Protective effects of melatonin against carbon tetrachloride hepatotoxicity in rats

Melatonin is an indolamine, mainly secreted by the pineal gland into the blood of mammalian species. The potential for protective effects of melatonin on carbon tetrachloride (CCl(4))-induced acute liver injury in rats was investigated in this work. CCl(4) exerts its toxic effects by generation of free radicals; it was intragastrically administered to male Wistar rats (4 g kg(-1) body weight) at 20 h before the animals were decapitated. Melatonin (15 mg kg(-1) body weight) was administered intraperitoneally three times: 30 min before and at 2 and 4 h after CCl(4) injection. Rats injected with CCl(4) alone showed significant lipid and hydropic dystrophy of the liver, massive necrosis of hepatocytes, marked increases in free and conjugated bilirubin levels, elevation of hepatic enzymes (alanine aminotransferase and aspartate aminotransferase) in plasma, as well as NO accumulation in liver and in blood. Melatonin administered at a pharmacological dose diminished the toxic effects of CCl(4). Thus it decreased both the structural and functional injury of hepatocytes and clearly exerted hepatoprotective effects. Melatonin administration also reduced CCl(4)-induced NO generation. These findings suggest that the effect of melatonin on CCl(4)-induced acute liver injury depends on the antioxidant action of melatonin.     

Protective effects of N-acetyl-L-cysteine against acute carbon tetrachloride hepatotoxicity in rats

In recent years, N-acetyl-L-cysteine (NAC) has been widely investigated as a potentially useful protective and antioxidative agent to be applied in many pathological states. The aim of the present work was further evaluation of the mechanisms of the NAC protective effect under carbon tetrachloride-induced acute liver injuries in rats. The rat treatment with CCl4 (4 g/kg, intragastrically) caused pronounced hepatolysis observed as an increase in blood plasma bilirubin levels and hepatic enzyme activities, which agreed with numerous previous observations. The rat intoxication was accompanied by an enhancement of membrane lipid peroxidation (1.4-fold) and protein oxidative damage (protein carbonyl group and mixed protein-glutathione disulphide formations) in the rat liver. The levels of nitric oxide in blood plasma and liver tissue significantly increased (5.3- and 1.5-fold, respectively) as blood plasma triacylglycerols decreased (1.6-fold). The NAC administration to control and intoxicated animals (three times at doses of 150 mg/kg) elevated low-molecular-weight thiols in the liver. The NAC administration under CCl4-induced intoxication prevented oxidative damage of liver cells, decreased membrane lipid peroxidation, protein carbonyls and mixed protein-glutathione disulphides formation, and partially normalized plasma triacylglycerols. At the same time the NAC treatment of intoxicated animals did not produce a marked decrease of the elevated levels of blood plasma ALT and AST activities and bilirubin. The in vitro exposure of human red blood cells to NAC increased the cellular low-molecular-weight thiol levels and retarded tert-butylhydroperoxide-induced cellular thiol depletion and membrane lipid peroxidation as well as effectively inhibited hypochlorous acid-induced erythrocyte lysis. Thus, NAC can replenish non-protein cellular thiols and protect membrane lipids and proteins due to its direct radical-scavenging properties, but it did not attenuate hepatotoxicity in the acute rat CCl4-intoxication model.     

Hepatoprotective activity of ellagic acid against carbon tetrachloride induced hepatotoxicity in rats

Administration of CCl4 to normal rats and consequent oral feeding with ellagic acid (50 mg/kg) provided a significant protection against the biochemical alterations in serum and liver produced by CCl4. In vitro experiments showed that liver microsomes from animals treated with ellagic acid and CCl4, decreased lipid peroxidation compared to microsome prepared from rats exposed to CCl4 alone.     

