The following research discussion is from a study funded by the U.S. National Institute of Health entitled: Boschniakia rossica prevents the carbon tetrachloride-induced hepatotoxicity in rat. It may be of interest to heavy drinkers.
It has been recognized that oxidative stress and generation of free radicals play a critical role in CCl4-induced liver injury. Therefore, some natural products with antioxidant activity have attracted great attention as potential functional ingredients to protect CCl4-induced liver injury.(5,20,21,25) Polysaccharides, important natural compounds widely existed in plants, animals and microorganism, have been demonstrated to possess potent antioxidative, anti-inflammatory activities and to protect liver injury induced by various chemicals.(26–28) Boschniakia rossica exhibits a number of beneficial effects against various types of degenerative diseases in humans, largely because its major ingredients, such as polysaccharides, phenylpropanoids and iridoids, have potent antioxidant activity.(2–5,13) Previous reports exhibited the potential prospects of BRPS as functional ingredient to prevent the inflammatory and ROS related diseases.(6–8) Therefore, we considered that BRPS is useful in the prevention of liver injuries induced by oxidative stress. In the present study, the capability of BRPS to protect against CCl4-induced hepatotoxicity was firstly investigated.
The liver injury induced by CCl4 is the best characterized system for xenobiotic-induced hepatotoxicity and are commonly used models for screening of the anti-hepatotoxic and/or hepatoprotective activities of drugs.(15,24) Our study showed that serum ALT, AST, and ALP activities and hepatic TBARS rapidly increased in parallel with CCl4 injection, indicating the induction of acute hepatotoxicity by CCl4. The acute hepatotoxic effects induced by CCl4 administration were confirmed histopathologically, revealing hepatocellular degeneration and necrosis. The obtained results are in accordance with those of the previous reports.(15,25–27) However, BRPS significantly lowered the CCl4-induced serum activities of ALT, AST and ALP, and reduced hepatic lipid peroxidation. This phenomenon was further confirmed by the results of histopathological examination, as evidenced by decrease in the severity of hepatic lesions.
It has been accepted that lipid peroxidation of hepatocyte membranes is one of the principal causes of CCl4-induced hepatotoxicity, and is mediated by the production of free radical derivatives of CCl4.(25) Therefore, the antioxidative activity and/or the inhibition of free radical generation are important in terms of protecting the liver from CCl4-induced damage.(24) Cells have a number of mechanisms to protect themselves from the toxic effects of free radicals, including free radical scavengers and chain reaction terminators such as SOD, CAT, GPx, GST and GR. GSH acts as a non-enzymatic antioxidant both intracellularly and extracellularly in conjunction with various enzymatic processes that reduce hydrogen peroxide and hydroperoxides and plays a primary role in the protection against trichloromethyl radical-induced liver damage. In this study, exposure to CCl4 caused GSH depletion and decreased activities of SOD, GPx, GST and GR in the liver, implying down-regulation of numerous antioxidative reactions in liver. BRPS-pretreated animals showed a considerable improvement in the hepatic antioxidative defense potentials. This suggests that BRPS may be able to protect against hepatic damage via a free radical scavenging property.
The liver is a major inflammatory organ, and inflammatory processes contribute to a number of pathological events after exposure to various hepatotoxins.(29) TNF-α is a pleiotropic proinflammatory cytokine mainly produced by activated macrophages and monocytes and is involved in many different biological and pathologic processes including inflammation, autoimmune diseases and cancer.(30) It is also known that TNF-α stimulates the release of cytokines from macrophages and induces the phagocyte oxidative metabolism and NO production. NO is a highly reactive oxidant that is produced through the action of iNOS, and plays an important role as a vasodilator, neurotransmitter and in the immunological system as a defense against tumor cells, parasites and bacteria.(31) However, certain evidences have found that excessive NO production by iNOS may lead to hepatic damage.(32,33) COX-2 is the enzyme responsible for the catalysis of prostaglandin E2 from arachidonic acid(34) and the induction of COX-2 is also closely related to NO production.(35) The current study confirmed significant increases in serum TNF-α, hepatic NO, iNOS and COX-2 protein expression after the CCl4 administration. These alterations were attenuated by BRPS treatment, which suggests that BRPS suppressed TNF-α, iNOS and COX-2 protein secretion and/or enhanced the degradation of these proteins. Accordingly, the possible mechanism of protection against CCl4-induced hepatotoxicity appears to be, at least in part, due to the suppressed inflammatory responses.
In addition, TNF-α also induces apoptosis through the adaptor proteins of Fas-associated death domain and TNFR-associated death domain to its receptor, which in turn leads to the activation of caspase-8. The activated caspase-8 directly activates caspase-3 which plays a pivotal role in cell apoptosis when being activated.(36,37) In our study, an obvious DNA fragmentation were observed in the mouse liver tissues obtained at 16 h after the CCl4 treatment. However, little hepatocyte DNA fragmentation was observed in the livers from the mice pretreated with BRPS. Data also demonstrated that BRPS inhibited caspase-3 cleavage and caspase-3 activities which were elevated after the CCl4 injection. This result suggested that pretreatment with BRPS may inhibit the CCl4-induced apoptosis and protect against hepatic damage via an anti-apoptotic function.
On the whole, it can be concluded that BRPS has a protective effect against CCl4-induced acute liver injury in mice and the hepatoprotective effect of BRPS may be due to the ability to suppress the inflammatory responses and apoptosis in combination with the ability to scavenge free radicals.Home
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