Protective effect of the herbal medicine Gan‑fu‑kang against carbon tetrachloride‑induced liver fibrosis in rats

Zhang,Caihua; Wang,Yanfu; Chen,Hong; Yang,Guang; Wang,Shaopeng; Jiang,Miaona; Cong,Li; Yuan,Lijun; Li,Hanshu; Jia,Yujie

doi:10.3892/mmr.2013.1587

Protective effect of the herbal medicine Gan‑fu‑kang against carbon tetrachloride‑induced liver fibrosis in rats

Authors:
- Caihua Zhang
- Yanfu Wang
- Hong Chen
- Guang Yang
- Shaopeng Wang
- Miaona Jiang
- Li Cong
- Lijun Yuan
- Hanshu Li
- Yujie Jia
View Affiliations

Affiliations: Department of Pathophysiology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China
Published online on: July 12, 2013 https://doi.org/10.3892/mmr.2013.1587
Pages: 954-962

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the effect of a herbal medicine formula, Gan‑fu‑kang (GFK), on the treatment of liver fibrosis in rats and the mechanisms via which it exerts its effect. Liver fibrosis was induced in rats by subcutaneous injection of carbon tetrachloride (CCl4) at 0.5 mg/kg body weight, twice a week for 8 weeks. The rats were randomly selected to receive saline or GFK at 31.25, 312.5 or 3,125 mg/kg body weight/day between weeks 9 and 20. An additional group of rats without CCl4 injection was used as the baseline. In the liver fibrosis model rats, an increase in plasma liver enzymes, fibrotic markers in serum and liver fibrosis, production of α‑smooth muscle actin, matrix metalloproteinase‑2 and tissue inhibitor of metalloproteinase‑1, synthesis of collagen and activation of the Wnt/β‑catenin signaling pathway were observed. GFK administration was found to significantly reduce these changes. Results of this study demonstrate that GFK has a protective and therapeutic effect on liver fibrosis induced by CCl4, which may be associated with its inhibitory activity on HSC proliferation and collagen synthesis, effectively downregulating Wnt/β‑catenin signaling.

