HPLC-HRMS/MS and anti-inflammatory effects of bunya pine resin through multifaceted pathway modulation: NUMB/NOTCH1/HES1/mTOR/ PI3K/HMGB1 signaling cascades

Abstract The oleoresins of the Araucaria bidwillii Hook. (A.B.) are commonly used for the treatment of several conditions. However, the full phytochemical profile of its active compounds and its mechanism of action to protect the liver from toxicity remain unclear. The purpose of this research was to investigate the complete set of data relating to the A.B. active metabolites and explore the hepatoprotective properties of AB ethanolic extract on MTX-induced liver injury mainly due to its anti-inflammatory role. Hepatic markers, oxidative stress, inflammatory mediators, the NOTCH/NICD signaling cascade, HES1 expression, HMGB1/TLR4, and the PI3K/mTOR axis were assessed. HPLC-HRMS/MS analysis of A.B. led to the annotation of fifteen compounds from different classes, where diterpenes are the dominant class. Additionally, A.B. (100 and 200 mg/kg) significantly decreased hepatic markers, oxidative stress, and inflammatory mediators. Moreover, the extract significantly increased NOTCH pathway stimulation and HES1 expression, accompanied by a significant decline in the NUMB and HMGB1/TLR4 axes. In addition, it significantly inhibited the PI3K/mTOR pathway, with a prominent effect at the higher dose. This study presents A.B. as a promising hepatoprotective agent through stimulation of the NOTCH pathway and inhibition of the HMGB1/TLR4 pathway, as well as the PI3K/mTOR/NF-κB axis, besides its antioxidant and anti-inflammatory effects.