Chronic Liver Injury In Rats Research Articles

Echinacoside Alleviates Carbon Tetrachloride-Induced Chronic Liver Injury by Modulating the NF-κB/NLRP3 Inflammasome Pathway.

The purpose of this study was to investigate the protective effect of echinacoside (Ech) on carbon tetrachloride (CCL4)-induced chronic liver injury in rats and its potential mechanisms. Thirty Sprague-Dawley (SD) rats were randomly divided into five groups: the Control group, the CCL4 group, the CCL4 + Ech 25 mg/kg group, the CCL4 + Ech 50 mg/kg group, and the CCL4 + Ech 100 mg/kg group. The rats were injected intraperitoneally with CCL4 solution twice a week to induce chronic liver injury, and Ech intervention lasted for 4 weeks. After the intervention, the liver and blood samples from rats were collected for subsequent analysis. Ech effectively reduced the levels of serum liver injury markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, alkaline phosphatase, and total bilirubin), attenuated the hepatocyte degeneration and necrosis, improved the severity of liver fibrosis, and inhibited the local inflammatory response of the liver in a dose-dependent manner. Ech effectively mitigated CCL4-induced chronic liver injury in rats by downregulating the NF-κB/NLRP3 inflammasome pathway.

Study on mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site on CCl_4-induced chronic liver injury in rats

This study aims to investigate the mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site(CGE) on the disease in carbon tetrachloride(CCl_4)-induced chronic liver injury model in rats. A chronic liver injury model was constructed by subcutaneous injection of CCl_4 olive oil solution, and after four weeks of CGE treatment, serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(AKP), hydroxyproline(HYP), interleukin-4(IL-4), interleukin-6(IL-6), malondialdehyde(MDA), superoxide dismutase(SOD), and tumor necrosis factor-α(TNF-α) were detected. Liver tissue was processed by hematoxylin-eosin(HE) staining and Masson staining to observe the structure of the rat liver. qPCR and Western blot were used to examine the expression of transforming growth factor-β1(TGF-β1)/small mothers against decapentaplegic(Smad), Toll-like receptor 4(TLR4), α-smooth muscle actin(α-SMA), and fibronectin(Fn) in rat liver tissue and hepatic stellate-T6(HSC-T6) and evaluate the inhibitory effect of CGE on HSC activation. The results showed that CGE could significantly reduce the serum levels of AST, ALT, AKP, HYP, and affect the levels of related inflammatory indexes including IL-4, IL-6, and TNF-α, and MDA in CCl_4-induced chronic liver injury in rats and had no effect on SOD activity, which could delay the process of liver injury, alleviate the hepatic collagen deposition and inflammatory infiltration, and had significant efficacy in mitigating chronic liver injury in rats. CGE could inhibit α-SMA and TLR4 protein expression in the liver tissue and reverse the increased TGF-β1/Smad, Fn, and TLR4-related expression in HSC-T6 in vitro. The above results indicated that CGE exerted hepatoprotective effects in rats by inhibiting HSC activation and alleviated CCl_4-induced chronic liver injury in rats and could ameliorate inflammatory response and slight liver fibrosis in rat liver tissue. Its pharmacodynamic mechanism might be related to TGF-β1/Smad and TLR4-related expression.

Boldine protects against carbon tetrachloride-induced chronic liver injury by regulating NF-κB signaling pathway.