Protective effects of ascorbic acid on hepatotoxicity and oxidative stress caused by carbon tetrachloride in the liver of Wistar rats

This study was planned to investigate the protective effect of l (+)‐ascorbic acid (Vit C) on CCl₄‐induced hepatotoxicity and oxidative stress in the liver of Wistar rats (Rattus Norvegicus, strain Wistar). Twenty‐four adult male Wistar rats were fed with standard rat chow diet for 10 days and randomly were divided into four groups of six each as follows: (1) control, (2) CCl₄, (3) “CCl₄ + Vit C”, (4) Vit C groups. CCl₄ was applied to rats belonging to CCl₄ and “CCl₄ + Vit C” groups subcutaneously at 1 mg kg^?1 dose CCl₄ for 3 days. Vit C applied to “CCl₄ + Vit C” and “Vit C” group rats intraperitoneally at 300 mg kg^?1 dose for 3 days. All rats were sacrificed and livers were quickly removed on the fourth day of the experiment. MDA, total glutathione (T.GSH) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‐PX) activities were measured in the liver of all groups of rats and also serum alanine amino transferase (ALT) and aspartate amino transferase (AST) activities were detected to determine liver functions in all groups of rats. Histopathological changes were evaluated by light and transmission electron microscopes. In “CCl₄ + Vit C” group, MDA level was significantly decreased (p < 0.05) and SOD, CAT, GSH‐PX activities were significantly increased (p < 0.005, 0.01, 0.05) respectively, T.GSH level was significantly increased (p < 0.005) and serum ALT and AST activities were significantly decreased (p < 0.01, 0.05), respectively, when compared with CCl₄ group. These results show that Vit C has a highly protective effect on hepatotoxicity and oxidative stress caused by CCl₄. Copyright © 2009 John Wiley & Sons, Ltd.     

Hepatoprotective and antioxidant effects of Hedera helix extract on acetaminophen induced oxidative stress and hepatotoxicity in mice

ABSTRACT

Exposure to high doses of acetaminophen is the most common cause of drug induced liver injury. We investigated the protective effects of Hedera helix extract against acetaminophen induced oxidative stress and hepatotoxicity using a mouse model. We used two control groups: group A was given 0.9% NaCl, group B was an acetaminophen control that was given a single injection of 600 mg/kg acetaminophen. T1?T4 groups were pretreated orally with different doses of H. helix extract. The mice were sacrificed and blood samples were collected to estimate the levels of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD) and total bilirubin. Liver samples also were used for histopathological studies. We found that acetaminophen significantly increased the levels of serum ALP, ALT, AST and MDA, and also significantly reduced the antioxidant factors, CAT, GPX and SOD. H. helix extract treatment produced a significant reduction in the levels of ALP, ALT, AST and MDA in serum and restored the levels of CAT, GPX and SOD to control levels. The histopathological findings were consistent with the biochemical findings. H. helix extract exhibited antioxidant and hepatoprotective effects against acetaminophen induced liver damage.     

Low-dose γ-ray irradiation reduces oxidative damage induced by CCl4 in mouse liver

We examined the effects of irradiation (50 cGy of γ-ray) reducing the oxidative damage in carbon tetrachloride (CCl₄)-hepatopathy mice. We made pathological examinations and analyzed transaminase activity (glutamic oxaloacetic transaminase and glutamic pyruvic transaminase), lipid peroxide level and the activities of endogenous antioxidants in the mouse. The irradiation was found to accelerate the recovery. Based on pathological examination as well as changes in each transaminase activity and lipid peroxide levels, it was shown that hepatopathy improved 3 d after the irradiation. The activities of glutathione reductase and glutathione peroxidase rapidly elevated after irradiation, and the total glutathione content gradually increased in the irradiation group. Both activities of γ-glutamylcysteine synthetase and catalase were higher than normal at all times after the irradiation and gradually increased. In addition, the γ-glutamylcysteine synthetase activity changed in a similar fashion to the total glutathione content. However, superoxide dismutase activity in both groups decreased and that of the irradiation group was significantly lower than that of the sham-irradiation group. These findings suggest that low-dose radiation relieved functional disorder at least in the liver of mice with active oxygen diseases.     

