Confusoside from Anneslea fragrans Alleviates Acetaminophen-Induced Liver Injury in HepG2 via PI3K-CASP3 Signaling Pathway

Abstract

Confusoside (CF), a major chemical compound in the leaves of Anneslea fragrans Wall., is a dihydrochalcone glycoside with excellent antioxidant and anti-inflammatory effects. However, the hepatoprotective effect of CF has not been described. This study aimed to explore the hepatoprotective effect of CF against acetaminophen (APAP)-induced hepatic injury in HepG2 cells. First, the potential hepatoprotective effect mechanisms of CF were predicted by network pharmacology and were thought to involve reducing inflammation and inhibiting apoptosis. Target proteins (phosphatidylinositol3-kinase (PI3K) and caspase-3 (CASP3)) were found via molecular docking analysis. To verify the predicted results, an analysis of biological indicators was performed using commercial kits and Western blotting. The results showed that CF significantly decreased the levels of liver injury biomarkers (ALT, AST, and LDH), strongly inhibited the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the NO level via inhibiting the activation of the NF-κB signaling pathway, and markedly regulated the expression levels of Bcl2, Bax, and cleaved-CASP3/9 proteins by activating the PI3K-CASP3 apoptosis pathway. The results demonstrated that CF has a therapeutic effect on APAP-induced liver injury by inhibiting intracellular inflammation and cell apoptosis, indicating that CF may be used as a potential reagent for the prevention and treatment of APAP-induced liver injury.

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“…TNF-α acts as a signalling molecule in the inflammatory response [54]. Increased levels of CASP-3 and TNF-α were observed in this study, which is in agreement with a previous study that APAP-induced inflammation in HepG2 Cells [55], suggesting that TNF-α and IL-17 signalling pathways were significantly enhanced by LPS treatment, based on findings from transcriptome analysis, which may be associated with cellular inflammatory and immune processes [56]. LPS-induced intestinal injury is usually characterised by the overproduction of inflammatory cytokines, such as TNFα, iNOS and IL-1β.…”

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

“…More importantly, PI3K is regulated as part of the downstream signaling pathway of EGFR; hence, the emergence of PI3K among the enriched targets is not surprising. In fact, the regulation of PI3K was suggested by many studies as a potential mechanism for abrogation of APAP toxicity. , It is worth noting that the ability of several triterpenes similar to boswellic acids to interact with this target is reported. , Moreover, thymol, which is part of the hybrid 5b , was reported to protect against xenobiotic-induced injury by the regulation of PI3K-related pathways. ,, …”

“…This binding mode suggests the ability of AKBA hybrids to mitigate APAP-induced hepatotoxicity by disrupting protein–protein interaction between the p110α and p85α complex ( Figure S1 ), which would consequently block the inhibitory action of p85α, 70 leading to the activation of PI3k signaling, which was reported as a promising approach in the management of APAP liver injury. 56 , 71 , 72 …”

Natural Products for Acetaminophen-Induced Acute Liver Injury: A Review

“…Secondly, CF can inhibit the NF-κB pathway, thereby reducing factors such as TNF-α, IL-1β, IL-6, and NO, and exerting anti-inflammatory effects [81]. CF can also regulate the expression of pro-apoptotic factors such as Bcl-2 anti-apoptotic factors, Bax, and caspase-3/9 by activating the PI3K-CASP3 apoptotic pathway [152]. Therefore, CF can reverse the effects of APAP on oxidative stress and the Nrf2 pathway, thereby protecting liver cells.…”