Sustained liver injuries predominantly promote oxidative stress and inflammation that lead to the progression of chronic liver disease (CLD), including fibrosis, cirrhosis, and hepatocellular carcinoma. Boldine, an alkaloid isolated from Peumus boldus, has been shown to have antioxidant and anti-inflammatory effects. Currently, there is no definitive treatment option available for CLD. Therefore, we investigated the hepatoprotective effect of boldine against carbon tetrachloride (CCl4 )-induced chronic liver injury in rats. CCl4 (2 mL/kg., b.w., i.p.) was administered twice weekly for 5 weeks to induce chronic liver injury in rats. Separate groups of rats were given boldine (20 mg/kg b.w., and 40 mg/kg b.w.) and silymarin (100 mg/kg b.w.) orally, daily. Serum transaminases, lipid peroxidation, and antioxidant levels were measured, and nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (cox-2), interleukin-1 β (IL-1β), and α-smooth muscle actin (α-SMA) gene and protein expressions were evaluated. CCl4 administration increased liver marker enzymes of hepatotoxicity in serum and oxidative stress markers, inflammatory genes and α-smooth muscle actin expression in liver tissue. Boldine concurrent treatment suppressed CCl4 -induced elevation of transaminase levels in serum, restored enzymic and non-enzymic antioxidants, and downregulated NF-κB, TNF-α, Cox-2 and IL-1β expressions, thereby suppressing hepatic inflammation. Boldine administration also repressed α-SMA expression. The results of this study demonstrate the antioxidant, anti-inflammatory, and antifibrotic properties of boldine, and it can be a potential therapeutic candidate in the treatment of CLD.

Hepatoprotective effect of the methanol extract of Luffa cylindrica fruit on carbon-tetrachloride induced chronic liver injury

Luffa cylindrica (Linn) commonly called sponge gourds has both medicinal and nutritional properties. It is used traditionally for the management of liver diseases. Herein, we investigated the hepatoprotective effect of the crude methanol extract of L. cylindrica fruit in rats chronically exposed to carbon tetrachloride (CCl4). Male rats were exposed to CCl4 twice a week for six weeks and the extract was administered five times a week for six weeks. Markers of liver toxicity, antioxidant enzymes and liver peroxidation were evaluated and histological analysis of the liver was carried out. Significant reduction in serum markers (ALT, AST and ALP), increase in antioxidant enzyme and reduction in lipid peroxidation compared to CCl4 were observed in rats exposed to both CCl4 and the extract. CCl4-induced liver lesions were ameliorated by the extract. These show the protective effect of the methanol extract of L. cylindrica on CCl4-induced chronic liver injury in rats.

A Preliminary Study on the Effect of Hydrogen Gas on Alleviating Early CCl4-Induced Chronic Liver Injury in Rats.

As a small-molecule reductant substance, hydrogen gas has an obvious antioxidant function. It can selectively neutralize hydroxyl radicals (•OH) and peroxynitrite (ONOO•) in cells, reducing oxidative stress damage. The purpose of this study was to investigate the effect of hydrogen gas (3%) on early chronic liver injury (CLI) induced by CCl4 and to preliminarily explore the protective mechanism of hydrogen gas on hepatocytes by observing the expression of uncoupling protein 2 (UCP2) in liver tissue. Here, 32 rats were divided into four groups: the control group, CCl4 group, H2 (hydrogen gas) group, and CCl4 + H2 group. The effect of hydrogen gas on early CLI was observed by serological tests, ELISA, hematoxylin and eosin staining, and oil red O staining. Immunohistochemical staining and Western blotting were used to observe the expression of UCP2 in liver tissues. We found that CCl4 can induce significant steatosis in hepatocytes. When the hydrogen gas was inhaled, hepatocyte steatosis was reduced, and the UCP2 expression level in liver tissue was increased. These results suggest that hydrogen gas might upregulate UCP2 expression levels, reduce the generation of intracellular oxygen free radicals, affect lipid metabolism in liver cells, and play a protective role in liver cells.

β-Sitosterol attenuates carbon tetrachloride-induced oxidative stress and chronic liver injury in rats.

