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Objectives: To measure the expression of matrix metalloproteinase (MMP)-2, tissue inhibitor of matrix metalloproteinase inhibitor (TIMP)-2, and CD147 in mice with chronic liver injury induced by carbon tetrachloride after treatment with the traditional Chinese medicine (TCM) "Compound T11"., Method: Sixty male ICR mice were divided randomly into 6 groups of 10: control (C), model (M), low-dose treatment (LT; 50 mg/mL of Compound T11), medium-dose treatment (MT, 100 mg/mL), high-dose treatment (HT, 150 mg/mL), and positive drug treatment (YT, 67.5 mg/mL). Each group was modeled for 7 weeks. Groups M, LT, MT, HT, and YT were injected (s.c.) with 20% carbon tetrachloride diluted with olive oil, and group C was given olive oil in the same way twice a week. After modeling, the treatment groups were administered Compound T11 at the concentrations shown above by oral gavage daily for 2 weeks, while group C was given 0.5% carboxymethyl cellulose sodium. After the final treatment, mice were killed and their liver tissues were excised. Immunohistochemical staining was performed to measure the protein expression of MMP-2, TIMP-2, and CD147, and western blotting was used to measure the protein expression of MMP-2, TIMP-2, CD147, and α-smooth muscle actin (SMA). MMP-2, TIMP-2, and CD147 mRNA expression was determined by quantitative fluorescence real-time PCR., Results: Compound T11 increased the protein expression of MMP-2 and CD147 and decreased the protein expression of TIMP-2 and α-SMA., Conclusions: Treatment of chronic liver injury by TCM Compound T11 may be associated with changes to the expression of MMP-2 and CD147, and the inhibition of TIMP-2 expression., (© 2018 S. Karger AG, Basel.)

Yu Gan Long (YGL) is a Chinese traditional herbal medicine that has been used in the treatment of liver fibrosis for many years in clinical practice. However, its anti-hepatofibrotic mechanism has not been studied yet. In this study, the effect and mechanism of YGL in reducing liver fibrosis was demonstrated in vivo. Our results showed that liver fibrosis biomarkers collagen IV (Col IV), type III precollagen (PCIII), hyaluronuc acid (HA) and laminin (LN), were increased after CCl 4 treatment and decreased by YGL. Among the liver fibrosis indicators, α-smooth muscle actin (α-SMA) was decreased by YGL in the CCl 4 -treated rats, while MMP2 and MMP9 was upregulated followed by TIMP1 downregulation. Proteins involved in liver fibrosis such as p-Smad2, p-Smad3 and Smad4 were down-regulated, while Smad7 protein was up-regulated by YGL after CCl 4 -induced liver damage. YGL also suppressed the increase of TGF-β1, TNF-α, IL-1β, IL-6, IL-4 and IL-17 A induced by CCl 4 treatment, while promoted IFN-γ expression. Finally, the transcription factors ROR-γt and GATA3 were decreased, while T-bet was increased after YGL treatment. These results suggested that YGL attenuated CCl 4 -induced hepatic fibrosis by accelerating the extracellular matrix degradation, blocking the TGF-β1/Smad signaling pathway and modulating the balance among IL-4, IL-17 A and IFN-γ, demonstrating YGL protective effect and its potential mechanisms in treating liver fibrosis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Liver fibrosis is a consequence of chronic liver disease that can progress to liver cirrhosis or even hepatocarcinoma. Fuzheng Huayu (FZHY), a Chinese herbal formula, has been shown to exert anti-fibrotic effects. To better understand the molecular mechanisms underlying the anti-fibrotic effects of FZHY, we analyzed transcriptomic and proteomic combination profiles in CCl 4 -induced liver fibrosis in rats, which were treated with extracted FZHY powder (0.35 g·kg -1 ·d -1 , ig) for 3 weeks. We showed that FZHY administration significantly improved liver function, alleviated hepatic inflammatory and fibrotic changes, and decreased the hydroxyproline content in the livers of CCl 4 -treated rats. When their liver tissues were examined using microarray and iTRAQ, we found 255 differentially expressed genes (fold change ≥1.5, P<0.05) and 499 differentially expressed proteins (fold change ≥1.2, P<0.05) in the FZHY and model groups. Functional annotation with DAVID (The Database for Annotation, Visualization and Integrated Discovery) showed that 15 enriched gene ontology terms, including drug metabolic process, response to extracellular stimulus, response to vitamins, arachidonic acid metabolic process, response to wounding, and oxidation reduction might be involved in the anti-fibrotic effects of FZHY; whereas KEGG pathway analysis revealed that eight enriched pathways, including arachidonic acid metabolism, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and drug metabolism might also be involved. Moreover, the protein-protein interaction network demonstrated that 10 core genes/proteins overlapped, with Ugt2a3, Cyp2b1 and Cyp3a18 in retinol metabolism pathway overlapped to a higher degree. Compared to the model rats, the livers of FZHY-treated rats had significantly higher mRNA and protein expression levels of Ugt2a3, Cyp2b1 and Cyp3a18. Furthermore, the concentration of retinoic acid was significantly higher in the FZHY-treated rats compared with the model rats. The results suggest that the anti-fibrotic effects of FZHY emerge through multiple targets, multiple functions, and multiple pathways, including FZHY-regulated retinol metabolism, xenobiotic metabolism by cytochrome P450, and drug metabolism through up-regulated Ugt2a3, Cyp2b1, and Cyp3a18. These genes may play important anti-fibrotic roles in FZHY-treated rats.

