ABSTRACT
AIM: Carvedilol is a nonselective beta-blocker used to reduce portal hypertension. This study investigated the effects and potential mechanisms of carvedilol in angiotensin II- (Ang II-) induced hepatic stellate cell (HSC) proliferation and contraction. METHODS: The effect of carvedilol on HSC proliferation was measured by Cell Counting Kit-8 (CCK-8). Cell cycle progression and apoptosis in HSCs were determined by flow cytometry. A collagen gel assay was used to confirm HSC contraction. The extent of liver fibrosis in mice was evaluated by hematoxylin-eosin (H&E) and Sirius Red staining. Western blot analyses were performed to detect the expression of collagen I, collagen III, α-smooth muscle actin (α-SMA), Ang II type I receptor (AT1R), RhoA, Rho-kinase 2 (ROCK2), and others. RESULTS: The results showed that carvedilol inhibited HSC proliferation and arrested the cell cycle at the G0/G1 phase in a dose-dependent manner. Carvedilol also modulated Bcl-2 family proteins and increased apoptosis in Ang II-treated HSCs. Furthermore, carvedilol inhibited HSC contraction induced by Ang II, an effect that was associated with AT1R-mediated RhoA/ROCK2 pathway interference. In addition, carvedilol reduced α-SMA expression and collagen deposition and attenuated liver fibrosis in carbon tetrachloride (CCl4)-treated mice. The in vivo data further confirmed that carvedilol inhibited the expression of angiotensin-converting enzyme (ACE), AT1R, RhoA, and ROCK2. CONCLUSIONS: The results indicated that carvedilol dose-dependently inhibited Ang II-induced HSC proliferation by impeding cell cycle progression, thus alleviating hepatic fibrosis. Furthermore, carvedilol could inhibit Ang II-induced HSC contraction by interfering with the AT1R-mediated RhoA/ROCK2 pathway.
Subject(s)
Angiotensin II/pharmacology , Carvedilol/pharmacology , Cell Proliferation/drug effects , Hepatic Stellate Cells/enzymology , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/metabolism , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Hepatic Stellate Cells/pathology , Humans , Liver Cirrhosis/enzymology , Liver Cirrhosis/pathology , Male , Mice , Receptor, Angiotensin, Type 1/metabolismABSTRACT
In this study, syringic acid-loaded TPGS liposome (SA-TPGS-Ls) was successfully prepared to improve oral bioavailability of syringic acid (SA). SA is a natural and notable antioxidant activity compound with its limited bioavailability ascribable to its poor aqueous solubility and fast elimination. Recently, TPGS has become a perfect molecular biomaterial in developing several carrier systems with sustained, controlled, and targeted the drug delivery. SA-TPGS-Ls was prepared via thin-film dispersion method and characterized in terms of particle size, stability, morphology, and encapsulation efficiency (EE). The results showed that SA-TPGS-Ls had regular spherical-shaped nanoparticles with EE of 96.48 ± 0.76%. The pharmacokinetic studies demonstrated a delayed MRT and prolonged t1/2, while relative oral bioavailability increased by 2.8 times. Tissue distribution showed that SA-TPGS-Ls maintained liver drug concentration while delayed elimination was also observed in the kidney. In CCl4-induced hepatotoxicity study, the activities of hepatic T-AOC, GSH-Px, CAT, GSH, and SOD were greatly elevated, while serum biological markers ALT, AST, and AKP were reduced after treatment of mice with SA-TPGS-Ls. Histopathological studies confirmed that SA-TPGS-Ls could remarkably improve the status of hepatic tissues. Collectively, SA-TPGS-Ls significantly improved the drug encapsulation efficiency, stability coupled with bioavailability of SA, hence increasing in vivo antioxidant activity of the drug.