Chronic liver diseases are clinically silent and responsible for significant morbidity and mortality worldwide. β-Sitosterol (BSS), major phytosterol in plants, has a wide spectrum of protective effect against various chronic ailments. We investigated the hepatoprotective effect of BSS against carbon tetrachloride (CCl4)-induced chronic liver injury in rats. Thirty rats were divided into five groups, with six animals in each group. Group I rats served as control while groups II, III, IV, and V rats were injected intraperitoneally with CCl4 (0.2mL/100g b.w. in olive oil (1:1)) for 7 consecutive weeks. After 7weeks, group II rats were left without any treatments and served as CCl4 alone group, while groups III, IV, and V rats were treated with BSS 25 and 50mg/kg b.w. and silymarin 100mg/kg b.w. as oral post-treatments respectively, for the next 4weeks. At the end of the experiment, hepatotoxicity marker enzymes in serum, oxidative stress, and fibrosis marker were analyzed. CCl4 administration caused significant elevation of marker enzymes of hepatotoxicity in serum and increased lipid peroxidation and fibrosis markers such as hydroxyproline, collagen, α-smooth muscle actin, vimentin, desmin, and matrix metalloproteinases 9 in liver tissue of rats. This treatment also caused a significant diminution of intracellular enyzmicantioxidants such as SOD and CAT in the liver tissue of rats. All the above adversities were significantly mitigated by the BSS post-treatments. The results suggest that BSS could have a hepatoprotective effect against oxidative stress-mediated CLD induced by CCl4.

SanWeiGanJiang San relieves liver injury via Nrf2/Bach1.

San Wei Gan jiang San (SWGJS) also called Jia Ga Song Tang, is widely used in ancient medicine for liver diseases. To identify the blood components of SWGJS. To determine the hepatoprotective effect and the mechanism of SWGJS by observing its effect on different degrees of liver damage and gene knockdown cells. SWGJS treated serum was analyzed by UPLC-MS to identify blood components. CCl4-induced chronic liver injury in rats was treated with SWGJS. The viscera index was calculated. Pathological changes of the liver were determined by HE staining and analysis of by following: GSH-Px and MDA in liver homogenate; ALT and AST in serum; mRNA expression of Nrf2, Bach1, and HO-1 by RT-PCR; Nrf2 and Bach1 in the nucleus and cytoplasm; HO-1 total expression by Western blot; silencing Nrf2 and Bach1 in human L-02cells by siRNA; MDA, GSH-Px, GST, and GR in cell supernatants; and GSH/GSSG within the cell. We found that 6-gingerol was one of the blood components in the serum treated with SWGJS. In CCl4-induced chronic liver injury in rats, SWGJS repaired the liver structure in the early stages of liver damage as evidenced by reduced ALT and AST in the serum, increased GSH-Px activity and decreased MDA levels in the liver over time. SWGJS has excellent antioxidant and hepatoprotective effects and prevents disease progression. The mechanism of SWGJS is related to the dynamics promoting Nrf2 entry to the nucleus and Bach1 exit from the nucleus. In L-02cells with silenced Nrf2, the antioxidant enzyme system was disordered, and the change in the cellular redox state was not conducive to antioxidative stress. However, in cells with silenced Bach1, the antioxidant enzyme system could be activated to promote cellular antioxidant stress. SWGJS had a combined effect on Nrf2 and Bach1 contributing to antioxidant properties and liver protection. SWGJS increased GSH-Px and HO-1, decreased MDA and increased the ratio of GSH/GSSG by upregulating the expression of Nrf2 to enhance its antioxidant effects. At the same time, SWGJS had a specific impact on decreasing Bach1. Its elevation of GST is due to the overall performance of increasing Nrf2 and decreasing Bach1. This mechanism of action embodies the characteristics of the multitarget impact of traditional medicine and the antioxidation effect of SWGJS. 6-Gingerol is one of the blood components of SWGJS. SWGJS can regulate antioxidant enzymes, protect against liver damage in different stages, and slow the progression of liver cell damage and liver disease by increasing Nrf2 and reducing Bach1 in the nucleus, dynamically regulating Nrf2/Bach1.

Antifibrotic effects of fermented black radish (Raphanus sativus L. var. niger) on chronic liver injury in rats

We evaluated the antifibrotic effects of fermented black radish (FBR) on carbon tetrachloride (CCl4)-induced chronic liver injury in rats. Serum biochemical analysis indicated that FBR treatment attenuated the upregulation of alanine aminotransferase and aspartate aminotransferase. Moreover, Sirius red staining and histopathological examination revealed decreased fibrosis and inflammation in FBR-treated rats compared with CCl4 + vehicle-treated rats. Western blot analysis of alpha-smooth muscle actin expression levels confirmed the downregulation of fibrosis in the FBR treatment group compared with the CCl4 + vehicle treatment group. These results suggest that FBR treatment suppressed liver fibrosis in CCl4-exposed rats.

