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- [Regulatory effects of Qinggan Huoxue Recipe on matrix metalloproteinases of alcoholic liver fibrosis rats]. [English Abstract, Journal Article]
- Zhongguo Zhong Xi Yi Jie He Za Zhi 2011 Nov; 31(11):1538-44.
To study the action mechanism of Qinggan Huoxue Recipe (QGHXR) and its dissembled recipes for treatment of alcoholic liver fibrosis (ALF) by observing their regulation on the expressions of matrix metalloproteinases (MMPs) and type 1 tissue inhibitor of metalloproteinase (TIMP-1).130 male SD rats were randomly divided into the blank control group (n=10), the CCI4 group (n=10), and the modeling group (n=110). Rats in the modeling group were intervened by complex factors dominated as alcohol. Eight weeks later they were randomly divided into 4 subgroups, i.e., the model group (n=25), the QGHXR group (n= 15), the Qinggan Recipe (QGR) group (n=15), and the Huoxue Recipe (HXR) group (n=15). Eight model rats were selected for pathological analysis to monitor the development of the modeling at the 4th, 8th, and 10th week of the experiment. The rest rats died during the modeling. Corresponding medicines were given to these treatment groups (at the dose of 4.75 g/kg, 1.50 g/kg, and 3.25 g/kg). All rats were killed at the end of the 12th week. The protein and mRNA expressions of MMP-2, MMP-9, and TIMP-1 were detected using Western blotting, fluorescent quantitative polymerase chain reaction, and immumofluorescence method.Compared with the blank control group, the expressions of MMP-2, MMP-9, and TIMP-1 significantly increased in the model group (1.81 +/- 0.28 versus 0.53 +/- 0.04, 1.60 +/- 0.16 versus 0.45 +/- 0.05, 1.20 +/- 0.02 versus 0.35 +/- 0.07, P < 0.01). Compared with the model group, QGHXR and its dissembled recipes all could decrease the protein and mRNA expressions of TIMP-1 (0. 56 +/- 0.05, 0.67 +/- 0.02, 0.70 +/- 0.02 versus 1.20 +/- 0.02, P < 0.05), increase the expressions of MMP-2 and MMP-9 (4.18 +/- 0.53, 2.70 +/- 0.40, 2.38 +/- 0.22 versus 1.81 +/- 0.28, 3.31 +/- 0.06, 2.56 +/- 0.20, 1.87 +/- 0.05 versus 1.60 +/- 0.16, P < 0.05, P < 0.01). QGHXR was superior to its dissembled recipes (P < 0.05, P < 0.01).The action mechanisms of QGHXR and its dissembled recipes might possibly be correlated with regulating MMPs.
- [Syndrome identification of CCl4 induced liver fibrosis model rats based on syndrome detecting from recipe used]. [English Abstract, Journal Article, Research Support, Non-U.S. Gov't]
- Zhongguo Zhong Xi Yi Jie He Za Zhi 2009 Mar; 29(3):246-50.
To further demonstrate the cognition upon the prominent effect of Yiguanjian and Xiayuxue Decoction on the CCI4 induced rat model of chronic liver fibrosis which have been verified in the previous studies. From the viewpoint of detecting TCM syndrome by recipe used, through this cognition the pathological features of the liver injury model manifesting a syndrome of "Gan-yin deficiency with blood stasis obstructing collaterals" were further explored.Wistar rats were randomly divided into the normal group, the model group, and the three medicated groups. All rats, except those in the normal group, were made into chronic liver injury model by subcutaneously injecting CCI4 for 12 weeks. Medication for the three medicated groups began from the 9th week after modeling, with oral administering of Yiguanjian (YGJ, a recipe has been verified to be effective for liver injury and fibrosis), Liuwei Dihuang Decoction (LWDH, a recipe with effects similar to YGJ) and Yinchenhao Decoction (YCHD, a recipe functioned differently) respectively for four weeks. Rats were sacrificed at the end of the experiment, changes of hepatic function, liver pathology and hydroxyproline (Hyp) content in the liver tissue were detected, and contents of Afamin and mRNA expression of alpha-smooth muscle actin (alpha-SMA) in the liver tissue were assayed as well with Real-time PCR.As compared with the normal group, the pathological figures of the chronic liver injury and fibrosis and hepatic function deterioration obviously appeared in the model rats, with the liver content of Hyp and alpha-SMA mRNA expression increased, and Afamin mRNA expression decreased significantly. In the YGJ treated group, the hepatic collagen hyperplasia and deteriorated hepatic function alleviated significantly after treatment, with content of Hyp significantly lowered, and mRNA expressions of alpha-SMA and Afamin restored to some extent (P < 0.05); the same effects on mRNA expressions of alpha-SMA and Afamin were shown in the LWDH treated group, also a decreasing trend of Hyp content (0.05 < P < 0.1), and a significant decreasing of alanine transaminase (ALT) activity was found; while in the YCHD treated group these pharmacological effects mentioned above were not observed at all.The pharmacological effects of LWDH and YGJ were similar to some degree, which gives support to the cognition that the feature of chronic liver injury model rat induced by CCI4 is attributable to yin-deficiency sydrome.
