Protective effect of (S)-bakuchiol from Psoralea corylifolia on rat liver injury in vitro and in vivo

The aim of this study was to investigate the protective effect of (S)-bakuchiol isolated from the seed of Psoralea corylifolia, on liver injury. Primary rat hepatocyte intoxication was induced by tert-butyl hydroperoxide (tBH), carbon tetrachloride (CCl4) or D-galactosamine (D-GalN). Liver injury was induced by either CCl4 or D-GalN in rats. In vitro, the cellular leakage of lactate dehydrogenase and cell viability following treatment with hepatotoxicants were significantly improved by bakuchiol treatment at a concentration range of 25-200 microM for tBH, 100-200 microM for CCl4 and 100-200 microM for D-GalN-induced hepatocyte injury. Treatment with bakuchiol significantly inhibited lipid peroxidation and intracellular glutathione depletion in hepatocytes induced by tBH, CCl4 or D-GalN. Treatment with bakuchiol (25 or 50 mg/kg, p.o.) at 1, 24 and 48 h after subcutaneous injection of CCl4 significantly reduced the levels of aspartate transaminase and alanine transaminase in serum. Histological observations revealed that fatty acid changes, hepatocyte necrosis and inflammatory cell infiltration in CCl4-injured liver was improved when treated with bakuchiol. Bakuchiol treatment (25 and 50 mg/kg, p.o.) also significantly reduced the levels of aspartate transaminase and alanine transaminase in an acute liver injury model induced by D-GalN. From these results, bakuchiol has a protective effect against tBH, CCl4 or D-GalN-induced hepatotoxicity in vitro or in vivo.     

白芍总甙对小鼠四氯化碳肝损伤模型的保护作用

白芍总甙(TGPs 40或80mg/kg·d~(-1)×3d,ip)可明显对抗四氯化碳(ig or sc)引起的小鼠血浆或血清谷丙转氨酶和血浆乳酸脱氢酶升高,但对谷草转氨酶的升高无明显影响。TGPs(40mg/kg·d~(-1)×3d,ip)对四氯化碳所致的肝病理组织改变有一定保护作用。提示TGPs可能具有保肝作用。     

Protective effects of Indigofera tinctoria L. against D-Galactosamine and carbon tetrachloride challenge on 'in situ' perfused rat liver

The effect of pre-treatment with Indigofera tinctoria (IT) extract against the toxicity of D-Galactosamine (D-GalN) and carbon tetrachloride (CCl4) during 'in situ' perfusion of the liver for 2 hr was studied in rats. Release of LDH and levels of urea in the liver effluent perfusate, was studied and the rate of bile flow was monitored. Perfusion with D-Galactosamine (5 mM) or carbon tetrachloride (0.5 mM) resulted in increased LDH leakage, decreased urea levels in the liver effluent and reduction in bile flow. IT pretreatment (500 mg/kg body weight) in vivo ameliorated D-GalN and CCl4 induced adverse changes towards near normalcy and thereby indicates its hepatoprotective effects in rats.     

Anti-hepatitic activity of ginesenoside ro1

Ginsenoside Ro, an oleanane-type saponin has been screened for activity in experimental models of acute and chronic hepatitis. Ginsenoside Ro (50 and 200 mg/kg, P.O.) inhibited the increase of serum glutamic oxaloacetic transaminase (s-GOT) and serum glutamic pyruvic transaminase (s-GPT) levels in D-galactosamine (GalN)- and carbon tetrachloride (CCl (4))-induced acute hepatitic rats. Ginsenoside Ro inhibited the increase of connective tissue in the liver of CCl (4)-induced chronic hepatitic rats. Ginsenoside Ro showed a stronger inhibitory effect on the GalN-induced acute hepatitic model than those of the aglycone of ginsenoside Ro, oleanolic acid, or glycyrrhizic acid and its aglycone, glycyrrhetinic acid.     