RETRACTED ARTICLE: Amygdalin reduces lipopolysaccharide-induced chronic liver injury in rats by down-regulating PI3K/AKT, JAK2/STAT3 and NF-κB signalling pathways

We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Yang Yang, Jie Zhao, Xiaoqin Song, Lifeng Li, Fuqin Li, Jia Shang & Wei-Wei Wang (2019) Amygdalin reduces lipopolysaccharide-induced chronic liver injury in rats by down-regulating PI3K/AKT, JAK2/STAT3 and NF-κB signalling pathways. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 2688–2697, DOI: https://doi.org/10.1080/21691401.2019.1634084 It has come to our attention that the full authorship and affiliations for this manuscript were changed entirely since submission. We have contacted the authors for an explanation, and they responded to all of our queries on the matter, but they were unable to provide a satisfactory explanation. The authors apologise for this situation. As determining authorship is core to the integrity of published work, we are therefore retracting the article. The corresponding author listed in this publication has been informed. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Effect of carvedilol versus propranolol on acute and chronic liver toxicity in rats

Non-selective β-blockers have largely been used for prophylaxis of bleeding from gastroesophageal varices, but their hepatic effects and their influence on the development of varices has yet to be clarified. This study examined whether carvedilol would reduce acute and chronic liver injury in rats in comparison to propranolol. Experiment (1) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) administered daily for 7 days by gavage on paracetamol (1500 mg/kg i.p.) -induced acute liver injury in rats. Experiment (2) Investigated the effects of carvedilol (1.2 mg/kg) and propranolol (4.0 mg/kg) by gavage daily for 8 weeks on CCl4 -induced chronic liver injury in rats. Biochemical markers and histopathology of the livers were studied. Liver perfusion studies were carried out on CCl4 treated rats. Experiment (1) Carvedilol significantly improved the functional state of the liver in paracetamol-induced acute toxic hepatitis to a greater extent than propranolol. This was evidenced by a greater reduction in elevated serum levels of ALT and AST, hepatic MDA and TNF-α, attenuation of the paracetamol-induced decrease in GSH, together with improvement in the histological architecture of the liver. Experiment (2) Carvedilol was superior to propranolol against CCl4-induced hepatic injury and fibrogenesis. It suppressed hepatic inflammation, attenuated hepatic oxidative stress, and inhibited HSC activation. Carvedilol also decreased portal perfusion pressure. These results suggest that carvedilol might be a therapeutic anti-fibrogenic candidate against hepatic fibrosis, protecting the liver from acute and chronic toxic injury, in addition to lowering portal pressure.

The Hepatoprotective Effect of Selenium-Enriched Yeast and Gum Arabic Combination on Carbon Tetrachloride-Induced Chronic Liver Injury in Rats.

Chronic liver diseases are the serious health problems, which increase the morbidity and mortality in the world today. Selenium-enriched yeast (SY) and Gum Arabic (GA) combination might be potential dietary agents could obviously ameliorate chronic liver damage, higher than GA and SY alone. They act to suppress the inflammation and inhibit the profibrotic response as well as support the liver regeneration.

Methanol extract of Nymphaea lotus ameliorates carbon tetrachloride-induced chronic liver injury in rats via inhibition of oxidative stress.

