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Chinese medicines as a resource for liver fibrosis treatment

Chinese Medicine volume 4, Article number: 16 (2009) Cite this article

Abstract

Liver fibrosis is a condition of abnormal proliferation of connective tissue due to various types of chronic liver injury often caused by viral infection and chemicals. Effective therapies against liver fibrosis are still limited. In this review, we focus on research on Chinese medicines against liver fibrosis in three categories, namely pure compounds, composite formulae and combination treatment using single compounds with composite formulae or conventional medicines. Action mechanisms of the anti-fibrosis Chinese medicines, clinical application, herbal adverse events and quality control are also reviewed. Evidence indicates that some Chinese medicines are clinically effective on liver fibrosis. Strict quality control such as research to identify and monitor the manufacturing of Chinese medicines enables reliable pharmacological, clinical and in-depth mechanism studies. Further experiments and clinical trials should be carried out on the platforms that conform to international standards.

Background

Liver fibrosis is a condition of abnormal proliferation of connective tissue due to various types of chronic liver injury often caused by viral infection and chemicals. Hepatitis B viral (HBV) infection is the major cause of liver fibrosis in China, whereas hepatitis C viral (HCV) infection and alcohol are the main causes in the United States, Europe and Japan [1–4]. Liver fibrosis may progress into liver cirrhosis and other complications coupled with carcinogenesis [5, 6]. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the over-expression and over-secretion of collagens, and consequently an excessive accumulation of extracellular matrix (ECM) proteins [7]. Research has been focused on the management of liver fibrosis including the elimination of primary diseases, immunomodulation, suppression of hepatocyte inflammation, prevention of death and damage of hepatocytes, inhibition of over-secretion and accumulation of ECM proteins, promotion of ECM degradation, improvement of microcirculation and metabolism of liver and reduction of complications [8]. The reversal of liver fibrosis and even cirrhosis has been documented [9].

Complementary and alternative treatments of liver fibrosis have been under active research worldwide [10–12]. In Chinese medicine, liver fibrosis is thought to be caused by 'poor blood circulation, toxin stagnation and a deficiency of healthy energy' (dysregulated metabolism). Thus, Chinese medicine therapy to treat liver fibrosis is mainly based on reducing blood stagnation, resolving stasis, eliminating toxins and enhancing body immunity.

This review aims to provide an overview on the types of Chinese medicines used to treat liver fibrosis.

Chinese medicines used to treat liver fibrosis

Compounds and extracts

Around 20 compounds or extracts from Chinese medicines have been reported to have liver protective and anti-fibrotic effects. Various studies on their chemistry and pharmacology as well as clinical trials have been carried out to study these compounds or extracts. Table 1 summarizes those with liver protection and anti-fibrotic effects demonstrated in various research reports [13–68].

Table 1 Anti-fibrosis effect of compounds or extracts derived from Chinese medicines
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Composite formulae

More than ten composite formulae for liver fibrosis have been reported [69–108]. Table 2 summarizes traditional composite formulae such as Yinchenhao Tang, Xiao Chaihu Tang, Buzhong Yiqi Tang and Renshen Yangrong Tang as well as modern formulae such as Fufang Jinsane, Danshen Taoxiong Tang, Ershen Zezhu Tang, Buqi Jianzhong Tang, Fangji Tang, Handan Ganle, Ganzhifu and Fuzheng Huayu.

Table 2 Anti-fibrosis effect of composite formulae
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Combination therapy

Studies [109–118] show that combination therapy improves clinical anti-fibrotic effects by using a single compound with composite formulae or Chinese medicines with conventional medicines (Table 3).

Table 3 Anti-fibrosis effect of combinations of single compound and formulae or Chinese medicines and conventional medicines
Full size table

Action mechanisms of Chinese medicines in treating liver fibrosis

Inhibition of viral replication

HBV and HCV infections account for most liver cirrhosis and primary liver cancer worldwide [6]. Certain Chinese medicines are anti-HBV and anti-HCV. Berberine markedly reduces viral production in vitro but is toxic to host cells [51]. Artemisinin and artesunate strongly inhibit viral production at concentrations that do not affect host cell viability; artesunate and lamivudine exhibit synergistic anti-HBV effects [51]. Another study shows that ascucubin inhibits HBV replication [63]. Nobiletin, the active ingredient of Citrus unshiu peel, has anti-HCV effects [94]. Clinical studies show that oxymatrine [28] is effective in reducing hepatitis B viral replication in patients with chronic hepatitis B. Xiao Chaihu Tang enhances production of interferon-gamma (IFN-γ) and antibodies against hepatitis B core and e antigen by peripheral blood mononuclear cells (PBMC) in patients with chronic hepatitis [82]. Handan Ganle inhibits viral DNA replication in patients with decompensated cirrhosis thereby leading to clinical improvement [102].

Immunomodulation action

Buzhong Yiqi Tang and Renshen Yangrong Tang demonstrate immunomodulation effects [91]. In a study on porcine serum-induced liver fibrosis in rats [92], Interleukin 13 (IL-13) levels are positively correlated with hydroxyproline (Hyp) contents in the liver. Buzhong Yiqi Tang and Renshen Yangrong Tang significantly suppress the increase of hepatic Hyp, while Xiao Chaihu Tang does not. Short-term and long-term studies [93] show that Renshen Yangrong Tang is effective in liver fibrosis. Further studies find that Renshen Yangrong Tang inhibits HCV infection, and that Gomisin A, an active component in the formula's Schisandra fruit, exhibits protective effects on immunological hepatopathy [94].

Anti-oxidation and anti-inflammation actions

Salvia miltiorrhizae (Danshen) extract [13] improves serum superoxide dismutase (SOD) activity and reduces malondialdehyde (MDA) content in both carbon tetrachloride (CCl4) and dimethylnitrosamine (DMN) induced hepatic fibrosis rat models. Salvia miltiorrhizae extract [18] increases hepatic glutathione levels and decreases peroxidation products in a dose-dependent manner. Taurine [27, 28] reduces oxidative stress and prevents progression of hepatic fibrosis in CCl4-induced hepatic damaged rats and inhibits transformation of the hepatic stellate cell (HSC). In chronic ethanol-induced hepatotoxicity or CCl4-induced rat liver fibrosis, Panax notoginseng (Tianqi) extract or total saponin extracted from Panax notoginseng reduces the generation of MDA, scavenges free radicals, increases liver and serum SOD content and reduces the accumulation of body lipid peroxide [44–46]. Ginkgo biloba (Yinxing) extract [49, 50] and berberine [54, 55, 60] exhibit anti-oxidation effects and suppress nuclear factor κB (NF-κB) in rats or cell culture. Yinchenhao Tang is used to treat liver fibrosis and portal hypertension through suppressing the activated HSC function by genipin, an absorbed form of its component, in CCl4-or pig-serum- induced rat liver fibrosis [72]. Lin et al. [68] find that the hepatoprotective effect of Solanum nigrum Linn extract on CCl4-induced liver fibrosis is achieved through blocking oxidative stress. Xiao Chaihu Tang [76, 83, 85] whose active components baicalin and baicalein function as a potent fibrosis suppressant via the inhibition of the oxidative stress in hepatocyte and HSC. Handan Ganle [99] is effective in protecting against liver fibrosis by inhibiting lipid peroxidation in hepatocytes and HSC in vivo.