Subject(s)
Antioxidants/administration & dosage , Antioxidants/pharmacokinetics , Gallic Acid/analogs & derivatives , Liposomes , Vitamin E/administration & dosage , Vitamin E/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/metabolism , Gallic Acid/administration & dosage , Gallic Acid/pharmacokinetics , Half-Life , Male , Mice , Nanoparticles , Particle Size , Polyethylene Glycols , Rats , Rats, Sprague-Dawley , Solubility , Tissue DistributionABSTRACT
Mitochondrion-localized retinol dehydrogenase 13 (Rdh13) is a short-chain dehydrogenase/reductase involved in vitamin A metabolism in both humans and mice. We previously generated Rdh13 knockout mice and showed that Rdh13 deficiency causes severe acute retinal light damage. In this study, considering that Rdh13 is highly expressed in mouse liver, we further evaluated the potential effect of Rdh13 on liver injury induced by carbon tetrachloride (CCl4). Although Rdh13 deficiency showed no significant effect on liver histology and physiological functions under regular culture, the Rdh13-/- mice displayed an attenuated response to CCl4-induced liver injury. Their livers also exhibited less histological changes and contained lower levels of liver-related metabolism enzymes compared with the livers of wild-type (WT) mice. Furthermore, the Rdh13-/- mice had Rdh13 deficiency and thus their liver cells were protected from apoptosis, and the quantity of their proliferative cells became lower than that in WTafter CCl4 exposure. The ablation of Rdh13 gene decreased the expression levels of thyroid hormone-inducible nuclear protein 14 (Spot14) and cytochrome P450 (Cyp2e1) in the liver, especially after CCl4 treatment for 48 h. These data suggested that the alleviated liver damage induced by CCl4 in Rdh13-/- mice was caused by Cyp2e1 enzymes, which promoted reductive CCl4 metabolism by altering the status of thyroxine metabolism. This result further implicated Rdh13 as a potential drug target in preventing chemically induced liver injury.
Subject(s)
Alcohol Oxidoreductases/deficiency , Chemical and Drug Induced Liver Injury/enzymology , Cytochrome P-450 CYP2E1/metabolism , Liver/drug effects , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Alcohol Oxidoreductases/genetics , Animals , Carbon Tetrachloride Poisoning/enzymology , Chemical and Drug Induced Liver Injury/pathology , Female , Immunohistochemistry , Liver/enzymology , Liver/pathology , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Acute hepatic failure involves in excessive oxidative stress and inflammatory responses, leading to a high mortality due to lacking effective therapy. Resolvin D1 (RvD1), an endogenous lipid mediator derived from polyunsaturated fatty acids, has been shown anti-inflammatory and anti-oxidative actions, however, whether RvD1 has protective effects on hepatic failure remains elusive. In this study, the roles and molecular mechanisms of RvD1 were explored in carbon tetrachloride (CCl4)-induced acute liver injury. Our results showed that RvD1 protected mice against CCl4-induced hepatic damage, as evaluated by reduced aminotransferase activities and malondialdehyde content, elevated glutathione and superoxide dismutase activities, and alleviated hepatic pathological damage. Moreover, RvD1 significantly attenuated serum tumor necrosis factor-α and interleukin-6 levels as well as hepatic myeloperoxidase activity, whereas enhanced serum IL-10 level in CCl4-administered mice. Further, RvD1 markedly up-regulated the expression and activity of heme oxygenase-1 (HO-1). However, inhibition of HO-1 activity reversed the protective effects of RvD1 on CCl4-induced liver injury. These results suggest that RvD1 could effectively prevent CCl4-induced liver injury by inhibition of oxidative stress and inflammation, and the underlying mechanism may be related to up-regulation of HO-1.
Subject(s)
Carbon Tetrachloride Poisoning , Docosahexaenoic Acids/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Heme Oxygenase-1/biosynthesis , Liver Failure, Acute , Membrane Proteins/biosynthesis , Up-Regulation/drug effects , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Carbon Tetrachloride Poisoning/prevention & control , Cytokines/biosynthesis , Liver Failure, Acute/enzymology , Liver Failure, Acute/pathology , Liver Failure, Acute/prevention & control , Male , Mice , Mice, Inbred BALB C , Oxidative Stress/drug effectsABSTRACT
It has been shown that phosphatidylcholine (PC) extracted from egg yolk possesses a variety of biological activities, such as anti-inflammatory and anti-oxidant effects, and prevents oxidative stress. The aim of this study was to evaluate the hepatoprotective effects of PC against carbon tetrachloride (CCl4), which is a well-known hepatotoxicant that causes extensive oxidative liver damage, and to investigate the mechanisms involved in this protective effect. Mice were treated with PC (0.1 ml, 10 or 100 mg/kg, orally) once daily for 5 consecutive days prior to CCl4 administration (0.1 ml, 20 mg/kg, intraperitoneally). The experimental data show that pretreatment with PC significantly prevented increases of serum aspartate transaminase, alanine transaminase, and alkaline phosphatase, and reduced reactive oxygen species levels. Histopathological evaluation of the liver also revealed that PC effectively ameliorated CCl4-induced hepatic injury and fibrosis. In addition, PC significantly counteracted the increase in glutathione levels and glutathione-S-transferase activity induced by CCl4. Concordantly, PC significantly decreased CCl4-induced upregulation of apoptotic proteins in the liver. These results suggest that PC exerts its protective effects against CCl4-induced hepatotoxicity via its activities as an anti-oxidant and free radical scavenger.
