Search

• Trilobatin (TLB), a naturally-occurring food additive, conquers FHF with a splendid safety profile. • TLB directly binds to COX2, suppressing inflammation and oxidative stress dependent on OXPHOS/TLR4/NLRP3 axis. • TLB might be a potential safe and efficient agent to conquer FHF. Fulminant hepatic failure (FHF) lacks efficient therapies notwithstanding increased comprehending of the inflammatory response and oxidative stress play crucial roles in the pathogenesis of this type of hepatic damage. Trilobatin (TLB), a naturally occurring food additive, is endowed with anti-inflammation and antioxidant properties. In current study, we evaluated the effect of TLB on FHF with a mouse model with d -galactosamine/lipopolysaccharide (GalN/LPS)-induced FHF and LPS-stimulated Kupffer cells (KCs) injury. Mice were randomly divided into seven groups: control group, TLB 40 mg/kg + control group, GalN/LPS group, TLB 10 mg/kg + GalN/LPS group, TLB 20 mg/kg + GalN/LPS group, TLB 40 mg/kg + GalN/LPS group, bifendate 150 mg/kg + GalN/LPS group. The mice were administered intragastrically TLB (10, 20 and 40 mg/kg) for 7 days (twice a day) prior to injection of GalN (700 mg/kg)/LPS (100 µg/kg). The KCs were pretreated with TLB (2.5, 5, 10 μM) for 2 h or its analogue (10 μM) or COX2 inhibitor (10 μM), and thereafter challenged by LPS (1 μg/ml) for 24 h. TLB effectively rescued GalN/LPS-induced FHF. Furthermore, TLB inhibited TLR 4/NLRP3/pyroptosis pathway, and caspase 3-dependent apoptosis pathway, along with reducing excessive cellular and mitochondrial ROS generation and enhancing mitochondrial biogenesis. Intriguingly, TLB directly bound to COX2 as reflected by transcriptomics, molecular docking technique and surface plasmon resonance assay. Furthermore, TLB failed to attenuate LPS-induced inflammation and oxidative stress in KCs in the absence of COX2. Our findings discover a novel pharmacological effect of TLB: protecting against FHF-induced pyroptosis and apoptosis through mediating ROS/TLR4/NLRP3 signaling pathway and reducing inflammation and oxidative stress. TLB may be a promising agent with outstanding safety profile to treat FHF. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Compound {(EMIM)2[Zn7(μ4-O)2(1,4-ndc)6]}n (1) (EMIM=1-ethyl-3-methylimidazolium and 1,4-ndc=1,4-naphthalenedicarboxylate) has been synthesized by using the mixed ionic liquids of 1-ethyl-3-methylimidazolium tetrafluoroborate and 1-ethyl-3-methylimidazolium l-lactate as solvent. Compound 1 has a 3D anionic framework with bcu-(424·64) topology based on a unique heptanuclear [Zn7(μ4-O)(μ2-COO)10] cluster as secondary building unit. The imidazolium cation [EMIM]+ of the ionic liquid acting as extra framework charge-balancing species occupies the channels of the 3D anionic framework. The roles of the ionic liquid in ionothermal synthesis and crystallization of compound 1 are briefly discussed. The thermal and photoluminescent properties of compound 1 have also been investigated. [Copyright &y& Elsevier]