Regulation of cytokines, collagen metabolism and inhibition of HSC

The fibrogenic process is regulated by TGF-β1 and the specific blockade of TGF-β1/Smad3 signalling may therapeutically intervene in the fibrosis of various tissues [119]. Most of the Chinese medicines listed in Tables 1 and 2 exhibit in vitro and in vivo inhibitory effects on TGF-β1. Salvianolic acid B (SA-B) inhibits HSC proliferation and collagen production and decreases the cellular TGF-β1 autocrine and Mitogen-Activated Protein Kinase (MAPK) activity, which may be the anti-fibrosis mechanism of SA-B [14, 17]. Paclitaxel, a compound isolated from Taxus brevifolia, suppresses the TGF-β1 signalling pathway between biliary epithelium cells and myofibroblasts and reduces collagen synthesis [120]. Yinchenhao Tang [71] regulates platelet-derived growth factor (PDGF)-BB-dependent signalling pathways of HSC in primary culture and attenuates the development of liver fibrosis induced by thioacetamide in rats. Among the components of Yinchenhao Tang, 3-methyl-1,6,8-trihydroxyanthraquinone (emodin) derived from Rhei rhizoma is the most active compound [72]. Genipin, a metabolite derived from Yinchenhao Tang, suppresses wound-induced cell migration and proliferation and decreases collagen type I, TGF β1 and α-smooth muscle actins (α-SMA) mRNA and protein expression [76]. Chen et al. [67] demonstrate that Gypenosides inhibits PDGF-induced HSCs proliferation through inhibiting the signalling pathway of PDGF-Akt-p70S6K and down-regulating cyclin D1 and D3 expression. Another study shows that ganoderic acids and ganoderenic acids in Ganoderma lucidum (Lingzhi) extract significantly inhibit the proliferation of HSCs by attenuating the blockade of PDGFβR phosphorylation [66]. Chen et al. [88] show that 0.5 g/kg/day of Xiao Chaihu Tang significantly reduces the serum level of the N-terminal pro-peptide of collagen type III (PIII NP) and the mRNA expression of TGF-β1 and PDGF in a rat bile duct ligated model.

Anti-apoptosis in hepatocyte and inducement of apoptosis in HSC

Yamamoto et al. [73] find that Yinchenhao Tang inhibits hepatocyte apoptosis induced by TGF-β1 in vitro. Another study [74] demonstrates that pre-treatment with Yinchenhao Tang markedly suppresses liver apoptosis/injury. Genipin, which is a principal ingredient of Yinchenhao Tang, suppresses Fas-mediated apoptosis in primary-cultured murine hepatocytes in vitro [73]. The resistance to Ca2+-induced mitochondrial permeability transition (MPT) is enhanced in liver mitochondria of genipin-treated mice [74]. These results suggest that the anti-apoptotic activity of genipin via the interference with MPT is a possible mechanism for the therapeutic effects of Yinchenhao Tang and that Yinchenhao Tang and its ingredient genipin protect hepatocyte from liver apoptosis/injury. Conversely, activated HSC plays a pivotal role in hepatic fibrosis, HSC apoptosis is involved in the mechanisms of spontaneous resolution of rat hepatic fibrosis, and the agent that induces HSC apoptosis has been shown to reduce experimental hepatic fibrosis in rats [121]. Considerable interest has been generated in uncovering the molecular events that regulate HSC apoptosis and discovering drugs that can stimulate HSC apoptosis in a selective manner. Ikeda et al. [75] find that Yinchenhao Tang induces HSC apoptosis in a time- and concentration-dependent manner as judged by the nuclear morphology, quantitation of cytoplasmic histone-associated DNA oligonucleosome fragments and caspase-3 activity. Thus, the induction of HSC apoptosis may be the mechanism whereby Yinchenhao Tang treats hepatic fibrosis. Tetrandrine [29] also induces apoptosis of T-HSC/Cl-6 cells and induces the activation of caspase-3 protease and subsequent proteolytic cleavage of poly (ADP-ribose) polymerase.

Synergistic effects on liver fibrosis and carcinogenesis

Berberine derived from berberis markedly reduces viral production in vitro [51]. In liver damage induced by paracetamol or CCl4, Berberis aristata fruit extract and berberine, its principal ingredient, show hepato-protective action [52, 53]. Berberine also exhibits antioxidative effects on tert-butyl hydroperoxide-induced oxidative damage in rat liver [54] and in the lipopolysaccharide (LPS) plus ischemia-reperfusion model [55]. Berberine abolishes acetaldehyde-induced NF-κB activity and cytokine production in a dose dependent manner, suggesting the potential role of berberine to treat alcoholic liver disease (ALD) [56]. In the rat liver fibrosis induced by multiple hepatotoxic factors (CCl4, ethanol and high cholesterol), the serum levels of ALT and AST and the hepatic content of MDA and Hyp are markedly decreased, while the activity of hepatic SOD is significantly increased in berberine-treated groups in a dose-dependent manner. In addition, histopathological changes, such as steatosis, necrosis and myofibroblast proliferation, are reduced and the expression of α-SMA and TGF-β1 is significantly down-regulated in the berberine-treated groups [57].

Clinically, berberine has been used in Japan to alleviate hypertyraminemia in patients with liver cirrhosis [58]. Berberine possesses anti-tumor effects in rats and mice with chemical-induced liver cancer [59] and anti-invasion in human lung cancer cell lines [60]. The mechanism may be related to its anti-inflammation effects [60, 61]. The inhibitory effects of two different doses of berberine in human liver cancer HepG2 cell lines display different effects: in HepG2 cells treated with 24.0 mg/L of berberine, an increase in the sub G0 phase that indicates cell death is observed in cell cycle analysis with flow cytometry, however, there is no significant increase in sub G0 in HepG2 cells treated with 4.0 mg/L of berberine [62]. These results demonstrate that the dosage of berberine is a meaningful factor in liver diseases treatment. Composite formulae, such as Xiao Chaihu Tang, not only inhibit viral replication, ameliorate inflammation and enhance regeneration of hepatic cells, but also inhibit HSC proliferation, suppress intra- and extra-cellular secretion, decrease the secretion of collagen and promote its degradation and re-absorption [79–90]. Shimizu et al. [83] show that Xiao Chaihu Tang functions as a potent anti-fibrosis agent via the inhibition of oxidative stress in hepatocytes and HSCs and that its active components are baicalin and baicalein. It should be noted that baicalin and baicalein are flavonoids with chemical structures very similar to silybinin which possess anti-fibrogenic activities. Several composite formulae have been used to improve ascites induced by hepatic cirrhosis in chronic hepatitis B (CHB) or chronic hepatitis C (CHC) patients. We demonstrate that Buqi Jianzhong Tang and Fangji Tang increase Na+ excretion and urine volume and reduce GOT and GPT in rats with CCl4- induced liver damage [89, 98]. Most of the Chinese medicines in Tables 1 and 2 reduce serum enzymes, i.e. aspartate transaminase (AST) and alanine transaminase (ALT). A study with multivariate analysis demonstrates that the mode of therapy and ALT levels are significant factors affecting HCC development [26]. Glycyrrhizin administered as Stronger Neo Minophagen C (SNMC) and Xiao Chaihu Tang exhibit this effect [24–26, 90] in long-term clinical trials. Considered to possess anti-carcinogenic properties, Xiao Chaihu Tang inhibits chemical hepatocarcinogenesis in animals, acts as a biological response modifier and suppresses the proliferation of hepatoma cells by inducing apoptosis and arresting the cell cycle. Among the active components of Xiao Chaihu Tang, baicalin, baicalein and saikosaponin have the ability to inhibit cell proliferation [90].

Efficiency and safety of Chinese medicines in treating liver fibrosis

Efficacy

Some anti-fibrosis Chinese medicines, such as Salvianolic acid B (SA-B), tetrandrine and oxymatrine, are clinically effective. SA-B reverses liver fibrosis in chronic hepatitis B patients. SA-B reduces the serum HA content and decreases the overall serum fibrosis markers better than IFN-γ [14]. A multi-centre, randomized, double-blind, placebo-controlled clinical trial shows that oxymatrine effectively reduces the DNA replication of HBV [34, 35] and the therapeutic effect is even stronger when used together with Xiao Chaihu Tang [110]. A double-blind, randomized, placebo-controlled phases I/II trial of intravenous glycyrrhizin for the treatment of chronic hepatitis C shows that glycyrrhizin lowers serum ALT and that the treatment has no effect on the RNA levels of HCV [23]. Long-term clinical trials in Japan and the Netherlands demonstrate that interferon non-responder patients with chronic hepatitis C and fibrosis stage 3 or 4 have a reduced incidence rate of HCC after glycyrrhizin therapy normalizes ALT levels [24, 25].

