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Abstract Details
Rocaglamide-A mitigates LPS-induced hepatic inflammation by modulating JNK/AP-1 signaling cascade and ROS production in hepatocytes.
UNLABELLED: Lipopolysaccharide (LPS), a gut-derived endotoxin, is a recognized risk factor for both Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Rocaglamide-A (Roc-A), a natural compound derived from the genus Aglaia, is known for its pharmacological and immunosuppressive effects on various cell types. Although our recent investigations have unveiled Roc-A's anti-adipogenic role in adipocytes, its mechanism in hepatic inflammation remains elusive. This study delves into Roc-A's protective effects on LPS-induced hepatic inflammation. Our results demonstrated that Roc-A treatment significantly reduced the LPS-induced production of inflammatory cytokines in hepatocytes. Intriguingly, Roc-A decreased LPS-induced production of reactive oxygen species (ROS), upregulated antioxidant gene expression, and downregulated endoplasmic reticulum (ER) stress-related gene expression. Mechanistically, Roc-A significantly attenuated LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1). Notably, this effect was abolished by the JNK activator Anisomycin, while the JNK inhibitor SP600125 enhanced it. Furthermore, Roc-A suppressed the expression of NF-κB target genes, including inducible nitric oxide synthase (iNOS), thereby alleviating iNOS-derived nitric oxide (NO) production. These findings collectively indicate that Roc-A has the potential to alleviate LPS-induced nitrosative/oxidative stress and hepatic inflammation by inhibiting JNK phosphorylation. Thus, Roc-A emerges as a promising anti-inflammatory intervention for LPS-induced hepatic inflammation.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43188-024-00263-y.