Nifuroxazide mitigates cholestatic liver injury by synergistic inhibition of Il-6/Β-catenin signaling and enhancement of BSEP and MDRP2 expression

• Published in: International immunopharmacology 2021-10, Vol.99, p.107931, Article 107931
• Main Authors: Nazmy, Entsar A., Helal, Manar G., Said, Eman
• Format: Article
• Language: English
• Subjects: Antigens; Attenuation; Bile; Bile acids; Binding sites; BSEP; Cell differentiation; Cholestasis; Diarrhea; Gallbladder diseases; Gene expression; Hepatocytes; Histochemical analysis; Homeostasis; Il-6; Inflammation; Inflammatory response; Injuries; Interleukin 6; Liver; MDRP2; Molecular docking; Multidrug resistance; Nifuroxazide; Proliferating cell nuclear antigen; Proteins; Strong interactions (field theory); Ursodeoxycholic acid; Β-catenin
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.107931

•NIF successfully reversed cholestasis to a similar extent compared to the mainstay drug, ursodeoxycholic acid.•NIF successfully mitigated cholestasis through synergistic inhibition of Il-6/Β-catenin pathways.•NIF directly enhanced the hepatic expression of bile acids transporters genes.•Molecular docking with β-catenin and bile salt export pump showed strong alignment and interaction. Cholestasis is a complex hepatic disorder underlined with retention of the highly toxic bile components within the hepatocytes. Nifuroxazide (NIF); a nitrofuran derivative, is widely used drug for treatment of acute and chronic diarrhea. The current study was performed to investigate the curative effect of NIF (25 and 50 mg/kg) on lithocholic acid (LCA)-induced cholestasis and compare the observed impact to that of ursodeoxycholic acid (UDCA). Intriguingly, NIF significantly attenuated LCA-induced cholestatic injury. NIF successfully reversed cholestatic injury to a similar extent compared to the mainstay drug, UDCA. NIF administration remarkably attenuated liver/body index and restored liver functions. Moreover, it restored the disrupted balance in oxidative homeostasis. On the other hand, NIF induced a marked improvement in histopathological and immuno-histochemical analysis of liver specimens. Ultimately, NIF mitigated inflammatory response and proliferative ability of hepatocytes with significant reduction in hepatic expression of proliferatingcellnuclearantigen(PCNA), cluster of differentiation 68 (CD68), interlukin-6 (Il-6) and β-catenin. Interestingly, NIF successfully increased bile transformation with increased the hepatic expression of bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MDRP2). Nevertheless, molecular docking of NIF with β-catenin and BSEP showed a better alignment inside the pocket with strong interaction for both protein binding sites. In conclusion, NIF attenuated experimentally-induced cholestatic dysfunction with an underlined synergistic inhibition of Il-6/Β-catenin pathways and direct enhancement of bile acids transporters gene expression.