Babao Dan (BBD), a traditional Chinese medicine, has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the protective effect of BBD on rat hepatic fibrosis induced by diethylnitrosamine (DEN) and explore it possible mechanism. BBD was administrated while DEN was given. After eight weeks, values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated that BBD significantly protected liver from damaging by DEN and had no obvious side effect on normal rat livers. Meanwhile, BBD attenuated hepatic inflammation and fibrosis in DEN-induced rat livers through histopathological examination and hepatic hydroxyproline content. Furthermore, we found that BBD inhibited hepatic stellate cells activation and proliferation without altering the concentration of lipopolysaccharide (LPS) in portal vein. In vitro study, serum from BBD treated rats (BBD-serum) could also significantly suppress LPS-induced HSCs activation through TLR4/NF-κB pathway. In addition, BBD-serum also inhibited the proliferation of HSCs by regulating TLR4/ERK pathway. Our study demonstrated that BBD may provide a new therapy strategy of hepatic injury and hepatic fibrosis.

Ethnopharmacological Relevance: Huangqi Decoction (HQD), a classical traditional Chinese medicine (TCM) formula, is used to treating liver injury in China. The aim of the study is to investigate mechanisms of HQD against dimethylnitrosamine (DMN)-induced liver fibrosis underlying metabolic profiles of bile acids., Materials and Methods: DMN-induced liver fibrosis rats were administrated HQD and its compounds, astragalosides (AS), glycyrrhizic acid (GA) and their combination. The anti-fibrosis effects were evaluated and targeted metabolomics by UPLC-MS was used to examine whether HQD had an influence on bile acid metabolism. The levels of mRNAs associated with bile acid metabolism were expressed by RT-PCR. Chenodeoxycholic acid (CDCA)-induced hepatic stellate cells (HSCs) proliferation and activation were examined using MTS assay and Western blot., Results: Histopathological changes and serum liver function in HQD group had significant improvements (P<0.01). Concentrations of free bile acids and taurine conjugates were significantly increased in DMN group (P<0.05). HQD and its compounds restored the increased bile acids to normal levels, and HQD was more effected on parts of bile acids. Furthermore, the levels of mRNAs related bile acid synthesis and reabsorption such as CYP7A1, CYP8B1, CYP27A1, OATP2, OATP3, OATP4 and NTCP were significantly down-regulated in DMN group (P<0.05), mRNAs related excretion such as MRP3 and BESP were up-regulated (P<0.01), and CYP7A1, CYP8B1, OATP3, OATP4, NTCP and MRP3 restored to normal levels by HQD treatment. Moreover, CDCA-induced HSCs proliferation and activation were weaken by HQD (P<0.05) with down-regulated α-SMA, TGF-β1, p-Smad2 and p-Smad3 expressions., Conclusions: HQD alleviated DMN-induced liver fibrosis with a better effect than its compounds, which may be involved in the regulation of bile acid metabolism enzyme. Moreover, HQD may inhibit CDCA-induced HSCs proliferation and