Abstract
This study aims to investigate the protective effects of morin hydrate (MH) against acute liver injury induced by carbon tetrachloride (CCl4) in mice and to elucidate the possible molecular mechanism of action. Mice were pretreated with MH (50 mg/kg body weight) or vehicle by oral gavage once daily for 5 days, followed by intraperitoneal injection of a single dose of CCl4 (1 ml/kg in olive oil). Mice were sacrificed 24 h later; the blood and liver samples were harvested for analysis. We also used the model of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in vitro and examined the effects of MH and its mechanism of action on the inflammatory response. Our results revealed that MH remarkably attenuated liver histopathological alterations, serum transaminases, hepatocytes death, and inflammatory response induced by CCl4. Importantly, MH reduced expression of the triggering receptor expressed on myeloid cells-1 (TREM-1) and toll-like receptor 4 (TLR4) both in vivo and in vitro experiments. This inhibitory effect MH on expression of the TREM-1 and TLR4 in cell culture was further heightened after TREM-1 knockdown with small interfering RNA (siRNA). Moreover, MH dramatically suppressed the inhibitor of kappa B α (IκBα) degradation and subsequent nuclear factor-kappa B (NF-κB) p65 translocation into the nucleus and NF-κB-mediated cytokines, such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6. Additionally, MH also ameliorated CCl4-induced oxidative stress by enhancing the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in the injured livers. Taken together, MH has hepatoprotective activity, and this effect may be elicited by attenuating macrophage-mediated inflammatory responses via inhibition TREM-1/TLR4/NF-κB signaling and by regulating hepatic oxidative stress via enhancement Nrf2/HO-1 antioxidant pathway.
Highlights
Acute liver injury is a common pathway to many liver diseases and remains a serious health problem worldwide associated with significant morbidity and mortality (Malhi and Gores, 2008; Bernal et al, 2010)
Mouse anti-NFκB p65 polyclonal antibody and rabbit anti-IκB monoclonal antibody were from Cell Signaling Technology (Boston, MA, USA); rabbit anti-tolllike receptor 4 (TLR4) monoclonal antibody was from Epitomics, Inc. (Burlingame, CA); rabbit anti-nuclear factor erythroid 2-related factor 2 (Nrf2) monoclonal antibody, rabbit anti-triggering receptor expressed on myeloid cells-1 (TREM-1) polyclonal antibody, rat anti-F4/80 monoclonal antibody, rabbit anti-heme oxygenase-1 (HO-1) polyclonal antibody, rabbit antiGAPDH monoclonal antibody, and rabbit anti-Lamin B1 monoclonal antibody were from Abcam (Cambridge, MA)
Because TREM-1 is reported to amplify the inflammatory response initiated by toll-like receptor (TLR) engagement (Ornatowska et al, 2007; Tammaro et al, 2017), we further investigated whether TLR4 signaling was inhibited by morin hydrate (MH) in acute liver injury
Summary
Acute liver injury is a common pathway to many liver diseases and remains a serious health problem worldwide associated with significant morbidity and mortality (Malhi and Gores, 2008; Bernal et al, 2010). Hepatic inflammation is a complex process that is a response to a wide range of stimuli that induce oxidative stress and injury to hepatocytes (Kubes and Mehal, 2012; Zhang et al, 2015; Li et al, 2016b; Hassan et al, 2017; Krenkel and Tacke, 2017). Several lines of evidence have indicated that inflammatory responses mediated by cytokines and chemokines play an important role in cell death and liver injury (Sims et al, 2010; Kubes and Mehal, 2012; Lu et al, 2012; Krenkel and Tacke, 2017)
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