Changes In Hepatic Tissue Research Articles

Liver protection provided by ulinastatin in rats with liver fibrosis

Objective To evaluate liver protection provided by ulinastatin in rats with liver fibrosis. Methods Fifty pathogen-free male Sprague-Dawley rats, weighing 180-220 g, aged 6-8 weeks, were randomly divided into 5 groups(n=10 each)using a random number table: control group(group C), carbon tetrachloride(CCl4)group, low-dose ulinastatin group(group L), medium-dose ulinastatin group(group M), and high-dose ulinastatin group(group H). Hepatic fibrosis was produced by subcutaneous injection of 50% CCl4 peanut oil solution two times a week for 8 weeks.After hepatic fibrosis was produced(at 9th week), ulinastatin 2.5×104, 5.0×104 and 10.0×104 U/kg were injected via the caudal vein in L, M and H groups, respectively, once a day for 7 days.Blood samples were collected after 24 h of fast on 8th day for determination of serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)concentrations by ELISA.The rats were then sacrificed and livers were removed for microscopic examination of pathologic changes with light microscope.The expression of interleukin-1β(IL-1β), IL-2, IL-6, IL-8, Toll-like receptor 4(TLR4), and tumor necrosis factor-alpha(TNF-α)mRNA and protein was detected by RT-PCR and Western blot. Results Compared with group C, the serum AST and ALT concentrations were significantly increased in CCl4, L and M groups, the expression of IL-1β, IL-2, IL-6, IL-8, TLR4 and TNF-α mRNA and protein was up-regulated in CCl4 group, and no significant change was found in the parameters mentioned above in group H. Compared with group CCl4, the serum AST and ALT concentrations were significantly decreased in M and H groups, no significant change was found in the serum AST and ALT concentrations in group L, and the expression of IL-1β, IL-2, IL-6, IL-8, TLR4 and TNF-α mRNA and protein was down-regulated in group H. The pathologic changes of hepatic tissues were attenuated in M and H groups as compared with group CCl4.The pathologic changes of hepatic tissues were almost recovered to the normal structure in group H. Conclusion Ulinastatin can produce liver protection in rats with liver fibrosis. Key words: Trypsin inhibitors; Liver fibrosis

Influence of vitamin D3on ultramicrostructural changes of hepatic tissue in rats with experimental hepatic injury

Influence of vitamin D₃on ultramicrostructural changes of hepatic tissue in rats with experimental hepatic injury

Coagulation‐driven platelet activation reduces cholestatic liver injury and fibrosis in mice

The coagulation cascade has been shown to participate in chronic liver injury and fibrosis, but the contribution of various thrombin targets, such as protease activated receptors (PARs) and fibrin(ogen), has not been fully described. Emerging evidence suggests that in some experimental settings of chronic liver injury, platelets can promote liver repair and inhibit liver fibrosis. However, the precise mechanisms linking coagulation and platelet function to hepatic tissue changes following injury remain poorly defined. To determine the role of PAR-4, a key thrombin receptor on mouse platelets, and fibrin(ogen) engagement of the platelet αII b β3 integrin (αIIb β3 ) in a model of cholestatic liver injury and fibrosis. Biliary and hepatic injury was characterized following 4 week administration of the bile duct toxicant α-naphthylisothiocyanate (ANIT) (0.025%) in PAR-4-deficient mice, mice expressing a mutant form of fibrin(ogen) incapable of binding integrin αII b β3 (Fibγ(Δ5) ), and wild-type mice. Elevated plasma thrombin-antithrombin and serotonin levels, hepatic fibrin deposition, and platelet accumulation in liver accompanied hepatocellular injury and fibrosis in ANIT-treated wild-type mice. PAR-4 deficiency reduced plasma serotonin levels, increased serum bile acid concentration, and exacerbated ANIT-induced hepatocellular injury and peribiliary fibrosis. Compared with PAR-4-deficient mice, ANIT-treated Fibγ(Δ5) mice displayed more widespread hepatocellular necrosis accompanied by marked inflammation, robust fibroblast activation, and extensive liver fibrosis. Collectively, the results indicate that PAR-4 and fibrin-αII b β3 integrin engagement, pathways coupling coagulation to platelet activation, each exert hepatoprotective effects during chronic cholestasis.

