Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology
Antioxidative, anti-inflammatory and hepatoprotective effects of resveratrol on oxidative stress-induced liver damage in tilapia (Oreochromis niloticus)
Graphical abstract
Introduction
In fish, the liver is the main organ for material and energy metabolism, its detoxification and phagocytosis show a protective effect on the organisms. In recent years, liver damage or dysfunction of fish is one of the most serious problems in aquaculture, often leading to metabolic disorder, low disease resistance and even death (Midhila and Chitra, 2015; Wolf and Wolfe, 2005; Zhao et al., 2011). The liver damage may be a result of numerous factors, such as xenobiotics, pathogenic microorganism, unfavorable temperature, crowding, etc., which is accompanied by reactive oxygen species (ROS) accumulation, lipid peroxidation and change of antioxidant activity (Abasubong et al., 2018; Costa et al., 2010; Hegazi et al., 2010; Meng et al., 2014; Telli et al., 2014; Ullah and Zorriehzahra, 2014). Thus many reports considered that overproduction of ROS and oxidative stress were major contributing factors in the pathophysiology of acute liver injury (Slaninova et al., 2009). Hydrogen peroxide (H2O2), a key member of ROS, not only plays an important role in the regulation of vital cellular processes, but also is considered as toxic byproduct. It can oxidize many biological molecules, like protein, lipid, carbohydrate, DNA and RNA, which may cause a disruption of redox signaling and significant oxidative stress, when there is an imbalance between oxidants and antioxidants in cell or tissues (Lennicke et al., 2015; Sies, 2017). Therefore, H2O2 is extensively used as a model chemical to investigate the mechanism of oxidative stress in different cells and species (Kalpana et al., 2009; Liu et al., 2001). In mammalian, H2O2-induced hepatocyte or liver damage was widely accepted and used to screen hepatoprotective and antioxidative agents (Jiang et al., 2017; Rahim et al., 2014).
ROS can activate/inactivate a number of signaling pathways and signaling mediators. Among them, nuclear factor-E2-related factor-2 (Nrf2), a transcription factor, plays a significant role in oxidative stress-induced liver injury (Rubiolo et al., 2008). It regulates the expression of array of phase II detoxifying/antioxidant enzymes such as UDP-NAD(P)H quinone oxidoreductase (NQO1), glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD) and heme oxygenase 1 (HO-1) to maintain homeostasis of redox state and prevent oxidative stress (Kaspar et al., 2009; Nguyen et al., 2009). Nrf2 is normally suppressed by binding to its inhibitor, Kelch-like erythroid cell-derived protein 1 (Keap1) in the cytosol, but under stimulation, it is activated by untying the Nrf2-Keap1 complex and translocated into the nucleus to mediate the phase II detoxifying/antioxidant enzymes (Kaspar et al., 2009; Ma, 2013). Previous studies suggested that Nrf2 signaling pathway as a vital target participated in protecting liver of numerous drugs including resveratrol, withaferin A and curcumin (Farombi et al., 2008; Liu et al., 2013; Palliyaguru et al., 2016; Rubiolo et al., 2008).
Toll-like receptor (TLR) family, the best-characterized cell surface receptors, plays key role in pathogen recognition and activation of the inflammatory response (Akira and Takeda, 2004). Increasing evidence has shown that surface TLRs, such as TLR2, can recognize multiple endogenous and exogenous stress signals to mediate inflammatory responses (Gill et al., 2010; Leemans et al., 2009). After recognition, TLR2 recruits adaptor protein Myd88 (myeloid differentiation primary response protein 88) for signal transduction, and activate nuclear factor kappa B (NF-κB), which leads to production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-8, etc. (Medzhitov, 2009). Activation of TLR2-dependent signaling pathway has been observed in liver injury in vitro and in vivo induced by some hepatotoxicant, such as alcohol, concanavalin A and carbon tetrachloride (CCl4) (Ma et al., 2015; Roh et al., 2015; Tu et al., 2012). The abnormal regulation of this process has been involved in inflammatory diseases, pathogen dissemination and autoimmune diseases (Ahmadishoar and Kariminik, 2017; Shi et al., 2018).