Protective effects of melatonin against carbon tetrachloride-induced hepatotoxicity in rats: a light microscopic and biochemical study

The aim of this study was to examine the protective effects of melatonin against CCl4-induced hepatotoxicity in the rat. Twenty-four male Wistar rats were divided into three groups. Group I was used as a control. Rats in group II were injected every other day with CCl4 for 1 month, whereas rats in group III were injected every other day with CCl4 and melatonin for 1 month. At the end of the experiment, all animals were killed by decapitation and blood samples were obtained. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and conjugated bilirubin levels were determined. For histopathological evaluation, livers of all rats were removed and processed for light microscopy. All serum biochemical parameters were significantly higher in animals treated with CCl4 than in the controls. When rats injected with CCl4 were treated with melatonin, significantly reduced elevations in serum biochemical parameters were found. In liver sections of the CCl4-injected group, necrosis, fibrosis, mononuclear cell infiltration, haemorrhage, fatty degeneration and formation of regenerative nodules were observed. Additionally, apoptotic figures, microvesicular steatosis and hydropic degeneration in hepatocytes were seen in this group. In contrast, the histopathological changes observed after administration of CCl4 were lost from rats treated with CCl4 and melatonin. Except for mild hydropic degeneration of the hepatocytes, a normal lobular appearance was seen in the livers of this group. The results of our study indicate that melatonin treatment prevents CCl4-induced liver damage in rats.     

Hepatic calcium-binding protein regucalcin is released into the serum of rats administered orally carbon tetrachloride

The change in calcium-binding protein regucalcin, mainly localized in liver, in the liver and serum of rats received a single oral administration of carbon tetrachloride (50%; 1.0 ml/100 g body weight) was investigated. The change of regucalcin mRNA levels in the liver was analyzed by Northern blotting using liver regucalcin cDNA (0.6 kb). At 10 and 24 h after the administration, liver regucalcin mRNA levels were reduced markedly. Moreover, regucalcin concentration in the liver and serum was estimated by enzyme-linked immunoadsorbent assay (ELISA) with rabbit-anti-regucalcin IgG. Administration of carbon tetrachloride (CCl₄) induced a significant decrease in liver regucalcin concentration and a corresponding elevation of serum regucalcin concentration at 24 h after the administration. An appreciable increase in serum regucalcin concentration was seen at 2 h after the administration. Meanwhile, serum transaminases (GOT and GPT) activities were significantly increased by CCl₄ administration, indicating that liver injury is induced. The present study demonstrates that hepatic regucalcin is released into the serum of rats administered orally CCl₄, suggesting that the estimation of serum regucalcin is a useful tool for diagnosis of liver injury.     

Correlations between common tests for assessment of liver damage: indices of the hepatoprotective activity of promethazine in carbon tetrachloride hepatotoxicity

The effects of promethazine (PM) on different aspects of the hepatotoxic action of CCl4 in the rat were investigated with the objective of finding rapid and reliable indicators of hepatoprotective effects. The study was based on definitive histological assessment of liver damage caused by CCl4 in the presence and absence of PM: PM (78 mumol kg-1, i.p.) protected against CCl4-induced hepatic necrosis 24 h after a low dose of CCl4 (1.3 mmol kg-1) but not against a higher dose (13.0 mmol kg-1). The large increases in plasma activities of GOT, GPT and LDH produced by dosing with CCl4 were partially inhibited by the administration of PM. PM and CCl4 caused a synergistic and long-lasting decrease in body temperature (2-3 degrees C for 8-10 h). Modifying the toxicity with PM, together with a low dose of CCl4, helped to minimize secondary effects of CCl4, to clarify the sequence of toxic events, and to assess the sensitivity of some standard tests of hepatotoxicity. Simultaneous measurement of over 20 commonly used biochemical screening tests in individual animals 3 or 6 h after treatment permitted direct correlation of a wide variety of concentrations, activities and effects. For example, liver CHCl3 concentrations (as a measure of CCl4 metabolism) correlate strongly with increases in diene conjugation of microsomal lipids (as a measure of CCl4-induced lipid peroxidation); malonaldehyde production appears to be less sensitive as a measure of lipid peroxidation in vivo than diene conjugation. The changes induced in each parameter and the correlations between them are discussed with reference to the overall nature of the hepatotoxic reaction and its modification by PM.     