Subject(s)
Carbon Tetrachloride Poisoning/prevention & control , Chemical and Drug Induced Liver Injury/prevention & control , Phosphatidylcholines/pharmacology , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Animals , Aspartate Aminotransferases/blood , Carbon Tetrachloride Poisoning/enzymology , Chemical and Drug Induced Liver Injury/enzymology , Male , Mice , Mice, Inbred ICRABSTRACT
GGPPS catalyses the expression of GGPP, a key protein in the mevalonate metabolic pathway. HMG-CoA reductase inhibitor statins can induce liver injury by inhibiting GGPP. However, the function of GGPPS in liver injury has not yet been revealed. In this study, we found that GGPPS increased in liver injury and that GGPPS deletion augmented liver injury and fibrosis. GGPPS inhibition induced hepatocyte apoptosis, inflammation and TGF-ß1 secretion, which activated hepatic stellate cells. Our findings imply that GGPPS deletion induces hepatocyte apoptosis, which makes the liver vulnerable to hepatotoxicity.
Subject(s)
Carbon Tetrachloride Poisoning/enzymology , Farnesyltranstransferase/metabolism , Hepatocytes/enzymology , Liver Cirrhosis/enzymology , Liver/enzymology , Animals , Carbon Tetrachloride Poisoning/genetics , Carbon Tetrachloride Poisoning/pathology , Farnesyltranstransferase/genetics , Gene Deletion , Hepatocytes/pathology , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Mice , Mice, Knockout , Polyisoprenyl Phosphates/biosynthesis , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
Objectives. The purpose of the study is to evaluate the hepatoprotective effect of rutin in carbon tetrachloride- (CCl4-) induced liver injuries in rat model. Methods. Forty male Wistar albino rats were divided into four groups. Group I was the control group and received dimethyl sulphoxide (DMSO) and olive oil. Group II received rutin. Groups III was treated with CCl4. Group IV was administered rutin after 48 h of CCl4 treatment. Liver enzymes level, lipid profile, lipid peroxidation, and hydrogen peroxide were measured. The genes expression levels were monitored by real time RT-PCR and western blot techniques. Results. CCl4 group showed significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), thiobarbituric acid reactive substances (TBAR), hydrogen peroxide (H2O2), and lipid profile and a significant decrease in glutathione peroxidase (GPx), glutathione S transferase (GST), catalase (CAT), paraoxonase-1 (PON-1), paraoxonase-3 (PON-3), peroxisome proliferator activated receptor delta (PPAR-δ), and ATP-binding cassette transporter 1 (ABAC1) genes expression levels. Interestingly, rutin supplementation completely reversed the biochemical and gene expression levels induced by CCl4 to control values. Conclusion. CCl4 administration causes aberration of genes expression levels in oxidative stress pathway resulting in DNA damage and hepatotoxicity. Rutin causes hepatoprotective effect through enhancing the antioxidant genes.
Subject(s)
Aryldialkylphosphatase/genetics , Carbon Tetrachloride/toxicity , Chemical and Drug Induced Liver Injury/metabolism , Oxidative Stress/genetics , Animals , Aryldialkylphosphatase/biosynthesis , Aryldialkylphosphatase/metabolism , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/genetics , Carbon Tetrachloride Poisoning/metabolism , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/genetics , Disease Models, Animal , Gene Expression/drug effects , Isoenzymes , Lipid Metabolism/drug effects , Liver/drug effects , Male , Random Allocation , Rats , Rats, Wistar , Rutin/pharmacologyABSTRACT
UNLABELLED: Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40-50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2(-/-) mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4 ) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2(-/-) mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic interleukin (IL)-6 expression but surprisingly lower levels of steatosis and serum alanine aminotransferase (ALT). Higher IL-6 levels were also detected in ethanol-treated precision-cut liver slices from ALDH2(-/-) mice and in Kupffer cells isolated from ethanol-fed ALDH2(-/-) mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the lipopolysaccharide (LPS)-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2(-/-) mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2(-/-) mice. Finally, ethanol-fed ALDH2(-/-) mice were more prone to CCl4 -induced liver inflammation and fibrosis than ethanol-fed wild-type mice. CONCLUSION: ALDH2(-/-) mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis by way of MAA-mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, by way of acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption.