- Hepatoprotective and curative properties of Kombucha tea against carbon tetrachloride-induced toxicity. [Journal Article, Research Support, Non-U.S. Gov't]
- J Microbiol Biotechnol 2009 Apr; 19(4):397-402.
Kombucha tea (KT) is sugared black tea fermented with a symbiotic culture of acetic acid bacteria and yeasts, which is said to be tea fungus. KT is claimed to have various beneficial effects on human health, but there is very little scientific evidence available in the literature. In the present study, KT along with black tea (BT) and black tea manufactured with tea fungus enzymes (enzyme-processed tea, ET) was evaluated for hepatoprotective and curative properties against CCl4-induced toxicity, using male albino rats as an experimental model by analyzing aspartate transaminase, alanine transaminase, and alkaline phosphatase in plasma and malondialdehyde content in plasma and liver tissues. Histopathological analysis of liver tissue was also included. Results showed that BT, ET, and KT have the potential to revert the CCl4-induced hepatotoxicity. Among the three types of teas tried, KT was found to be more efficient than BT and ET. Antioxidant molecules produced during the fermentation period could be the reason for the efficient hepatoprotective and curative properties of KT against CCI4-induced hepatotoxicity.
- Accelerative effect of leflunomide on recovery from hepatic fibrosis involves TRAIL-mediated hepatic stellate cell apoptosis. [Journal Article, Research Support, Non-U.S. Gov't]
- Life Sci 2009 Apr 10; 84(15-16):552-7.
Hepatic fibrosis is reversible, associated with apoptosis of activated hepatic stellate cells (HSCs) as injury subsides, thus providing potential targets for therapy. Little is known, however, about the course of this condition. The objective of this study was to elucidate the mechanism by which Kupffer cells regulate HSC biology during regression of hepatic fibrosis and the effect of leflunomide on this process.We harvested Kupffer cells from rats during spontaneous recovery from liver fibrosis induced by carbon tetrachloride (CCl4) and prepared recovery Kupffer cell conditioned medium (KCCM). Culture-activated HSCs were pretreated in the absence or presence of A771726, the active metabolite of leflunomide, and then stimulated with recovery KCCM.Following stimulation with recovery KCCM, HSCs showed a decrease in proliferation and an increase in apoptosis by a caspase-dependent mechanism. Furthermore, pretreatment with A771726 markedly enhanced these effects. Real-time quantitative PCR (Q-PCR) analysis showed increased expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in Kupffer cells during the spontaneous recovery phase. The pro-apoptotic function of KCCM prepared from TRAIL siRNA-treated Kupffer cells was obviously decreased, suggesting that TRAIL played an important role in recovery from hepatic fibrosis. Moreover, A771726 enhanced recovery KCCM-induced apoptosis of HSCs by a mechanism involving the inhibition of nuclear factor-kappa B (NF-kappaB) activation.Our results showed the role of TRAIL in the apoptosis of activated HSCs that is induced by Kupffer cells prepared from livers recovering from CCI4-induced fibrosis and provided insights into the resolution of fibrosis and the mechanisms by which leflunomide might act upon liver fibrosis.
- Choleretic activity of 2-demethoxycarbonyl-2-ethoxycarbonyl-11-deoxymisoprostol on the model of CCl4-induced hepatitis. [Journal Article, Research Support, Non-U.S. Gov't]
- Bull Exp Biol Med 2008 Feb; 145(2):223-4.
