Genistein decreases liver fibrosis and cholestasis induced by prolonged biliary obstruction in the rat

Fibrosis accompanies most chronic liver disorders and is a major factor contributing to hepatic failure. Therefore, the need for an effective treatment with the aim of modifying the clinical course of this disease is evident. The aim of this work is to determine whether genistein, which has been shown to modulate the physiology and pathophysiology of liver, is able to decrease experimental liver fibrosis and cholestasis. In male Wistar rats, the common bile duct was ligated. Administration of genistein (5 microg rat-1, day-1, p.o.) began four weeks after biliary obstruction and continued for a further four weeks. The liver was used for histological and ultrastructural analysis and for collagen quantification (hydroxyproline content). The degradation of Matrigel(R) and collagen type I was determined in homogenized liver. Bilirubins and enzyme activities were measured in serum. Genistein was able to improve normal liver histology, ultrastructure, collagen content, and biochemical markers of liver damage. It also increased Matrigel(R) and collagen type I degradation. In summary, the present report shows that genistein inhibits the fibrosis and cholestasis induced by prolonged biliary obstruction in the rat. Genistein has therapeutic potential against liver fibrosis.     

Induced hypothyroidism accelerates the regression of liver fibrosis in rats

BACKGROUND AND AIM: It has been shown in previous studies that hypothyroidism prevents the development of liver fibrosis in bile duct ligated rats and in rats chronically treated with thioacetamide (TAA). In recent years, regression of liver fibrosis (occurring spontaneously or during treatment) has been demonstrated in rodent models such as bile duct ligation and CCl(4) administration. Therefore, in the present study, the potential therapeutic effect of hypothyroidism on liver fibrosis was investigated. METHODS: Liver fibrosis was induced in rats by administration of TAA (200 mg/kg, i.p., twice weekly) for 12 weeks. Hypothyroidism was then induced by either methimazole (0.04%) or propylthiouracil (0.05%) administered in drinking water for 8 weeks. Control euthyroid rats received normal drinking water. Hypothyroidism was confirmed by a significant elevation of serum thyroid-stimulating hormone levels. RESULTS: Eight weeks after the cessation of TAA administration, spleen weight, histological score of liver fibrosis, and hepatic hydroxyproline content were significantly lower in both groups of hypothyroid rats as compared to euthyroid controls (P < 0.001). In vitro studies using the rat hepatic stellate cell line HSC-T6 using northern blot analysis and zymography, respectively, showed that high concentrations of triiodotyronine (T(3)) enhanced transforming growth factor (TGF)-beta-induced collagen I gene expression, and reduced metalloproteinase (MMP)-2 secretion, implying that reducing the levels of T(3) may contribute to resolution of fibrosis. Additionally, low T(3) concentration inhibited HSC-T6 proliferation. CONCLUSION: Pharmacologically induced hypothyroidism accelerates the resolution of liver fibrosis in rats. This beneficial effect may in part be due to prevention of T(3)-induced stimulation of collagen synthesis and reduction of MMP-2 secretion.     

The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction

BACKGROUND/AIMS: Our aim was to investigate whether the antioxidant quercetin might protect against liver injury in chronically biliary obstructed rats. METHODS: Secondary biliary cirrhosis was induced by 28 days of bile duct obstruction. Animals received quercetin at 75, 150 and 300 micromol x kg body wt(-1) x day(-1) i.p. through the experimental period or at 150 micromol x kg body wt(-1) x day(-1) i.p. for the last 2 weeks. RESULTS: Bile duct obstruction resulted in a decrease in the activities of antioxidant enzymes. Liver oxidised/reduced (GSSG/GSH) glutathione ratio, hepatic and mitochondrial thiobarbituric acid reactive substances (TBARS) and collagen content were significantly increased and a marked fibrosis and bile ductular proliferation was observed. Quercetin corrected the reduction in glutathione concentration and partially prevented the increase in collagen concentration, TBARS and GSSG/GSH ratio. Treatment resulted in a significant preservation of the activities of antioxidant enzymes, a less pronounced fibrosis and a marked inhibition of bile ductular proliferation. Maximal effects were reached with the intermediate quercetin dose given for 2 or 4 weeks. CONCLUSIONS: Quercetin reduces liver oxidative damage, ductular proliferation and fibrosis in biliary-obstructed rats. These effects suggest that it might be a useful agent to preserve liver function in patients with biliary obstruction.     