Subject(s)
Aldehyde Dehydrogenase/genetics , Fatty Liver, Alcoholic/enzymology , Hepatitis/enzymology , Liver Cirrhosis/enzymology , Acetaldehyde/metabolism , Aldehyde Dehydrogenase/blood , Aldehyde Dehydrogenase/deficiency , Aldehyde Dehydrogenase 1 Family , Aldehyde Dehydrogenase, Mitochondrial , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/genetics , Central Nervous System Depressants/pharmacokinetics , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/genetics , Cytochrome P-450 CYP2E1/metabolism , Ethanol/pharmacokinetics , Fatty Liver, Alcoholic/genetics , Female , Hepatitis/genetics , Isoenzymes/metabolism , Kupffer Cells/enzymology , Liver Cirrhosis/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress/drug effects , Oxidative Stress/physiology , Retinal Dehydrogenase/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
The results of the study of activity of digestive proteases (pepsin, trypsin, chymotrypsin) in homogenates of stomach, pancreas and duodenum in experimental animals have been presented. Rats were exposed to intoxication with carbon tetrachloride (subcutaneous administration of a 50% oil solution of CCl4 in the dose of 0.5 ml per 100 g body weight) for three days and then they were given analysed oils (black nut, walnut and flax oil) intragastrically by gavage at a dose of 0.2 ml per day within 23 days. Pepsin level in gastric mucosa homogenates and chymotrypsin activity in pancreatic homogenates were determined by method of N.P. Pyatnitskiy based on on the ability of enzymes to coagulate dairy-acetate mixture, respectively, at 25 degrees C and 35 degrees C. Trypsin activity in homogenates of pancreatic was determined by method of Erlanger - Shaternikova colorimetrically. It has been established that intoxication with CCl4 decreased the synthesis of proteolytic enzymes of the stomach (by 51%) and pancreas (by 70-78%). Injections of analysed vegetable oils to animals contributed to the normalization of proteolytic enzymes synthesis. The conclusion that there are prospects of using the analysed vegetable oils containing large quantity of polyunsaturated fatty acids (omega-3 and omega-6) for the correction of detected biochemical abnormalities has been done.
Subject(s)
Carbon Tetrachloride Poisoning/drug therapy , Chymotrypsin/metabolism , Digestive System/drug effects , Pepsin A/metabolism , Plant Oils/therapeutic use , Trypsin/metabolism , Administration, Oral , Animals , Carbon Tetrachloride Poisoning/enzymology , Chymotrypsin/biosynthesis , Digestive System/enzymology , Disease Models, Animal , Gastric Mucosa/drug effects , Gastric Mucosa/enzymology , Male , Pancreas/drug effects , Pancreas/enzymology , Pepsin A/biosynthesis , Plant Oils/administration & dosage , Rats , Trypsin/biosynthesisABSTRACT
Liver fibrosis is characterized by the deposition and increased turnover of extracellular matrix. This process is controlled by matrix metalloproteinases (MMPs), whose expression and activity dynamically change during injury progression. MMP-19, one of the most widely expressed MMPs, is highly expressed in liver; however, its contribution to liver pathology is unknown. The aim of this study was to elucidate the role of MMP-19 during the development and resolution of fibrosis by comparing the response of MMP-19-deficient (MMP19KO) and wild-type mice upon chronic liver CCl(4)-intoxication. We show that loss of MMP-19 was beneficial during liver injury, as plasma ALT and AST levels, deposition of fibrillar collagen, and phosphorylation of SMAD3, a TGF-ß1 signaling molecule, were all significantly lower in MMP19KO mice. The ameliorated course of the disease in MMP19KO mice likely results from a slower rate of basement membrane destruction and ECM remodeling as the knockout mice maintained significantly higher levels of type IV collagen and lower expression and activation of MMP-2 after 4 weeks of CCl(4)-intoxication. Hastened liver regeneration in MMP19KO mice was associated with slightly higher IGF-1 mRNA expression, slightly increased phosphorylation of Akt kinase, decreased TGF-ß1 mRNA levels and significantly reduced SMAD3 phosphorylation. In addition, primary hepatocytes isolated from MMP19KO mice showed impaired responsiveness towards TGF-ß1 stimulation, resulting in lower expression of Snail1 and vimentin mRNA. Thus, MMP-19-deficiency improves the development of hepatic fibrosis through the diminished replacement of physiological extracellular matrix with fibrotic deposits in the beginning of the injury, leading to subsequent changes in TGF-ß and IGF-1 signaling pathways.