Short-term dietary restriction modulates liver lipid peroxidation in carbon tetrachloride-intoxicated rats

We investigated whether dietary restriction (DR) can protect the liver against the acute toxicity of carbon tetrachloride (CCl4). Adult female Wistar rats received a quantum of diet representing 75 and 50 percent of the food intake of control rats fed ad libitum (25% and 50% daily regimen, respectively) for 30 days. A single dose of CCl4 (3 mL kg(-1) b.w.) was administered subcutaneously at the end of the feeding period. Lipid peroxidation, as thiobarbituric acid reactive substance, conjugated dienes, lipid hydroperoxides and the hepatic markers alanine transaminase, aspartic transaminase, and alkaline phosphatase were significantly decreased in food-restricted rats. The enzymic antioxidants superoxide dismutase, catalase, glutathione peroxidase and the non-enzymic antioxidant glutathione were significantly increased in both groups. The magnitude of liver damage after CCl4 treatment was lower in food-restricted animals than in ad libitum-fed animals. The results suggest that dietary restriction increases the resistance of the liver and protects against oxidative insult produced by an acute dose of CCl4.     

Pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5 ,6,5',6'dimethylenedioxybiphenyl-2-carboxylic acid-2'-carboxylate monohydrochloride in rats with CCl4-induced acute hepatic failure

The pharmacokinetics and hepatoprotective effects of 2-methylaminoethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybip henyl-2-carboxylic acid-2'-carboxylate monohydrochloride (DDB-S) have been investigated in rats with CCl4-induced acute hepatic failure. To study the pharmacokinetics of DDB-S, rats were divided into a control group and a CCl4-intoxicated group. DDB-S 50 mg kg(-1) was administered by intravenous bolus injection to both groups of rats. In the CCl4-intoxicated rats the plasma concentrations of DDB-S were significantly higher, the area under the plasma concentration-time curve from time zero to time infinity was significantly greater (6-46 vs 3.34 mg min mL(-1)), and the total body (7.74 vs 15.0 mL min(-1) kg(-1)), renal (2.55 vs 5.10 mL min(-1) kg(-1)), nonrenal (5.07 vs 9.65 mL min(-1) kg(-1)), and biliary (1.48 vs 2.69 mL min(-1) kg(-1)) clearances were significantly slower compared with the control rats. This could be due to decreased hepatic cytochrome P450 activity and impaired kidney function induced by CCl4. To study the hepatoprotective effects of DDB-S, rats were divided into three groups, control rats and CCl4-intoxicated rats with or without DDB-S pretreatment (50 mg kg(-1) i.p.). The effects of DDB-S pretreatment on CCl4-induced liver injury were considerable; the serum levels of alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly lower by 54.3, 44.6 and 67.2%, respectively, compared with the CCl4-intoxicated-only group. In an in-vitro study, rat hepatocytes were exposed to fresh medium containing 10 mM CCl4 and various concentrations of DDB-S (10 or 100 microg mL(-1)). The levels of alanine transaminase and aspartate transaminase in the medium were measured as an indicator of hepatocyte injury. DDB-S dose-dependently decreased the levels of alanine transaminase and aspartate transaminase compared with CCl4-intoxication only. These results indicate that DDB-S has hepatoprotective activity.     

Hepatoprotective effect of Himoliv, a polyherbal formulation in rats

The effect of Himoliv (HV) was evaluated in carbon tetrachloride or paracetamol induced hepatotoxicity in rats. Liver necrosis was produced by administering single dose of either carbon tetrachloride (CCl4, 1 ml/kg, 50% v/v with olive oil, s.c.) or paracetamol (PC, 1 g/kg, p.o.). The liver damage was evidenced by elevated levels of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and serum alkaline phosphatase (ALP) and hepatic thiobarbituric acid reacting substances (TBARS) and superoxide dismutase (SOD). HV pretreatment (0.5 and 1.0 ml/kg, p.o.) significantly (P < 0.001) reduced CCl4 or PC-induced elevations of the levels of SGOT, SGPT, ALP and TBARS, while the reduced concentration of SOD due to CCl4 or PC was reversed. Silymarin (25 mg/ kg, p.o.), a known hepatoprotective drug showed similar results.     