View Figures

View References

1	Friedman SL: Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 275:2247–2250. 2000. View Article : Google Scholar : PubMed/NCBI
2	Cheng M and Yang C: The Basic Study and Clinical Research on Hepatic Fibrosis. First edition. First Jumbo Publishing Co; California, USA: 2002
3	Moreira RK: Hepatic stellate cells and liver fibrosis. Arch Pathol Lab Med. 131:1728–1734. 2007.PubMed/NCBI
4	Wu J and Zern MA: Hepatic stellate cells: a target for the treatment of liver fibrosis. J Gastroenterol. 35:665–672. 2000. View Article : Google Scholar : PubMed/NCBI
5	Mann J and Mann DA: Transcriptional regulation of hepatic stellate cells. Adv Drug Deliv Rev. 61:497–512. 2009. View Article : Google Scholar : PubMed/NCBI
6	Gäbele E, Brenner DA and Rippe RA: Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosci. 8:d69–d77. 2003.PubMed/NCBI
7	Zou YH, Yang Y, Li J, et al: Potential therapeutic effects of a traditional Chinese formulation, BJ-JN, on liver fibrosis induced by carbon tetrachloride in rats. J Ethnopharmacol. 120:452–457. 2008. View Article : Google Scholar : PubMed/NCBI
8	Purps O, Lahme B, Gressner AM, Meindl-Beinker NM and Dooley S: Loss of TGF-beta dependent growth control during HSC transdifferentiation. Biochem Biophys Res Commun. 353:841–847. 2007. View Article : Google Scholar : PubMed/NCBI
9	Borkham-Kamphorst E, van Roeyen CR, Ostendorf T, Floege J, Gressner AM and Weiskirchen R: Pro-fibrogenic potential of PDGF-D in liver fibrosis. J Hepatol. 46:1064–1074. 2007. View Article : Google Scholar : PubMed/NCBI
10	Brewster UC, Setaro JF and Perazella MA: The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. Am J Med Sci. 326:15–24. 2003. View Article : Google Scholar : PubMed/NCBI
11	Cadigan KM and Nusse R: Wnt signaling: a common theme in animal development. Genes Dev. 11:3286–3305. 1997. View Article : Google Scholar : PubMed/NCBI
12	Lin X, Zhang S, Huang Q, et al: Protective effect of Fufang-Liu-Yue-Qing, a traditional Chinese herbal formula, on CCl4 induced liver fibrosis in rats. J Ethnopharmacol. 142:548–556. 2012. View Article : Google Scholar : PubMed/NCBI
13	Xu TT, Jiang MN, Li C, Che Y and Jia YJ: Effect of Chinese traditional compound, Gan-fu-kang, on CCl(4)-induced liver fibrosis in rats and its probable molecular mechanisms. Hepatol Res. 37:221–229. 2007. View Article : Google Scholar : PubMed/NCBI
14	Gao Y, Song LX, Jiang MN, Ge GY and Jia YJ: Effects of traditional chinese medicine on endotoxin and its receptors in rats with non-alcoholic steatohepatitis. Inflammation. 31:121–132. 2008. View Article : Google Scholar : PubMed/NCBI
15	Lee PN, Pang K, Matus DQ and Martindale MQ: A WNT of things to come: evolution of Wnt signaling and polarity in cnidarians. Semin Cell Dev Biol. 17:157–167. 2006. View Article : Google Scholar : PubMed/NCBI
16	Zhao J, Kim KA and Abo A: Tipping the balance: modulating the Wnt pathway for tissue repair. Trends Biotechnol. 27:131–136. 2009. View Article : Google Scholar : PubMed/NCBI
17	Lustig B and Behrens J: The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol. 129:199–221. 2003.PubMed/NCBI
18	Kikuchi A and Yamamoto H: Tumor formation due to abnormalities in the β-catenin-independent pathway of Wnt signaling. Cancer Sci. 99:202–208. 2008.
19	Zhang B, Zhou KK and Ma JX: Inhibition of connective tissue growth factor overexpression in diabetic retinopathy by SERPINA3K via blocking the WNT/beta-catenin pathway. Diabetes. 59:1809–1816. 2010. View Article : Google Scholar : PubMed/NCBI
20	Morrisey EE: Wnt signaling and pulmonary fibrosis. Am J Pathol. 162:1393–1397. 2003. View Article : Google Scholar : PubMed/NCBI
21	Habas R and Dawid IB: Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol. 4:22005. View Article : Google Scholar : PubMed/NCBI
22	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
23	Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL and MacDougald OA: Inhibition of adipogenesis by Wnt signaling. Science. 289:950–953. 2000. View Article : Google Scholar : PubMed/NCBI
24	Cheng JH, She H, Han YP, et al: Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 294:G39–G49. 2008. View Article : Google Scholar : PubMed/NCBI
25	Lou JL, Jiang MN, Li C, et al: Herb medicine Gan-fu-kang attenuates liver injury in a rat fibrotic model. J Ethnopharmacol. 128:131–138. 2010. View Article : Google Scholar : PubMed/NCBI
26	National Institutes of Health. Guide for the Care and Use of Laboratory Animals. Sixth edition. National Acadamies Press; Washington, D.C: 1985
27	Nie QH, Cheng YQ, Xie YM, Zhou YX and Cao YZ: Inhibiting effect of antisense oligonucleotides phosphorthioate on gene expression of TIMP-1 in rat liver fibrosis. World J Gastroenterol. 7:363–369. 2001.PubMed/NCBI
28	Dignani JD, Lebovitz RM and Roeder RG: Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11:1475–1489. 1983. View Article : Google Scholar : PubMed/NCBI