Therapeutic administration of 11-deoxymisoprostol had a hepatoprotective effect, which manifested in a decrease in the content of alanine transaminase and aspartate transaminase in blood plasma, and produced a choleretic effect in rats with CCI4-induced toxic hepatitis.
- Hepatotoxicity of carbon tetrachloride: protective effect of Gongronema latifolium. [Journal Article]
- Pak J Pharm Sci 2008 Jul; 21(3):268-74.
The protective effect of the ethanolic extract of Gongronema latifolium (GLE) on carbon tetrachloride (CCI4) induced hepatic toxicity was studied. Liver enzymes studied included alanine aminotransferase (ALT), aspartate aminotraferase (AST), and alkaline phosphates (ALP). Hepatic injuries involved with possible necrosis which may have contributed to its possible pathogenesis was explored. Administration of toxicant only showed that the ALT level was significantly (P<0.05) increased to 345.83% when compared to control. Pretreatment with Gongronema latifolium extract (GLE) non-significantly (P<0.05) decreased to 13.08% when compared to those treated with toxicant only. Also under experimental conditions, increasing the concentration of Gongronema latifoluim extract (GLE) non-significantly (P<0.05) decreased dose-dependently the level of ALT to 18.20%. The AST level was non-significantly (P<0.05) increased to 41.55% on treatment with toxicant only. Pretreatment with GLE decreased the AST level non-significantly (P<0.05) to 25.76%. No evident increase or decrease in the level of ALP was observed. Treatments with toxicant showed liver cells filled with uniformly distributed dense small fat droplets, large nuclei, inflamed cells and evidence of necrosis and fibrosis. Pretreatment with 100mg/kg of the extract showed microvesicular fatty change with no evidence of inflammation, necrosis or fibrosis. The protective effect of the GLE was more pronounced in ALT and AST. However, the GLE has a strong modulatory effect against the hepatocellular damage induced by carbon tetrachloride.
- Using artificial burrows to evaluate inhalation risks to burrowing mammals. [Journal Article, Research Support, U.S. Gov't, Non-P.H.S.]
- Integr Environ Assess Manag 2008 Oct; 4(4):425-30.
Since the onset of plutonium production at the U.S. Department of Energy's Hanford Site, several hundred cubic meters of carbon tetrachloride (CCl4) has been discharged to the soil column, resulting in a dispersed CCI4 vapor plume in the subsurface. Inhalation of volatile organic chemicals could be an important exposure pathway for burrowing animals there. Historical levels of CCl4 in soil pore gas exceeded the inhalation ecological screening level for CCl4. Thus, the inhalation exposure pathway was evaluated with the use of artificial burrows deployed at locations that had elevated levels of CCl4 in soil gas. Artificial burrows were designed on the basis of information available for Hanford Site fossorial wildlife. After installation, the artificial burrow atmosphere was sampled and analyzed for CCl4 and its degradation products: chloroform, methylene chloride, and chloromethane. Sampling was repeated on 3 occasions to capture varying atmospheric conditions affecting exposure concentrations. CCl4 was detected in the artificial burrows, and maximum exposures were observed during relatively low barometric conditions. The highest CCl4 detections were still well below the inhalation-based ecological screening level and CCl4 degradation products were never detected. This study shows that artificial burrows are an efficient method for obtaining relevant exposure data and illustrates the utility of directly measuring the medium for exposure under ecologically realistic conditions.
- Disruption of the Smad7 gene enhances CCI4-dependent liver damage and fibrogenesis in mice. [Journal Article, Research Support, Non-U.S. Gov't]
- J Cell Mol Med 2008 Oct; 12(5B):2130-44.