Evaluation of acute toxicity of genabilic acid (menbutone 10%) in rabbits

A complete investigation of the acute toxicity of a choleretic compound, menbutone, was performed in rabbits, including lethal dose for 50% of rabbits determination, clinical signs observation and in vivo and post-mortem examinations. Haematological, biochemical and histopathological changes resulting from intramuscular injection of menbutone were also investigated at dose 400 mg/kg body weight. Acute toxicity of menbutone at dose of 400 mg/kg BW induced interstitial myocarditis and multifocal necrosis, whereas serum creatine phosphokinase, creatinine phosphokinase-MB isoenzyme and aspartate aminotransferase activities were significantly increased. Elevation of serum alanine aminotransferase and alkaline phosphatase activities and total bilirubin level associated with lowered albumin content was consistent with histopathological changes of hepatic tissues; hepatic necrosis and fatty infiltration were pronounced indicators of injuries. Renal tubular necrosis and interstitial nephritis were also observed in intoxicated rabbits. Menbutone also induced variations in some haematological parameters. We concluded that acute toxicity of menbutone in rabbits occurred at accidental high doses, as the lethal dose was about 50 fold over the recommended therapeutic dose for other animals. Cardiac muscle, liver and kidneys are the main target organs for menbutone toxicity. Menbutone is not recommended for use in rabbits suffering from any cardiacand hepatic disorders, especially in overdosing situations.

Wireless monitoring of liver hemodynamics in vivo.

Liver transplants have their highest technical failure rate in the first two weeks following surgery. Currently, there are limited devices for continuous, real-time monitoring of the graft. In this work, a three wavelengths system is presented that combines near-infrared spectroscopy and photoplethysmography with a processing method that can uniquely measure and separate the venous and arterial oxygen contributions. This strategy allows for the quantification of tissue oxygen consumption used to study hepatic metabolic activity and to relate it to tissue stress. The sensor is battery operated and communicates wirelessly with a data acquisition computer which provides the possibility of implantation provided sufficient miniaturization. In two in vivo porcine studies, the sensor tracked perfusion changes in hepatic tissue during vascular occlusions with a root mean square error (RMSE) of 0.135 mL/min/g of tissue. We show the possibility of using the pulsatile wave to measure the arterial oxygen saturation similar to pulse oximetry. The signal is also used to extract the venous oxygen saturation from the direct current (DC) levels. Arterial and venous oxygen saturation changes were measured with an RMSE of 2.19% and 1.39% respectively when no vascular occlusions were induced. This error increased to 2.82% and 3.83% when vascular occlusions were induced during hypoxia. These errors are similar to the resolution of a commercial oximetry catheter used as a reference. This work is the first realization of a wireless optical sensor for continuous monitoring of hepatic hemodynamics.

The protective mechanism of schisandrin A in d-galactosamine-induced acute liver injury through activation of autophagy

Context: The principal bioactive lignan of Schisandra chinensis fructus, commonly used for traditional Chinese medicine, is schisandrin A. Schisandrin A has been widely reported as being very effective for the treatment of liver disease. However, the mechanisms of its protective effects in liver remain unclear.Objective: To explore the hepatoprotective mechanisms of schisandrin A.Materials and methods: d-Galactosamine (d-GalN)-induced liver injury in mice was used as a model. Schisandrin A was examined for its protective mechanisms using hematoxylin–eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), western blotting and real-time PCR (RT-PCR).Results: Aspartate amino-transferase (AST) and alanine transaminase (ALT) levels in the schisandrin A group were significantly decreased (p < 0.01) compared with those in the d-GalN-treated group. HE results showed that the pathological changes in hepatic tissue seen in the d-GalN-treated were reduced in the schisandrin A/d-GalN-treated group, with the morphological characteristics being close to those of the control (untreated) group. Western blotting results showed that schisandrin A can activate autophagy flux and inhibit progression of apoptosis. The immune function of the schisandrin A-pretreated group was assayed by flow cytometry. It was found that the mechanism may involve activated autophagy flux, inhibited apoptosis, and improved immunity in response to liver damage.Conclusion: Our results show that the hepatoprotective mechanisms of schisandrin A may include activation of autophagy flux and inhibition of apoptosis. These results provide pharmacological evidence supporting its future clinical application.