Nymphaea lotus (NL) is an aquatic perennial plant used traditionally in the management of various liver diseases. In this study, the protective effect of methanol extract of NL against carbon tetrachloride (CCl4)-induced chronic hepatotoxicity in rats was investigated. Male Wistar rats were assigned into six groups of five rats each. Group I received corn oil (0.5 mL p.o.) and served as control, group II received CCl4 (1 mL/kg i.p., 1:3 in corn oil), group III received NL (200 mg/kg), and groups IV, V, and VI received CCl4+NL (50, 100, and 200 mg/kg, respectively) for 6 weeks. Twenty-four hours after the last exposure, rats were bled and killed. The activities of alanine aminotransaminase (ALT), aspartate aminotransferase (AST), and levels of total bilirubin (TB) in the serum, thiobarbituric acid reactive substances (TBARS), superoxide dismutase, catalase, glutathione peroxidase (GPx) and glutathione (GSH) in the liver, and histopathology of the liver were determined using standard procedures. NL significantly (p<0.05) lowered the levels of ALT, AST, and TB and exhibited antioxidant potentials in rats exposed to CCl4 relative to the control values. Specifically, NL at 100 and 200 mg/kg significantly (p<0.05) increased CCl4-induced decrease in hepatic GSH and GPx and also decreased the level of hepatic TBARS in CCl4-intoxicated rats. Histopathological findings revealed cellular infiltration and fibrosis in rats that received CCl4 only, which were ameliorated in rats that received NL+CCl4. The data suggest that NL exhibited hepatoprotective effects in CCl4-intoxicated rats via antioxidative mechanism.

Hepatoprotective Effect of Silymarin and Propolis in Chemically Induced Chronic Liver Injury in Rats

According to World Health Organization (WHO), chronic liver disease is a major problem that causes significant morbidity and mortality in both western and developing countries. However, till now no ideal hepatoprotective agents are available in the modern system. This has increased the need to depend on complementary and alternative systems of medicine. Silymarin and propolis among phytochemicals that show anti-inflammatory, healing, antioxidant and several other promising properties. Our aim is to investigate protective effect of silymarin and propolis in chemically induced chronic liver injury in rats. A total of 60 male albino rats (90±10 days old) were divided equally into ten groups: (6 rats per each group). The experiment lasted along four months, through which all groups except for group 1 and 6 were given silymarin and propolis. Liver injury was induced in groups 6, 7, 8,9,10 while other groups were injected with saline and oil of the same volume as following. Group 1: served as control –ve, the rats were fed on basal ration and water ad libitum. Group 2 (silymarin 100 mg/ kg b.wt). Group 3 (propolis 100 mg/kg b.wt). Group 4 (propolis 150 mg/kg b.wt). Group 5 (propolis 200 mg/kg b.wt). Group 6 served as control +ve (DEN+CCl4). Group 7 (liver injury+ silymarin 100 mg/ kg b.wt). Group 8 (liver injury+ propolis 100 mg /kg b.wt). Group 9 (liver injury + propolis 150 mg/kg b.wt). Group 10 (liver injury + propolis 200 mg/kg b.wt). Blood samples were collected from all groups after four months and serum was separated for biochemical analysis of liver functions and tumar markers Administration of DEN+CCl4 significantly increased liver weight, liver/body weight index, AST, ALT, ALP, GGT, AFP and CEA while, body weight, total protein, albumin and A/G ratio were markedly decreased. Treatment with silymarin and propolis caused a significant reduction in serum levels of AST, ALT, ALP, GGT and tumor markers moreover, loss of body weight and liver/body weight index were successfully decreased while, total protein and albumin were increased by those natural products. The results indicate a protective effect for silymarin and propolis against hepatic injury induced by DEN+CCl4 that may be due to their ability to block the bioactivity of those hepatotoxicants and their antioxidant properties.

Influences of keratinocyte growth factor - mesenchymal stem cells on chronic liver injury in rats

To study the effects of keratinocyte growth factor (KGF) modified umbilical cord mesenchymal stem cells (MSC) on chronic liver injury in rats, adenovirus carrying human KGF gene (Ad-KGF) was used. Rat liver injury model was established by subcutaneous injection of CCl4 - olive oil solution; 56 male Wistar rats were randomly divided into normal control, model, MSC, KGF, and KGF/MSC groups. Of all three treatments, KGF/MSC had the most obvious therapeutic effects on liver injury, and cell injections did not cause adverse reaction. The experiment provides new data for clinical research of KGF/MSC and possible methods for liver injury treatment.