Antioxidants vitamin E and C attenuate hepatic fibrosis in biliary-obstructed rats

INTRODUCTION Hepatic fibrosis is a highly integrated cellular response to tissue injury[1]. It is essentially characterized by activation of hepatic stellate cells, secretion and accumulation of extracellular matrix proteins[2]. Various causes of cholesta…     

Effect of the regulation of retinoid X receptor‐α gene expression on rat hepatic fibrosis

Aim: To study the effect of retinoid X receptor‐α (RXR‐α) expression on rat hepatic fibrosis. Methods: Rat hepatic fibrosis was induced by CCl₄, and the rats were randomly divided into an early‐phase hepatic fibrosis group (2 weeks) and a sustained hepatic fibrosis group (8 weeks). They were then divided into four groups (normal control, hepatic fibrosis, negative control and RXR‐α groups). A recombinant lentiviral expression vector carrying the rat RXR‐α gene was injected into the rats to induce RXR‐α expression by intraportal infusion, hepatic tissue pathological examination was performed, and hydroxyproline content was detected. Hepatic stellate cells (HSC) were cultured in vitro, an RXR‐α lentivirus vector was used to activate HSC, and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) activation was assayed to detect HSC proliferation. Results: In vivo experiments indicated that in the sustained hepatic fibrosis group, there were significant differences in the hydroxyproline content, and expression of RXR‐α, α‐smooth muscle actin (α‐SMA) and type I collagen (P < 0.01). However, in the early‐phase hepatic fibrosis group, hydroxyproline content and the protein level of RXR‐α showed no significant difference compared with the normal control group (P > 0.05). In vitro studies revealed that expression of RXR‐α significantly inhibited expression of α‐SMA and type I collagen in activated HSC (P < 0.01), as well as HSC proliferation (P < 0.01). Conclusion: The increased RXR‐α gene expression inhibited HSC activation and proliferation and the degree of hepatic fibrosis.     

Long-term administering low anticoagulant activity heparin can lessen rat hepatic fibrosis induced by either CCl(4) or porcine serum injection.

BACKGROUND/AIM: Heparin or heparin-derived molecules have been demonstrated to have a renoprotective activity in a number of experimental nephropathies and anti-fibrotic effect on pulmonary fibrosis induced by Bleomycin. However, the effectiveness of low anticoagulant activity heparin (LAAH) in the treatment of liver fibrosis has not been well defined. We are here demonstrating by both biochemical and morphological methods that long term LAAH administering can considerably decrease the hepatic fibrosis in rats elicited by carbon tetrachloride (CCl(4)) or injection of porcine serum. And its inhibition of fibrosis may be associated with the intervention of ERK signal transduction pathway and down-regulation of AP-1 activity in hepatic stellate cells. METHODS: LAAH were given to rats that subjected to CCl(4) or porcine serum injection induced liver fibrosis regimens up to 10 weeks. Immunohistochemical stainings for collagen types I and III plus image analysis as well as measurement of hydroxyproline content in the livers were carried out to evaluate the fibrosis of livers in rats. The activated HSCs (strong positive immunohistochemical staining for alpha-smooth actin) in the livers were counted under microscopy. The activities of extracellular signal-regulated kinase (ERK) in HSCs in vitro were estimated by the Western blot. Activator protein-1 (AP-1) activity in nuclear proteins of HSCs was measured by the electrophoresis motility shift assay (EMSA). RESULTS: The immunohistochemical staining plus image analysis showed that LAAH administration could reduce the contents of collagen types I and III to 16.48% and 27.94% of those in saline administration control in livers of rats treated with CCl(4) or 30.98% and 35.43% of those in saline administration control in livers of rats subjected to injection of porcine serum. Meanwhile, LAAH could decrease the content of hydroxyproline in the livers of rats treated with CCl(4) or injection of porcine serum by 32.83% or 32.41%, respectively. Long-term administration of LAAH can remarkably reduce the alpha-SMA positive cells only in the fibrotic livers induced by CCl(4). In vitro studies of HSCs showed that LAAH could inhibit the PDGF-BB augmented both expression and phosphorylation of ERK proteins and AP-1 activity in a dose-dependent manner. CONCLUSIONS: Long-term administering LAAH can suppress the hepatic fibrosis either induced by CCl(4) or injection of porcine serum. The mechanism of its anti-fibrotic effect may partly be related to the inference of ERK signal transduction pathway and AP-1 activity in activated hepatic stellate cells.     