Generating normal reference values for examinations of the liver using Acoustic Radiation Force Impulse Virtual Touch Tissue Quantification (ARFI-VTTQ) elastography and comparison with Acoustic Radiation Force Impulse Virtual Touch Imaging and Quantification (ARFI-VTIQ) elastography: First results of a pilot study

Purpose: The work-up of diseases affecting the hepatic parenchyma often requires liver biopsy. Acoustic Radiation Force Impulse Virtual Touch Tissue Quantification (ARFI-VTTQ) elastography permits quantitative measurement of tissue elasticity. The new elastography method using Acoustic Radiation Force Impulse Virual Touch Imaging and Quantification (ARFI-VTIQ) provides the additional capability for visual representation of tissue elasticity. Reliable use of these methods for assessing pathological changes in hepatic tissue requires establishment of normal reference ranges for findings returned by ARFI-VTTQ and ARFI-VTIQ in the healthy liver.

ATTENUATING EFFECT OF UVARIA NARUM (DUNAL) WALL. LEAVES ON THIOACETAMIDE INDUCED HEPATIC INJURY

The objective of the present study was to evaluate the he patoprotective potential of U varia narum leaf extract at two different doses (200 and 400 mg / kg b.w.) against thioacetamide induced Hepatic injury . Thioacetamide at dose of 100 mg / kg induced l iver toxicity , which was ass essed by quantifying the serum h epatic biomarkers like SGPT, SGOT, ALP, total and direct bilirubin , serum biochemical parameters like albumin, total protein, cholesterol, triglycerides, glucose and urea and oxidative parameters like glutathione, catalas e, s uperoxide dismutase and lipid peroxidation in hepatic tissue. Further study was supported by histopathology studies. The results revealed that Silymarin (100 mg / kg b.w.) and Uvaria narum leaf extract at both doses prevented the elevation of serum hepatic biomarkers and also altered serum biochemical parameters dose de pendently. Whereas decrease in l ip id peroxidation and elevation in catalase, g lutathione and superoxide dismutase was observed in Silymarin and extract treated a nimals. Histopathological changes in hepatic tissue also supported the dose dep endent protective effect of Uvaria narum leaf extract . The results were comparable to reference standard Silymarin.

Anti-inflammatory and anti-oxidative effects of corilagin in a rat model of acute cholestasis

BackgroundNowadays, treatments for cholestasis remain largely nonspecific and often ineffective. Recent studies showed that inflammatory injuries and oxidative stress occur in the liver with cholestasis. In this study, we would use corilagin to treat the animal model of acute cholestasis in order to define the activity to interfere with inflammation-related and oxidative stress pathway in cholestatic pathogenesis.MethodsRats were administrated with alpha-naphthylisothiocyanate to establish model of cholestasis and divided into corilagin, ursodeoxycholic acid, dexamethasone, model and normal groups with treatment of related agent. At 24h, 48h and 72h time points after administration, living condition, serum markers of liver damage, pathological changes of hepatic tissue, nuclear factor (NF)-kappaB, myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) were examined and observed.ResultsCompared to model group, corilagin had remarkable effect on living condition, pathological manifestation of liver tissue, total bilirubin, direct bilirubin, (P<0.01), but no effect on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). With corilagin intervention, levels of MPO, MDA and translocation of NF-κB were notably decreased, and levels of SOD and NO were markedly increased (P<0.05 or P<0.01).ConclusionsIt is shown that corilagin is a potential component to relieve cholestasis through inflammation-related and oxidation-related pathway.