Effect of Pharmacopuncture on Chronic Liver Injury in Rats

[Abstract] Objectives : Alcohol-related liver disease is a major cause of morbidity and mortality worldwide. The present study was undertaken to determine whether Ganoderma lucidum pharmacopuncture(GLP) could protect against chronic liver injury induced by ethanol intoxication in rats. Methods : Sprague-Dawley rats were divided into 4 groups: normal, control, normal saline pharmacopuncture(NP), and GLP, with 8 animals in each. Each group, except normal, received ethanol orally. The NP and GLP groups were treated daily with NP and GLP respectively. The control group was not treated. All rats except the normal group were intoxicated for 4 weeks by oral administration of EtOH(6 g/kg BW). Two acupuncture points were used: Qimen(LR14) and Taechung(LR3). Body weight, histopathological analysis, liver function, activities of antioxidant enzymes, and immunohistochemistry were assessed. Results : GLP reduced the histological changes due to chronic liver injury induced by EtOH and significantly reduced the increase in the alanine aminotransfer ase(ALT) and aspartate aminotransferase(AST) enzymes. It significantly reversed the superoxide dismutase(SOD) and the catalase activities(CAT). It also significantly decreased BAX a nd increased Bcl-2 immunoreactivity expression.

Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats

Sinapic acid is a member of the phenylpropanoid family and is abundant in cereals, nuts, oil seeds, and berries. It exhibits a wide range of pharmacological properties. In this study, we investigated the hepatoprotective and antifibrotic effects of sinapic acid on dimethylnitrosamine (DMN)-induced chronic liver injury in rats. Sinapic acid remarkably prevented DMN-induced loss of body weight. This was accompanied by a significant increase in levels of serum alanine transaminase, aspartate transaminase, and liver malondialdehyde content. Furthermore, sinapic acid reduced hepatic hydroxyproline content, which correlated with a reduction in the expression of type I collagen mRNA and histological analysis of collagen in liver tissue. Additionally, the expression of hepatic fibrosis-related factors such as α-smooth muscle actin and transforming growth factor-β1 (TGF-β1), were reduced in rats treated with sinapic acid. Sinapic acid exhibited strong scavenging activity. In conclusion, we find that sinapic acid exhibits hepatoprotective and antifibrotic effects against DMN-induced liver injury, most likely due to its antioxidant activities of scavenging radicals, its capacity to suppress TGF-β1 and its ability to attenuate activation of hepatic stellate cells. This suggests that sinapic acid is a potentially useful agent for the protection against liver fibrosis and cirrhosis.

Investigation of the “dose–time–response” relationships of rhubarb on carbon tetrachloride-induced liver injury in rats

The present study investigated the liver protection and toxicity of rhubarb against carbon tetrachloride (CCl4)-induced chronic liver injury in rats. The rats were treated by intraperitoneal injection of 10% CCl4 for 12 weeks. At the end of week 4, rhubarb at doses of 40 g kg(-1) (high-dose group), 20 g kg(-1) (medium-dose group) and 10 g kg(-1) (low-dose group) was intragastrically administered to CCl4-treated rats once a day for three weeks. At the end of week 16, all rats were maintained for 1 month without any administration. At the end of weeks 8, 12, 16 and 20, the general status of rats, histopathology of liver, serum alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), total bilirubin (TBIL) and hyaluronic acid (HA) levels were observed, respectively. Combined with clustering analysis and correspondence analysis, the "dose-time-response" relationships of rhubarb on the liver injury rats were synthetically investigated. High dose (40 g kg(-1)) of rhubarb exhibited a significant protective effect on injured liver by reversing the biochemical parameters and histopathological changes. But, this hepatoprotective effect will be weakened, even be transferred to toxicity with increasing the administration dose and time of rhubarb. These results were consistent with the histopathological observation and the determination of serum levels. The safety should be considered simultaneously in the long-term and high dose use of rhubarb, the liver function and change should be regularly detected. This study provided some useful references for the clinical rational use of rhubarb and other herbal medicinal products.