Hepatoprotective effects of Solanum nigrum Linn extract against CCl(4)-induced oxidative damage in rats

Solanum nigrum L. (SN) is an herbal plant that has been used as hepatoprotective and anti-inflammation agent in Chinese medicine. In this study, the protective effects of water extract of SN (SNE) against liver damage were evaluated in carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats. Sprague-Dawley (SD) rats were orally fed with SNE (0.2, 0.5, and 1.0 g kg(-1) bw) along with administration of CCl4 (20% CCl4/corn oil; 0.5 mL kg(-1) bw) for 6 weeks. The results showed that the treatment of SNE significantly lowered the CCl4-induced serum levels of hepatic enzyme markers (GOT, GPT, ALP, and total bilirubin), superoxide and hydroxyl radical. The hepatic content of GSH, and activities and expressions of SOD, GST Al, and GST Mu that were reduced by CCl4 were brought back to control levels by the supplement of SNE. Liver histopathology showed that SNE reduced the incidence of liver lesions including hepatic cells cloudy swelling, lymphocytes infiltration, hepatic necrosis, and fibrous connective tissue proliferation induced by CCl4 in rats. Therefore, the results of this study suggest that SNE could protect liver against the CCl4-induced oxidative damage in rats, and this hepatoprotective effect might be contributed to its modulation on detoxification enzymes and its antioxidant and free radical scavenger effects.     

Adverse impact of carbon tetrachloride on metabolic function in mice

Carbon tetrachloride (CCl₄), a potent hepatotoxin, is linked to the histopathological outcomes of inflammatory or oxidative stress, and cell death. However, further study of additional dysmetabolism induced by CCl ₄ toxicant has not yet been investigated. In current study, chronical and acute exposures of CCl ₄ in mice were used to unmask the biological molecular mechanism responsible for insulin-dependent metabolic disorder. In experimental methods, a number of biochemical assays were used in assessment of biological impacts on insulin-produced pancreas and insulin-responsive hepatocyte after long- and short-term exposures of CCl ₄ toxicant, respectively. As a result, data from oral glucose tolerance test showed that CCl ₄ exposures induced glucose tolerance and disrupted blood insulin and glucagon levels time-dependently. Meanwhile, biochemical and histocytological analyses further indicated that CCl ₄ exposures significantly resulted in liver cell damage, induced abnormal changes of hepatic and skeletal glycogen synthesis. In addition, acute CCl ₄-exposed mice showed reduced functional proteins of glucose transporter 2 (GLUT2), insulin receptor β, insulin receptor substrate 1, glycogen synthase kinase 3β (GSK3β), p-AKT ^Ser473 associated with AKT signaling pathway in liver cells, whereas acute CCl ₄ exposure downregulated the endogenous expressions of the insulin and glucagon hormonal proteins in the pancreas. Taken together, the current findings highlight that CCl ₄ impaired insulin-dependent glucose homeostasis through modulating hepatocellular AKT signaling pathway in acute CCl ₄ exposure and GLUT2/GSK3β pathway in chronic CCl ₄-exposed liver cells.     

TNF-alpha and leptin in experimental liver fibrosis models induced by carbon tetrachloride and by common bile duct ligation

In this study we investigated TNF-alpha and leptin levels in two different liver fibrosis models induced by carbon tetrachloride (CCl(4)) and common bile duct ligation (CBDL). A total of 36 male rats of Albino-Wistar strain were allocated to three groups. One of the groups was the control. The second group received 0.15 ml 100 g(-1) CCl(4) subcutaneously for 6 weeks, 3 days per week. The third group underwent common bile duct ligation (CBDL) and was monitored for 4 weeks. Histopathological investigation included fibrosis, steatosis and inflammation. Serum IL-6 and TNF-alpha levels were analysed by ELISA methods and leptin was analysed by RIA. Fibrosis and steatosis increased significantly in the CCl(4) group in comparison with the CBDL group (p < 0.01; p < 0.001). Leptin and TNF-alpha levels in CCl(4) group were higher than those in the CBDL and control groups (p < 0.05). TNF-alpha and leptin levels were not related to each another in either the CCl(4) group or the CBDL group (r=0.22, p > 0.05; r=0.19, p > 0.05). The IL-6 level was higher in the CCl(4) group in relation to severity of inflammation (p < 0.05). TNF-alpha and leptin levels were higher in animals with liver fibrosis induced by CCl(4), than they were in those whose liver fibrosis was induced by common bile duct ligation. Leptin and TNF-alpha may be less effective on the development of liver fibrosis in the group which underwent common bile duct ligation.     