Pharmacological Evaluation of Gatifloxacin in Chemically Induced Hepatocarcinogenesis: A New Tool for Hepatocellularcarcinoma Treatment

Abstract Introduction: Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. In this study Gatifloxacin an antimicrobial drug which has been banned due to some serious adverse effects evaluated for the other pharmacological activities. Data from the present investigation suggest that Gatifloxacin suppresses the tumors and decrease the biochemical markers which are elevated in HCC. Objective: This study is an attempt to evaluate the potential chemopreventive influence of Gatifloxacin in hepatocarcinogenic rats. Hepatocarcinogeneis was induced by a single intraperitoneal injection of diethylnitrosamine (DENA) in phosphate buffer (200 mg/kg). Results and conclusion: Experimental animals exposed to DENA caused a significant alteration in serum indices of liver enzymes glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), acid phophatase (AP), total cholesterol (TC), triglycerides (TG) and high density lipoproteins (HDL), total proteins (TPR) and blood glucose level in tested animals. Results also revealed severe histological and immunohistochemical changes in hepatic tissues. These included disorganized hepatic parenchyma, appearance of pseudoacinar and trabecular arrays of hepatocytes and alterations in alpha fetoprotein (AFP) levels. Administration of Gatifloxacin relatively improved the biochemical parameters to values approximating those of the normal controls. SGOT, SGPT, ALP, level was significantly decreased (p<0.001, p<0.01, p<0.001 respectively) in therapeutic control while TPR, ALB level was significantly increased (p<0.001, p<0.001 respectively) and delayed the initiation of carcinogenesis. Rats treated with Gatifloxacin only showed altered levels of liver enzymes, arrhythmic symptoms and abdominal fat deposition. In conclusion, DENA significantly changes the biological enzymatic activities in serum and the integrity of hepatic tissues. Hence, Gatifloxacin proved to possess the potential for the treatment of hepatocellularcarcinomas in rats exposed to DENA.

Effects of pretreatment with etomidate on the contents of alanine transaminase, aspartate transaminase, malondialdehyde and superoxide dismutase in dogs with hepatic ischemia/reperfusion injury

Objective To investigate the effects of pretreatment with etomidate on hepatic injury and the contents of alanine transaminase (ALT),aspartate transaminase (AST) in plasma and malondialdehyde (MDA),superoxide dismutase (SOD) in hepatic tissue during hepatic ischemia/repeffusion injury(HI/RI) in dogs.Methods 20 adult healthy hybrid canines were randomly divided into 4 groups(n=5): Sham group(group S),ischemia/reperfusion group (group I/R),low dosage of Etomidate group(group El,0.6 mg/kg) and high dosage of Etomidate group (group E2,1.5 mg/kg).Canines in all groups were injected Etomidate or NS except group S.The porta hepatis of canines in group S was separated without ligation.The model of HI/RI were established by ligating porta hepatis.The biochemical indicators of ALT and AST in plasma were measured at 4 time points: before blocked,30 min after ischemis,l,2 h after repeffusion.The contents of MDA and activity of SOD in hepatic tissue were also measured.Hepatic tissue was observed with light microscope after operation.Results Compared with group S,group I/R,group E1 and group E2 increased the level of ALT and AST in plasma (P＜0.01).Compared with group I/R,the level of ALT,AST in group E1 and group E2 decreased significantly(P＜0.01),moreover,group E2 decreased more obviously.Reperfusion 2 h: ALT: (2911±89) U/L(group I/R),(863±95) U/L(group E2); AST: (2722±103) U/L(group I/R),(1056±115) U/L(group E2)].Compared with group S,group I/R,group E1 and group E2 increased the level of MDA and group I/R decreased the expression level of SOD,group E1 and group E2 increased the level of SOD in hepatic tissue (P＜0.01).Compared with group I/R,group E1 and group E2 decreased significantly the level of MDA and increased significantly the level of SOD in hepatic tissue (P＜0.01),and group E2 more obviously[MDA:(21.70±-2.01) nmol·mg-1·prot-1 (group I/R),(12.69±1.02) nmol·mg-1·prot-1 (group E2),SOD: (191±12) nmol·mg-1 ·prot-1(group I/R),(634±26) nmol· mg-1·prot-1 (group E2)].Light microscope showed evidently that the pathological changes of hepatic tissue were more slight in group E1 and group E2 than that in group I/R,and group E2 more slight than group El.Conclusions Pretreatment with etomidate has protective effects on hepatic ischemia reperfusion injury,and it is related to the control lipid peroxidation of etomidate.And the protective effects of high dosage of etomidate (1.5 mg/kg) was more reliable. Key words: Etomidate ; Pretreatment ; Hepatic ischemia/reperfusion ; Alanine transaminase ; Aspartate transaminase; Malondialdehyde; Superoxide dismutase