29	Castera L: Assessing liver fibrosis. Expert Rev Gastroenterol Hepatol. 2:541–552. 2008. View Article : Google Scholar
30	Faria SC, Ganesan K, Mwangi I, et al: MR imaging of liver fibrosis: current state of the art. Radiographics. 29:1615–1635. 2009. View Article : Google Scholar : PubMed/NCBI
31	Watson MR, Wallace K, Gieling RG, et al: NF-kappaB is a critical regulator of the survival of rodent and human hepatic myofibroblasts. J Hepatol. 48:589–597. 2008. View Article : Google Scholar : PubMed/NCBI
32	Tsukada S, Parsons CJ and Rippe RA: Mechanisms of liver fibrosis. Clin Chim Acta. 364:33–60. 2006. View Article : Google Scholar
33	Friedman SL: Liver fibrosis-from bench to bedside. J Hepatol. 38:S38–S53. 2003. View Article : Google Scholar
34	Fowell AJ and Iredale JP: Emerging therapies for liver fibrosis. Dig Dis. 24:174–183. 2006. View Article : Google Scholar : PubMed/NCBI
35	Sturgill MG and Lambert GH: Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function. Clin Chem. 43:1512–1526. 1997.PubMed/NCBI
36	Achliya GS, Wadodkar SG and Dorle AK: Evaluation of hepatoprotective effect of Amalkadi Ghrita against carbon tetrachloride-induced hepatic damage in rats. J Ethnopharmacol. 90:229–232. 2004. View Article : Google Scholar : PubMed/NCBI
37	Leroy V: Other non-invasive markers of liver fibrosis. Gastroenterol Clin Biol. 32(6 Suppl 1): 52–57. 2008. View Article : Google Scholar : PubMed/NCBI
38	Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar
39	Lotersztajn S, Julien B, Teixeira-Clerc F, Grenard P and Mallat A: Hepatic fibrosis: molecular mechanisms and drug targets. Annu Rev Pharmacol Toxicol. 45:605–628. 2005. View Article : Google Scholar : PubMed/NCBI
40	Li D and Friedman SL: Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy. J Gastroenterol Hepatol. 14:618–633. 1999. View Article : Google Scholar : PubMed/NCBI
41	Han YP: Matrix metalloproteinases, the pros and cons, in liver fibrosis. J Gastroenterol Hepatol. 21(Suppl 3): S88–S91. 2006. View Article : Google Scholar : PubMed/NCBI
42	Lichtinghagen R, Michels D, Haberkorn CI, et al: Matrix metalloproteinase (MMP)-2, MMP-7 and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol. 34:239–247. 2001. View Article : Google Scholar : PubMed/NCBI
43	Arthur MJ, Mann DA and Iredale JP: Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis. J Gastroenterol Hepatol. 13:S33–S38. 1998.PubMed/NCBI
44	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
45	Chilosi M, Poletti V, Zamò A, et al: Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol. 162:1495–1502. 2003. View Article : Google Scholar : PubMed/NCBI
46	Königshoff M, Balsara N, Pfaff EM, et al: Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 3:e21422008.PubMed/NCBI
47	Luk JM, Wang X, Liu P, et al: Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation. Liver Int. 27:879–890. 2007. View Article : Google Scholar : PubMed/NCBI
48	He W, Dai C, Li Y, Zeng G, Monga SP and Liu Y: Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol. 20:765–776. 2009. View Article : Google Scholar : PubMed/NCBI
49	Brack AS, Conboy MJ, Roy S, et al: Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 317:807–810. 2007. View Article : Google Scholar : PubMed/NCBI
50	Jiang F, Parsons CJ and Stefanovic B: Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol. 45:401–409. 2006. View Article : Google Scholar : PubMed/NCBI
51	Myung SJ, Yoon JH, Gwak GY, et al: Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS Lett. 581:2954–2958. 2007. View Article : Google Scholar : PubMed/NCBI
52	Kordes C, Sawitza I and Häussinger D: Canonical Wnt signaling maintains the quiescent stage of hepatic stellate cells. Biochem Biophys Res Commun. 367:116–123. 2008. View Article : Google Scholar : PubMed/NCBI
53	MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: components, mechanisms and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI
54	Ying J, Li H, Yu J, et al: WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res. 14:55–61. 2008. View Article : Google Scholar : PubMed/NCBI
55	Albrecht JH and Hansen LK: Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes. Cell Growth Differ. 10:397–404. 1999.PubMed/NCBI
56	Houseknecht KL, Cole BM and Steele PJ: Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review. Domest Anim Endocrinol. 22:1–23. 2002. View Article : Google Scholar : PubMed/NCBI
57	Galli A, Crabb DW, Ceni E, et al: Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology. 122:1924–1940. 2002. View Article : Google Scholar : PubMed/NCBI
58	Liu J and Farmer SR: Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem. 279:45020–45027. 2004.
59	Moldes M, Zuo Y, Morrison RF, et al: Peroxisome-proliferator-activated receptor gamma suppresses Wnt/betacatenin signalling during adipogenesis. Biochem J. 376:607–613. 2003. View Article : Google Scholar : PubMed/NCBI