Transforming growth factor-beta (TGF-beta) signalling is induced in liver as a consequence of damage and contributes to wound healing with transient activation, whereas it mediates fibrogenesis with long-term up-regulation in chronic disease. Smad-dependent TGF-beta effects are blunted by antagonistic Smad7, which is transcriptionally activated as an immediate early response upon initiation of TGF-beta signalling in most cell types, thereby providing negative feedback regulation. Smad7 can be induced by other cytokines, e.g. IFN-gamma, leading to a crosstalk of these signalling pathways. Here we report on a novel mouse strain, denoted S7DeltaE1, with a deletion of exon I from the endogenous smad7 gene. The mice were viable and exhibited normal adult liver architecture. To obtain insight into Smad7-depend-ent protective effects, chronic liver damage was induced in mice by carbon tetrachloride (CCI4) administration. Subsequent treatment, elevated serum liver enzymes indicated enhanced liver damage in mice lacking functional Smad7. CCI4-dependent Smad2 phosphorylation was pronounced in S7DeltaE1 mice and accompanied by increased numbers of alpha-smooth muscle actin positive 'activated' HSCs. There was evidence for matrix accumulation, with elevated collagen deposition as assessed morphometrically in Sirius red stained tissue and confirmed with higher levels of hydroxyproline in S7DeltaE1 mice. In addition, the number of CD43 positive infiltrating lymphocytes as well as of apoptotic hepatocytes was increased. Studies with primary hepatocytes from S7DeltaE1 and wild-type mice indicate that in the absence of functional Smad7 protein, hepatocytes are more sensitive for TGF-beta effects resulting in enhanced cell death. Furthermore, S7DeltaE1 hepatocytes display increased oxidative stress and cell damage in response to CCI4, as measured by reactive oxygen species production, glutathione depletion, lactate dehydrogenase release and lipid peroxidation. Using an ALK-5 inhibitor all investigated CCI4 effects on hepatocytes were blunted, confirming participation of TGF-beta signalling. We conclude that Smad7 mediates a protective effect from adverse TGF-beta signalling in damaged liver, re-iterating its negative regulatory loop on signalling.
- Hepatoprotective and antioxidative effects of total phenolics from Laggera pterodonta on chemical-induced injury in primary cultured neonatal rat hepatocytes. [Journal Article, Research Support, Non-U.S. Gov't]
- Food Chem Toxicol 2007 Aug; 45(8):1349-55.
Although Laggera pterodonta as a folk medicine has been widely used for several centuries to ameliorate some inflammatory ailments as hepatitis in China, there have been no studies of the hepatoprotective and antioxidative effects of this plant. In this paper, the hepatoprotective effect of total phenolics from L. pterodonta (TPLP) against CCI4-, D-GalN-, TAA-, and t-BHP-induced injury was examined in primary cultured neonatal rat hepatocytes. TPLP inhibited the cellular leakage of two enzymes, hepatocyte ASAT and ALAT, caused by these chemicals and improved cell viability. Moreover, TPLP afforded much stronger protection than the reference drug silibinin. Meanwhile, DPPH and superoxide radicals scavenging activities of TPLP were also determined. The present investigation is the first to report chemical-induced injury model in primary cultured neonatal rat hepatocytes and provide evidence for the hepatoprotective and antioxidative effects of L. pterodonta. Neutralizing reactive oxygen species by nonenzymatic mechanisms may be one of main mechanisms of TPLP against chemical-induced hepatocyte injury. Furthermore, The total phenolic content of L. pterodonta and its main component type were quantified, and its principle components isochlorogenic acids were isolated and authenticated. These data support the folkloric uses of L. pterodonta in the treatment of hepatitis.
- [Establishment of a rat model of alcoholic liver fibrosis induced by complex factors]. [English Abstract, Journal Article, Research Support, Non-U.S. Gov't]
- Zhong Xi Yi Jie He Xue Bao 2006 May; 4(3):281-4.
To establish a model of alcoholic liver fibrosis (ALF) in rats induced by complex factors.Forty-seven healthy male rats were divided into three groups: normal control group (n=12), minor CCl4 group (n=12) and complex factors group (n=27). The rats in the complex factors group were fed a complex diet including alcohol, corn oil and pyrazole, and administered with intraperitoneal injection of minor CCl4 to induce ALF. During induction process, the histopathological changes of liver tissue and the values of liver-to-body weight ratio were both observed regularly. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (gamma-GT) in these three groups were all examined at the 12th week of the induction process.At the 12th week of the induction process, the model of ALF induced by complex factors was successfully established in rats, and the histopathological presentations showed alcoholic fatty liver, hepatitis and liver fibrosis in a sequence along with the induction process. The value of liver-to-body weight ratio and the serum levels of ALT, AST and gamma-GT of rats in the complex factors group were all significantly different from those in the other two groups.It is a steady and effective way to induce ALF in rats with complex diet and minor CCI4 injection.