Effect of Ganoderma lucidum polysaccharides on oxidative stress of hyperlipidemic fatty liver in rats

To study the effect of Ganoderma lucidum polysaccharides on oxidative stress of hyperlipidemic fatty liver in rats. Seventy-two SD rats were randomly divided into six groups, namely the normal control group (NG), the model group (MG), the G. lucidum polysaccharides groups of low, middle and high dose (GLPs-LG, GLPs-MG, GLPs-HG) and the Simvastatin group (SV). The rats were fed with high fat diet to establish the model of hyperlipidemic fatty liver in rats. After administration for 12 weeks, rats in each group were tested with the following indexes: total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) in serum as well as the contents of SOD, MDA, GSH-Px and T-AOC in hepatic tissues. Histopathological changes of hepatic tissues were observed under light glass. The contents of TC, TG and LDL-C were significantly increased in the model group (P < 0.01). Compared with the model group, both the GLPs-M group and the GLPs-H group showed significant decreases in TC, TG and LDL-C (P < 0.05 or P < 0.01), while the GLPs-H group showed a notable increase in HDL-C (P < 0.05). Compared with the model group, both the GLPs-M group and the GLPs-H group showed significant decreases in MDA (P < 0.05 or P < 0.01) and notable increases in SOD, GSH-Px, T-AOC (P < 0.05 or P < 0.01). The GLPs-M group and the GLPs-H group proved a remarkable alleviation in fatty degeneration of hepatic cells. G. lucidum polysaccharides can significantly reduce the blood fat level of hyperlipidemic fatty liver in rats and effectively inhibit oxidant stress, showing the effect on preventing and treating hyperlipidemic fatty liver in rats to some extent.

Protective Effect of Arabic Gum on liver Injury Experimentally Induced by Gentamycin in Mice

This research was conducted to evaluate the effect of Arabic gum (Ag) on hepatotoxicity induced by gentamycin in mice. Forty adult male Bulb/c mice were used. The animal were divided into four groups (Gs) each group 10 animals. G1 considered as control, G2 treated with gentamycin(40mg/kg/day) for 8 days (i.p.). G3 treated with Ag (10 gm/kg/day) for 8 days administrated orally. Then G4 treated with both gentamycin and Ag for 8 days. Biochemically, the results showed a significant decrease in levels of serum ALT and AST in G4 as compared with G2 . Moreover, serum Glutathione (GSH) in G4 also elucidate a significant increasing in its level, as well as a significant decrease in levels of malondialdihyde (MDA). Histopathologically, liver sections of animals in G4 revealed an ameliorative effects of Ag as compared with its compatible tissue sections of G2. Liver of mice treated with Ag (G3) showed an apoptosis in hepatocytes. In conclusion, treatment of hepatotoxicity by Arabic gum , showed melioration in histopathological changes in hepatic tissues in addition to have ability for induction of apoptosis and meliorating liver picture.

Hepatoprotective activity of methanolic extract of Hiptage bengalensis leaves against CCl4-induced hepatotoxicity in rats

The objective of the present study was to evaluate hepatoprotective activity of methanolic extract of Hiptage bengalensis (L.) kurz (MEHB) in rats. Hepatic damage was induced by administration of carbontetrachloride(1 ml/kg, b.w, p.o.) in combination with liquid paraffin (1:1) as a single dose on 7th day. The extent of liver damage was studied by estimating biochemical parameters. Administration of MEHB (200 mg & 400 mg/kg) for 6 days before carbontetrachloride administration showed a significant reduction (p < 0.01) of serum liver damage enzymes markers-aspartate transaminase, alanine transaminase, total bilirubin and alkaline phosphatase (ALP). Histopathological changes of hepatic tissue were also evaluated in control and MEHB treated groups. Results also indicated that MEHB possessed potential antioxidant effect by increasing the levels of glutathione and also possessed free radical scavenging activities. The hepatoprotective effect of Hiptage bengalensis (L.) kurz was comparable to standard drug silymarin (50 mg/kg).