Subject(s)
Liver Cirrhosis/enzymology , Matrix Metalloproteinases, Secreted/genetics , Animals , Carbon Tetrachloride Poisoning/enzymology , Cell Proliferation , Chronic Disease , Disease Models, Animal , Disease Progression , Hepatocytes/cytology , Insulin-Like Growth Factor I/metabolism , Liver Cirrhosis/chemically induced , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Transforming Growth Factor beta/metabolismABSTRACT
AIM: To investigate the mechanisms underlying the protective effects of quercetin-rutinoside (rutin) and its aglycone quercetin against CCl(4)-induced liver damage in mice. METHODS: BALB/cN mice were intraperitoneally administered rutin (10, 50, and 150 mg/kg) or quercetin (50 mg/kg) once daily for 5 consecutive days, followed by the intraperitoneal injection of CCl(4) in olive oil (2 mL/kg, 10% v/v). The animals were sacrificed 24 h later. Blood was collected for measuring the activities of ALT and AST, and the liver was excised for assessing Cu/Zn superoxide dismutase (SOD) activity, GSH and protein concentrations and also for immunoblotting. Portions of the livers were used for histology and immunohistochemistry. RESULTS: Pretreatment with rutin and, to a lesser extent, with quercetin significantly reduced the activity of plasma transaminases and improved the histological signs of acute liver damage in CCl(4)-intoxicated mice. Quercetin prevented the decrease in Cu/Zn SOD activity in CCl(4)-intoxicated mice more potently than rutin. However, it was less effective in the suppression of nitrotyrosine formation. Quercetin and, to a lesser extent, rutin attenuated the inflammation in the liver by down-regulating the CCl(4)-induced activation of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α) and cyclooxygenase (COX-2). The expression of inducible nitric oxide synthase (iNOS) was more potently suppressed by rutin than by quercetin. Treatment with both flavonoids significantly increased NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO-1) expression in injured livers, although quercetin was less effective than rutin at an equivalent dose. Quercetin more potently suppressed the expression of transforming growth factor-ß1 (TGF-ß1) than rutin. CONCLUSION: Rutin exerts stronger protection against nitrosative stress and hepatocellular damage but has weaker antioxidant and anti-inflammatory activities and antifibrotic potential than quercetin, which may be attributed to the presence of a rutinoside moiety in position 3 of the C ring.
Subject(s)
Carbon Tetrachloride Poisoning/complications , Chemical and Drug Induced Liver Injury/prevention & control , Free Radical Scavengers/therapeutic use , Liver/drug effects , Quercetin/therapeutic use , Rutin/therapeutic use , Animals , Biphenyl Compounds/chemistry , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Dose-Response Relationship, Drug , Free Radical Scavengers/administration & dosage , Free Radical Scavengers/chemistry , Immunohistochemistry , Injections, Intraperitoneal , Liver/enzymology , Liver/pathology , Liver Function Tests , Male , Mice , Mice, Inbred BALB C , Molecular Structure , Nitric Oxide/chemistry , Oxidative Stress/drug effects , Picrates/chemistry , Quercetin/administration & dosage , Quercetin/chemistry , Rutin/administration & dosage , Rutin/chemistryABSTRACT
The present study was undertaken to evaluate the effect of the aqueous extract of Podophyllum hexandrum against free radical-mediated damage and also explore its anticancer activity. The extract exhibited significant activity in scavenging 1, 1-diphenyl-2-picryl-hydrazyl radicals, (â¢)OH radical-mediated DNA damage, and lipid peroxide production in rat liver microsomes. The extract was also tested for its reducing abilities. The activity of liver marker enzymes and antioxidant defense enzymes in rat liver homogenate was assessed in control and carbon tetrachloride (CCl(4))-treated animals. It was observed that CCl(4)-induced changes viz., increases in the activities of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, a decrease in reduced glutathione as well as decreases in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. All these parameters showed reversal when pretreated with aqueous extract of P. hexandrum. Podophylotoxin and etoposide are the two known anticancer agents derived from P. hexandrum and interestingly the aqueous extract of P. hexandrum showed a typical DNA ladder formation in HL-60 cells confirming its role as an inducer of apoptosis. The results obtained suggest that the plant extract exhibits inhibition of and free radical production and lipid peroxidation, increase in antioxidant enzyme activities, revealing its antioxidant properties, and is also able to show potent anticancer activity as depicted by its ability to cause fragmentation of DNA.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carbon Tetrachloride Poisoning/drug therapy , Drugs, Chinese Herbal/pharmacology , Free Radical Scavengers/pharmacology , Alanine Transaminase/metabolism , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Aspartate Aminotransferases/metabolism , Berberidaceae , Biphenyl Compounds/metabolism , Carbon Tetrachloride Poisoning/enzymology , Catalase/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/enzymology , DNA Damage/drug effects , Drugs, Chinese Herbal/therapeutic use , Free Radicals/metabolism , Glutathione Peroxidase/metabolism , Glutathione Reductase/metabolism , Glutathione Transferase/metabolism , HL-60 Cells , Humans , Lipid Peroxidation/drug effects , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Picrates/metabolism , Rats , Rats, Wistar , Superoxide Dismutase/metabolismABSTRACT
The objective was to study the in-vivo hepatoprotective effect of aerial parts of Haloxylon salicornicum (Moq.) Bunge (Family: Chenopodiaceae) in order to validate its traditional use in hepatobiliary disorders, by native people of Cholistan desert, Pakistan. Aerial parts (ethanolic extract) of Haloxylon salicornicum (HS), (500 and 750 mg/kg/day, p.o. for 7 days) were evaluated on CCl(4) intoxicated rabbits (0.75 ml/kg., s/c.) by serum biochemical parameters and liver histopathological observations. Silymarin (100 mg/kg/day, p.o. for 7 days) was used as a standard hepatoprotective drug. CCl(4) intoxicated group had elevated levels of SGOT, SGPT and ALP significantly but TB level was normal as compared to control group. HS extract (both doses of 500 and 750 mg/kg) showed hepatoprotective effect by significant restoration of SGOT, SGPT, ALP and TB levels as compared to CCl4 control. 500 mg/kg doses of HS extract produced more significant results as compared to 750 mg/kg doses and Silymarin. Histopathological examination of liver tissues further substantiated these findings. Therefore, outcome of the present study validate the traditional claims on hepatoprotective effects of Haloxylon salicornicum (aerial parts).
