Embelin Ameliorates Diethylnitrosamine-Induced Liver Injury Through Down-Regulation of Apoptosis, Oxidative Stress and Inflammation by Influencing the Shh/Gli1 Signaling Pathways

Abstract

Diethylnitrosamine (DEN) is a highly toxic compound with teratogenic, mutagenic, and carcinogenic properties. Embelin, a natural benzoquinone derived from Embelia ribes, has shown potential therapeutic effects. This study evaluated embelin's impact on biochemical, histopathological, and gene expression changes in DEN-induced liver injury. Twenty-eight male Wistar albino rats were assigned to four groups: Sham, Embelin (E), DEN, and DEN + E. DEN groups received a single intraperitoneal dose of 200 mg/kg DEN, while E and DEN + E groups were administered 1.2 mg/kg embelin for 14 days. Liver enzyme levels, lipid profiles, total antioxidant status (TAS), and total oxidant status (TOS) were measured. RT-PCR analysis was performed to assess sonic hedgehog (Shh, Ptch1, Smo, Gli1), inflammatory (TNF-α, IL-6, IL-1β) and apoptotic (Tp53, casp3, Bcl-2, Bax) gene expression in liver tissue. Histopathological examination showed that DEN induced fibrosis, congestion, apoptosis, and bile pigment accumulation, which were significantly mitigated by embelin. Embelin decreased liver enzyme and lipid levels, increased the activity of TAS, which is an antioxidant capacity, decreased the gene expression levels of pro-inflammatory cytokines TNF-α, IL-6, IL-1β, and the activation of the Shh signaling pathway. It also increased the expression of Bcl-2 and decreased the gene expression levels of Tp53, Casp3, Bax, and inhibited liver apoptosis. These results imply that embelin may have a therapeutic effect on DEN-induced liver damage by preventing degenerative liver problems, regulating liver functions, suppressing oxidative stress, the inflammatory and apoptotic response, and modulating the Shh signaling pathways.