activation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aim: To investigate the hepatoprotective effect of a Cichorium intybus L. extract (CIE) on CCl4-induced hepatic fibrosis in rats., Methods: Seventy-two male Wistar albino rats were randomly divided into six groups of twelve rats each. The normal control group was allowed free access to food and water. Liver injury was performed in the remaining five groups with an i.p. injection of a 1.0 mL/kg CCl4 and olive oil (2:3 v/v) mixture, twice weekly for 8 weeks. All rats, with the exception of the injury model group, were intragastrically (i.g.,) administered quantum satis (q.s.) dosages [CIE group: 6, 18, and 54 mg/kg, respectively; Fu Fang Bie Jia Ruan Gan Pian (FFBJRGP) group: 780 mg/kg]. The oral administration of different drugs was performed on the day before CCl4 administration and subsequently once per day for 8 wk. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) in the rat livers were measured. Histopathological changes in the liver were assessed for each group using HE staining and a Masson Trichrome examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was examined by immunohistochemical analysis., Results: CIE at oral doses of 6, 18, and 54 g/kg per day showed a significant hepatoprotective effect, especially at a dose of 54 g/kg per day. CIE doses reduced the levels of AST (149.04 ± 34.44, P < 0.01), ALT (100.72 ± 27.19, P < 0.01), HA (548.50 ± 65.09, P < 0.01), LN (28.69 ± 3.32, P < 0.01) and Hyp (263.33 ± 75.82, P < 0.01). With regards to hepatoprotective activity, the CIE dose of 54 g/kg per day produced the largest significant effect by increasing GSH (3.11 ± 0.81), SOD (269.98 ± 33.77, P < 0.01) and reducing MDA (2.76 ± 0.51, P < 0.01) levels in the liver. The expressions of TGF-β1 and α-SMA were measured by immunohistology and found to be significantly reduced by CIE in a dose-dependent manner., Conclusion: CIE may effectively protect against CCl4-induced hepatic fibrosis in rats; thus, it is a promising anti-fibrotic therapeutic agent.

A comparison of analysis in evaluating the hepatoprotective action of fractional ethanolic (F0), ethyl acetic (F1), n-butanol (F2) and aqueous (F3) extracts of E. ulmoides Oliv. (EUO) against thioacetamide (TAA) induced hepatic damage was studied in mice. The extract (453 mg/kg-F0, 104 mg/kg-F1, 95 mg/kg-F2 and 237 mg/kg-F3 body weight, po, once daily for 15 days) restored serum marker enzymes levels to normal in TAA treated mice. The biochemical biomarkers viz., total protein, albumin and total bilirubin were also restored forward normal level expression pattern of liver protein profile of mice by using sodium dodecyl sulfate polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis showed 144 spots in TAA administered group which were significantly reduced in EUO extracts treated group. Among the four extracts ethyl acetate (F1) and n-butanol (F2) extracts showed more significant liver protection. TAA induced injury can be correlated with its high phenolic content in these extracts which may have hepatoprotective effects in regulating liver proteins by scavenging free radicals.

Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

Chunggan extract (CGX) is a hepatotherapeutic herbal formula which has been traditionally used for patients suffering from various hepatic disorders. This study aimed to elucidate antifibrotic effect and mechanisms of CGX in thioacetamide (TAA) model. Hepatic fibrosis was induced in 45 Sprague-Dawley rats by TAA (200 mg kg(-1), intraperitoneally [ip]) on twice per week for 12 weeks. CGX (100 or 200 mg kg(-1), per oral [po]) was administrated once a day throughout the experiment. CGX treatment ameliorated serum biomarkers. CGX administration significantly attenuated distortion of histopathologic finding, and accumulation of hydroxyproline and malondialdehyde (MDA). CGX treatment significantly decreased transforming growth factor-beta (TGF-β) concentrations and inactivated hepatic stellate cells (HSCs). CGX treatment drastically restored glutathione (GSH) system, while inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α) significantly down-regulated in liver tissue. CGX showed antifibrotic effect in thioacetamide-induced chronic liver injury model. Its corresponding mechanisms may be mediated via anti-oxidative stress property sustaining GSH system and inhibition of ROS production.

Objectives: The study was to investigate the prevention effects and possible mechanism of Yu Ping Feng San fractioned polysaccharide (YPF-P) on CCl(4)-induced liver fibrosis in rats., Methods: YPF-P was prepared from root of Astragalus membranaceus, rhizome of Atractylodes macrocephaia and root of Raidix saposhnikoviae, and compared with polysaccharide from root of Astragalus membranaceus (AP). Hepatic fibrosis was induced by subcutaneous injection with carbon tetrachloride twice weekly for 12 weeks in Sprague-Dawley rats. YPF-P, AP and colchicine were administered intragastrically daily to carbon tetrachloride-treated rats. Histopathological changes of the liver and hepatic stellate cells were evaluated by Masson staining and transmission electron microscopy, respectively. Markers of fibrosis were determined by radioimmunoassay, biochemistry assay and ELISA. The mRNA expressions of tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-13 (MMP-13), procollagen I and collagen III were detected by RT-PCR., Key Findings: YPF-P dose-dependently alleviated the degree of liver fibrosis and inhibited hepatic stellate cell transformation into myofibroblast-like cells, markedly reduced the elevated levels of hyaluronic acid, laminin, type IV collagen, type III procollagen, hydroxyproline and transforming growth factor beta-1, suppressed procollagen I, collagen III and TIMP-1 expression, and improved the TIMP-1/MMP-13 ratio. MMP-13 expression was only promoted moderately by YPF-P. Compared with AP, YPF-P showed more potency on most markers except laminin, type IV collagen and MMP-13 mRNA., Conclusions: YPF-P prevented the progress of rat liver fibrosis induced by carbon tetrachloride and had a more potent preventative effect. The preventative effect may be associated with the ability of YPF-P to inhibit the synthesis of matrix collagen and balance the TIMP/MMP system.

Objectives: It was found that total flavonoids from Litsea coreana Levl. (TFLC), which is a traditional Chinese medicine, had a preventive effect against hepatic steatosis in our previous study. This study was designed to evaluate whether TFLC could improve liver fibrosis in rats., Methods: The liver fibrosis model rats were treated with composite factors of high-fat emulsion (10 ml/kg) via gavage accompanied by a subcutaneous injection of low-dose CCl(4). Thirty rats were given composite factors plus TFLC (100, 200, 400 mg/kg), respectively, for 8 weeks., Key Findings: The results showed that TFLC (200 and 400 mg/kg) treatment significantly reduced the elevation of liver index (liver weight/body weight) and spleen index (spleen weight/body weight), alanine transaminase, aspartate aminotransferase, hyaluronic acid, laminin, procollagen III N-terminal peptide, procollagenase IV and hydroxyproline. In addition, TFLC treatment improved the morphologic changes of hepatic fibrosis, suppressed expression of alpha-smooth muscle actin, collagen I, transforming growth factor (TGF)-beta1 and TGFbeta receptor (TGFbetaR)1, and increased peroxisome proliferator-activated receptor-gamma expression in the liver of hepatic fibrosis rats., Conclusions: In conclusion, TFLC is able to ameliorate liver injury and protect rats from liver fibrosis. This process may be related to inhibiting the expression of transforming growth factor-beta1 and increasing the expression of peroxisome proliferator-activated receptor-gamma.

