Abstract
The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl4-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.
Highlights
The liver, the largest digestive gland in human body, carries out the metabolism of carbohydrates, proteins, and lipids, but is involved in secretion and biotransformation
The results showed that LPS stimulation stimulation significantly activated the Toll-like receptor 4 (TLR4)/NF-κB/COX-2 signaling, as evidenced by the significantly activated the TLR4/NF-κB/COX-2 signaling, as evidenced by the up-regulated protein up-regulated protein levels of TLR4, p-p65, and COX-2
We found that ZER exhibits a hepatoprotective activity against CCl4 -induced acute liver injury (ALI) by reducing the level of oxidative stress and inhibiting the inflammatory response
Summary
The liver, the largest digestive gland in human body, carries out the metabolism of carbohydrates, proteins, and lipids, but is involved in secretion and biotransformation. A large amount of evidence indicates that oxidative stress and inflammation are two of the most important pathogenic mechanisms for hepatic disease [4]. Acute administration of CCl4 to rodents, which rapidly leads to oxidative stress and an inflammatory response, is the most widely accepted in vivo experimental model [5,6] and is extensively used to identify new, effective drugs and investigate the underlying mechanisms [7,8]. The toxic effects observed in CCl4 intoxication come from a toxic metabolite of CCl4 , trichloromethylperoxy radical, which triggers lipid peroxidation and oxidative stress [4,9]. CCl4 intoxication causes localized necrosis of liver tissues, followed by the activation of Kupffer cells [10].
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