Simvastatin inhibits activation of hepatic stellate cells and promotes activation of adenosine monophosphate-activated protein kinase

To investigate the underlying molecular mechanism of the cholesterol-blocking drug, simvastatin, in treating nonalcoholic fatty liver fibrosis. A rat model of nonalcoholic fatty liver fibrosis was established by feeding Wistar rats a fat-rich diet. After treatment with simvastatin (4 mg/kg/day), liver histological specimens were stained with hematoxylin-eosin and Masson's trichrome for microscopic analysis. Expression of adenosine monophosphate-activated protein kinase-alpha (AMPKa) was evaluated by reverse transcription-polymerase chain reaction (RT-PCR; for mRNA) and Western blotting (protein). The levels of serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor-alpha (TNFa) were measured by standard biochemical assays. The human hepatic stellate cell line, LX-2 (quiescent or activated), was treated with transforming growth factor-beta 1 (TGF-b1) alone, simvastatin alone, or TGF-b1 + simvastatin. RT-PCR and Western blotting were used to determine changes in AMPKa mRNA and protein expression, respectively. In the rat model of nonalcoholic fatty liver fibrosis, the extent of pathological changes in hepatic tissues correlated with severity of disease progression. The levels of serum TC, TG, ALT, AST and TNFa were increased significantly in model rats (vs. healthy controls; all, P less than 0.01). AMPKa mRNA expression and activity was significantly decreased in model rats (vs. healthy controls; P less than 0.01 and P less than 0.05, respectively). Simvastatin, treatment significantly improved all of these parameters in model rats (vs. untreated model rats; all, P less than 0.05). In vitro simvastatin treatment of human HSCs significantly increased AMPKa activity (quiescent LX-2: 0.93+/-0.10 vs. 0.72+/-0.09, activated LX-2: 0.72+/-0.10 vs. 0.54+/-0.10, q=7.00, 6.00; all, P less than 0.01), decreased a-smooth muscle actin expression (mRNA: 0.30+/-0.02 vs. 0.36+/-0.02, protein: 0.30+/-0.03 vs. 0.38+/-0.02, q=11.245, 11.216; all, P less than 0.01), and decreased collagen I expression (mRNA: 0.30+/-0.03 vs. 0.37+/-0.03, protein: 0.25+/-0.03 vs. 0.33+/-0.03, q=8.791, 11.163; all, P less than 0.01). Simvastatin may improve nonalcoholic fatty liver fibrosis by inducing AMPK phosphorylation.

Potential chemoprevention of diethylnitrosamine-induced hepatocarcinogenesis in rats: Myrrh (Commiphora molmol) vs. turmeric (Curcuma longa)

The aim of the present study was to assess the potential chemopreventive effects of myrrh (Commiphora molmol) vs. turmeric (Curcuma longa) in hepatocarcinogenic rats induced by a single intraperitoneal injection of diethylnitrosamine (DENA) (200mg/kg body weight). Ninety male Wistar rats used in this study were randomly divided into six equal groups (n=15). Group 1 rats served as negative controls; group 2 received a single i.p. injection of DENA and served as positive controls. Rats in both groups were fed on basal diet. Group 3 rats were fed a diet containing 5% turmeric, whereas group 4 rats were fed a diet containing 2% myrrh. Rats in groups 5 and 6 received a single i.p. injection of DENA and were fed diets containing 5% turmeric and 2% myrrh, respectively. The study demonstrated that DENA caused a significant increase in serum indices of liver enzymes and also severe histological and immunohistochemical changes in hepatic tissues. These included disorganized hepatic parenchyma, appearance of pseudoacinar and trabecular arrays of hepatocytes and alterations in CD10-immunoreactivity. Dietary supplementation of turmeric relatively improved the biochemical parameters to values approximating those of the negative controls and delayed the initiation of carcinogenesis. In contrast, myrrh did not improve the biochemical parameters or delay the hepatocarcinogenesis. Both turmeric and myrrh induced significant biochemical and histological changes in non-treated rats. In conclusion, DENA significantly changes the biological enzymatic activities in serum and the integrity of hepatic tissues. Phytochemicals with potential hepatoprotective effects must be applied cautiously owing to their potential hepatotoxicity.