Subject(s)
Chenopodiaceae/chemistry , Liver/drug effects , Phytotherapy/methods , Plant Extracts/therapeutic use , Protective Agents/therapeutic use , Animals , Carbon Tetrachloride Poisoning/drug therapy , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Ethanol/chemistry , Female , Liver/enzymology , Liver/pathology , Liver Function Tests/methods , Male , Pakistan , Plant Components, Aerial/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Protective Agents/chemistry , Protective Agents/pharmacology , Rabbits , Silymarin/pharmacologyABSTRACT
A comparison of analysis in evaluating the hepatoprotective action of ethanolic extract of M. azedarach (MAE) and P. longum (PLE) with their combination biherbal extract (BHE) against carbon tetrachloride (CCl4) induced hepatic damage is reported in albino rats. There was a marked elevation of serum marker enzyme levels in CCl4 treated rats, which were restored towards normalization in the drug (MAE and/or PLE:50 mg/kg body weight po, once daily for 14 days) treated animals. The biochemical parameters like total protein, total bilirubin, total cholesterol, triglycerides, and urea were also restored towards normal levels. The combined BHE showed more significant reduction of the enzymes than MAE or PLE against CCl4 induced hepatotoxicity. The results strongly indicate that BHE has more potent hepatoprotective action than MAE or PLE individually against CCl4 induced hepatic damage in rats. Among these extracts, BHE showed similar hepatoprotective action to silymarin, which was the positive control in this study.
Subject(s)
Carbon Tetrachloride Poisoning/drug therapy , Liver/drug effects , Melia azedarach , Phytotherapy , Piper , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Drug Synergism , Drug Therapy, Combination , Free Radical Scavengers/administration & dosage , Liver/enzymology , Liver/pathology , Male , Plant Extracts/administration & dosage , Plants, Medicinal , Rats , Rats, WistarABSTRACT
Wu-Ling-Shen, a lesser study medicinal fungus (Xylaria nigripes), is popular for treating insomnia and trauma in the traditional Chinese medicine. In this study, our aim was to examine the protective effects of X. nigripes extract on carbon tetrachloride (CCl(4))-induced acute hepatotoxicity in mice, and its content of polyphenolic constituents. The X. nigripes aqueous extract (XN-T) at 500 and 1000 mg/kg was given intragastrically to mice for 9 consecutive days, followed by receiving subcutaneously 2 mL/kg of 40% CCl(4) in olive oil to induce hepatotoxicity. Blood and liver tissues were collected for biochemical and histological analyses. Analysis of polyphenolic compounds was performed by RP-HPLC. Results showed that XN-T at 500 and 1000 mg/kg significantly prevented the elevation of serum glutamate oxalate transaminase (sGOT), serum glutamate pyruvate transaminase (sGPT), and liver thiobarbituric acid reactive substances (TBARS) levels, and caused an increase in the liver superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) concentrations, as well as serum total antioxidant activity in the CCl(4)-induced hepatotoxicated mice. It was as good as silymarin (100 mg/kg) in normalization of oxidative stress parameters. Furthermore, liver histological observation also showed an obvious amelioration in the liver conditions in XN-T-treated animals. XN-T was found to contain a higher level of epicatechin, catechin, and p-coumaric acid. These results conclude that XN exerts effective protection against CCl(4)-induced liver injury in mice, and its mechanism of action could be through the effects of antioxidants on reducing the oxidative stress.