Objective: To investigate the prevention and treatment of experimental liver fibrosis in rats by Semen Hoveniae extracts (SHE)., Methods: Rats liver fiborsis model was induced by carbon tetrachloride (CCl4). SD rats were randomly divided into six groups: the normal control group, the model control group, the positive control group and the SHE groups. The level of serum procollgan type-III (PC-III), hyaluronic acid (HA), laminin (LN) and liver function were measured, respectively. Liver histological examination was made., Results: SHE could ameliorate CCl4-induced liver fibrosis significantly. The lever of serum PC-III, HA, LN decreased and liver function was improved. The histological examination also demonstrated its anti-fibrotic effect., Conclusion: SHE have anti-fibrotic effect on liver in vivo, and may have potential value for clinical use.

Objective: To study the effects of Bushen Rougan Recipe (BSRGR), a compound traditional Chinese herbal medicine, on hepatic fibrosis in rats induced by dimethylnitrosamine (DMN), and to explore its preliminary mechanism., Methods: A total of 40 male Wistar rats were randomly divided into normal control group (n=10), untreated group (n=15), and BSRGR group (n=15). Except for the rats in normal control group, hepatic fibrosis in rats was induced by peritoneal injection of DMN for 4 weeks. And the rats in the BSRGR group were also intragastrically administered BSRGR within the 4-week course. At the end of the 4-week course, rats were all sacrificed. The liver functions were determined by automatic biochemistry analyzer, including serum total bilirubin (Tbil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin. Expressions of connective tissue growth factor (CTGF) and collagen type I mRNA in liver tissue were detected by reverse transcription polymerase chain reaction., Results: It was found that the serum Tbil level and the activities of AST, ALT were declined in the BSRGR group as compared with those in the untreated group (P<0.01). The serum albumin content in the BSRGR group was increased as compared with that in the untreated group (P<0.01). The expressions of collagen type I and CTGF mRNAs in the untreated group were higher than those in the BSRGR group (P<0.01)., Conclusion: BSRGR can decrease the expressions of collagen type I and CTGF mRNAs in the rats with hepatic fibrosis, which may be one of possible mechanisms in treating hepatic fibrosis.

Piper betel leaves (PBL) are used in Chinese folk medicine for the treatment of various disorders. PBL has the biological capabilities of detoxication, antioxidation, and antimutation. In this study, we evaluated the antihepatotoxic effect of PBL extract on the carbon tetrachloride (CCl(4))-induced liver injury in a rat model. Fibrosis and hepatic damage, as reveled by histology and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were induced in rats by an administration of CCl(4) (8%, 1 ml/kg body weight) thrice a week for 4 weeks. PBL extract significantly inhibited the elevated AST and ALT activities caused by CCl(4) intoxication. It also attenuated total glutathione S-transferase (GST) activity and GST alpha isoform activity, and on the other hand, enhanced superoxide dismutase (SOD) and catalase (CAT) activities. The histological examination showed the PBL extract protected liver from the damage induced by CCl(4) by decreasing alpha-smooth muscle actin (alpha-sma) expression, inducing active matrix metalloproteinase-2 (MMP2) expression though Ras/Erk pathway, and inhibiting TIMP2 level that consequently attenuated the fibrosis of liver. The data of this study support a chemopreventive potential of PBL against liver fibrosis.