In China and Japan, many composite formulae are used to treat liver fibrosis and cirrhosis (Table 2) and the pharmacological effects and mechanisms have been demonstrated [69–94]. Experimental and clinical studies show that Handan Ganle is effective [99–102]. Fuzheng Huayu, another modern formula, has also been intensively studied [104–107]. The results suggest that Fuzheng Huayu's anti-fibrosis effects may be associated with the inhibition of liver collagen production [104]. Further study reveals that the conditioned medium from activated HSC stimulates the quiescent HSC proliferation and type I collagen secretion and that the drug serum inhibits this stimulating action and vascular endothelial growth factor (VEGF) secretion from the activated HSC. Fuzheng Huayu acts effectively against the autocrine activation pathway of HSC [105].

A recent study demonstrates the action of Fuzheng Huayu against HSC activation via the fibronectin/integrin-5β1 signalling pathway [107]. Another study shows that Fuzheng Huayu alleviates liver fibrosis without any adverse events [106]. A systematic review analyzes the efficacy and safety of Fuzheng Huayu in treatment of CHB fibrosis [108] based on clinical trials with placebo and/or random control (other positive Chinese medicines and conventional drugs). Seven studies on Fuzheng Huayu in the treatment of CHB fibrosis (total 590 cases) are included in the systematic review. This systematic review concludes that Fuzheng Huayu has significant improvement of serum fibrosis index and pathology of liver biopsy (class S in fibrosis) without observable adverse events, although some included studies are of low quality and are small randomized clinical trials.

The combined therapy with ursodeoxycholic acid and glycyrrhizin is safe and effective in improving liver-specific enzyme abnormalities, and may be an alternative to interferon in chronic hepatitis C viral infection, especially for interferon-resistant or unstable patients [110]. The antiviral efficacy of Bushen granule (BSG) coupled with marine injection (MI) to treat chronic hepatitis B was more effective than lamivudine treatment [118]. Other reports of therapeutic value gained through combining conventional and Chinese medicines can be found in Table 3[112–117].

Safety

There have been reports on adverse events and hepatotoxicity caused by herbal medicines [122]. Xiao Chaihu Tang, used alone or in combination with interferon, may induce acute interstitial pneumonia in patients with chronic active hepatitis [113, 114]. Glycyrrhizin injection may induce fatal biliary cirrhosis [123]. A one-year study demonstrates that Chinese medicines caused hepatotoxicity in patients with chronic hepatitis B [124]. Some of hepatic veno-occlusive diseases have been ascribed to toxicity of herbs; however, the toxic compounds remain to be determined. Hepatic veno-occlusive disease may result from pyrrolizidine alkaloids which are found in numerous plants worldwide. Systematic toxicological knowledge of Chinese medicines is available [125].

Adverse events in the cases of herbal toxicity are in fact very complex. The fatal biliary cirrhosis case [123] was a 50-year-old woman suffering from a diffuse skin rash, high fever and jaundice immediately after a second injection of glutathione and stronger neo-minophagen C, which contains glycyrrhizin. It is difficult to determine the cause of the adverse events to be indeed glycyrrhizin (which is extracted from Glycyrrhiza uralensis) for the following reasons: (1) no literature has shown the hepatotoxicity of glycyrrhizin until now; (2) stronger neo-minophagen C includes 0.1% cysteine and 2.0% glycine in physiological saline solution as well as 0.2% glycyrrhizin, and is also combined with glutathione; and (3) the clinical indication of glycyrrhizin was clear enough (glycyrrhizin is only used in chronic liver hepatitis without bile duct obstruction, which is Yinchenhao Tang's indication in Chinese medicine clinical practice), and glycyrrhizin has no anti-fibrotic effect in rats with fibrosis induced by bile duct ligation and scission [65].

Evidence against Chinese medicines

While ample evidence supports Chinese medicines in treating liver fibrosis, some recent reviews on clinical trials did not find significant effects. Levy et al. [126] review the use of silymarin, glycyrrhizin, Xiao Chaihu Tang, Phyllanthus amarus, Picrorrhiza kurroa, Compound 861, CH-100 and LIV.52 used to treat chronic liver diseases. Dhiman et al. [127] review Phyllanthus, Silybum marianum (milk thistle), glycyrrhizin and LIV.52 used to treat liver diseases. However, neither review recommends the use of herbal medicines to treat chronic liver diseases.

SA-B, Glycyrrhizin, Xiao Chaihu Tang and Yinchenhao Tang are used to treat chronic liver diseases in China and Japan. The major active herb is coptis, of which berberine is the major active component [128]. According to Chinese medicine theory, we use coptis to treat various liver diseases and cancer in Hong Kong [129]. We also propose to replace bear bile with coptis in Chinese medicine practice [130].

Further studies on pharmacological actions and clinical efficacies of the anti-fibrosis effects of Chinese medicines are warranted. Systematic reviews to evaluate clinical studies on the efficacy and safety of Chinese medicines are also necessary. An exemplifying strategy for these studies is demonstrated in Figure 1.

Figure 1
figure 1

Research chart of Chinese medicines for liver fibrosis. The re-evaluation involved in pharmaceutical and medical research including herb quality control, mechanism study and clinical trial will be carried out on standardized international platforms.

Full size image

Conclusion

Evidence indicates that some Chinese medicines are clinically effective in treating liver fibrosis. Strict quality control of Chinese medicines is critical [131] for pharmacological, clinical and in-depth mechanism studies [132]. Experiments and clinical trials should be carried out on the platforms that conform to international standards [133].

Abbreviations

ECM:

extracellular matrix

HSC:

hepatic stellate cell

CAM:

complementary and alternative medicine

SA-B:

salvianolic acid B

HBV:

hepatitis B virus

HCV:

hepatitis C virus

CHB:

chronic hepatitis B

CHC:

chronic hepatitis C

AST (= GOT):

aspartate aminotransferase

ALT (= GPT):

alanine aminotranferease

TGF-β1:

transforming growth factor beta1

Smad3:

SMAD family member 3

Smad7:

SMAD family member 7

smurf2:

Smad ubiquitination regulatory factor 2

TIMP:

tissue inhibitors of metalloproteases

MMP:

matrix metalloproteinase

MAPK:

mitogen-activated protein kinase

NF-κB:

nuclear factor-κB

PDGF:

platelet-derived growth factor

PPARgamma:

proliferator-activated receptor gamma

SOD:

superoxide dismutase

Hyp:

hydroxyproline

HA:

hyaluronic acid

α-SMA:

α-smooth muscle actins

IFN-γ:

interferon-gamma

IFN-α:

interferon-alfa

LN:

laminin

PCIII:

type III procollagen

CIV:

type IV collagen

Tbil:

total bilirubin

TNF-α:

tumor necrosis factor alfa

PIIINP:

the N-terminal pro-peptide of collagen type III

MPT:

mitochondrial permeability transition

Alb:

albumin

BCAA:

branched chain amino acid

AAA:

aromatic amino acid

FN/integrin:

fibronectin (FN)-integrin-5β1 complex.

References

  1. Yuen MF, Lai CL: Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2000, 15 (Suppl): E20-4. 10.1046/j.1440-1746.2000.02123.x.

    PubMed  Google Scholar 

  2. Seeff LB, Hoofnagle JH: The national institutes of health consensus development conference management of hepatitis C 2002. Clin Liver Dis. 2003, 7: 261-87. 10.1016/S1089-3261(02)00078-8.

    PubMed  Google Scholar 

  3. Koike K: Antiviral treatment of hepatitis C: present status and future prospects. J Infect Chemother. 2006, 12: 227-32. 10.1007/s10156-006-0460-0.

    CAS  PubMed  Google Scholar 

  4. Tsukamoto H, Lu SC: Current concepts in the pathogenesis of alcoholic liver injury. FASEB J. 2001, 15: 1335-49. 10.1096/fj.00-0650rev.

    CAS  PubMed  Google Scholar 

  5. Heidelbaugh JJ, Bruderly M: Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician. 2006, 74: 756-62.

    PubMed  Google Scholar 

  6. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP: The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006, 45: 529-38. 10.1016/j.jhep.2006.05.013.