细胞增殖与凋亡相关蛋白质在大鼠肝纤维化形成与消减中的动态变化

目的通过对四氯化碳诱导纤维化大鼠肝组织蛋白质组的分析，研究与增殖、凋亡相关蛋白质在肝纤维化过程中的动态变化，探讨细胞增殖与凋亡在肝纤维化形成及发展中的作用。方法将Wistao大鼠随机分为正常组、模型组。模型组大鼠皮下注射40％四氯化碳一橄榄油溶液，每周2次，共l2周，停止刺激后再观察4周。分别于第4、8、12、l6周末分批取材。留取肝组织分别做病理组织学、羟脯氨酸检查与蛋白质的分步提取。蛋白质定量后进行二维电泳，凝胶银染，用PDQUEST 2-DE图像分析软件对获得的蛋白质图谱进行分析，运用基质辅助激光解吸电离飞行时间质谱（MALDI—TOF—MS）鉴定30多个差异表达的蛋白质。结果从第1周开始模型组大鼠肝组织的胶原沉积、羟脯氨酸持续增高，在12周最高（P〈0．05），l6周下降（P〈0．05），各时间点模型组与正常组比较差异有统计学意义（P〈0．05）；模型组大鼠肝组织蛋白质组较正常组也有较大改变。经MALDI-TOF-MS鉴定与细胞增生相关的蛋白质或酶为：细胞增殖核抗原p120与p40、细胞周期蛋白F和泛素结合酶UBC7；与细胞凋亡相关的蛋白质主要有胱门蛋白酶12，只在模型组大鼠肝组织表达。结论与细胞增生、凋亡的相关蛋白质表达量在肝纤维化发生发展的不同阶段呈动态变化；在肝纤维化形成过程中细胞增生与凋亡受到相关蛋白质的调节。     

Prevention of hepatic cirrhosis in rats by hydroxyl radical scavengers.

BACKGROUND/AIMS: Reactive oxygen species and oxidative stress were implicated in hepatic stellate cell activation and liver fibrosis. The aim of the present study was to examine whether the administration of free radical scavengers in vivo would prevent experimentally-induced hepatic cirrhosis in rats. METHODS: Cirrhosis was induced by administration of thioacetamide (TAA; 200 mg/kg, i.p.) twice/week, for 12 weeks. Rats were treated concurrently with either dimethylsulfoxide (DMSO; 4 g/kg, s.c. or p.o.) or dimethylthiourea (DMTU; 200 mg/kg i.p.) three times a week. RESULTS: Liver fibrosis (histopathological score, spleen weight, and hepatic hydroxyproline) was abolished in rats treated with TAA and either DMSO or DMTU (P < 0.001). Accordingly, the hepatic expression of alpha smooth muscle actin, tissue inhibitor of metalloproteinase 2 and collagen alpha1 (I) gene were inhibited. The hepatic level of methane-sulfinic acid (produced by the interaction of DMSO with hydroxyl radicals) was increased in rats treated with TAA + DMSO (P = 0.0005) and decreased after pretreatment of these rats with DMTU (P = 0.008). However, the hepatic levels of malondialdehyde, lipid peroxides and protein carbonyls were not lower in the DMSO- and DMTU-treated groups. CONCLUSIONS: The administration of free radical scavengers prevented the development of TAA-induced liver cirrhosis probably associated with decreased oxidative stress.     

