Abstract
To investigate the toxicity, protective effects, and action mechanism of gallotannin-enriched extracts isolated from Galla Rhois (GEGR) against carbon tetrachloride (CCl4)-induced hepatotoxicity in Institute for Cancer Research (ICR) mice, alterations in serum biochemical indicators, histopathological structure, antioxidative status, hepatic apoptosis-related proteins, and liver fibrosis regulating factors were measured in mice pretreated with GEGR for five days before CCl4 injection. The GEGR/CCl4 treated group showed decreased levels of three serum marker enzymes (ALP, AST, and ALT) representing liver toxicity, although LDH levels remained constant. Necrotic area indicating hepatic cell death significantly inhibited, while malondialdehyde (MDA) concentration and superoxide dismutase (SOD) expression were dramatically recovered in the GEGR preadministrated group. In mechanism analyses of GEGR, the formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the GEGR/CCl4 treated group. The level of pro-inflammatory cytokines, TNF-α and IL-6, as well as the phosphorylation of p38 and JNK in the TNF-α downstream signaling pathway was rapidly recovered in the GEGR/CCl4 treated group, while anti-inflammatory cytokine (IL-10) increased slightly in the same group. Furthermore, the GEGR/CCl4 treated group showed a significant decrease in collagen accumulation results from alleviation of MMP-2 expression, TGF-β1 secretion and the phosphorylation of Smad2/3. Taken together, these results suggest that GEGR may induce remarkable protective effects against hepatic injury induced by CCl4 treatment through upregulation of the anti-inflammatory and antioxidant system.
Highlights
The liver is the primary organ responsible for metabolism of drugs and chemicals including paracetamol, known as acetaminophen, diclofenac, and N-nitrosocompounds, as well as the primary target of many toxic chemicals such as carbon-tetrachloride (CCl4 ) and aflatoxin [1]
The level of IL-10 mRNA was not changed in the vehicle/CCl4 treated group relative to the no treatment group; this level rapidly increased in the gallotannin-enriched extracts isolated from Galla Rhois (GEGR) treated groups (Figure 5A). These results suggest that GEGR pretreatment can effectively prevent the inflammatory response induced by CCl4 treatment through suppression of pro-inflammatory cytokines and upregulation
Our results demonstrated that GEGR pretreatment is associated with the prevention of the hepatocytes apoptosis, liver inflammation, and fibrosis via suppression of oxidative stress induced by CCl4 treatment
Summary
The liver is the primary organ responsible for metabolism of drugs and chemicals including paracetamol, known as acetaminophen, diclofenac, and N-nitrosocompounds, as well as the primary target of many toxic chemicals such as carbon-tetrachloride (CCl4 ) and aflatoxin [1]. Nutrients 2016, 8, 107 is a well-known hepatotoxin that induces hepatic damage, necrosis [2], and apoptosis [3]. CCl4 -induced liver injuries are mediated through the activation of cytochrome P450 to produce reactive intermediates such as trichloromethyl free radical (CCl3 ‚ ) and trichloromethyl peroxy radical (CCl3 OO‚ ). These radicals can bind to cellular molecules (nucleic acids, proteins, and lipids), impairing lipid metabolism and initiating hepatic cancer [5]. The inhibition of production and activation of free radicals is considered a very important factor for the prevention and treatment of CCl4 -induced liver injury
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