    PubMed  Google Scholar 

  7. Wells RG: The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol. 2005, 39: 158-61. 10.1097/01.mcg.0000155516.02468.0f.

    Google Scholar 

  8. Friedman SL: Liver fibrosis–from bench to bedside. J Hepatol. 2003, 38 (Suppl 1): 38-53. 10.1016/S0168-8278(02)00429-4.

    Google Scholar 

  9. Friedman SL: Reversibility of hepatic fibrosis and cirrhosis–is it all hype?. Nat Clin Pract Gastroenterol Hepatol. 2007, 4 (5): 236-7. 10.1038/ncpgasthep0813.

    PubMed  Google Scholar 

  10. Schuppan D, Jia JD, Brinkhaus B, Hahn EG: Herbal products for liver diseases: a therapeutic challenge for the new millennium. Hepatolog. 1999, 30 (4): 1099-104. 10.1002/hep.510300437.

    CAS  Google Scholar 

  11. Shimizu I: Antifibrogenic therapies in chronic HCV infection. Infect Disord Drug Targets. 2001, 1 (2): 227-40. 10.2174/1568005014606053.

    CAS  Google Scholar 

  12. Seeff LB, Lindsay KL, Bacon BR, Kresina TF, Hoofnagle JH: Complementary and alternative medicine in chronic liver disease. Hepatology. 2001, 34 (3): 595-603. 10.1053/jhep.2001.27445.

    CAS  PubMed  Google Scholar 

  13. Xie HM, Hu YY, Gu HT, Nagano Y, Ji G, Liu P: Study of Salviae miltiorrhizae on liver fibrosis in rats induced by CCl4 and DMN. Zhongxiyi Jiehe Ganbing Zazh. 1999, 9: 16-8.

    Google Scholar 

  14. Liu P, Hu YY, Liu C, Zhu DY, Xue HM, Xu ZQ, Xu LM, Liu CH, Gu HT, Zhang ZQ: Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B. World J Gastroenterol. 2002, 8: 679-85.

    CAS  PubMed  Google Scholar 

  15. Lee TY, Wang GJ, Chiu JH, Lin HC: Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats. J Pharm Pharmacol. 2003, 55: 1561-8. 10.1211/0022357022098.

    CAS  PubMed  Google Scholar 

  16. Wang H, Chen XP, Qiu FZ: Salviae miltiorrhizae ameliorates cirrhosis and portal hypertension by inhibiting nitric oxide in cirrhotic rats. Hepatobiliary Pancreat Dis Int. 2003, 2: 391-6.

    PubMed  Google Scholar 

  17. Zhao JF, Liu CH, Hu YY, Xu LM, Liu P, Liu C: Effect of salvianolic acid B on Smad3 expression in hepatic stellate cells. Hepatobiliary Pancreat Dis Int. 2004, 3: 102-5.

    CAS  PubMed  Google Scholar 

  18. Lee TY, Chang HH, Wang GJ, Chiu JH, Yang YY, Lin HC: Water-soluble extract of Salvia miltiorrhiza ameliorates carbon tetrachloride-mediated hepatic apoptosis in rats. J Pharm Pharmacol. 2006, 58: 659-65. 10.1211/jpp.58.5.0011.

    CAS  PubMed  Google Scholar 

  19. Yamamura Y, Kotaki H, Tanaka N, Aikawa T, Sawada Y, Iga T: The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats. Biopharm Drug Dispos. 1997, 18: 717-25. 10.1002/(SICI)1099-081X(199711)18:8<717::AID-BDD54>3.0.CO;2-U.

    CAS  PubMed  Google Scholar 

  20. Wang JY, Guo JS, Li H, Liu SL, Zern MA: Inhibitory effect of glycyrrhizin on NF-kappaB binding activity in CCl4- plus ethanol-induced liver cirrhosis in rats. Liver. 1998, 18: 180-5.

    CAS  PubMed  Google Scholar 

  21. Iino S, Tango T, Matsushima T, Toda G, Miyake K, Hino K, Kumada H, Yasuda K, Kuroki T, Hirayama C, Suzuki H: Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol Res. 2001, 19: 31-40. 10.1016/S1386-6346(00)00079-6.

    CAS  PubMed  Google Scholar 

  22. Cai Y, Shen SZ, Wang JY: Effects of glycyrrhizin on genes expression during the process of liver fibrosis. Zhonghua Yixue Zazhi. 2003, 83: 1122-5.

    CAS  PubMed  Google Scholar 

  23. Rossum Van TGJ, Vulto AG, Hop WC, Brouwer JT, Niesters HG, Schalm SW: Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double blind, randomised, placebo controlled phase I/II trial. J Gastroenterol Hepatol. 1999, 14: 1093-9. 10.1046/j.1440-1746.1999.02008.x.

    Google Scholar 

  24. Veldt BJ, Hansen BE, Ikeda K, Verhey E, Suzuki H, Schalm SW: Long-term clinical outcome and effect of glycyrrhizin in 1093 chronic hepatitis C patients with non-response or relapse to interferon. Scand J Gastroenterol. 2006, 41: 1087-94. 10.1080/00365520600641365.

    CAS  PubMed  Google Scholar 

  25. Ikeda K, Arase Y, Kobayashi M, Saitoh S, Someya T, Hosaka T, Sezaki H, Akuta N, Suzuki Y, Suzuki F, Kumada H: A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig Dis Sci. 2006, 51: 603-9. 10.1007/s10620-006-3177-0.

    CAS  PubMed  Google Scholar 

  26. Rino Y, Tarao K, Morinaga S, Ohkawa S, Miyakawa K, Hirokawa S, Masaki T, Tarao N, Yukawa N, Saeki H, Takanashi Y, Imada T: Reduction therapy of alanine aminotransferase levels prevent HCC development in patients with HCV-associated cirrhosis. Anticancer Res. 2006, 26 (3B): 2221-6.

    PubMed  Google Scholar 

  27. Wang ZR, Chen XM, Li DG: Tetrandrine inhibits expressions of c-fos and c-jun mRNA in fibrosis liver of rats. Shanghai Yixue. 2003, 26: 332-4.

    CAS  Google Scholar 

  28. Wang H, Chen XP, Qiu FZ: Tetrandrine increased hepatic expression of nitric oxide synthase type II in cirrhotic rats. World J Gastroenterol. 2004, 10: 1923-7.

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Zhao YZ, Kim JY, Park EJ, Lee SH, Woo SW, Ko G, Sohn DH: Tetrandrine induces apoptosis in hepatic stellate cells. Phytother Res. 2004, 18: 306-9. 10.1002/ptr.1435.

    CAS  PubMed  Google Scholar 

  30. Chen YW, Li DG, Wu JX, Chen YW, Lu HM: Tetrandrine inhibits activation of rat hepatic stellate cells stimulated by transforming growth factor-beta in vitro via up-regulation of Smad 7. J Ethnopharmacol. 2005, 100: 299-305. 10.1016/j.jep.2005.03.027.

    CAS  PubMed  Google Scholar 

  31. Hsu YC, Chiu YT, Lee CY, Wu CF, Huang YT: Anti-fibrotic effects of tetrandrine on bile-duct ligated rats. Can J Physiol Pharmacol. 2006, 84: 967-76. 10.1139/Y06-050.

    CAS  PubMed  Google Scholar 

  32. Hsu YC, Chiu YT, Cheng CC, Wu CF, Lin YL, Huang YT: Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis. J Gastroenterol Hepatol. 2007, 22: 99-111. 10.1111/j.1440-1746.2006.04361.x.

    CAS  PubMed  Google Scholar 

  33. Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF, Guo C: Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Acta Pharmacol Sin. 2001, 22: 183-6.

    PubMed  Google Scholar 

  34. Chen YX, Mao BY, Jiang JH: Relationship between serum load of HBV-DNA and therapeutic effect of oxymatrine in patients with chronic hepatitis B. Zhongguo Zhongxiyi Jiehe Zazhi. 2002, 22: 335-6.

