甘草次酸保肝功效的通路作用机制

甘草的活性成分包括甘草甜素(glycyrrhizin,GL)和甘草次酸(glycyrrhetinic acid,GA),而GA是甘草中的主要生物活性成分,是GL的主要代谢产物,部分GL通过细菌在肠内代谢为GA。在许多以往的研究中已经证实其具有多种药理学效果,例如抗炎、抗过敏、抗致癌、抗损伤和抗氧化特性以及肝脏保护。最近的研究表明,GA可以降低逆转录因子、二氧化钛纳米粒子和环磷酰胺诱导的肝毒性,并且可以保护免受四氯化碳诱导的肝损伤。已报道的GA的保肝作用机制主要归因于诱导抗氧化剂防御,抑制炎症反应和细胞色素P450表达,本文将对GA在不同信号通路中发挥保肝作用进行综述。     

The effects of dietary flaxseed on the Fischer 344 rat: I. Development, behaviour, toxicity and the activity of liver gamma-glutamyltranspeptidase

The effect of exposure to, followed by consumption of, 10% flax chow from the 18th day of gestation to the 86th day after birth was examined in male and female Fischer 344 rats. Growth curves of the flax chow-fed rats were identical to those of regular chow-fed rats, as were such developmental milestones as pinna development, growth of hair and eye opening. Acoustical startle and the righting reflexes, developmental behavioural indices, were also the same. Blood glucose levels were comparable in flax chow-fed and regular chow-fed rats at all stages of development, indicating that flax is without effect on glucose balance. There were no signs of toxicity in the flax chow-fed rats since their plasma levels of alanine aminotransferase and gamma-glutamyltranspeptidase (gammaGT) were the same as those of regular chow-fed rats. The activity of gammaGT displayed an increase in the livers of flax chow-fed rats after puberty, more so in the male-four-fold-than in the female-1.38-fold. This is suggestive of an estrogenic effect which implicates an effect of an estrogenic flax lignan. An hepatobeneficial effect of the flax-induced increase in liver gammaGT is discussed. In summary, dietary 10% flax chow is without long-term effect on growth, development and behaviour, is non-toxic and may be hepatoprotective.     

The effects of dietary flaxseed on the Fischer 344 rat: II. Liver gamma-glutamyltranspeptidase activity

The effect of 10% flax chow consumption from the 30th to the 130th day after birth was examined in male Fischer 344 rats. The effects of both the high lignan/high oil Norlin strain and a high lignan/low oil Solin strain of flaxseed were compared. Physically and behaviourally there were no differences in rats belonging to the three dietary groups at any time. At 50 and 100 days of dietary exposure, blood glucose levels were the same in Norlin and Solin flax chow-fed and as well as regular chow-fed rats; there were no signs of toxicity in the Norlin and Solin flax-fed rats since their plasma levels of alanine aminotransferase were the same and equal to those of regular chow-fed rats. The activity of gamma-glutamyltranspeptidase (gammaGT) displayed an increase in the liver homogenates of flax chow-fed rats. This increase was the same in Norlin and Solin flax-fed rats at 50 and 100 days. Thus the liver effect was not oil, but lignan, likely secoisolariciresinol diglucoside (SDG), induced and was effected early on, and sustained, after flax exposure. The degree of heat activation of liver homogenate gammaGT was the same in regular chow-fed and flax chow-fed rats. Compared to liver homogenate gammaGT activity, the soluble form of gammaGT was expressed at very low levels while the plasma membrane-bound form of gammaGT was expressed at very high levels in rat liver in both regular chow-fed and flax chow-fed rats. There was no effect of flax feeding on the soluble form of liver gammaGT which was expressed at a very low level. Flax feeding effected an increase in the activity of gammaGT in isolated plasma membrane fractions which mirrored that in liver homogenates: the same degree of increase was seen in Norlin flax chow-fed and Solin flax chow-fed rats. Flax consumption effects an increase in the activity of liver gammaGT at the level of the plasma membrane which is lignan dependent, physiologically relevant and may be linked to hepatoprotection against injury through an increase in reduced glutathione.     

神经降压素对醋氨酚引起肝损伤的保护作用及其与谷胱甘肽系统的关系

本工作观察了神经降压素对醋氨酚引起的小鼠在体肝脏和离体肝细胞损伤的保护作用及其与谷胱甘肽系统的关系,结果表明,ＮＴ在整体和离体肝细胞增能减轻醋氨酚诱导的转氨酶的漏出,且在离体肝细胞部分翻转了醋氨酚引起的ＤＮＡ合成速率的下降,在离体肝细胞醋氨酚使细胞内还原谷胱甘肽,谷胱甘肽总含量和谷胱甘肽过氧化物酶活性均降低,但氧化型谷胱甘肽含量无明显改变。ＮＴ预处理后再给予醋氨酚,则ＧＳＨ含量和谷胱甘肽过氧化物醋     

Total flavonoids,extracted from Polygonum knotweed L,exert beneficial hepatoprotection against liver injury