Protective effect of glycoprotein isolated from Ulmus davidiana Nakai on carbon tetrachloride-induced mouse liver injury

This study was carried out to evaluate the hepatoprotective activity of glycoprotein isolated from the stems of Ulmus davidiana Nakai (UDN), which has been used as an anti-inflammatory agent in folk medicine. We evaluated lipid peroxidation in glucose/glucose oxidase (G/GO)-induced BNL CL.2 cells and measured thiobarbituric acid reactive substances (TBARS), lactate dehydrogenase (LDH), nitric oxide (NO), antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)), activity of cytotoxic-related signals (hepatic cytochrome c, nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1)) and levels of plasma lipids (triglyceride (TG) and total cholesterol (TC)) in carbon tetrachloride (CCl(4,) 1.0 mL kg(-1))-induced A/J mouse. The results in G/GO-induced BNL CL.2 cells showed that UDN glycoprotein had a dose-dependent inhibitory effect on lipid peroxidation. The results in carbon tetrachloride (CCl(4,) 1.0 mL kg(-1))-induced A/J mouse indicated that treatment with UDN glycoprotein (40 mg kg -1) lowered LDH activity and TBARS formation, and increased NO production and antioxidant enzymes activity, compared with control. Also, our finding from CCl(4)-treated mice after pretreatment with UDN glycoprotein demonstrated that the activity of cytotoxic-related signals decreased but the levels of plasma lipids increased, compared with CCl(4) treatment alone. Here, we speculate that UDN glycoprotein has a protective character to CCl(4)-induced mouse liver injury.     

Dietary diacetylene falcarindiol induces phase 2 drug-metabolizing enzymes and blocks carbon tetrachloride-induced hepatotoxicity in mice through suppression of lipid peroxidation

Falcarindiol is a diacetylenic natural product containing unique carbon-carbon triple bonds. Mice were orally administrated falcarindiol (100 mg/kg), and drug-metabolizing and antioxidant enzymes were monitored in several tissues of mice. Treatment with falcarindiol was found to increase glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 activities in liver, small intestine, kidney, and lung. No changes were observed in cytochrome P450 (CYP) 1A known to activate procarcinogens. Western blot analysis revealed that various GST subunits including GSTA4, which plays an important role in the detoxification of alkenals produced from lipid peroxides, were induced in liver, small intestine, and kidney of falcarindiol-treated mice. Additionally, we investigated the protective effects of falcarindiol against hepatotoxicity induced by carbon tetrachloride (CCl(4)) and the mechanism of its hepatoprotective effect. Pretreatment with falcarindiol prior to the administration of CCl(4) significantly suppressed both an increase in serum alanine transaminase/aspartate transaminase (ALT/AST) activity and an increase in hepatic thiobarbituric acid reactive substance levels without affecting CCl(4)-mediated degradation of CYP2E1. Formation of hexanoyl-lysine and 4-hydroxy-2(E)-nonenal-histidine adducts, lipid peroxidation biomarkers, in homogenates from the liver of CCl(4)-treated mice was decreased in the group of mice pretreated with falcarindiol. These results suggest that the protective effects of falcarindiol against CCl(4) toxicity might, in part, be explained by anti-lipid peroxidation activity associated with the induction of the GSTs including GSTA4.     

Effect of 'Arogyavardhini' against carbon tetrachloride induced hepatic damage in albino rats

'Arogyavardhini'-an indigenous formulation was evaluated for its hepatoprotective activity in rats, using two models of carbon tetrachloride (CCl4) hepatic damage, one simulating vital hepatitis and the other simulating fatty change. The protective effect was assessed from serum aspartate transaminase (AST) and alkaline phosphatase levels and from histopathological changes in liver. The results revealed that 'Arogyavardhini' (5 mg/100g, PO daily) was effective in minimizing the changes in serum levels of AST and alkaline phosphatase induced by CCI. The protective effect was also evident on histopathological examination.     

Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats

Astaxanthin is one of many carotenoids present in marine animals, vegetables and fruits. Since carotenoids are known to have antioxidant properties, we tested to determine if astaxanthin could have protective effects in the CCl4-treated rat liver by activating the antioxidant system. Astaxanthin blocked the increase of glutamate-oxalacetate transaminase (GOT) and glutamate-pyruvate transaminase (GTP) activity and thiobarbituric acid reactive substances (TBARS) in response to carbon tetrachloride (CCl4), while causing an increase in glutathione (GSH) levels and superoxide dismutase (SOD) activities in the CCl4-treated rat liver. These results suggest that astaxanthin protects liver damage induced by CCl4 by inhibiting lipid peroxidation and stimulating the cellular antioxidant system.     

Targeting of liposomal flavonoid to liver in combating hepatocellular oxidative damage

The efficacy of mannosylated liposome formulations with Quercetin (QC, a flavonoid antioxidant isolated from indigenous origin) has been tested in vivo against carbon tetrachloride(CCl 4 )-induced liver oxidative damage in rats. Single subcutaneous injection of CCl 4 (40% v/v in olive oil; 1 ml/kg) induces the generation of toxic oxygen radicals and results in hepatocellular damage. The increased serum enzyme levels (glutamate pyruvate transaminase, alkaline phosphatase) and hepatocellular conjugated diene levels by CCl 4 induction were significantly lowered due to pretreatment with mannosylated liposomal QC (MLQ) (0.5 ml liposomal suspension containing 0.27 mg QC), whereas the same amount of free QC was found to be ineffective. In addition, the effectiveness of MLQ on CCl 4 -induced acute liver damage also was evaluated by tissue histopathological examination. Damage produced by CCl 4 in liver reverted to normal with pretreatment of MLQ.     

Meloxicam modulates oxidative stress status, inhibits prostaglandin E2, and abrogates apoptosis in carbon tetrachloride-induced rat hepatic injury

The current study aimed at investigating the potential hepatoprotective property and mechanism of meloxicam (MEL) against carbon tetrachloride (CCl(4))-induced hepatocellular damage in rats. Subcutaneous administration of CCl(4) (2 mL/kg, twice/week for 8 weeks) induced hepatocellular damage substantiated by hematoxylin and eosin staining and significant elevation in serum aspartate transaminase, alanine transaminase, and total bilirubin. In addition, CCL(4) treatment led to elevation in liver contents of lipid peroxidation marker (malondialdehyde), prostaglandin E2, active caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and reduction in the activities of superoxide dismutase, catalase, glutathione-S-transferase, and reduced glutathione in the liver tissue. Prior oral treatment with MEL (5 mg/kg, twice/week) retained the normal liver histology and significantly restored all of these parameters close to normal values. These results demonstrated the hepatoprotective utility of MEL against the CCl(4)-induced liver injury which might ascribe to its antioxidant, free radical scavenging, antiapoptotic and anti-inflammatory effects.     

Free radical scavenging and hepatoprotective actions of the medicinal herb, Crassocephalum crepidioides from the Okinawa Islands

Free radical scavenging and protective actions against chemically induced hepatotoxicity of Crassocephalum crepidioides were investigated. A water extract of C. crepidioides strongly scavenged superoxide anion, hydroxyl radical and also stable radical 1,1-diphenyl-2-picrylhydrazyl. Galactosamine (GalN, 400 mg/kg) and lipopolysaccharide (LPS, 0.5 microg/kg) induced hepatotoxicity of rats as seen by an elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and of lipid peroxidation in liver homogenates was significantly depressed when the herbal extract was given intraperitoneally 1 and 15 h before GalN and LPS treatment. Similarly, carbon tetrachloride (CCl4) induced liver injury as evidenced by an increase in AST and ALT activities in serum was also inhibited by the extract pretreatment. Isochlorogenic acids, quercetin and kaempferol glycosides were identified as active components of C. crepidioides with strong free radical scavenging action. These results demonstrate that C. crepidioides is a potent antioxidant and protective against GalN plus LPS- or CCl4-induced hepatotoxicity.     