    PubMed  Google Scholar 

  35. Mao YM, Zeng MD, Lu LG: Capsule oxymatrine in treatment of hepatic fibrosis due to chronic viral hepatitis: a randomized, double blind, placebo-controlled, multicenter clinical study. World J Gastroenterol. 2004, 10: 3269-73.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Kato J, Ido A, Hasuike S, Uto H, Hori T, Hayashi K, Murakami S, Terano A, Tsubouchi H: Transforming growth factor-beta-induced stimulation of formation of collagen fiber network and anti-fibrotic effect of taurine in an in vitro model of hepatic fibrosis. Hepatol Res. 2004, 30: 34-41. 10.1016/j.hepres.2004.04.006.

    CAS  PubMed  Google Scholar 

  37. Miyazaki T, Karube M, Matsuzaki Y, Ikegami T, Doy M, Tanaka N, Bouscarel B: Taurine inhibits oxidative damage and prevents fibrosis in carbon tetrachloride-induced hepatic fibrosis. J Hepatol. 2005, 43: 117-25. 10.1016/j.jhep.2005.01.033.

    CAS  PubMed  Google Scholar 

  38. Chen ZZ, Wang H: Inhibitory Effects of tetramethylpyrazine on experimental hepatic fibrosis in rats. Zhong Xiyi Jiehe Ganbing Zazhi. 1997, 7: 156-8.

    Google Scholar 

  39. Tan LX, Li XS, Liu ZQ, Liu LY: Effects of combination therapy of rehin and tetramethylpyrazine on experimental hepatic fibrosis induced by tetrachloride. Zhonghua Ganzangbing Zazhi. 2004, 12: 692-3.

    CAS  PubMed  Google Scholar 

  40. Zhan Y, Li D, Wei H, Wang Z, Huang X, Xu Q, Lu H: Emodin on hepatic fibrosis in rats. Chin Med J (Engl). 2000, 113: 599-601.

    CAS  Google Scholar 

  41. Zhan YT, Liu B, Li DG, Bi CS: Mechanism of emodin for anti-fibrosis of liver. Zhonghua Ganzangbing Zazhi. 2004, 12: 245-6.

    PubMed  Google Scholar 

  42. Yang W, Chen H, Jiang Y: Inhibitive effect of curcumin and amiloride on the fibrosis of rat hepatic stellate cells induced by oxidative stress. Zhongyaocai. 2003, 26: 795-8.

    PubMed  Google Scholar 

  43. Zheng S, Chen A: Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro. Biochem J. 2004, 384: 149-57. 10.1042/BJ20040928.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Lin CF, Wong KL, Wu RS, Huang TC, Liu CF: Protection by hot water extract of Panax notoginseng on chronic ethanol-induced hepatotoxicity. Phytother Res. 2003, 17: 1119-22. 10.1002/ptr.1329.

    PubMed  Google Scholar 

  45. Shii XF, Liu Q, Liu L, Xu M: Effect of total saponin of Panax Notoginseng on liver fibrosis in rats. Zhongyao Yaoli yu Linchuang. 2004, 20: 12-4.

    Google Scholar 

  46. Park WH, Lee SK, Kim CH: A Korean herbal medicine, Panax notoginseng, prevents liver fibrosis and hepatic microvascular dysfunction in rats. Life Sci. 2005, 76 (15): 1675-90. 10.1016/j.lfs.2004.07.030.

    CAS  PubMed  Google Scholar 

  47. Gong HY, Wang KQ, Tang SG: Effects of cordyceps sinensis on T lymphocyte subsets and hepatofibrosis in patients with chronic hepatitis B. Hunan Yike Daxue Xuebao. 2000, 25: 248-50.

    CAS  PubMed  Google Scholar 

  48. Liu YK, Shen W: Inhibitive effect of cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism. World J Gastroenterol. 2003, 9: 529-33.

    PubMed  Google Scholar 

  49. Ding J, Yu J, Wang C, Hu W, Li D, Luo Y, Luo H, Yu H: Ginkgo biloba extract alleviates liver fibrosis induced by CCl4 in rats. Liver International. 2005, 25: 1224-32. 10.1111/j.1478-3231.2005.01169.x.

    CAS  PubMed  Google Scholar 

  50. Liu SQ, Yu JP, Chen HL, Luo HS, Chen SM, Yu HG: Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats. Am J Chin Med. 2006, 34: 99-114. 10.1142/S0192415X06003679.

    CAS  PubMed  Google Scholar 

  51. Romero MR, Efferth T, Serrano MA, Castano B, Macias RI, Briz O, Marin JJ: Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an "in vitro" replicative system. Antiviral Res. 2005, 68: 75-83. 10.1016/j.antiviral.2005.07.005.

    CAS  PubMed  Google Scholar 

  52. Gilani AH, Janbaz KH: Preventive and curative effects of berberis aristata fruit extract on paracetamol- and CCl4-induced hepatotoxicity. Phytotherapy Res. 1995, 9: 489-94. 10.1002/ptr.2650090705.

    Google Scholar 

  53. Janbaz KH, Gilani AH: Studies on preventive and curative effects of berberine on chemical-induced hepatotoxicity in rodents. Fitoterapia. 2000, 71: 25-33. 10.1016/S0367-326X(99)00098-2.

    CAS  PubMed  Google Scholar 

  54. Hwang JM, Wang CJ, Chou FP, Tseng TH, Hsieh YS, Lin WL, Chu CY: Inhibitory effect of berberine on tert-butyl hydroperoxide-induced oxidative damage in rat liver. Arch Toxicol. 2002, 76: 664-70. 10.1007/s00204-002-0351-9.

    CAS  PubMed  Google Scholar 

  55. Yokozawa T, Ishida A, Kashiwada Y, Cho Ej, Kim Hy, Ikeshiro Y: Coptidis Rhizoma: protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components. J Pharm Pharmacol. 2004, 56: 547-56. 10.1211/0022357023024.

    CAS  PubMed  Google Scholar 

  56. Hsiang CY, Wu SL, Cheng SE, Ho TY: Acetaldehyde-induced interleukin-1beta and tumor necrosis factor-alpha production is inhibited by berberine through nuclear factor-kappaB signaling pathway in HepG2 cells. J Biomed Sci. 2005, 12: 791-801. 10.1007/s11373-005-9003-4.

    CAS  PubMed  Google Scholar 

  57. Zhang BJ, Xu D, Guo Y, Ping J, Chen LB, Wang H: Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors. Clin Exp Pharmacol Physiol. 2008, 35 (3): 303-9. 10.1111/j.1440-1681.2007.04819.x.

    CAS  PubMed  Google Scholar 

  58. Watanabe A, Obata T, Nagashima H: Berberine therapy of hypertyraminemia in patients with liver cirrhosis. Acta Med Okayama. 1982, 36 (4): 277-81.

    CAS  PubMed  Google Scholar 

  59. Anis KV, Rajeshkumar NV, Kuttan R: Inhibition of chemical carcinogenesis by berberine in rats and mice. J Pharm Pharmacol. 2001, 53: 763-8. 10.1211/0022357011775901.

    CAS  PubMed  Google Scholar 

  60. Peng PL, Hsieh YS, Wang CJ, Hsu JL, Chou FP: Inhibitory effect of berberine on the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Toxicol Appl Pharmacol. 2006, 214: 8-15. 10.1016/j.taap.2005.11.010.

    CAS  PubMed  Google Scholar 

  61. Kuo CL, Chi CW, Liu TY: The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett. 2004, 203: 127-37. 10.1016/j.canlet.2003.09.002.

    CAS  PubMed  Google Scholar 

  62. Tan Yl, Goh D, Ong ES: Investigation of differentially expressed proteins due to the inhibitory effects of berberine in human liver cancer cell line HepG2. Mol Biosyst. 2006, 2: 250-8. 10.1039/b517116d.

    CAS  PubMed  Google Scholar 

  63. Chang IM: Liver-protective activities of aucubin derived from traditional oriental medicine. Res Commun Mol Pathol Pharmacol. 1998, 102: 189-204.