Decreased collagen accumulation by a prolyl hydroxylase inhibitor in pig serum-induced fibrotic rat liver

Hepatic fibrosis was induced in rats by repeated i.p. injections of pig serum. The hepatic hydroxyproline content increased to 2.1 times the normal control level at 6 weeks and to 3.2 times at 10 weeks. When P-1894B, an inhibitor of prolyl hydroxylase, was administered, there was a dose-dependent inhibition of the increase to nearly normal control levels at 6 and 10 weeks. There was also by histology a dose-dependent reduction in the degree of hepatic fibrosis. Hepatocellular damage was minimal and its extent did not vary with the degree of fibrosis or the treatment. P-1894B dose dependently reduced the hydroxylation of peptidyl proline in the fibrotic liver. These data suggest that P-1894B inhibited hepatic fibrogenesis by direct action on collagen but not by protection against hepatocellular damage leading to collagen formation. A prolyl hydroxylase inhibitor may be a candidate for use in treatment of hepatic fibrosis.     

Antifibrotic effects of green tea on in vitro and in vivo models of liver fibrosis

AIM: To examine the protective effect of green tea extract (GT) on hepatic fibrosis in vitro and in vivo in dimethylnitrosamine (DMN)-induced rats. METHODS: HSC-T6, a rat hepatic stellate cell line, was used as an in vitro assay system. Cell proliferation,collagen content, and type 1 collagen expression were examined in activated HSC-T6 cells. Collagen was determined by estimating the hydroxyproline content.In rats with DMN-induced hepatic fibrosis, serum aspartate aminotransferase and alanine aminotransferase concentrations, liver hydroxyproline and lipid peroxides were determined. Pathologic changes were examined by hematoxylin & eosin staining.RESULTS: GT administration prevented the development of hepatic fibrosis in the rat model of DMN-induced liver fibrosis. These results were confirmed both by liver histology and by quantitative measurement of hepatic hydroxyproline content, a marker of liver collagen deposition. Accordingly, inhibition of proliferation, reduced collagen deposition, and type 1 collagen expression were observed in activated HSC-T6 cells following GT treatment. These results imply that GT reduced the proliferation of activated HSC and down regulated the collagen content and expression of collagen type 1, thereby ameliorating hepatic fibrosis. tea administration can effectively improve liver fibrosis caused by DMN, and may be used as a therapeutic option and preventive measure against hepatic fibrosis.     

Effect of sensory denervation with capsaicin on liver fibrosis induced by common bile duct ligation in rat

Hepatic fibrosis represents an important stage in the progression of chronic liver disease to cirrhosis. In the present paper we have investigated whether capsaicin-sensitive neuropeptide-containing sensory neurons may participate in the development of liver fibrosis. The expression of hepatic fibrosis induced by common bile duct obstruction has been studied both in capsaicin- and vehicle-treated rats. Common bile duct-induced liver fibrosis was less marked in capsaicin-treated rats than in vehicle-treated rats. Diffuse alterations of liver parenchyma structure with marked collagen deposition and nodular regeneration occurred 8 weeks after common bile duct ligation in vehicle-treated animals, while none of the capsaicin-treated rats exhibited the formation of complete connective septa altering the parenchyma architecture. Both vehicle- and capsaicin-treated rats showed an increasing number of desmin-positive cells in the perivenular zone, but the density of these cells was lower in treated animals than in untreated rats. The hydroxyproline content of the liver increased after common bile duct ligation in a time-dependent manner. Eight weeks after bile duct obstruction vehicle-treated rats showed a 7-fold increase of liver collagen content in comparison to normal animals. This enhancement was about 3.5-fold in capsaicin-treated rats. These findings raise the possibility that the peripheral release of neuropeptides stored in sensory nerves might participate in the development of liver fibrosis following common bile duct obstruction.     