Resveratrol (3,4,5-trihydroxy-trans-stilbene), a dietary polyphenol, exists in Polygonum cuspidatum, mulberries, peanuts, grape and red wine (Bhat et al., 2001). It has a variety of biological activities including antioxidation, hepatoprotection, anti-inflammation, immunostimulation, modulation of lipid metabolism, and so on (Baur and Sinclair, 2006). Several investigations have focused the protective effects of resveratrol against certain forms of oxidant damage, through a hydrogen-electron donation from its hydroxyl group (Chanvitayapongs et al., 1997; Rubiolo et al., 2008). In rat, mice or human, in vivo and in vitro studies have shown that resveratrol provided protection against liver and hepatocytes damage induced by several well-known hepatotoxicants such as CCl4, aflatoxin B1 and H2O2 (Elagamy, 2010; Fan et al., 2009; Nah et al., 2005). In fish, administration of resveratrol promoted growth (Wilson et al., 2015), modulated innate and inflammatory (Castro et al., 2008), improved lipid and glucose metabolism (Zhang et al., 2017) and attenuated oxidative stress (Liu et al., 2015). However, its protective effect and mechanism on oxidative stress-induced liver injury in fish has not been investigated. Therefore, this study was aim to assess the potential protective effects of resveratrol against liver damage caused by H2O2 in tilapia and further investigate the roles of Nrf2 and TLR2-Myd88-NF-κB signaling pathways in liver protection of fish.
Section snippets
Materials and reagents
H2O2 was obtained from Keygen Biotech Co., Ltd., (Nanjing, China). Resveratrol (98% purity) was purchased from Nanjing herb source Bio-Tech Co., Ltd. (Nanjing, China). Commercially available kits for glutamate pyruvate transaminase (GPT), glutamate oxalate transaminase (GOT), alkaline phosphatase (AKP), total protein (TP), albumin (Alb), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione (GSH) were procured from Jiancheng Institute of Biotechnology (Nanjing, China).
Effect of resveratrol on hepatic damage
To evaluate the H2O2-induced liver injury and the protection of resveratrol, the levels of serum GPT, GOT, AKP, TP and Alb were measured. As shown in Table 2, there was a significant increase in the activities of GPT, GOT and AKP, and a significant decrease in levels of TP and Alb in H2O2-treated group (P < 0.05 or P < 0.01). After the administration of resveratrol, the changes of these parameters except Alb in resveratrol treatment at dose of 0.6 g/kg diet were effectively restrained compared
Discussion
The main finding of this work was that resveratrol exerted significant protection against liver injury induced by H2O2 in tilapia, which was consistent with previous reports (Elagamy, 2010; Fan et al., 2009; Wang et al., 2015). In our work, H2O2 treatment caused a prominent increase in serum marker enzymes (GPT, GOT and AKP) and histological changes in the liver, indicating the liver injury in tilapia. Besides, decreased TP and Alb levels were also seen in H2O2-treated group. Nevertheless, all
Conclusions
In conclusion, our results showed that resveratrol availably ameliorated the H2O2-induced liver injury, inflammation and immunosuppression in tilapia. And these biochemical effects were regulated by Nrf2 and TLR2-Myd88-NF-κB singling pathways (Fig. 8). Resveratrol can activate Nrf2 signaling pathway, which enhances the production of SOD, CAT, GSH, NQO1, HO-1 and GSTa to depress H2O2-mediated oxidative stress. The activation of Nrf2 signaling pathway can further inhibit oxidative stress-induced
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by Central Public-interest Scientific Institution Basal Research Fund, Freshwater Fisheries Research Center, CAFS (NO.2017JBFZ01); National Natural Science Foundation of China (NO.31702318); and Jiangsu Provincial Natural Science Foundation of China (NO.BK20170218).
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Both authors contributed equally to this work.