    CAS  PubMed  Google Scholar 

  64. Park KS, Chang IM: Anti-inflammatory activity of aucubin by inhibition of tumor necrosis factor-alpha production in RAW 264.7 cells. Planta Med. 2004, 70: 778-9. 10.1055/s-2004-827211.

    CAS  PubMed  Google Scholar 

  65. Park EJ, Ko G, Kim J, Sohn DH: Antifibrotic effects of a polysaccharide extracted from Ganoderma lucidum, glycyrrhizin, and pentoxifylline in rats with cirrhosis induced by biliary obstruction. Biol Pharm Bull. 1997, 20: 417-20.

    CAS  PubMed  Google Scholar 

  66. Wang GJ, Huang YJ, Chen DH, Lin YL: Ganoderma lucidum extract attenuates the proliferation of hepatic stellate cells by blocking the PDGF receptor. Phytother Res. 2008, 23: 833-9. 10.1002/ptr.2687.

    Google Scholar 

  67. Chen MH, Chen SH, Wang QF, Chen JC, Chang DC, Hsu SL, Chen CH, Sheue CR, Liu YW: The molecular mechanism of gypenosides-induced G1 growth arrest of rat hepatic stellate cells. J Ethnopharmacol. 2008, 117: 309-17. 10.1016/j.jep.2008.02.009.

    CAS  PubMed  Google Scholar 

  68. Lin HM, Tseng HC, Wang CJ, Lin JJ, Lo CW, Chou FP: Hepatoprotective effects of Solanum nigrum Linn extract against CCl4-induced oxidative damage in rats. Chem Biol Interact. 2008, 171: 283-93. 10.1016/j.cbi.2007.08.008.

    CAS  PubMed  Google Scholar 

  69. Kobayashi H, Horikoshi K, Yamataka A, Lane GJ, Yamamoto M, Miyano T: Beneficial effect of a traditional herbal medicine (inchin-ko-to) in postoperative biliary atresia patients. Pediatr Surg Int. 2001, 17: 386-9. 10.1007/s003830000561.

    CAS  PubMed  Google Scholar 

  70. Sakaida I, Tsuchiya M, Kawaguchi K, Kimura T, Terai S, Okita K: Herbal medicine Inchin-ko-to (TJ-135) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol. 2003, 38: 762-9. 10.1016/S0168-8278(03)00094-1.

    PubMed  Google Scholar 

  71. Imanishi Y, Maeda N, Otogawa K, Seki S, Matsui H, Kawada N, Arakawa T: Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats. J Hepatol. 2004, 41: 242-50. 10.1016/j.jhep.2004.04.005.

    PubMed  Google Scholar 

  72. Inao M, Mochida S, Matsui A, Eguchi Y, Yulutuz Y, Wang Y, Naiki K, Kakinuma T, Fujimori K, Nagoshi S, Fujiwara K: Japanese herbal medicine Inchin-ko-to as a therapeutic drug for liver fibrosis. J Hepatol. 2004, 41: 584-91. 10.1016/j.jhep.2004.06.033.

    PubMed  Google Scholar 

  73. Yamamoto M, Ogawa K, Morita M, Fukuda K, Komatsu Y: The herbal medicine Inchin-ko-to inhibits liver cell apoptosis induced by transforming growth factor beta 1. Hepatology. 1996, 23: 552-9.

    CAS  PubMed  Google Scholar 

  74. Yamamoto M, Miura N, Ohtake N, Amagaya S, Ishige A, Sasaki H, Komatsu Y, Fukuda K, Ito T, Terasawa K: Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice. Gastroenterology. 2000, 118: 380-9. 10.1016/S0016-5085(00)70220-4.

    CAS  PubMed  Google Scholar 

  75. Ikeda H, Nagashima K, Yanase M, Tomiya T, Arai M, Inoue Y, Tejima K, Nishikawa T, Watanabe N, Kitamura K, Isono T, Yahagi N, Noiri E, Inao M, Mochida S, Kume Y, Yatomi Y, Nakahara K, Omata M, Fujiwara K: The herbal medicine inchin-ko-to (TJ-135) induces apoptosis in cultured rat hepatic stellate cells. Life Sci. 2006, 78: 2226-33. 10.1016/j.lfs.2005.09.024.

    CAS  PubMed  Google Scholar 

  76. Kitano A, Saika S, Yamanaka O, Ikeda K, Reinach PS, Nakajima Y, Okada Y, Shirai K, Ohnishi Y: Genipin suppresses subconjunctival fibroblast migration, proliferation and myofibroblast transdifferentiation. Ophthalmic Res. 2006, 38 (6): 355-60. 10.1159/000096231.

    CAS  PubMed  Google Scholar 

  77. Lee TY, Chang HH, Chen JH, Hsueh ML, Kuo JJ: Herb medicine Yin-Chen-Hao-Tang ameliorates hepatic fibrosis in bile duct ligation rats. J Ethnopharmacol. 2007, 109: 318-24. 10.1016/j.jep.2006.07.042.

    PubMed  Google Scholar 

  78. Lee TY, Chang HH, Kuo JJ, Shen JJ: Changes of hepatic proteome in bile duct ligated rats with hepatic fibrosis following treatment with Yin-Chen-Hao-Tang. Int J Mol Med. 2009, 23: 477-84.

    CAS  PubMed  Google Scholar 

  79. Miyamura M, Ono M, Kyotani S, Nishioka Y: Effects of sho-saiko-to extract on fibrosis and regeneration of the liver in rats. J Pharm Pharmacol. 1998, 50: 97-105.

    CAS  PubMed  Google Scholar 

  80. Sakaida I, Matsumura Y, Akiyama S, Hayashi K, Ishige A, Okita K: Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol. 1998, 28: 298-306. 10.1016/0168-8278(88)80017-5.

    CAS  PubMed  Google Scholar 

  81. Kayano K, Sakaida I, Uchida K, Okita K: Inhibitory effects of the herbal medicine Sho-saiko-to (TJ-9) on cell proliferation and procollagen gene expressions in cultured rat hepatic stellate cells. J Hepatol. 1998, 29: 642-9. 10.1016/S0168-8278(98)80161-X.

    CAS  PubMed  Google Scholar 

  82. Yamashiki M, Nishimura A, Huang XX, Nobori T, Sakaguchi S, Suzuki H: Effects of the Japanese herbal medicine "Sho-saiko-to" (TJ-9) on interleukin-12 production in patients with HCV-positive liver cirrhosis. Dev Immunol. 1999, 7: 17-22. 10.1155/1999/62564.

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Shimizu I, Ma YR, Mizobuchi Y, Liu F, Miura T, Nakai Y, Yasuda M, Shiba M, Horie T, Amagaya S, Kawada N, Hori H, Ito S: Effects of Sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats. Hepatology. 1999, 29 (1): 149-60. 10.1002/hep.510290108.

    CAS  PubMed  Google Scholar 

  84. Ono M, Miyamura M, Kyotani S, Saibara T, Ohnishi S, Nishioka Y: Effects of Sho-saiko-to extract on liver fibrosis in relation to the changes in hydroxyproline and retinoid levels of the liver in rats. J Pharm Pharmacol. 1999, 51: 1079-84. 10.1211/0022357991773429.

    CAS  PubMed  Google Scholar 

  85. Kusunose M, Qiu B, Cui T, Hamada A, Yoshioka S, Ono M, Miyamura M, Kyotani S, Nishioka Y: Effect of Sho-saiko-to extract on hepatic inflammation and fibrosis in dimethylnitrosamine induced liver injury rats. Biol Pharm Bull. 2002, 25 (11): 1417-21. 10.1248/bpb.25.1417.

    CAS  PubMed  Google Scholar 

  86. Kitade Y, Watanabe S, Masaki T, Nishioka M, Nishino H: Inhibition of liver fibrosis in LEC rats by a carotenoid, lycopene, or a herbal medicine, Sho-saiko-to. Hepatol Res. 2002, 22: 196-205. 10.1016/S1386-6346(01)00132-2.

