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Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of drug-induced liver injury worldwide, which is significantly linked to oxidative stress and sterile inflammation. Salidroside is the main active component extracted from Rhodiola rosea L., with anti-oxidative and anti-inflammatory activities. Herein, we investigated the protective effects of salidroside on APAP-induced liver injury and its underlying mechanisms. Pretreatment with salidroside reversed the impacts of APAP on cell viability, LDH release, and cell apoptosis in L02 cells. Moreover, the phenomena of ROS accumulation and MMP collapse caused by APAP were reverted by salidroside. Salidroside elevated the levels of nuclear Nrf2, HO-1, and NQO1. Using PI3k/Akt inhibitor LY294002 further confirmed that salidroside mediated the Nrf2 nuclear translocation through the Akt pathway. Pretreatment with Nrf2 siRNA or LY294002 markedly prevented the anti-apoptotic effect of salidroside. Additionally, salidroside reduced the levels of nuclear NF-κB, NLRP3, ASC, cleaved caspase-1, and mature IL-1β elevated by APAP. Moreover, salidroside pretreatment increased Sirt1 expression, whereas Sirt1 knock-down diminished the protective activities of salidroside, simultaneously reversing the up-regulation of the Akt/Nrf2 pathway and the down-regulation of NF-κB/NLRP3 inflammasome axis mediated by salidroside. We then used C57BL/6 mice to establish APAP-induced liver injury models and found that salidroside significantly alleviated liver injury. Furthermore, western blot analyses showed that salidroside promoted the Sirt1 expression, activated the Akt/Nrf2 pathway, and inhibited the NF-κB/NLRP3 inflammasome axis in APAP-treated mice. The findings of this study support a possible application of salidroside in the amelioration of APAP-induced hepatotoxicity., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

The seeds of Herpetospermum pedunculosum (Ser.) C.B. Clarke, a well-known Tibetan medicine in China, are rich in kinds of bioactive lignans. In this phytochemical investigation on H. pedunculosum, sixteen undescribed lignans, named as herpedulins A - P together with 24 known ones were isolated from the ethyl acetate extract of its seeds. Their structures including the absolute configurations were determined by HR MS, 1D and 2D NMR experiments, and comparison of their experimental ECD spectra with calculated ones or literature data. High content screening experiments revealed that 9 compounds could promote the expression of farnesoid X receptor in guggulsterone-induced human normal liver cells L02 cells significantly. Further molecular docking results demonstrated that herpedulin E, J and K exhibited best docking scores (9.70, 9.28 and 10.31, respectively). Hydrogen bonding and hydrophobic interactions might contribute to the main interaction of active compounds with FXR., (Copyright © 2021 Elsevier Ltd. All rights reserved.)