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Hepatoprotective potential of standardized Ficus species in intrahepatic cholestasis rat model: Involvement of nuclear factor-κB, and Farnesoid X receptor signaling pathways

El-hawary, Seham S., Ali, Zeinab Y., Younis, Inas Y.
Journal of ethnopharmacology 2019 v.231 pp. 262-274
Ficus auriculata, Ficus thonningii, Ficus trigonata, acute oral toxicity, animal models, antioxidant activity, blood serum, caffeic acid, chlorogenic acid, cholesterol, chromatography, computer simulation, drugs, hepatocyte growth factor, hepatoprotective effect, intrahepatic cholestasis, leaves, liver function, mechanism of action, nutritive value, oxidative stress, phospholipids, rats, rutin, signal transduction, sodium-potassium-exchanging ATPase, therapeutics, toxicity testing, traditional medicine, transcription factor NF-kappa B, tumor necrosis factor-alpha, ursodeoxycholic acid
Ficus is an important commercial crop not only for its nutritive value but also, for its medicinal value. Several Ficus species have been traditionally used in the Egypt, Indian and Chinese as carminative, astringent, antibacterial, hepatoprotective, and hypolipidemic agents.To standardize and compare the possible hepatoprotective potential of the ethanolic extract of leaves of five tested Ficus species namely: Ficus mysorensis Roth ex Roem. & Schult, Ficus pyriformis Hook. & Arn., Ficus auriculata Lour., Ficus trigonata L., and Ficus spragueana Mildbr. & Burret in the intrahepatic cholestasis rat model induced by 17α-Ethinylestradiol (EE) and to explore the mechanism of action with respect to their phytochemical constituents.Determination of the total phenolic and flavonoid contents, chromatographic examination and acute oral toxicity test were performed on the tested Ficus extracts. Animals were divided into 8 groups. Group 1, served as control for 2 weeks. Group 2, untreated cholestatic rats. Groups 3–8, pretreated with Ficus extracts (100 mg/Kg/day, p.o) or ursodeoxycholic acid (as reference drug) for 2 weeks and injected by EE in the last 5 days. Serum liver function test, 5′-nucleotidase (5′-N), total bile acids (TBA), total cholesterol (T.C) and phospholipids were assayed. Also, hepatic Na+/K+-ATPase, nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), hepatocyte growth factor (HGF), hemeoxygenase-1 (HO-1), and markers of oxidative stress were investigated. Furthermore, molecular docking study was performed to explore the ability of the major constituents of Ficus to interact with Farnesoid X receptor (FXR).Four phenolic compounds (gallic, chlorogenic acid, caffeic acids and rutin) were identified. Chlorogenic acid and rutin represented the major constituents of Ficus extracts. Simultaneous administration of Ficus extracts with EE effectively: i- preserved liver function, TBA, T.C and phospholipids, ii- suppressed the pro-inflammatory cytokines (NF-κB and TNF-α), iii- enhanced hepatic regeneration (HGF) and antioxidant defense system. Furthermore, molecular docking reveals that rutin and chlorogenic acid effectively act as FXR agonists.Among the tested extracts, Ficus spragueana Mildbr. & Burret enriched with phenolics exhibited a pronounced hepatoprotective activity and may provide a new therapeutic approach for estrogen-induced cholestasis.