    CAS  PubMed  Google Scholar 

  87. Sakaida I, Hironaka K, Kimura T, Terai S, Yamasaki T, Okita K: Herbal medicine Sho-saiko-to (TJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (TIMPs) in rat stellate cell. Life Sci. 2004, 74: 2251-63. 10.1016/j.lfs.2003.09.059.

    CAS  PubMed  Google Scholar 

  88. Chen MH, Chen JC, Tsai CC, Wang WC, Chang DC, Tu DG, Hsieh HY: The role of TGF-beta 1 and cytokines in the modulation of liver fibrosis by Sho-saiko-to in rat's bile duct ligated model. J Ethnopharmacol. 2005, 97 (1): 7-13. 10.1016/j.jep.2004.09.040.

    PubMed  Google Scholar 

  89. Kakumu S, Yoshioka K, Wakita T, Ishikawa T: Effect of TJ-9 Sho-saiko-to (Kampo medicine) on interferon gamma and antibody production specific for hepatitis B virus antigen in patients with type B chronic hepatitis. Int Immunopharmacol. 1991, 13: 141-6. 10.1016/0192-0561(91)90091-K.

    CAS  Google Scholar 

  90. Shimizu I: Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma. J Gastroenterol Hepatol. 2000, 15 (Suppl): D84-90. 10.1046/j.1440-1746.2000.02138.x.

    PubMed  Google Scholar 

  91. Abe S, Ishibshi H, Tansho S, Hanazawa R, Komatsu Y, Yamaguchi H: Protective effect of oral administration of several traditional Kampo-medicines on lethal Candida infection in immunosuppressed mice. Nippon Ishinkin Gakkai Zasshi. 2000, 41: 115-9.

    CAS  Google Scholar 

  92. Ochi T, Kawakita T, Nomoto K: Effects of Hochu-ekki-to and Ninjin-youei-to, traditional Japanese medicines, on porcine serum-induced liver fibrosis in rats. Immunopharmacol Immunotoxicol. 2004, 26: 285-98. 10.1081/IPH-120037726.

    PubMed  Google Scholar 

  93. Cyong JC, Ki SM, Iijima K, Kobayashi T, Furuya M: Clinical and pharmacological studies on liver diseases treated with Kampo herbal medicine. Am J Chin Med. 2000, 28: 351-60. 10.1142/S0192415X00000416.

    CAS  PubMed  Google Scholar 

  94. Suzuki M, Sasaki K, Yoshizaki F, Oguchi K, Fujisawa M, Cyong JC: Anti-hepatitis C virus effect of citrus unshiu peel and its active ingredient nobiletin. Am J Chin Med. 2005, 33: 87-94. 10.1142/S0192415X05002680.

    CAS  PubMed  Google Scholar 

  95. Song SL, Gong ZJ, Zhang QR: Therapeutic effect and mechanism of traditional Chinese compound decoction of Radix Curcumae, Rhzoma Sparganii, Rhizoma Zedoariae on fibrotic liver in rats. Zhong Caoyao. 2004, 35: 293-6.

    Google Scholar 

  96. Lu ZL, Li JC, Liu JD: Experimental study of effects of TCM formulas on regulation of peritoneal lymphatic stomata and urine sodium in liver fibrosis mouse model. Zhongguo Zhongyiyao Xinxi Zazhi. 2000, 7: 25-6.

    Google Scholar 

  97. Feng Y, Nagamatu T, Suzuki Y, Kawata T, Koike T: The diuretic effects of Wakan-yaku prescription on normal rats and various pathological models. Wakan Iyakugaku Zasshi. 1996, 13: 484-485.

    Google Scholar 

  98. Feng Y, Nagamatu T, Suzuki Y, Kawata T, Feng YG, Kobayashi S, Koike T: Pharmacological studies of diuretic Wakan-yaku formulations: its application and evaluation of Pharmacological screening. Wakan Iyakugaku Zasshi. 2000, 17: 122-30.

    Google Scholar 

  99. Li CX, Li L, Lou J, Yang WX, Lei TW, Li YH, Liu J, Cheng ML, Huang LH: The protective effects of traditional Chinese medicine prescription, han-dan-gan-le, on CCl4-induced liver fibrosis in rats. Am J Chin Med. 1998, 26: 325-32. 10.1142/S0192415X98000361.

    CAS  PubMed  Google Scholar 

  100. Li C, Luo J, Li L, Cheng M, Huang N, Liu J, Waalkes MP: The collagenolytic effects of the traditional Chinese medicine preparation, Han-Dan-Gan-Le, contribute to reversal of chemical-induced liver fibrosis in rats. Life Sci. 2003, 72: 1563-71. 10.1016/S0024-3205(02)02448-7.

    CAS  PubMed  Google Scholar 

  101. Yang Q, Xie RJ, Geng XX, Luo XH, Han B, Cheng ML: Effect of Danshao Huaxian capsule on expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in fibrotic liver of rats. World J Gastroenterol. 2005, 11: 4953-6.

    PubMed Central  PubMed  Google Scholar 

  102. Cheng ML, Lu T, Yao YM, Geng XX: Danshao huaxian capsule in treatment of decompensated cirrhosis resulting from chronic hepatitis B. Hepatobiliary Pancreat Dis Int. 2006, 5: 48-51.

    PubMed  Google Scholar 

  103. Wang LC, Zhao LS, Tang H: Experimental study of liver fibrosis reversal effect of warming-yang compound formula ganzhifu. Zhongguo Zhongxiyi Jiehe Zazhi. 2006, 26: 63-7.

    PubMed  Google Scholar 

  104. Liu C, Liu P, Liu CH, Zhu XQ, Ji G: Effects of Fuzhenghuayu decoction on collagen synthesis of cultured hepatic stellate cells, hepatocytes and fibroblasts in rats. World J Gastroenterol. 1998, 4: 548-549.

    CAS  PubMed  Google Scholar 

  105. Liu C, Jiang CM, Liu CH, Liu P, Hu YY: Effect of Fuzhenghuayu decoction on vascular endothelial growth factor secretion in hepatic stellate cells. Hepatobiliary Pancreat Dis Int. 2002, 1: 207-10.

    PubMed  Google Scholar 

  106. Liu P, Hu YY, Liu C, Xu LM, Liu CH, Sun KW, Hu DC, Yin YK, Zhou XQ, Wan MB, Cai X, Zhang ZQ, Ye J, Zhou RX, He J, Tang BZ: Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B. World J Gastroenterol. 2005, 11: 2892-9.

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Liu CH, Hu YY, Xu LM, Liu C, Liu P: Effect of Fuzheng Huayu formula and its actions against liver fibrosis. Chin Med. 2009, 4: 12-10.1186/1749-8546-4-12.

    PubMed Central  PubMed  Google Scholar 

  108. He Q, Yang DG, Li L, Zhong BL, Zeng XM: The 24 week effectiveness of Fuzheng Huayu capsule for CHB liver fibrosis: a systematic assessment. Zhongguo Xunzheng Yixue Zazhi. 2008, 8: 892-7.

    Google Scholar 

  109. Okuno T, Arai K, Shindo M: Efficacy of interferon combined glycyrrhizin therapy in patients with chronic hepatitis C resistant to interferon therapy. Nippon Rinsho. 1994, 52: 1823-7.

    CAS  PubMed  Google Scholar 

  110. Tsubota A, Kumada H, Arase Y, Chayama K, Saitoh S, Ikeda K, Kobayashi M, Suzuki Y, Murashima N: Combined ursodeoxycholic acid and glycyrrhizin therapy for chronic hepatitis C virus infection: a randomized controlled trial in 170 patients. Eur J Gastroenterol Hepatol. 1999, 11: 1077-83. 10.1097/00042737-199910000-00002.

    CAS  PubMed  Google Scholar 

  111. Sun WH, Song MQ, Liu ZJ: Combination therapy for hepatic fibrosis in 64 patients with hepatitis using Xiao-chai-hu-tang and Matrine injection. Zhongxiyi Jiehe Ganbing Zazhi. 2003, 13: 41-2.