Antioxidant and hepatoprotective actions of the medicinal herb Artemisia campestris from the Okinawa Islands

The antioxidant action of Artemisia campestris was examined in vitro and in vivo. A water extract of A. campestris showed a strong scavenging action of 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl and superoxide anion radicals. When the extract was given intraperitoneally to mice prior to carbon tetrachloride (CCl4) treatment, CCl4-induced liver toxicity, as seen by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities, was significantly reduced. Depression of the elevation of serum enzyme levels after CCl4-treatment was also observed by oral administration of the extract. In that case, CCl4-derived lipid peroxidation in the liver was decreased by the extract treatment. These results suggest that the extract of A. campestris scavenges radicals formed by CCl4 treatment resulting in protection against CCl4-induced liver toxicity.     

Metabolic Activation of PCBs to Carcinogens in Vivo - A Review

Our earlier studies have shown that extracts derived from potato peel (PPE) are rich in polyphenols and possess strong antioxidant activity both in vitro and in vivo. The objective of the present study was to investigate its potential to offer protection against acute liver injury in rats. Rats pretreated with PPE (oral, 100mg/kgb.w./day for 7 days) were administered a single oral dose carbon tetrachloride (CCl(4), 3ml/kg b.w., 1:1 in groundnut oil) and sacrificed 8h of post-treatment. Hepatic damage was assessed by employing biochemical parameters (transaminase enzyme levels in plasma and liver [AST-aspartate transaminase; ALT-alanine transaminase, LDH-lactate dehydrogenase]). Further, markers of hepatic oxidative damage were measured in terms of malondialdehyde (MDA), enzymic antioxidants (CAT, SOT, GST, GPX) and GSH (reduced glutathione) levels. In addition, the CCl(4)-induced pathological changes in liver were evaluated by histopathological studies. Our results demonstrated that pretreatment of rats with PPE significantly prevented the increased activities of AST and ALT in serum, prevented the elevation of hepatic MDA formation as well as protected the liver from GSH depletion. PPE pretreatment also restored CCl(4)-induced altered antioxidant enzyme activities to control levels. The protective effect of PPE was further evident through the decreased histological alterations in liver. Our findings provide evidences to demonstrate that PPE pretreatment significantly offsets CCl(4)-induced liver injury in rats, which may be attributable to its strong antioxidant propensity.     

Glycoprotein isolated from Ulmus davidiana NAKAI protects against carbon tetrachloride-induced liver injury in the mouse

Ulmus davidiana NAKAI (UDN) has traditionally been used for healing of inflammatory diseases. This study was carried out to investigate the hepatoprotective effect of the glycoprotein isolated from UDN in carbon tetrachloride (CCl4)-induced liver injury. We evaluated the activities of alanine aminotransferase (ALT), lactate dehydrogenase (LDH), thiobarbituric acid-reactive substances (TBARS), and antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)] activities in CCl4-treated mice. When mice were treated with CCl4 in the absence of UDN glycoprotein, the activities of ALT, LDH, and TBARS were increased, while the antioxidant enzymes activities were decreased. However, when the mice were treated with CCl4 in the presence of UDN glycoprotein, the activities of ALT, LDH, and TBARS were significantly reduced and SOD, CAT, and GPx activities were remarkably increased. In addition, UDN glycoprotein increased the nitric oxide production and decreased the nuclear factor-kappa B and activator protein-1 activation in CCl4-treated mice. We also investigated the protective effects of UDN glycoprotein in glucose/glucose oxidase (G/GO)-induced cytotoxicity in primary cultured mouse hepatocytes. UDN glycoprotein markedly inhibited the cell death induced by G/GO. These results suggest that UDN glycoprotein protects against CCl4-induced liver injury in the mouse.     