Subject(s)
Carbon Tetrachloride Poisoning/drug therapy , Chemical and Drug Induced Liver Injury/drug therapy , Plant Extracts/pharmacology , Xylariales/chemistry , Alanine Transaminase/blood , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Aspartate Aminotransferases/blood , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/metabolism , Catalase/metabolism , Catechin/pharmacology , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Coumaric Acids/pharmacology , Glutathione Peroxidase/metabolism , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver/pathology , Male , Medicine, Chinese Traditional/methods , Mice , Mice, Inbred ICR , Oxidative Stress/drug effects , Plant Extracts/isolation & purification , Propionates , Silymarin/pharmacology , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
BACKGROUND: Andrographis paniculata is a health food used extensively in Southeast Asia, India and China and contains the pharmacologically important phytochemical andrographolide. Although andrographolide has antihepatotoxic activity, its bioavailability from A. paniculata is restricted by its rapid clearance and high plasma protein binding. The aim of this study was to formulate a herbosome of andrographolide with a naturally occurring phospholipid in order to enhance the bioavailability and hepatoprotective activity of andrographolide in rats. RESULTS: Andrographolide herbosome equivalent to 25 and 50 mg kg(-1) andrographolide significantly protected the liver of rats, restoring hepatic enzyme activities with respect to carbon tetrachloride-treated animals (P < 0.05 and P < 0.01 respectively). The rat plasma concentration of andrographolide obtained from the complex equivalent to 25 mg kg(-1) andrographolide (C(max) = 9.64 microg mL(-1)) was higher than that obtained from 25 mg kg(-1) andrographolide (C(max) = 6.79 microg mL(-1)), and the complex maintained its effective plasma concentration for a longer period of time. CONCLUSION: The results proved that the andrographolide complex produced by this method has better bioavailability and hence improved hepatoprotective activity compared with andrographolide at the same dose. Andrographolide complexation is therefore helpful in solving the problem of rapid clearance and low elimination half-life associated with andrographolide from A. paniculata.
Subject(s)
Andrographis/chemistry , Anti-Inflammatory Agents/administration & dosage , Carbon Tetrachloride Poisoning/drug therapy , Chemical and Drug Induced Liver Injury/drug therapy , Diterpenes/administration & dosage , Liver/drug effects , Plant Extracts/administration & dosage , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Biological Availability , Carbon Tetrachloride , Carbon Tetrachloride Poisoning/blood , Carbon Tetrachloride Poisoning/enzymology , Chemical and Drug Induced Liver Injury/blood , Chemical and Drug Induced Liver Injury/enzymology , Diterpenes/pharmacology , Diterpenes/therapeutic use , Liposomes/pharmacology , Liposomes/therapeutic use , Liver/enzymology , Male , Phospholipids , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Rats , Rats, WistarABSTRACT
This study evaluated the antioxidant properties of Ficus glomerata fruits using in vitro and in vivo assay. In order to find in vitro antioxidant properties, extract/fractions from F. glomerata were studied for TPC, AOA, RP, DPPH*, O2*-, *OH scavenging activities and LPO. Among all the extract/fractions, FEF has shown potent antioxidant activity and was also found effective in protecting oxidative DNA damage. The in vivo evaluation of oxidative stress (LPO) and antioxidant defenses (concentration of GSH, as well as CAT and SOD activities) were measured in CCl4 induced toxic rats. FEF was found to inhibit the toxicity as seen from the decreased LPO and increased GSH, SOD and CAT levels. FEF has higher phenolic content and showed the presence of gallic, chlorogenic and ellagic acid. Based on these results, it is concluded that F. glomerata protects tissues from oxidative stress and these effects are probably related to the antioxidant properties.