2-Mercaptoethane sulfonate (MESNA) protects against biliary obstruction-induced oxidative damage in rats.

The aim of this study was to assess the antioxidant and antifibrotic effects of chronic administration of 2-mercaptoethane sulfonate (MESNA) on oxidative liver damage and fibrosis induced by biliary obstruction in rats. Liver fibrosis was induced in male Wistar albino rats by bile duct ligation and scission (BDL). MESNA (150mg/kg, i.p.) or saline was administered for 28 days. At the end of the experiment, rats were killed by decapitation. Serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were determined to assess liver function. Tumor necrosis factor-alpha (TNF-alpha) and lactate dehidrogenase (LDH) were also assayed in serum samples. Liver tissues were taken for determination of the free radicals, hepatic malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant; myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. Hepatic collagen content, as a fibrosis marker was also determined. Serum AST, ALT, LDH and TNF-alpha levels were elevated in the BDL group as compared to control group, while this increase was significantly decreased by MESNA treatment. BDL caused a significant (p<0.05-0.001) decrease in GSH levels while MDA levels and MPO activity were increased in the liver tissue. These changes were reversed by MESNA treatment. Collagen contents of the liver tissue was increased by BDL (p<0.001), and reversed back to the control levels with MESNA. Since MESNA administration alleviated the BDL-induced oxidative injury of the liver and improved the hepatic functions, it seems likely that MESNA with its antioxidant and antifibrotic properties, may be of potential therapeutic value in protecting the liver fibrosis and oxidative injury due to biliary obstruction.     

A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis.

BACKGROUND: Nuclear factor kappa B (NF-kappaB) activation, proinflammatory cytokines, and reactive oxygen species have been implicated as mediators of liver injury and fibrogenesis. We have shown recently that pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF-kappaB activation, was protective in a rat model of acute liver failure. The aim of the present study was to examine the efficacy of PDTC in a chronic rat model of thioacetamide (TAA)-induced hepatic fibrosis. METHODS: Liver cirrhosis was induced by intraperitoneal injections of TAA (200 mg/kg) twice weekly for 12 weeks. Two groups of rats also received PDTC (either 20 or 60 mg/kg, i.p. for 12 weeks). RESULTS: TAA administration induced liver cirrhosis, which was inhibited by PDTC in a dose-dependent manner. The histopathologic score of fibrosis, the spleen weight, and hepatic hydroxyproline were significantly lower in the rats treated with TAA+PDTC compared with TAA only (P<0.001). The hepatic levels of thiobarbituric acid reactive substances and protein carbonyls after 12 weeks of treatment were also lower in the rats treated with TAA+PDTC (P=0.02 and 0.01, respectively), indicating reduced oxidative stress. Immunohistochemical studies and in situ hybridization demonstrated inhibition of stellate cell (alpha smooth muscle actin positive) activation, tissue inhibitor of metalloproteinase-2, and collagen alpha1(I) gene expression in the livers of the PDTC-treated rats. As determined by Northern blot analysis, PDTC had no inhibitory effect on collagen alpha1(I) gene expression in the rat hepatic stellate cells-T6 cells in vitro. CONCLUSIONS: PDTC inhibits the development of liver cirrhosis in TAA-treated rats. The mechanism of action is associated with decreased oxidative stress and hepatic necroinflammation.     

