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Irinotecan (CPT-11) is used as chemotherapeutic drug for treatment of colorectal cancer. However, without satisfactory treatments, its gastrointestinal toxicities such as diarrhea and intestinal inflammation severely restrained its clinical application. Roots of Aucklandia lappa Decne. are used as traditional Chinese medicine to relieve gastrointestinal dysfunction and dehydrocostus lactone (DHL) is one of its main active components. Nevertheless, the efficacy and mechanism of DHL against intestinal mucositis remains unclear. The present study aimed to investigate the protective effects of DHL on CPT-11-induced intestinal mucositis and its underlying mechanisms. The protective effect of DHL was investigated in CPT-11-induced mice and lipopolysaccharide (LPS)+CPT-11 induced THP-1 macrophages. Body weight, diarrhea score, survival rate, colon length, and histopathological changes in mice colon and jejunum were analyzed to evaluate the protective effect of DHL in vivo. And DHL on reducing inflammatory response and regulating TLR4/NF‐κB/NLRP3 pathway in vivo and in vitro were explored. Moreover, DHL on the interaction between TLR4 and MD2 was investigated. And silencing TLR4 targeted by siRNA was performed to validate the mechanisms of DHL on regulating the inflammation. DHL prevented CPT-11-induced intestinal damage, represented by reducing weight loss, diarrhea score, mortality rate and the shortening of the colon. Histological analysis confirmed that DHL prevented intestinal epithelial injury and improved the intestinal barrier function in CPT-11 induced mice. Besides, DHL significantly downregulated the level of inflammatory cytokines by inhibiting TLR4/NF-κB/NLRP3 signaling pathway in CPT-11-induced mice and LPS+CPT-11-induced THP-1 macrophages. In addition, DHL blocked TLR4/MD2 complex formation. Molecular docking combined with SIP and DARTS assay showed that DHL could bind to TLR4/MD2 and occludes the hydrophobic pocket of MD2. Furthermore, Silencing TLR4 abrogated the effect of DHL on LPS+CPT-11 induced inflammatory response in THP-1 macrophages. Additionally, DHL ameliorate the CPT-11-induced intestinal mucositis without affecting the anti-tumor efficacy of CPT-11 in the tumor xenograft mice. This study found that DHL exhibited the anti-inflammatory effects in CPT-11-induced intestinal mucositis by inhibiting the formation of TLR4/MD2 complex and then regulation of NF-κB/NLRP3 signaling pathway. DHL is potentially served as a novel strategy of combined medication with CPT-11. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Apoptosis and NLRP3 inflammasome activation occur in APAP-induced liver injury. • Salidroside prevents ROS-dependent mitochondrial apoptosis in APAP-treated L02 cells by activating the Akt/Nrf2 pathway. • Salidroside inhibits NF-κB/NLRP3 axis during APAP-induced liver damage. • The protective effects of salidroside against APAP-induced hepatotoxicity were associated with the Sirt1-mediated Akt/Nrf2 pathway and the NF-B/NLRP3 inflammasome axis. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Sixteen undescribed compounds were isolated from Herpetospermum pedunculosum. • The absolute configurations were determined via quantum chemical calculations. • 9 compounds could promote FXR expression in guggulsterone-induced L02 cells. • Molecular interactions of compounds with FXR were analyzed by in silico methods. [ABSTRACT FROM AUTHOR]