Subject(s)
DNA Breaks, Single-Stranded/drug effects , Ficus/chemistry , Free Radical Scavengers/pharmacology , Lipid Peroxidation/drug effects , Oxidative Stress/drug effects , Plant Extracts/pharmacology , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/prevention & control , Food Analysis , Free Radical Scavengers/analysis , Fruit/chemistry , Glutathione/metabolism , In Vitro Techniques , Oxidoreductases/metabolism , Phenols/analysis , Rats , Rats, Sprague-DawleyABSTRACT
The possible modulatory effect of methanolic extract of Vernonia amygdalina (MEVA), a plant widely consumed in the tropics and used locally in the treatment of fever, jaundice, stomach disorders and diabetes on the toxicity of CCl(4), was investigated in male rats. Oral administration of CCl(4) at a dose of 1.2g/kg body weight 3 times a week for 3 weeks significantly induced marked hepatic injury as revealed by increased activity of the serum enzymes ALT, AST, SALP and gamma-GT. Methanolic extract of V. amygdalina administered 5 times a week for 2 weeks before CCl(4) treatment at 250 and 500 mg/kg doses of the extract ameliorated the increase in the activities of these enzymes. Likewise the methanolic extract of V. amygdalina reduced the CCl(4)-induced increase in the concentrations of cholesterol, triglyceride and phospholipid by 37.8%, 30.6% and 8.5%, respectively, and a reduction in the cholesterol/phospholipids ratio. These parameters were however increased at 750 mg/kg extract pretreatment. CCl(4)-induced lipid peroxidation was likewise attenuated by 57.2% at 500 mg/kg dose of the methanolic extract of V. amygdalina. Similarly, administration of the extract increased the activities of the antioxidant enzymes: superoxide dismutase, glutathione S-transferase and reduced glutathione concentration significantly at 500 mg/kg (P<0.05) and catalase activity at 500-1000 mg/kg doses. These results suggest that methanolic extract of V. amygdalina leaves posseses protective effect against CCl(4)-induced hepatotoxicity by the antioxidant mechanism of action.
Subject(s)
Antioxidants/pharmacology , Carbon Tetrachloride Poisoning/prevention & control , Liver/drug effects , Phytotherapy/methods , Plant Extracts/pharmacology , Vernonia , Animals , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Lipid Peroxidation/drug effects , Liver/pathology , Male , Oxidative Stress/drug effects , Plant Leaves/chemistry , Rats , Rats, Wistar , Vernonia/chemistryABSTRACT
A herbal preparation "Compound Codyceps-TCM-700C (CC-700C)" was tested for hepatoprotective effect against the carbon tetrachloride induced liver damages in Sprague-Dawley rat model for a period of 6-weeks. Two dosage levels of CC-700C, respectively 286.2 mg/kg-bw (L-TCM) and 2862 mg/kg-bw (H-TCM), and a positive control Silymarin (Sigma) were used to compare their therapeutic effect. Both CC-700C's and Silymarin showed nontoxic in nature, as evidenced by body weight gain, organ weights and appearance including liver, spleen, and kidney. The activities of aspartate aminotransferase (AST) and alanine-aminotransferase (ALT) were more effectively suppressed by CC-700C than Silymarin. In addition, all levels of serum bilirubin, serum albumin, triglyceride (TG), total cholesterol (TC), platelet count (PLT), and prothrombin time (PT) except TG were shown effectively restored to normal values by CC-700C and Silymarin. Moreover, although levels of glutathione (GSH), glutathione reductase (GSH-Rd), and superoxide dismutase (SOD) were equally maintained by these three preparations, glutathione peroxidase (GSH-Px) was suppressed only by H-TCM, and SOD only by Silymarin. In contrast, the activity of catalase efficiently recovered to control level on administration of CC-700C, being far better than Silymarin. Finally the liver collagen content, an indication of fibrosis, was also significantly suppressed by CC-700C, better effect was by L-TCM, but both levels were superior to Silymarin. Conclusively, the herbal preparation "Compound Cordyceps TCM-700C" is a potent hepatoprotective preparation. For therapeutic use, a dosage of 286.2 mg/kg-bw would be sufficiently effective.
Subject(s)
Carbon Tetrachloride Poisoning/prevention & control , Drugs, Chinese Herbal/therapeutic use , Protective Agents/therapeutic use , Silymarin/therapeutic use , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/metabolism , Body Weight/drug effects , Carbon Tetrachloride Poisoning/enzymology , Carbon Tetrachloride Poisoning/pathology , Drug Evaluation, Preclinical , Drugs, Chinese Herbal/pharmacology , Liver/pathology , Male , Organ Size/drug effects , Phytotherapy , Rats , Rats, Sprague-DawleyABSTRACT
Encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure and the mechanisms underlying hepatic encephalopathy are still not fully known. Considering that creatine kinase (CK) play a crucial role in brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of hepatic encephalopathy, we evaluated CK activity in hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex of rats submitted to acute administration of carbon tetrachloride or acetaminophen. The effects of the administration of antioxidants, N-acetylcysteine (NAC) plus deferoxamine (DFX) in association, and taurine, were also evaluated. Our findings demonstrated that carbon tetrachloride inhibited CK activity in cerebellum; acetaminophen inhibited the enzyme in cerebellum and hippocampus. CK activity was not affected in other brain areas. The administration of NAC plus DFX reversed the inhibition of CK activity caused by carbon tetrachloride in cerebellum and by acetaminophen in cerebellum and hippocampus. On the other hand, taurine was not able to reverse the inhibition in CK activity. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after hepatic failure may be involved in the pathogenesis of hepatic encephalopathy.