Objective: To observe the effect of Fuzheng Jiangan formula( FZJGF) on liver fibrosis using immune induced liver fibrosis rat model., Method: The rat models with immunity liver fibrosis were induced by the human serum albumin. Rats were treated with normal saline, FZJGF (9. 85,39. 4 g x kg(-1) , two dosage groups) and Colchicine (0. 000 1 g . kg(-1) ). The activities of ALT, AST, contents of ALB and TP, and A/G, The contents of Laminin (LN), Hyaluronic acid (HA) and collagen type IV (IV-C) in rat serum were measured by radioimmunoassay method. The level of hydroxyproline (Hyp) in liver was detected by chemistry method. The pathological changes of liver tissue were observed by HE and Von-Gieson staining., Result: FZJGF could significant decrease the serum activities of ALT and AST, and increase the levels of TP,Alb and ratio A/G. The levels of LN, HA and IV-C were decreased significantly after the treatment using FZJGF. The pathological improvements were observed. FZJGF could markedly alleviate the deposition of collageneous fiber, and reduce the liver pseudoluboli and the fibrosis scores in the liver tissue compared with model group., Conclusion: FZJGF can inhibit formation and development of rat hepatic fibrosis induced by the human serum albumin.

Apoptosis is one of the events that are involved in liver fibrogenesis. Thus, factors that affect apoptosis may be used to modulate liver fibrosis. We have recently reported that Salvia miltiorrhiza plays a protective role in carbon tetrachloride (CCl4)-induced hepatic fibrosis. In this study, we aimed to evaluate whether S. miltiorrhiza modulated CCl4-induced hepatic apoptosis in rats. Male Wistar rats were given orally either vehicle or water-extract of S. miltiorrhiza (50 mg kg(-1) twice daily) for nine weeks beginning from the start of CCl4 administration. A group of normal rats was included for comparison. Hepatocyte DNA fragmentation and cytosolic caspase-3 and caspase-8 activity were determined in the experimental animals. Hepatic cytosolic Bax, Bcl-2, cytochrome c, and calpain-mu expressions were measured by Western blot analysis. Hepatic mitochondrial glutathione levels were assessed by colorimetric assay. Compared with normal rats, rats receiving CCl4 alone showed profound DNA fragmentation associated with an increased cytosolic fraction of cytochrome c and calpain-mu protein expressions and a decreased mitochondrial glutathione level. In contrast, a decreased laddering of DNA fragmentation was noted in rats receiving CCl4 plus S. miltiorrhiza extract. The mitochondrial glutathione level was significantly increased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. Additionally, cytosolic caspase-3 activity and cytosolic fractions of Bax, Bcl-2, cytochrome c, and calpain-mu protein expressions were decreased in rats receiving CCl4 plus S. miltiorrhiza extract compared with those receiving CCl4 alone. The cytosolic caspase-8 activity in rats receiving CCl4 alone was no different from those receiving CCl4 plus S. miltiorrhiza extract. These results indicated that chronic administration of S. miltiorrhiza ameliorated CCl4-mediatd hepatic apoptosis in rats. This effect may be related to the antioxidant properties of S. miltiorrhiza.

Background/aims: We studied the effect of Inchin-ko-to (TJ-135), a herb medicine that has been clinically used for liver cirrhosis in Japan, on liver fibrosis in a rat model and on the function of stellate cells., Methods: Rat liver fibrosis was generated by thioacetamide (TAA) administration. DNA synthesis was assessed by 5-bromo-2'-deoxyuridine incorporation assay. Protein expression was analysed by western blotting. Collagen and fibronectin mRNA expression were analysed by reverse transcription-polymerase chain reaction (RT-PCR)., Results: TJ-135 improved liver fibrosis induced in rats by TAA administration. TJ-135 reduced collagen deposition and the expression of smooth muscle alpha-actin in fibrotic liver tissues and decreased the serum level of hyaluronic acid. In primary-cultured stellate cells, TJ-135 suppressed DNA synthesis and the expression of collagen alpha 1(I), collagen III, and fibronectin mRNAs. It hampered DNA synthesis and migration of PDGF-BB-stimulated stellate cells through inhibiting phosphorylation of PDGF receptor-beta and down-stream signaling pathways. Among TJ-135 components, 3-methyl-1,6,8-trihydroxyanthraquinone (emodin) derived from Rhei rhizoma was found to be the most active molecule., Conclusions: TJ-135 and emodin regulate PDGF-dependent events in stellate cells and attenuate the development of liver fibrosis. Their clinical use may be beneficial for the therapy of human liver fibrosis.

