Environmental Toxicology and Pharmacology 50 (2017) 175–182 Contents lists available at ScienceDirect Environmental Toxicology and Pharmacology j o ur na l ho mepage: www.elsevier.com/locate/etap The NF-B inhibitor celastrol attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats Ghada S. El-Tanbouly a , Mohammed S. El-Awady b,∗ , Nermeen A. Megahed c , Hatem A. Salem b , Hassan A. El-Kashef a,b a Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for science and technology, Gamasa, Egypt b Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt c Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt a r t i c l e i n f o Article history: Received 7 October 2016 Received in revised form 12 January 2017 Accepted 3 February 2017 Available online 4 February 2017 Keywords: Celastrol CLP IL-6 NF-B TLR-4 5-LOX a b s t r a c t Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-B) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-B inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1 mg/kg, i.p., 1 h before CLP) was illustrated after 24 h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotrans- ferase (-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-B/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti- inflammatory effect by attenuating NF-B activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6. © 2017 Elsevier B.V. All rights reserved. 1. Introduction Sepsis is a serious clinical syndrome that initiates over-response of host defense, leading to septic shock and multi-organ dysfunc- tion syndrome (MODS), which is a major cause of mortality in intensive care units (Bime et al., 2016). Sepsis-associated hepatic dysfunction is expanded among septic patients (Tsai et al., 2015). There is a traditional consideration that sepsis-associated hepatic dysfunction is a late incident. However, hepatic dysfunction is pre- sented recently in several studies as an early incident in sepsis (Groger et al., 2016). To investigate sepsis and associated multi-organ dysfunc- tion, cecal ligation and puncture (CLP) model is used as an Abbreviations: CLP, Cecal ligation and puncture; NFBia, nuclear fac- tor inhibitory protein kappa-B alpha; TLR-4, toll-like receptor-4; 5-LOX, 5-lipoxygenase. ∗ Corresponding author. E-mail address: mohamshh@yahoo.com (M.S. El-Awady). experimentally-induced polymicrobial sepsis that mimics the human sepsis condition (Cuenca et al., 2010). Inflammation is basic in many acute inflammatory conditions including sepsis (Gorbunov et al., 2013). Previous studies showed that sepsis is a severe systemic inflammation and resulted in inflammatory and immune responses represented in the activation of the toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-B) pathway (Fan et al., 2016) and the exaggerated production of pro- inflammatory cytokines such as: interleukin-1 beta (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-) (Gerin et al., 2016). In addition, activation of NF-B results in increased gene expression and biosynthesis of pro-inflammatory mediators in sepsis (Ang et al., 2011). Accordingly, sepsis research concentrated on expand- ing anti-inflammatory strategies. Unfortunately, many treatments that may produce modification in systemic inflammation haven’t achieved the expected success to reduce mortality rate in clinical trials (Gavins et al., 2012). Consequently, pharmacologically active compounds extracted from natural products have been identified to innovate anti- inflammatory therapeutic strategies based on their molecular http://dx.doi.org/10.1016/j.etap.2017.02.002 1382-6689/© 2017 Elsevier B.V. All rights reserved.