Comparison of toxic reaction of Tripterygium wilfordii multiglycoside in normal and adjuvant arthritic rats

Tripterygium wilfordii multiglycoside (GTW), an authorized Chinese patent drug, is used for treatment of rheumatoid arthritis and other immune disease. This study was to determine whether GTW induced different toxic reactions in adjuvant arthritis rats (AA rats) compared to those in normal rats. To prepare arthritic rat model, male Sprague-Dawley (SD) rats were immunized by injecting complete Freund's Adjuvant into right hind footpad. And then, GTW was given to rats intragastrically at dosage of 7 or 105 mg kg(-1)day(-1) from day 15 to day 28 after immunization. Routine clinical parameters and histopathologic changes of liver, kidney and testis were examined. Metabolic profiling in serum of groups was analyzed by LC-MS. A principal component analysis (PCA) and partial-least-squares discriminate analysis (PLS-DA) were carried out combined with mass spectrometry (MS) data set. All the quantitative data were performed by two-way ANOVA analysis following Student's t-test. Treatment with GTW at both doses could diminish the right and left hind paws swelling. There was slight lipoid degeneration in hepatic tissue of normal rats treated by high dose of GTW, but there were not distinctly pathological changes in hepatic tissue of AA rats treated by GTW. Compared normal rats administered with GTW, no statistically significant difference in the serum alanine aminotransferase (ALT), creatinine (CRE), and blood urea nitrogen (BUN) levels were observed. However, the serum aspartate aminotransferase (AST) level was significant decreased in AA rats under exposure GTW compared with normal rats in the same conditions (p<0.05), which indicated that GTW could offer a different liver toxic reaction in normal and AA rats. The metabolic analysis showed that a clear separation of PCA and PLS-DA score spot in normal rats, but not separation was seen in AA rats perturbed with low dosage GTW. The result indicated low dosage GTW might arouse a general toxic in normal rats but not in AA rats. The biomarker analysis showed that the level of lysophosphatidylcholines (LPCs) was down-regulated, but the level of ursodeoxycholic acid (UDCA) and chenodexycholic acid (CDCA) was up-regulated in AA rats compared with normal rats under exposure GTW. According to pathway analysis of metabolic markers, we conceived that LPC, UDCA and CDCA were the critical intermediates of choline and fatty acid metabolism. And the lipid metabolism was a correlative outcome of GTW induced toxicity in the liver in physiological condition animals. Taken together, GTW could induce different toxic reactions between normal and AA rats, and the lipid metabolism might be part of the mechanism for the hepatic lipidosis or the other liver injury.

Biochemical liver function after partial hepatic resection with or without partial hepatic vascular exclusion

The aim of the present study was to assess the advantages and disadvantages of liver vascular partial exclusion (LVPE) (liver dysfunction due to ischemia) during liver resection in patients submitted to partial hepatectomy. A total of 114 patients were submitted to partial hepatectomy (minor versus major resections) with LPVE being used in 57 of them but not in the remaining 57. Patient age ranged from 35 to 73 years and 57 % were women. Mitochondrial function was assessed 30 minutes after liver resection in the remnant liver and serum aminotransferases were determined before surgery and for seven days postoperatively. LPVE time ranged from 30 to 60 minutes. Data were analyzed statistically by the Student T test (5 % level of significance). Mitochondrial function was similar in the minor and major liver resections. The maximum postoperative aminotransferase peak was similar in the groups with and without LPVE. LPVE did not induce mitochondrial changes in hepatic tissue in either type of surgery, and aminotransferase levels were similar for patients with and without LPVE. Thus, the results show that LPVE is a safe procedure that does not induce the significant changes typical of ischemia and reperfusion in the liver remnant.