A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats

BACKGROUND: p160ROCK is a direct Rho target which mediates Rho-induced assembly of focal adhesions and stress fibers. We previously reported that Rho signaling pathways are involved in the activation of hepatic stellate cells (HSC) in vitro. The aim of the present study was to test the hypothesis that an inhibitor specific for p160ROCK (Y27632) could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Y27632 was given orally at 30 mg/kg daily for 4 weeks after the first injection of DMN. The degree of fibrosis was evaluated by image analysis and also by measurements of collagen and hydroxyproline content in the liver. The expression of alpha-smooth muscle actin (alpha-SMA) in the liver and in the primary cultured HSC was also evaluated. Semi-quantitative RT-PCR was performed to evaluate the expression of type I collagen mRNA in the liver. RESULTS: Y27632 treatment significantly decreased the occurrence of DMN-induced hepatic fibrosis and reduced the collagen and hydroxyproline content and alpha-SMA expression in the liver. The expression of alpha-SMA in HSC was also suppressed in vitro. CONCLUSIONS: These findings indicate that inhibitors of the Rho-ROCK pathway might be useful therapeutically in hepatic fibrosis.     

Ameliorative effect of Ganoderma lucidum on carbon tetrachloride-induced liver fibrosis in rats

AIM: To investigate the effects of Reishi mushroom, Ganoderma lucidum extract (GLE), on liver fibrosis induced by carbon tetrachloride (CO) in rats. METHODS: Rat hepatic fibrosis was induced by CCl4. Forty Wistar rats were divided randomly into 4 groups: control, CCl4, and two GLE groups. Except for rats in control group, all rats were administered orally with CCl4 (20%, 0.2 mL/100 g body weight) twice a week for 8 weeks. Rats in GLE groups were treated daily with GLE (1 600 or 600 mg/kg) via gastrogavage throughout the whole experimental period. Liver function parameters, such as ALT, AST, albumin, and albumin/globulin (A/G) ratio, spleen weight and hepatic amounts of protein, malondiladehyde (MDA) and hydroxyproline (HP) were determined. Histochemical staining of Sirius red was performed. Expression of transforming growth factorβ1 (TGF-β1), methionine adenosyltransferase (MAT1) 1A and MAT2A mRNA were detected by using RT-PCR. RESULTS: CCU caused liver fibrosis, featuring increase in plasma transaminases, hepatic MDA and HP contents, and spleen weight; and decrease in plasma albumin, A/G ratio and hepatic protein level. Compared with CCU group, GLE (600, 1 600 mg/kg) treatment significantly increased plasma albumin level and A/G ratio (P<0.05) and reduced the hepatic HP content (P<0.01). GLE (1 600 mg/kg) treatment markedly decreased the activities of transaminases (P<0.05), spleen weight (P<0.05) and hepatic MDA content (P<0.05); but increased hepatic protein level (P<0.05). Liver histology in the GLE (1 600 mg/kg)-treated rats was also improved (P<0.01). RT-PCR analysis showed that GLE treatment decreased the expression of TGF-β1(P<0.05-0.001) and changed the expression of MAT1A (P<0.05-0.01) and MAT2A (P<0.05-0.001). CONCLUSION: Oral administration of GLE significantly reduces CCl4-induced hepatic fibrosis in rats, probably by exerting a protective effect against hepatocellular necrosis by its free-radical scavenging ability.     

Role of hepatic vitamin A and lipocyte distribution in experimental hepatic fibrosis

ABSTRACT— Lipocytes are the major site of hepatic vitamin A storage, and they have been demonstrated to lose their vitamin A content in the process of hepatic fibrosis. To investigate the relationship between hepatic vitamin A content and the degree of hepatic fibrosis, we measured levels of retinyl palmitate and retinol in the CCl₄-induced fibrotic liver using high-performance liquid chromatography. We estimated hepatic collagen content using a spectrophotometric analysis with sirius red, and also by measuring hydroxyproline levels. Lipocytes were detected by an immunoperoxidase method with anti-desmin antibody, and were counted morphometrically through a Texture Analyzing System. A significant negative correlation was observed between the level of retinyl palmitate and collagen content (r = –0.64) as well as the hydroxyproline level (r = –0.69) in the CCl₄-induced fibrotic liver. In the process of fibrosis, hepatic retinol levels were elevated in association with a decrease in retinyl palmitate. In particular in the early stage of fibrosis, lipocytes increased remarkably in number in fibrotic areas in spite of a decrease in total hepatic vitamin A. The present study suggests that an increase in hepatic retinol as well as a decrease in retinyl palmitate may facilitate the process of hepatic fibrosis produced by lipocytes.     