Propolis protects CYP 2E1 enzymatic activity and oxidative stress induced by carbon tetrachloride

Induction of CYP 2E1 by carbon tetrachloride (CCl₄) is one of the central pathways by which CCl₄ generates oxidative stress in hepatocytes. Experimental liver injury was induced in rats by CCl₄ to determine toxicological actions on CYP 2E1 by microsomal drug metabolizing enzymes. In this report, ethanolic extract of propolis at a dose of 200 mg/kg (po) was used after 24 h of toxicant administration to validate its protective potential. Intraperitoneal injection of CCl₄ (1.5 ml/kg) induced hepatotoxicity after 24 h of its administration that was associated with elevated malonyldialdehyde (index of lipid peroxidation), lactate dehydrogenase and γ-glutamyl transpeptidase release (index of a cytotoxic effect). Hepatic microsomal drug metabolizing enzymes of CYP 2E1 showed sharp depletion as assessed by estimating aniline hydroxylase and amidopyrine N-demethylase activity after CCl₄ exposure. Toxic effect of CCl₄ was evident on CYP 2E1 activity by increased hexobarbitone induced sleep time and bromosulphalein retention. Propolis extract showed significant improvement in the activity of both enzymes and suppressed toxicant induced increase in sleep time and bromosulphalein retention. Choleretic activity of liver did not show any sign of toxicity after propolis treatment at a dose of 200 mg/kg (id). Histopathological evaluation of the liver revealed that propolis reduced the incidence of liver lesions including hepatocyte swelling and lymphocytic infiltrations induced by CCl₄. Electron microscopic observations also showed improvement in ultrastructure of liver and substantiated recovery in biochemical parameters. Protective activity of propolis at 200 mg/kg dose was statistically compared with positive control silymarin (50 mg/kg, po), a known hepatoprotective drug seems to be better in preventing hepatic CYP 2E1 activity deviated by CCl₄. These results lead us to speculate that propolis may play hepatoprotective role via improved CYP 2E1 activity and reduced oxidative stress in living system.     

Extracts of Phellinus linteus grown on germinated brown rice suppress liver damage induced by carbon tetrachloride in rats

Extracts of Phellinus linteus (EPB), grown on germinated brown rice, protected rats from liver injury induced by carbon tetrachloride (CCl4). Peroxidation products in the liver were decreased to 10% by EPB. Catalase and superoxide dismutase activities were significantly decreased to 55% and 39% by CCl4 administration, but EPB blocked this effect, resulting in enzyme activities at control levels. Expression of cytochromeP450 2E1 (CYP2E1) protein was significantly decreased to 88% in CCl4-treated rats but remained at control levels when EPB was also administered. EPB did not affect the altered fatty acid composition induced by CCl4. The hepatoprotective effect of EPB may be mediated by EPB's prevention of CCl4-induced CYP2E1 degradation.     

Hepatoprotective effect of Herpetospermum caudigerum Wall. on carbon tetrachloride‐induced hepatic fibrosis in rats

Tibetan medicine Herpetospermum caudigerum Wall. (HCW) has long been employed to treat hepatitis, inflammatory diseases and jaundice according to the records of “The Four Medical Tantras” in China. This study was investigated to explore the protective effects of HCW on hepatic fibrosis and the possible mechanism in a rat model. Hepatic fibrosis was established by intragastric administration of 3 ml/kg carbon tetrachloride (CCl₄) twice a week for 6 weeks. CCl₄‐treated rats were received HCW (1 and 3 g/kg/d) and silymarin (0.1 g/kg/d) from 3 to 6 weeks. The results showed that HCW could significantly decrease the levels of AST, ALT, HA, LN, PCIII, Col IV, TNF‐α, IL‐1β and IL‐6. Moreover, HCW could effectively inhibit collagen deposition and reduce the pathological damage. Analysis experiments finally exhibited that HCW was able to markedly inhibit hepatic fibrosis by modulating the expressions of NF‐κB p65, IκBα, Samd3 and TGF‐β1 proteins. Therefore, our results suggest that HCW has hepatoprotective activity against CCl₄‐induced hepatic fibrosis in rats by regulating the inflammatory responses.     