    Google Scholar 

  112. Li Z, Liao HH, Wu MJ, Lin ZH: Study of combination therapy of Interferon-gamma and Xiao-chai-hu-tang for patients with liver fibrosis. Zhongxiyi Jiehe Ganbing Zazhi. 2001, 11 (Suppl): 95-

    Google Scholar 

  113. Xiong F, Sun J, Xiong W: Clinical observation of combination therapy of Interferon and Xiao-chai-hu-tang for patients with liver fibrosis. Hubei Zhongyi Zazhi. 2003, 25: 10-11.

    Google Scholar 

  114. Nakagawa A, Yamaguchi T, Takao T, Amano H: Five cases of drug-induced pneumonitis due to Sho-saiko-to or interferon-alpha or both. Nihon Kyobu Shikkan Gakkai Zasshi. 1995, 33 (12): 1361-1366.

    CAS  PubMed  Google Scholar 

  115. Ishizaki T, Sasaki F, Ameshima S, Shiozaki K, Takahashi H, Abe Y, Ito S, Kuriyama M, Nakai T, Kitagawa M: Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. Eur Respir J. 1996, 9: 2691-6. 10.1183/09031936.96.09122691.

    CAS  PubMed  Google Scholar 

  116. Liu AL, Wei M, Zeng ZG, Sun JX, Yang M, Yan SY: Combination therapy of Xiao-chai-hu-tang and Tiopronin for patients with liver fibrosis. Shaanxi Zhongyi. 2005, 26: 873-4.

    CAS  Google Scholar 

  117. Chen YS: The efficacy of combining Lamivudine with Salvia miltiorrhiza on the treatment of chronic hepatitis B liver fibrosis. Redai Yixue Zazhi. 2003, 3: 207-9.

    Google Scholar 

  118. Chen JJ, Tang BX, Wang LT, Chen XR: Clinical study on effect of bushen granule combined with marine injection in treating chronic hepatitis B of Gan-shen deficiency with damp-heat syndrome type. Zhongguo Zhongxiyi Jiehe Zazhi. 2006, 26: 23-7.

    CAS  PubMed  Google Scholar 

  119. Liu X, Hu H, Yin JQ: Therapeutic strategies against TGF-beta signalling pathway in hepatic fibrosis. Liver Int. 2006, 26: 8-22. 10.1111/j.1478-3231.2005.01192.x.

    PubMed  Google Scholar 

  120. Choi HS, Savard CE, Choi JW, Kuver R, Lee SP: Paclitaxel interrupts TGF-beta1 signaling between gallbladder epithelial cells and myofibroblasts. J Surg Res. 2007, 141: 183-91. 10.1016/j.jss.2006.12.558.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Elsharkawy AM, Oakley F, Mann DA: The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis. 2005, 10: 927-39. 10.1007/s10495-005-1055-4.

    CAS  PubMed  Google Scholar 

  122. Stickel F, Patsenker E, Schuppan D: Herbal hepatotoxicity. J Hepatol. 2005, 43: 901-10. 10.1016/j.jhep.2005.08.002.

    PubMed  Google Scholar 

  123. Ishii M, Miyazaki Y, Yamamoto T, Miura M, Ueno Y, Takahashi T, Toyota T: A case of drug-induced ductopenia resulting in fatal biliary cirrhosis. Liver. 1993, 13: 227-31.

    CAS  PubMed  Google Scholar 

  124. Yuen MF, Tam S, Fung J, Wong DK, Wong BC, Lai CL: Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther. 2006, 24: 1179-86. 10.1111/j.1365-2036.2006.03111.x.

    CAS  PubMed  Google Scholar 

  125. Feng Y: Basic and Clinical Toxicology of Chinese Medicines. 2009, Hong Kong: Commercial Press,

    Google Scholar 

  126. Levy C, Seeff LD, Lindor KD: Use of herbal supplements for chronic liver diseases. Clin Gastroenterol Hepatol. 2004, 2: 947-56. 10.1016/S1542-3565(04)00455-0.

    CAS  PubMed  Google Scholar 

  127. Dhiman RK, Chawla YK: Herbal medicines for liver diseases. Dig Dis Sci. 2005, 50: 1807-12. 10.1007/s10620-005-2942-9.

    CAS  PubMed  Google Scholar 

  128. Ye X, Feng Y, Tong Y, Ng KM, Tsao SW, Lau GKK, Sze C, Zhang Y, Tang J, Shen J, Kobayashi S: Hepatoprotective effects of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced acute liver hepatotoxicity in rats. J Ethnopharmacol. 2009, 124: 130-6. 10.1016/j.jep.2009.04.003.

    CAS  PubMed  Google Scholar 

  129. Feng Y, Luo WQ, Zhu SQ: Explore new clinical application of Huanglian and corresponding compound prescriptions from their traditional use. Zhongguo Zhongyao Zazhi. 2008, 33: 1221-5.

    PubMed  Google Scholar 

  130. Feng Y, Siu K, Wang N, Ng KM, Tsao SW, Nagamatsu T, Tong Y: Bear bile: dilemma of traditional medicinal use and animal protection. J Ethnobiol Ethnomed. 2009, 5: 2-10.1186/1746-4269-5-2.

    PubMed Central  PubMed  Google Scholar 

  131. Zhao ZZ, Hu YN, Liang ZT, Yuen JPS, Jian ZH, Lueng KSY: Authentication is fundamental for standardization of Chinese Medicines. Planta Medica. 2006, 72: 1-10. 10.1055/s-2006-947209.

    Google Scholar 

  132. Geerts A, Rogiers V, Sho-saiko-to : the right blend of Traditional oriental medicine and liver cell biology. Hepatology. 1999, 29: 282-3. 10.1002/hep.510290129.

    CAS  PubMed  Google Scholar 

  133. Angell M, Kassirer JP: Alternative medicine-the risks of untested and unregulated remedies (Editorial). N Engl J Med. 1998, 339: 839-41. 10.1056/NEJM199809173391210.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study was financially supported by grants from the Research Council of the University of Hong Kong (Project Codes: 10208005 and 10400413), the University Grants Committee (UGC) of Hong Kong (Project Code: 764708M), the Pong Ding Yuen Endowment Fund for Education and Research in Chinese-Western Medicine (Project Code: 20005274) and the Government-Matching Grant Scheme (4th Phase, Project Code: 20740314). The authors would like to thank Prof SP Lee and Dr GKK Lau for their assistance in revising the manuscript.

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Authors and Affiliations

  1. School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road,Hong Kong, Pokfulam, PR, China

    Yibin Feng, Ning Wang & Yao Tong

  2. Department of Medicine, The University of Hong Kong, 21 Sassoon Road,Hong kong, Pokfulam, PR, China

    Kwok-Fan Cheung

  3. Department of Cell Biology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR, China

    Ping Liu

  4. Department of Pharmacobiology and Therapeutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpakuku, Nagoya, 468-8503, Japan

    Tadashi Nagamatsu

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  1. Yibin Feng
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  2. Kwok-Fan Cheung
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  3. Ning Wang
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  4. Ping Liu
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  5. Tadashi Nagamatsu
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  6. Yao Tong
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Correspondence to Yao Tong.

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Competing interests

Fuzhen Huayu is a herbal product developed by PL's institution at the Shanghai University of Traditional Chinese Medicine. The authors declare that they have no competing interests for other Chinese medicines discussed in the present study.

Authors' contributions

YBF and YT conceived the study, interpreted the data and revised the manuscript. YBF retrieved and analyzed the data and drafted the manuscript. KFC and NW retrieved the data from Chinese journals and translated them into English. PL and TN supervised some of the experiments. All authors read and approved the final version of the manuscript.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Feng, Y., Cheung, KF., Wang, N. et al. Chinese medicines as a resource for liver fibrosis treatment. Chin Med 4, 16 (2009). https://doi.org/10.1186/1749-8546-4-16

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  • DOI: https://doi.org/10.1186/1749-8546-4-16

Keywords

Chinese Medicine

ISSN: 1749-8546

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