Objective: To investigate the anti-liver fibrosis effect of total glucosides of Centella asiatica (GCA) in experimental rats., Methods: Rat liver fibrosis model was induced by injecting dimethylnitrosamine (DMN) intraperitoneally for 6 weeks. Rats were randomly divided into 6 groups, the normal group, the model group, the positive control group treated by colchicine, and the three GCA groups treated by high, moderate and low dosage of GCA through gastrogavage started simultaneously with the modeling. At the end of the experiment, levels of serum total protein (TP), albumin (ALB), alanine transaminase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), laminin (LN) were measured, and the pathology of liver tissue was observed., Results: The liver function in the GCA groups was improved, the levels of serum ALT, AST, HA were significantly lower than those in the model group (P < 0.05). Histopathological observation showed that GCA has significant anti-liver fibrosis effect., Conclusion: GCA has significant preventive and therapeutic effect on DMN induced liver fibrosis in rats.

Objective: To investigate the effects of antioxidant curcumin and Na+/H+ exchanger inhibitor amiloride on the fibrosis of rat hepatic stellate cells (HSC) induced by oxidative stress in vitro., Methods: HSC were incubated with 0.1 mmol/L ferric nitrilotriacetate complex (FeNTA). MTT colorimetry was used for assaying proliferation of HSC. Cytotoxicity was measured by LDH colorimetry. Collagen type I accummulation in the culture media was measured by ELISA. Intracellular malonildialdehyde (MDA), SOD, GSH and GSH-Px levels in the culture media were measured by respective reagent boxes., Results: HSC incubation with FeNTA resulted in a significant production of intracellular MDA and GSH, associated with decrease of SOD and GSH-PX activity. Exposure of HSC to FeNTA significantly enhanced the number of proliferating HSC and collagen type I levels in the culture medium. All these effects were reversed by the antioxidant curcumin and by the Na+/H+ exchanger inhibitor amiloride. Combining curcumin with amiloride had better effects on the fibrosis of rat hepatic stellate cells induced by oxidative stress than curcumin or amiloride., Conclusion: The effects of combination of antifibrosis drugs curcumin and amiloride on different targets of HSC are superior to curcumin or amiloride.

Han-Dan-Gan-Le (HDGL), a Chinese herb preparation composed of Stephaniat tetrandra, Salvia miltorrhiza, Radix paeoniae, Astragalus membranaceus, and Ginkgo biloba, has been used to treat human liver fibrosis. This study was designed to examine the therapeutic effect of HDGL on chemical-induced liver fibrosis in adult Wistar rats. Liver fibrosis was produced in rats by carbon tetrachloride (1.2 ml CCl(4)/kg, 2 times/week, after an initial dose of 5.0 ml CCl(4)/kg, sc), plus a diet of 20% fat, 0.05% cholesterol (continuous) and 30% alcohol in the drinking water ad libitum (every other day) for 8 weeks. HDGL (0.5 and 1.0 g/kg, ig, daily for 6 weeks) was administered to rats 72 hrs after the last dose of CCl(4) to examine its therapeutic effects on chemical-induced liver fibrosis. Upon pathological examination, the HDGL treatment had significantly reversed chemical-induced liver fibrosis and other hepatic lesions. Hepatic collagen accumulation induced by CCl(4) was markedly reduced by HDGL treatment, as evidenced by hepatic collagen content and by immunohistochemical analysis of type-I collagen in liver. HDGL appeared to stimulate the collagenolytic process in the liver, as a 30-50% increase in urinary excretion of hydroxyproline was observed with HDGL treatment as compared to rats only given CCl(4). In conclusion, HDGL can effectively reverse chemically induced liver fibrosis, and this appears to be due, at least in part, to the stimulation of hepatic collagenolysis, resulting in a resolution of hepatic fibrosis.

