and xylazine anesthesia. Liver damage markers such as alanine aminotransferase (ALT), alkaline phosphatase (AP),γ-glutamyl transpeptidase (γ-GTP), reduced glutathione (GSH), glycogen content, lipid peroxidation (LPO) and collagen content were measured. The enzymatic activity of glutathione peroxidase (GPx) was assessed. Liver histopathology was performed utilizing Masson's trichrome and hematoxylin-eosin stains. Zymography assays for MMP-9 and MMP-2 were carried out. Hepatic TGF-β, α-SMA, CTGF, Col-I, MMP-13, NF-κB, IL-1, IL-10, Smad7, Smad3, pSmad3 and pJNK proteins were detectedwestern blot.

RESULTS: NAR administration prevented increases in ALT, AP,γ-GTP, and GPx enzymatic activity; depletion of GSH and glycogen; and increases in LPO and collagen produced by chronic CClintoxication (<0.05). Liver histopathology showed a decrease in collagen deposition when rats received NAR in addition to CCl. Although zymography assays showed that CClproduced an increase in MMP-9 and MMP-2 gelatinase activity; interestingly, NAR administration was associated with normal MMP-9 and MMP-2 activity (<0.05). The anti-inflammatory, antinecrotic and antifibrotic effects of NAR may be attributed to its ability to prevent NF-κB activation and the subsequent production of IL-1 and IL-10 (<0.05). NAR completely prevented the increase in TGF-β, α-SMA, CTGF, Col-1, and MMP-13 proteins compared with the CCl-treated group (<0.05). NAR prevented Smad3 phosphorylation in the linker region by JNK since this flavonoid blocked this kinase (<0.05).

CONCLUSION: NAR prevents CClinduced liver inflammation, necrosis and fibrosis, due to its antioxidant capacity as a free radical inhibitor and by inhibiting the NF-κB, TGF-β-Smad3 and JNK-Smad3 pathways.

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