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Published on: April 28, 2020
Casticin Alleviates Acetaminophen-Induced Acute Liver Injury by Modulating the TLR4/MyD88/TRAF6/NF-κB Signaling
Salman H Alotaibi1, Mahmoud M Samaha1, Manar G Helal1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
Pharmaceuticals (Basel, Switzerland)
|July 28, 2026
Summary
Casticin, a natural flavonoid, protects the liver from acetaminophen overdose by reducing oxidative stress and inhibiting the TLR4 signaling pathway. This study demonstrates its potential as a protective agent against drug-induced liver injury.
Area of Science:
- Pharmacology and Toxicology
- Natural Product Chemistry
- Immunology
Background:
- Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), characterized by oxidative stress and innate immune activation.
- Casticin, a flavonoid, possesses known antioxidant and anti-inflammatory properties.
- The toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/tumor necrosis factor receptor-associated factor 6 (TRAF6)/nuclear factor kappa B (NF-κB) pathway is implicated in APAP-induced liver damage.
Purpose of the Study:
- To investigate the protective effects of casticin against APAP-induced hepatotoxicity in a mouse model.
- To elucidate the role of casticin in modulating the TLR4/MyD88/TRAF6/NF-κB signaling pathway during APAP overdose.
Main Methods:
- Establishment of APAP-induced ALI in mice, with groups receiving casticin (low and high dose) or N-acetylcysteine (NAC) as a control.
- Administration of casticin for three days prior to APAP to assess preventive potential.
- Biochemical assays (ALT, AST, ALP), histological examination, lipid peroxidation assessment, antioxidant status evaluation, and molecular analyses (Western blotting, ELISA, qPCR, immunohistochemistry) to measure pathway component and cytokine levels.
Main Results:
- APAP overdose significantly increased liver injury markers (ALT, AST, ALP), hepatic architecture deterioration, lipid peroxidation, and oxidative stress.
- APAP elevated pro-inflammatory cytokines (TNF-α, IL-6), decreased IL-10, and upregulated key signaling molecules (TLR4, MyD88, TRAF6, NF-κB p65).
- Casticin treatment dose-dependently ameliorated these APAP-induced effects, reducing liver damage and suppressing the TLR4 signaling pathway, with efficacy comparable to NAC.
Conclusions:
- Casticin demonstrates significant hepatoprotective effects against APAP-induced acute liver injury.
- The protective mechanism involves the suppression of oxidative stress and the inhibition of the TLR4/MyD88/TRAF6/NF-κB inflammatory signaling cascade.
- Casticin holds promise as a preventive agent for acetaminophen-induced hepatotoxicity.
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