The Molecular Mechanism Of α-Lipoic Acid、Chlorogenic Acid Antagonist Oxidative Stress In Vivo

Cyclophosphamide (CYP) is one of anti-tumor drugs which is widely used in clinical treatment. It has broad anti-tumor spectrum and smaller side effects than other Nitrogen mustard.The urotoxicity of CYP is not based on direct alkylating activity but on the formation of renally excreted4-hydroxy metabolites,in particular acrolein.Hemorrhagic cystitis (HC) is a major dose-limiting side-effect of CYP. Mesna contains a sulfhydryl compound that binds acrolein within the urinary tract and detoxifies it; the resulting inert thioether dose not induce damage to the uroepithelium.Although mesna has been widely used as an agent against CYP-induced cystitis, HC has been encountered cliniclly.The incidence of this side-effect is higher in patients receiving a high intravenous CYP dose.It has recently been shown that increasing reactive nitrogen species (RNS) and reactive oxygen species (ROS) production is involved in the detrimental effects of CYP on the bladder.The overproduction of ROS and RNS during inflammation leads to considerable oxidant stress,cellular injury, and necrosis via several mechanisms incluing peroxidation of membrane lipids, protein denaturation, and DNA damage. Although there were many studies about antioxidants antagonist oxidative stress in vivo, and the molecular mechamism more focus on the regulation of inflammatory cytokines, there were less deeply studies about the molecular mechamism of antioxidant antagonist oxidative stress in vivo. This experiment objected to explore the protective roll and the molecular mechanism of α-LA in CYP induced acute bladder injury, to provide some experient basements for the clinical use of α-LA.The40male kun-ming mice were randomly divided into5groups:Control group、 model group、Mesna pretreated group、α-LA pretreated group and VC pretreated group, with8mice in each group. After24h of cystitis induction, mice were anesthetized and decapitated.The bladders were removed intact,evacuated of residual urine, cleaned to remove connective and lipoid tissue from around the wall, and weighted to determine if edema was present;Histopatological examination were performed to investigate if bladder structure were changed; to determine the changes of ROS level、MDA content and antioxidant enzymes activities. The objection were to evalucate if α-LA can antagonist Cyclophosphamid induce oxidative stress in vivo.we also explore its molecular mechanism by observing the changes of ERK、JNK、p38expression levels. This article draw the following conclusions ultimately:(1), α-LA and VC can protect bladder tissue from CYP induced damage and antagonist CYP induce oxidative stress in vivo.(2), It appears that the protection property of α-LA、VC contributed to the inhibition of the CYP-induced phosphorylation of MAPKs through a modulation of ROS. Pentachlorophenol(PCP) is a major industrial and agricultural biocide that has been used primarily as a wood preservative.In China and other developing countries,PCP has also been used to kill snails to prevent snail fever.PCP is a potent carcinogen.Following chronic exposure of mice to PCP, hepatocellular carcinomas or adenomas, hemangiosarcomas,and phaeochromocytomas were observed. PCP is oxidatively dechlorinated to produce tetrachlorohydroquinone(TCHQ) by licer microsomal cytochrome P450s from rats and humans in vitro and by rodents in vivo.TCHQ can be further oxidized to tetrachloro-1,4-benzoquinone(TCBQ) via its corresponding semiquinone, the tetrachlorosemiquinone radical(TCSQ). TCBQ has also been used as a common intermediates of chemistry dyes and seed dressing agents. Its worldwise usage and relative stablity make PCP an ubiquitous environmental pollutant.Redox cycling of compound with a quinoid structure can produce large amounts of ROS, which in turn can induce oxidative stress. Liver tissue is a magor detoxification and metabolism organ, the metabolism of TCBQ can injure the liver.Chlorogenic acid (CGA) is a polyphenolic compound, which is abundunt in bud and flowers of many plants.CGA exhibits cardioprotective effects, lipid hyper-oxidation inhibitory activity, and anti-tumor activity, in addition to anti-oxidant activities associated with free radical scavenging. This experiment objected to explore the roll and significance of CGA in TCBQ induced acute hepatic injury, to provide some experiment basement for the clinic use of CGA.The32male kun-ming mice were randomly divided into4groups:Control group、 model group、CGA group and CGA pretreated group,with8mice in each group. After24h of hepatic injury induction, the serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) and antioxidant enzymes activities were detected by diagnostic kits. Histopatological examination were performed to investigate if bladder structure were changed; to determine the changes of ROS level、MDA content and antioxidant enzymes activities. The objection were to evalucate if CGA can antagonist TCBQ induced acute hepatic injury in vivo.we also explore its molecular mechanism by observing the changes of HO-1、NQO1expression levels.This article draw the following conclusions ultimately:(1)、CGA can protect liver tissue from TCBQ induced acute damage and antagonist TCBQ induce oxidative stress in vivo.(2)、It appears that the protection property of CGA contributed to the inhibition of the TCBQ-induced activation of Nrf2-ARE signaling pathway through a modulation of ROS.