Gypenoside is a saponins extract derived from the Gynostemma pentaphyllum. The purpose of this study was to evaluate the hepatoprotective and antifibrotic potential of Gypenoside on chronic liver injury induced by CCl4 for 8 wks. The results indicated that the increase of SGOT, SGPT activities in CCl4 liver injury were significantly reduced by treatment with Gypenoside. It also elevated the A/G ratio. For the study of anti-fibrotic potential, Gypenoside reduced the collagen content by 33%. These phenomena were confirmed by pathologic observation; thinner bands of liver collagen were found. The results suggest that Gypenoside has hepatoprotective and anti-fibrotic activities.

Objective: To study the effect of DHZC on liver fibrosis., Method: Immuno-injured fibrosis in rats was induced by bovine serum albumin and DHZC was given during and after the model production respectively. Hepatic collagen contents, pathology of liver and serum hyaluronic acid were measured. Colchicine was used as control., Result: It shows that the liver fibrosis rates of the DHZC treated group during and after the model production were 72.7% and 71.2% respectively, while those of the untreated and colchicine group were 92.3%-100%. Compared with the untreated group, there was a remarkable decrease of hepatic collagen contents in the DHZC-treated rats., Conclusion: DHZC have thus been proved helpful in reversing liver fibrosis to some extent.

Background/aim: A herbal medicine, Sho-saiko-to (TJ-9), has recently been orally administered to patients with chronic liver disease in Japan and has been reported to inhibit the development of hepatocellular carcinoma. The aim of this study was to investigate whether TJ-9 has an inhibitory effect on the development of preneoplastic lesions and liver fibrosis in rats., Methods: The effects of the TJ-9 were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis model in 16-week-old male Wistar rats., Results: TJ-9 (1% w/w) prevented fibrosis, as indicated by reduced hydroxyproline content in the liver and inhibition of the increase in a serum marker of fibrosis (hyaluronic acid), without reducing the increase in serum alanine aminotransferase and aspartate aminotransferase. TJ-9 also reduced the expression of type III procollagen alpha 1 mRNA in the liver, as well as the proliferation of myofibroblast-like cells (activated stellate cells, activated Ito cells). Furthermore, TJ-9 reduced the number of preneoplastic lesions, detected as enzyme-altered (glutathione S-transferase placental form-positive) lesions, in the liver., Conclusions: These results indicate that the herbal medicine Sho-saiko-to (TJ-9) prevents fibrosis as well as preneoplastic lesions, not by inhibiting hepatocyte cell death but by inhibiting the activation of stellate cells, which are considered to be the main collagen-producing cells, leading to a reduction in the development of preneoplastic lesions.

Han-Dan-Gan-Le, a Chinese medicine preparation composed of Salvia miltorrhiza, Radix paeoniae, Astragalus membranaceus, Stephania tetrandra, and dried leaves of Ginkgo biloba, has been used successfully to treat human liver fibrosis and cirrhosis for years. This study was designed to examine the mechanisms of the protection. Male Wistar rats were given CCl4 (1.2 ml/kg, 2 times/week), 20% fat diet, and 30% alcohol in drinking water (every other day) for 6 weeks. Han-Dan-Gan-Le (0.5 and 1.0 g/kg, p.o., daily for 6 weeks) was administered to rats simultaneously to examine the protective effects against CCl4-induced liver fibrosis. The experimentally-induced liver fibrosis and other morphological alterations were significantly ameliorated by Han-Dan-Gan-Le. Han-Dan-Gan-Le treatments decreased CCl4-induced hepatic collagen accumulation by more than 50%, and significantly increased urinary excretion of hydroxyproline. The CCl4-induced lipid peroxidation in liver and serum was ameliorated as a result of Han-Dan-Gan-Le treatment, possibly by restoring the activity of superoxide dismutase activity in liver and erythrocytes, In conclusion, Han-Dan-Gan-Le is effective in protecting against liver fibrosis. The mechanisms of the protection appear to be due to its antioxidant properties and the modulation of hepatic collagen metabolism.