Ellagic acid mitigates alpha-naphthyl isothiocyanate-induced cholestasis in rats via FXR activation and inflammatory pathway modulation

Hamza Ahmed Taher; Munaf Hashim Zalzala

doi:10.1515/jcim-2024-0425

Article

Ellagic acid mitigates alpha-naphthyl isothiocyanate-induced cholestasis in rats via FXR activation and inflammatory pathway modulation

Hamza Ahmed Taher and Munaf Hashim Zalzala

Published/Copyright: February 11, 2025

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From the journal Journal of Complementary and Integrative Medicine Volume 22 Issue 2

Abstract

Objectives

The liver is vital for metabolism, detoxification, storage, and secretion. Cholestasis, in which bile flow is hindered, can cause serious harm to the liver. This study examines the potential of ellagic acid to prevent cholestasis in male rats that has been caused by alpha-naphthyl isothiocyanate (ANIT).

Method

Male rats were divided into four groups for an 8-day study. The control group received 5 % dimethyl sulfoxide (DMSO) orally for eight days and maize oil (1 mL/kg, orally) 48 h before sacrifice. The ANIT Group received 5 % DMSO orally for 8 days, the ANIT (100 mg/kg, orally) administered on the 6th day, 48 h before sacrifice. The low-Dose Ellagic Acid + ANIT Group was given ellagic acid (5 mg/kg, orally) for eight days, with ANIT (100 mg/kg, orally) on the 6th day, 48 h prior to sacrifice. The high-Dose Ellagic Acid + ANIT Group received ellagic acid (10 mg/kg, orally) for eight days, the ANIT (100 mg/kg, orally) on the 6th day, 48 h before sacrifice. Different biochemical and histopathological analyses were conducted to assess the protective effects of ellagic acid on ANIT-induced liver injury.

Results

ANIT significantly elevated serum of liver enzymes. It caused severe bile duct inflammation and reduced bile salt export pump (BSEP) and Na+-taurocholate cotransporting polypeptide (NTCP) expression, indicating liver injury. Ellagic acid treatment mitigated these changes, improving biochemical parameters and reducing liver damage. ANIT-induced cholestasis results in bile acid accumulation due to decreased BSEP and NTCP expression linked to impaired farnesoid X receptor (FXR) signaling. Ellagic acid restored BSEP and NTCP levels via FXR activation, reducing bile acids and inflammatory markers IL-1β and TNF-α. Ellagic acid also enhanced SIRT1 activity, further improving FXR function and bile acid homeostasis.

Conclusions

Ellagic acid exhibits protective effects against cholestasis by enhancing the FXR signaling and ntcp and bsep expression with mitigating liver damage and inflammation.

Keywords: ellagic acid; cholestasis; alpha-naphthyl isothiocyanate; FXR

Corresponding author: Hamza Ahmed Taher, Directorate of Health Diyala, Ministry of Health, Baghdad, Iraq, E-mail: hamza.ahmed2200m@copharm.uobaghdad.edu.iq

Acknowledgments

The authors are grateful to College of Pharmacy/Baghdad University for providing essential research support and facilities for conducting this research.

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved the submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

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Received: 2024-11-25

Accepted: 2025-01-07

Published Online: 2025-02-11

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Articles in the same Issue

https://doi.org/10.1515/jcim-2024-0425

Keywords for this article

ellagic acid; cholestasis; alpha-naphthyl isothiocyanate; FXR