Antioxidant and Hepatoprotective Effects of Murdannia bracteata Methanol Extract

Murdannia bracteata (C. B. Clarke) is a local plant that is widely used in Malaysia as a traditional remedy for various diseases of the kidney and liver, including inflammation and cancer. In the present study, we investigated the antioxidant and hepatoprotective activities of M. bracteata methanol extract (MB). 2,2′-diphenyl-1-picrylhydrazyl radical scavenging activity, lipid peroxidation inhibition and trolox equivalent antioxidant capacity of MB were determined. The hepatoprotective activity of MB was studied using a CCl 4-induced liver toxicity model in rats. The hepatoprotective effect was assessed by monitoring the plasma malondialdehyde level and serum alanine transaminase and aspartate transaminase activities. Histopathological changes of hepatic tissue were also investigated. The results indicated that MB possessed potential antioxidant, lipid peroxidation inhibition and free radical scavenging activities. Pretreatment of rats with MB (500 mg/kg and 1000 mg/kg per os) before induction of CCl 4-induced hepatotoxicity showed a dose-dependent reduction in the necrotic changes in hepatic tissue. The increases in plasma malondialdehyde level, serum alanine transaminase and aspartate transaminase activities were also significantly inhibited by MB. The total phenolic content of MB determined using Folin-Ciocalteu assay was found to be 10%. The results of the present study indicated that the hepatoprotective effect of MB is most likely due to its antioxidant and free radical scavenging properties.

Influence of Ultrasound Induced Cavitation on Magnetic Resonance Imaging Contrast in the Rat Liver in the Presence of Macromolecular Contrast Agent

Local drug delivery by ultrasound (US)-induced cavitation is a promising strategy for increasing the drug concentration at the target location and for decreasing the systemic toxicity effects. The presence of microbubbles during sonication at the targeted location improves the likelihood for cavitation that can be exploited to increase the capillary permeability. The objective of this work was to evaluate the magnetic resonance imaging (MRI) contrast changes in hepatic tissue in vivo, induced by US-triggered cavitation and destruction of microbubbles (Sonovue), in the presence of a coinjected blood pool MRI contrast agent (Vistarem) used as a reporter macromolecule. The potential tissue damage induced by microbubbles destruction was also evaluated by histology. The change in the hepatic distribution of the macromolecular MRI contrast agent associated with cavitation was monitored at 1.5 T with a look-locker fast inversion recovery sequence to map the longitudinal relaxation rates, before and during 1 hour after intravenous administration of Vistarem and Sonovue. In 1 group of rats (n = 5), these microbubbles were immediately destroyed with a clinical echograph, using a high mechanical index (MI = 1.5) at low frequency (2 MHz). The control group (n = 7) received identical injections without application of US. The parametric relaxation rate images were computed, and the changes in time were analyzed to account for the potential effect of microbubble destruction by US on the permeability of the hepatic vessels. The animals were killed 1 day after the experiment for routine histology of the liver. For both groups of animals, after an initial increase, a transient decay of the longitudinal relaxation rate was observed, followed by a constant plateau after 20 minutes. The analysis of the mean relaxation rates in the liver showed significant (P < 0.01) higher values for the group with destruction of microbubbles as compared with the control group. The US-triggered cavitation and destruction of microbubble with the proposed protocol suggests an increased concentration of Vistarem of a factor 2 in the hepatic tissue. No tissue damage was observed at the microscopic analysis. The absence of tissue alterations indicates that the destruction of this US contrast agent could be safe in vivo under an appropriate choice of the sonication parameters. This approach opens new perspectives for translation toward clinical applications of local drug delivery. Ultrasound-mediated microbubble destruction may help in increasing the local concentration of a drug currently limited by the endothelial barrier. In addition, it may help in reducing the systemic toxicity to normal cells in standard chemotherapies, because the enhanced capillary permeability effect can be spatially adjusted by selecting the sonicated region.