Plasma amino acid levels after carbon tetrachloride induced acute liver damage. A dose-response and time-response study in rats

Summary The aims of the present study were to assess the changes of individual plasma amino acid levels in relation (1) to the severity of liver damage and (2) to the process of liver recovery. Acute liver injury was induced by an intragastric administration of CCl₄ diluted in olive oil in doses of 2, 4 and /or 6 g of CCl₄ per kg b.w. The control rats received olive oil only. Animals were sacrificed at 16, 24, 48 and 96 hours after treatment. The severity of liver injury was assessed by histological examination, by changes in ALT and AST in the blood plasma and by changes in liver weight. Statistical analysis was carried by ANOVA, p < 0.05 was considered significant. The Spearman rank correlation coefficient was used as a measure of the degree of linear relationship between variable and dose. In the period of the development of acute liver damage, i.e. at 16 and 24 hours after treatment, an increase in blood plasma amino acid levels and positive correlations with the dose of CCl₄ were observed for most individual amino acids. The only exception was arginine which decreased in a dose dependent manner. At a phase of liver recovery, i.e. at 48 and 96 hours after CCl₄ treatment, the concentrations of some individual amino acids decreased below the control values. The negative correlation with the dose of CCl₄ occurred for taurine and isoleucine (at 48 hours) and taurine, threonine, valine, methionine, isoleucine and leucine (at 96 hours).     

Hepatoprotective effect of bis(4‐methylbenzoyl) diselenide against CCl4‐induced oxidative damage in mice

From a pharmacological point of view, organoseleniums are compounds with important and interesting antioxidant and biological activities. The aim of this study was to evaluate the hepatoprotective effect of bis(4‐methylbenzoyl) diselenide (BMD) against carbon tetrachloride (CCl₄)–induced oxidative damage in mice. The animals received BMD (25 mg/kg p.o., for 3 days), and after 1 day, CCl₄ (1 mg/kg body weight) was administered by intraperitoneal route. One day after the CCl₄ exposure, the animals were euthanized for biochemical and histological analysis. Treatment with BMD (25 mg/kg p.o.) protected against aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma‐glutamyl transferase and lactate dehydrogenase activity increases induced by CCl₄ plasma exposure. Treatment with BMD (25 mg/kg) protected against increases in thiobarbituric reactive species and decreasing non‐protein thiols and ascorbic acid levels in liver of mice. Catalase and superoxide dismutase activity inhibition in the liver caused by CCl₄ were protected by treatment with BMD (25 mg/kg). Glutathione S‐transferase activity was inhibited by CCl₄ and remained unaltered even after treatment with BMD. Sections of liver from CCl₄‐exposed mice presented an intense infiltration of inflammatory cells and loss of the cellular architecture. BMD (25 mg/kg) attenuated CCl₄‐induced hepatic histological alterations. The results demonstrated the hepatoprotective effects of BMD in the mouse liver, possibly by modulating the antioxidant status. Copyright © 2012 John Wiley & Sons, Ltd.     

Protective mechanism of Lygodium flexuosum extract in treating and preventing carbon tetrachloride induced hepatic fibrosis in rats

The protective effect of Lygodium flexuosum extract in preventive and curative treatments of CCl(4) induced fibrosis was quantified. Hepatic fibrosis was induced in male Wistar rats by CCl(4) administration (150 microL/100 gm rat weight, oral) twice a week for 10 weeks. In preventive treatment daily doses of L. flexuosum n-hexane extract (200 mg/kg, p.o) were administered for 10 weeks. In curative treatment L. flexuosum extract (200 mg/kg, p.o) was given for 2 weeks after the establishment of fibrosis for 10 weeks. Treatment with the n-hexane extract (200 mg/kg) reduced the mRNA levels of proinflammatory cytokines, growth factors and other signaling molecules, which are involved in hepatic fibrosis. The expression levels of tumor necrosis factor-alpha, interleukin-1beta, transforming growth factor-beta1, procollagen-I, procollagen-III and tissue inhibitor of metalloproteinase-1 were elevated during carbon tetrachloride administration and reduced the levels to normal by the treatment with the extract treatment. The increased levels of matrix metalloproteinase-13 in extract treated rats were indicative of the protective action of L. flexuosum n-hexane extract. In conclusion, L. flexuosum n-hexane extract functions as a potent fibrosuppresant, effectively reverses carbon tetrachloride-induced hepatic fibrosis in curative treatment and reduces the effects of ongoing toxic liver injury in preventive treatment by promoting extracellular matrix degradation in the fibrotic liver.     