桑黄治疗大鼠肝纤维化实验研究

目的:研究桑黄对肝纤维化的治疗作用。方法:采用四氯化碳诱导大鼠肝纤维化模型,实验分正常对照组、模型对照组、桑黄高、中剂量组,观察血清酶学,血清胶原成分含量及肝组织病理变化。结果:桑黄高、中、低剂量对肝纤维化有明显的治疗作用,能显著降低血清氨基转移酶水平和胶原成分含量,抑制肝组织内胶原纤维增生。结论:桑黄可用于治疗肝纤维化,且疗效与剂量呈正相关。     

Beta-carotene (provitamin A) decreases the severity of CCl4-induced hepatic inflammation and fibrosis in rats

Earlier data from experiments in rats have shown that administration of retinyl esters (vitamin A) strongly influences the effects of CCl₄ on the liver. The accumulation of collagen was inhibited, but an increase in CCl₄-toxicity with high mortality was observed. The present study was conducted to examine the effects of β-carotene (provitamin A) on CCl₄-related general and hepatic toxicity in rats. Oral administration of β-carotene during CCl₄-treatment resulted, biochemically, in a significantly lower increase in the hydroxyproline liver content and, histopathologically, in less severe liver fibrosis as compared with the liver of rats not treated with β-carotene. The study also showed that β-carotene administration could prevent the long-term loss of retinoids from the CCl₄-injured liver. No significant toxic effects of β-carotene, as previously found with retinyl esters (vitamin A), were observed. This experimental study suggests that β-carotene has the therapeutic potential to decrease the severity of liver fibrosis without marked toxicity.     

绞股蓝总皂苷对四氯化碳诱导大鼠肝纤维化的防治作用

目的:观察绞股蓝总皂苷对四氯化碳( CCl4)诱导的大鼠肝纤维化的防治作用.方法:采用CCl4诱导的大鼠肝纤维化模型,分为正常组(Z,n=6)、模型组(M,n=8)、绞股蓝总皂苷组(J,n=8)、秋水仙碱(Q,n=8).造模6周末开始给药(股蓝总皂苷200mg/kg体重、秋水仙碱0.1mg/kg体重),给药3周.观察:①大鼠体重、肝脾比值的变化;②血清丙氨酸氨基转移酶(ALT)、门冬氨酸氨基转移酶(AST)、谷氨酰转肽酶(GGT)活性、白蛋白( Alb)、总胆红素(TBil)含量、肝组织羟脯氨酸(Hyp)含量;③肝组织超氧化物歧化酶(SOD)活性及丙二醛(MDA)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)含量;④肝组织病理及胶原沉积情况.结果:①M组大鼠血清ALT、AST、GGT、TBil显著升高,Alb显著降低;J和Q组大鼠血清ALT、AST、GGT、TBil显著下降,Alb显著升高;②M组大鼠肝组织Hyp含量显著升高,J组及Q组大鼠肝组织Hyp含量显著下降;③肝组织HE染色显示:M组大鼠肝细胞脂肪变性,大量纤维结缔组织增生,假小叶形成.J组及Q组大鼠肝细胞脂肪变性减轻,纤维增生减少,少见完整假小叶结构.天狼星红染色显示:M组大鼠肝窦周胶原沉积明显,形成较厚汇管区和中央静脉间的纤维间隔,J组和Q组大鼠肝脏汇管区胶原纤维染较M组明显减轻;④M组大鼠肝组织SOD活性及GSH含量明显降低,MDA含量显著升高.J组大鼠肝组织SOD活性显著提高.结论:绞股蓝总皂苷具有显著抗CCl4诱导的大鼠肝纤维化及氧化损伤的作用.