Evaluation of the toxicological properties and hepatoprotective effects of PAI-N002, a mixture of herbal extracts, in rats

The short-term toxicity of PAI-N002, a mixture of Schizandra chinensis, Astragalus membranaceus, Artemisia capillaris, and Coriolus versicolor extracts (1 : 1 : 1 : 1), was evaluated in rats. This study also investigated the protective effect of PAI-N002 on liver injury induced by the co-administration of ethanol and carbon tetrachloride (EC) in rats. PAI-N002 was virtually non-toxic to rats after a single oral administration, with LD50 values > 5,000 mg/kg. The subacute toxicity study showed that 2-week repeated oral dose of PAI-N002 did not cause any adverse effects on clinical signs, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross findings, and organ weights in rats given up to 1,000 mg/kg/day. When rats with EC-induced hepatotoxicity were treated with PAI-N002 at 250 mg/kg/day for 28 days, PAI-N002 treatment significantly improved EC-induced hepatic injury, as evidenced by the decline of serum AST and ALT activities and decreased histopathological alterations. PAI-N002 also had an antioxidant benefit by decreasing the lipid peroxidative product malondialdehyde and increasing the levels of the antioxidant glutathione and the activities of the antioxidant enzymes catalase, superoxide dismutase, and glutathione-S-transferase. These results indicate that the short-term treatment of rats with PAI-N002 has no harmful effects and that PAI-N002 has hepatoprotective and antioxidant properties in EC-induced chronic liver injury in rats.

Synergistic hepatoprotective effect of Schisandrae lignans with Astragalus polysaccharides on chronic liver injury in rats

The aim of this study was to investigate the synergistic hepatoprotective effect of lignans from Fructus Schisandrae chinensis (LFS) with Astragalus polysaccharides (APS) on chronic liver injury in male Sprague-Dawley rats. Subcutaneous injection of 10% CCl(4) twice a week for 3 months resulted in significantly (p<0.001) elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the liver, significantly elevated levels (p<0.001) of malondialdehyde (MDA), lowered levels of reduced glutathione (GSH) (p<0.05) and catalase (CAT) (p<0.001), superoxide dismutase (SOD) (p<0.01)were observed following CCl(4) administration. 'LFS+ASP' treatment of rats at doses of 'LFS (45mg/kg)+APS (150mg/kg)' and 'LFS (135mg/kg)+APS (450mg/kg)' displayed hepatoprotective and antioxidative effects than the administration of either LFS or APS, as evident by lower (p<0.005 or 0.001) levels of serum ALT, AST, ALP and hepatic MDA (p<0.001) concentration, as well as higher SOD (p<0.05 or 0.005), CAT activities(p<0.01 or 0.005), GSH concentration (p<0.05 or 0.005) compared to the toxin treated group. Histopathological examinations revealed severe fatty degeneration in the toxin group, and mild damage in groups treated with 'LFS+APS' were observed. The coefficients drug interaction (CDI) between each individual drug and their combination (at the same dose of their single treatment) of these foregoing parameters were all less than 1, indicating that LFS and APS display hepatoprotective and antioxidant properties and act in a synergistic manner in CCl(4) induced liver injury in rats.

Protective effect of Acacia confusa bark extract and its active compound gallic acid against carbon tetrachloride-induced chronic liver injury in rats

Acacia confusa Merr. (Leguminosae), a species native to Taiwan, is widely distributed on the hills and lowlands of Taiwan, and has been traditionally used as a medicine. The hepatoprotective effects of A. confusa bark extract (ACBE) and its active constituent gallic acid were evaluated against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. CCl4-induced hepatic pathological damage and significantly increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malondialdehyde (MDA) in plasma, and cytochrome P4502E1 (CYP2E1) protein expression in hepatic samples, and decreased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) in erythrocytes. Treatment with ACBE, gallic acid or silymarin could decrease significantly the AST, ALT, and MDA levels in plasma, and CYP2E1 expression in liver tissues, and increase the activities of SOD and GPX in erythrocyte when compared with CCl4-treated group. Liver histopathology also showed that ACBE, gallic acid or silymarin could significantly reduce the incidence of liver lesions induced by CCl4. These results suggested that the ACBE and gallic acid exhibit potent hepatoprotection against CCl4-induced liver damages in rats, and the hepatoprotective effects of ACBE and gallic acid may be due to the modulation of antioxidant enzymes activities and inhibition of lipid peroxidation and CYP2E1 activation.