Potential hepatoprotective activity of ononitol monohydrate isolated from Cassia tora L. on carbon tetrachloride induced hepatotoxicity in wistar rats

Ononitol monohydrate, structurally similar to glycoside was isolated from Cassia tora L. leaves. Fifty Male rats were divided into five groups. Group I served as normal control. Group II, III and IV rats were induced hepatotoxicity by CCl₄ administering single dose of CCl₄ on 8th day only. Group III was treated with ononitol monohydrate (20 mg/kg body weight) and group IV was treated with reference drug silymarin (20 mg/kg body weight) both dissolved in corn oil and administering for 8 days. Ononitol monohydrate with corn oil alone was given for 8 days (group V). At the end of the experimental period all the animals were sacrificed and analyzed for biochemical parameters to assess the effect of ononitol monohydrate treatment in CCl₄ induced hepatotoxicity. In in vivo study, ononitol monohydrate decreased the levels of serum transaminase, lipid peroxidation and TNF-α but increased the levels of antioxidant and hepatic glutathione enzyme activities. Compared with reference drug silymarin ononitol monohydrate possessesed high hepatoprotective activity. Histopathological results also suggested the hepatoprotective activity of ononitol monohydrate with no adverse effect. Hence we conclude that ononitol monohydrate is a potent hepatoprotective agent.     

吡非尼酮对四氯化碳诱导的小鼠肝纤维化的影响

目的：研究吡非尼酮对四氯化碳诱导的小鼠肝纤维化的影响。方法：选用8周健康雄性SPF级ICR小鼠40只,随机分为4组（n=10）：肝纤维化模型组（CCL₄组）、吡非尼酮低剂量组（PFD-L组）、吡非尼酮高剂量组（PFD-H组）及正常对照组。CCL₄肝纤维化模型采用0.4 ml/只10%的CCL₄大豆油溶液进行小鼠腹腔注射制备,低剂量、高剂量吡非尼酮干预组在造模后采用120 mg/kg、240 mg/kg吡非尼酮（PFD）灌胃,正常对照组采用与前三组等量的生理盐水腹腔注射的方法。全自动生化仪检测血清中谷丙转氨酶（ALT）、谷草转氨酶（AST）、碱性磷酸酶（ALP）;取肝脏组织HE染色观察组织的病理学变化;荧光定量PCR法测定肝脏中α-平滑肌肌动蛋白（α-SMA）相关基因的表达,酶联反应法检测肝纤维化指标透明质酸（HA）、层粘连蛋白（LN）、Ⅳ型胶原（IV-C）。结果：与正常组相比,CCL₄组小鼠肝小叶结构明显破坏,胶原纤维沉积明显,可见假小叶形成;血清ALT、AST、ALP均显著升高（P<0.05）;血清肝纤维化指标HA、LN、IV-C均显著升高（P<0.05）;α-SMA基因的表达水平也显著升高（P<0.05）。PFD-L组和PFD-H组小鼠AST、ALT、ALP相较于CCL₄组明显降低,PFD-L组和PFD-H组小鼠血清肝纤维化指标HA、LN、IV-C相较于CCL₄组明显降低,α-SMA基因的表达也受到抑制（P<0.05）。病理学观察发现,PFD-L组小鼠的肝纤维化程度减轻,胶原纤维减少,仅见少量假小叶;PFD-H组小鼠细胞排列恢复,小叶结构轻度紊乱,未见明显假小叶,恢复效果比PFD-L组好。结论：吡非尼酮对于肝纤维化有一定的治疗作用,其可成为肝纤维化早期干预的新药物。