2,4二-羟基二苯甲酮对CCl_4所致小鼠急性肝损伤的保护作用

目的:探索2,4-二羟基二苯甲酮对CCl4所致急性肝损伤的保护作用。方法:采用CCl4致小鼠急性肝损伤模型,染毒24 h后,测定血清中丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天冬氨酸氨基转移酶(aspartate aminotransferase,AST)和乳酸脱氢酶(lactate dehydrogenase,LDH)的活性;留取肝脏组织,常规石蜡包埋切片,HE染色,光镜观察肝脏组织病理变化;制备肝匀浆,测定肝中还原型谷胱甘肽(reducedglutathione hormone,GSH)、氧化型谷胱甘肽(oxidized glutathione,GSSG)和丙二醛(malondialdehyde,MDA)的含量。结果:与对照组比较,模型组小鼠血清中ALT,AST和LDH活性升高,肝组织中GSH/GSSG比值下降,MDA含量增加,肝小叶中心出现大量坏死细胞;2,4-二羟基二苯甲酮各剂量组血清ALT,AST和LDH水平明显降低,使肝组织中GSH/GSSG比值升高,MDA含量下降,肝小叶中心变性坏死细胞减少,坏死区域缩小。结论:2,4-二羟基二苯甲酮对CCl4引起的小鼠急性...     

Effect of black tea on lipid peroxide and glutathione levels in female rats

The effects of black tea (Camellia sinensis L.) on lipid peroxidation and glutathione (GSH) levels in carbon tetrachloride (CCl4)-treated female Wistar rats were examined. Two control groups and one treatment group were tested. The control groups were fed with a standard diet, while the black tea group was fed the standard diet plus 6% by weight dried black tea leaves. At the end of 2 months, a single dose of CCl4 (1 ml/kg, i.p.) in olive oil was administered to rats in one of the control groups and the black tea group. They were sacrificed after 2 hours. Rats in the other control group were administered olive oil in a similar fashion. Measurements were made of lipid peroxide levels in liver and plasma, glutathione levels in liver, and alanine transaminase (ALT) and aspartate transaminase (AST) activities in plasma. Liver lipid peroxide levels, plasma ALT and AST activities were significantly decreased in the black tea group compared with the CCl4-treated control group, while plasma lipid peroxide levels were not. These results are parallel to those previously found with Wistar male rats. Glutathione levels, however, were not significantly affected, in contrast to the data relating to male rats, either after CCl4 or black tea treatments. The results of our study add to the findings that black tea attenuates CCl4-induced hepatic injury but also indicates the susceptibility of glutathione levels to endocrinological effects.     

Hepatocurative and antioxidant profile of HP-1, a polyherbal phytomedicine

HP-1 a herbal formulation comprising of Phyllanthus niruri and extracts of Terminalia belerica, Terminalia chebula, Phyllanthus emblica and Tinospora cordifolia has been evaluated for hepatoprotective activity against carbon tetrachloride (CCl4) induced toxicity. Results show that HP-1 reversed the leakage of lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) and prevented the depletion of glutathione (GSH) levels in a primary monolayer culture of rat hepatocytes (in vitro). HP-1 attenuated the serum toxicity as manifested in elevated levels of transaminases (glutamate oxaloacetate transaminase (GOT), and GPT) The antioxidative enzymes in liver (catalase and superoxide dismutase (SOD)) were restored to normal values after the oral administration of HP-1. HP-1 suppressed the formation of the superoxide anion radical and reduced CCl4 mediated lipid peroxidation (LPO). Silymarin and antioxidants (ascorbic acid, beta-carotene and alpha-tocopherol) were used for comparison. The present study showed that HP-1 is a potential hepatoprotective formulation with an additional attribute of being anti-peroxidative.