Hepatic function is of great concern in metabolic and immunological homeostasis. Traditionally, medical management to liver damage may benefit from phytomedicine, such as Chinese herbs. In southern China, Polygonum perfoliatum L can contribute to alleviating pathological symptoms of liver disease, such as hepatitis. However, bioactive compounds of hepatoprotection in this herb are still less to be investigated. In this study, clinical data of patients with drug-induced liver injury were collected on the basis of serological analyses. In addition, we extracted and identified total flavonoids from Polygonum perfoliatum L (TFPPL) before implementing biochemical experiments in vivo. In human data, the blood contents of liver function enzymes were visibly elevated, and the percentage of immune cells were abnormally changed. The data from the animal study showed that TFPPL-treated carbon tetrachloride-exposed mice resulted in reduced absolute liver mass and lowered blood levels of liver functional enzymes (alanine transaminase and aspartate transaminase). In enzyme-linked immunosorbent assay, the comparable data indicated that serological tumor necrosis factor α (TNF-α), interleukin 6, and heat shock protein 90 (Hsp90) contents were reduced in TFPPL-treated mice. In histopathological observations, TFPPL-treated mice exhibited reduced hepatocellular Hsp90, TNF-α, nuclear factor κ-light-chain-enhancer of activated B cells-p65 positive cells, and lowered Bax and caspase-3-labeled cells in the livers. Further, intrasplenic integrin β1, 5′-nucleotidase, and antigen KI-67 positive cells were increased after TFPPL treatments. Taken together, our present findings demonstrate that herb-extracted TFPPL exert potential hepatoprotective activities against chemical-induced liver damage in mice, possibly through the pharmacological mechanisms of inhibiting inflammatory stress and apoptosis, inactivating Hsp90 bioactivity in the liver, and improving splenic immunocompetence.     

Bovine milk-derived α-lactalbumin prevents hepatic fibrosis induced by dimethylnitrosamine via nitric oxide pathway in rats

The present study was designed to evaluate the hepatoprotective potential of α-lactalbumin (αLA) against dimethylnitrosamine (DMN)-induced toxic insults in the rat liver. The liver damage was induced in rats by the repeated administration of DMN (10 mg/kg, i.p.) on three consecutive days per week for three weeks. The rats were maintained on either a standard AIN-93 M or αLA-enriched diet starting one week before the DMN injection until the termination of the experiment. The DMN treatment produced a progressive increase in the plasma markers (aspartate aminotransferase, alanine aminotransferase, total bililbin, hyarulonic acid, and matrix metalloproteinase-2) in 28 days after the first DMN injection. Dietary treatment with αLA significantly reduced the DMN-induced damage toward normalcy. N^Ｇ-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, significantly attenuated the hepatoprotective effect of αLA. These findings show that αLA has a marked suppressive effect on hepetic fibrosis through a nitric oxide-mediated mechanism.     

达肝清对小鼠免疫性肝损伤的保护作用

采用卡介苗(BCG)+脂多糖(LPS)造成免疫性肝损伤动物模型,观察达肝清对小鼠血清ALT、AST活性及肝组织匀浆SOD、MDA、GSH-PX水平的影响,并观察肝组织病理学改变。结果表明:达肝清可明显降低小鼠血清中ALT、AST活性,同时能减少肝匀浆MDA含量,并能使降低的肝匀浆SOD、GSH-PX活性升高。该实验属首次报道。     

Inhibition of poly(ADP-ribose) polymerase-1 attenuates the toxicity of carbon tetrachloride

Carbon tetrachloride (CCl₄) is routinely used as a model compound for eliciting centrilobular hepatotoxicity. It can be bioactivated to the trichloromethyl radical, which causes extensive lipid peroxidation and ultimately cell death by necrosis. Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) can rapidly reduce the levels of β-nicotinamide adenine dinucleotide and adenosine triphosphate and ultimately promote necrosis. The aim of this study was to determine whether inhibition of PARP-1 could decrease CCl₄-induced hepatotoxicity, as measured by degree of poly(ADP-ribosyl)ation, serum levels of lactate dehydrogenase (LDH), lipid peroxidation, and oxidative DNA damage. For this purpose, male ICR mice were administered intraperitoneally a hepatotoxic dose of CCl₄ with or without 6(5H)-phenanthridinone, a potent inhibitor of PARP-1. Animals treated with CCl₄ exhibited extensive poly(ADP-ribosyl)ation in centrilobular hepatocytes, elevated serum levels of LDH, and increased lipid peroxidation. In contrast, animals treated concomitantly with CCl₄ and 6(5H)-phenanthridinone showed significantly lower levels of poly(ADP-ribosyl)ation, serum LDH, and lipid peroxidation. No changes were observed in the levels of oxidative DNA damage regardless of treatment. These results demonstrated that the hepatotoxicity of CCl₄ is dependent on the overactivation of PARP-1 and that inhibition of this enzyme attenuates the hepatotoxicity of CCl₄.     

Protective Effect of Cornuside against Carbon Tetrachloride-Induced Acute Hepatic Injury

This study elucidated the effects of cornuside on carbon tetrachloride (CCl₄)-induced hepatotoxicity. Rats were treated intraperitoneally with 0.5 mL/kg of CCl₄. Sixteen h after CCl₄ treatment, the levels of serum aminotransferases, tumor necrosis factor-α (TNF-α), and lipid peroxidation were significantly elevated, whereas the hepatic antioxidative enzyme activities were decreased. These changes were attenuated by cornuside. Histological studies also indicated that cornuside inhibited CCl₄-induced liver damage. Furthermore, the contents of hepatic nitrite, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were elevated after CCl₄ treatment, while cytochrome P450 2E1 (CYP2E1) expression was suppressed. Cornuside treatment inhibited the formation of liver nitrite, and reduced the overexpression of iNOS and COX-2 proteins, but restored the liver CYP2E1 content as compared with the CCl₄-treated rats. Our data indicate that cornuside protects the liver from CCl₄-induced acute hepatotoxicity, perhaps due to its ability to restore the CYP2E1 function and suppress inflammatory responses, in combination with its capacity to reduce oxidative stress.