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Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

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Abstract

The present study was designed to examine the potential preventive and curative effects of curcumin, resveratrol, imatinib, rosiglitazone, losartan and bosentan (BOS) on Schistosoma mansoni-induced liver fibrosis in mice. Induction of liver fibrosis was produced in male Swiss mice by subcutaneous injection of S. mansoni cercariae per mouse. Mice were left for 28 days before starting the experiment then mice were divided into two main groups. The first group was further subdivided into experimental groups and started drug treatment at day 28 after infection and continued for 2 weeks in order to evaluate the potential preventive effects of the mentioned drugs on S. mansoni-induced liver fibrosis. The second group of mice were left for 2 weeks and then treated with praziquantel for two consecutive days to eradicate the worms and so stop egg disposition and further fibrosis development. Mice were then subdivided into the experimental groups and drug treatment was started for 2 weeks to evaluate their efficacy to decrease the developed fibrosis. At the end of the experiment period, mice were killed and serum was collected for the estimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and albumin. Liver tissue was taken for the estimation of hepatic hydroxyproline content and histopathological examination to confirm the biochemical results. Results of the study indicate that curcumin and imatinib have potent antifibrotic activity both in suppressing and reversing S. mansoni-induced liver fibrosis, while resveratrol has beneficial effects only in suppressing the development of S. mansoni-induced liver fibrosis.

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References

  • Allam G (2009) Immunomodulatory effects of curcumin treatment on murine Schistosomiasis mansoni. Immunobiology 214:712–727

    Article  PubMed  CAS  Google Scholar 

  • Andrade ZA, Grimaud JA (1988) Morphology of chronic collagen resorption: a study on the late stages of schistosomal granuloma involution. Am J Pathol 132:L389–L399

    Google Scholar 

  • Andrade ZA, Guerret S, Fernandes AL (1999) Myofibroblasts in schistosomal portal fibrosis of man. Mem Inst Oswaldo Cruz 94:87–93

    PubMed  CAS  Google Scholar 

  • Anselmi K, Subbotin VM, Nemoto E, Gandhi CR (2002) Accelerated reversal of carbon tetrachloride-induced cirrhosis in rats by the endothelin receptor antagonist TAK-044. J Gastroenterol Hepatol 17:589–597

    Article  PubMed  CAS  Google Scholar 

  • Aono Y, Nishioka Y, Inayama M, Ugai M, Kishi J, Uehara H, Izumi K, Sone S (2005) Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 171:1279–1285

    Article  PubMed  Google Scholar 

  • Barbosa Junior AA, Pfeifer U, Andrade ZA (1993) Role of fat-storing cells in schistosomal hepatic fibrosis of mice. Virchows Arch B Cell Pathol Incl Mol Pathol 64:91–96

    Article  Google Scholar 

  • Beham-Schmid C, Apfelbeck U, Sill H, Tsybrovsky O, Höfler G, Haas OA, Linkesch W (2002) Treatment of chronic myelogenous leukemia with the tyrosine kinase inhibitor STI571 results in marked regression of bone marrow fibrosis. Blood 99:381–383

    Article  PubMed  CAS  Google Scholar 

  • Bergman I, Loxley R (1963) Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Anal Chem 35:1961–1965

    Article  CAS  Google Scholar 

  • Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H, Genina O, Helpern Z, Pines M (2007) Prevention of liver cirrhosis in rats by curcumin. Liver Int 27:373–383

    Article  PubMed  CAS  Google Scholar 

  • Chainani-Wu N (2003) Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med 9:161–168

    Article  PubMed  Google Scholar 

  • Chang D, Ramalho LNZ, Ramalhob FS, Martinelli ALC, Zucoloto S (2006) Hepatic stellate cells in human Schistosomiasis mansoni: a comparative immunohistochemical study with liver cirrhosis. Acta Trop 97:318–323

    Article  PubMed  CAS  Google Scholar 

  • Chatterjee S, Vrolix G, Depoortere I, Peeters T, van Marck E (2005) The therapeutic effect of the neuropeptide hormone somatostatin on Schistosoma mansoni caused liver fibrosis. BMC Infect Dis 5:45

    Article  PubMed  Google Scholar 

  • Cheng JC, Fang JG, Chen WF, Zhou B, Yang L, Liu ZL (2006) Structure–activity relationship studies of resveratrol and its analogues by the reaction kinetics of low density lipoprotein peroxidation. Bioorg Chem 34:142–157

    Article  PubMed  Google Scholar 

  • Cheng Y, Ping J, Xu LM (2007) Effects of curcumin on peroxisome proliferator-activated receptor γ expression and nuclear translocation/redistribution in culture-activated rat hepatic stellate cells. Chin Med J 120:794–801

    PubMed  CAS  Google Scholar 

  • Chitsulo L, Engels D, Montresor A, Savioli L (2000) The global status of schistosomiasis and its control. Acta Trop 77:41–55

    Article  PubMed  CAS  Google Scholar 

  • Cho JJ, Hocher B, Herbst H, Jia JD, Ruehl M, Hahn EG, Riecken EO, Schuppan D (2000) An oral endothelin—a receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis. Gastroenterology 118:1169–1178

    Article  PubMed  CAS  Google Scholar 

  • Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murph SJ, Limper AH, Leof EB (2004) Imatinib mesylate inhibits the profibrogenic activity of TGF-[beta] and prevents bleomycin mediated lung fibrosis. J Clin Invest 114:1308–1316

    PubMed  CAS  Google Scholar 

  • De Gottardi A, Unternaehrer M, Saegesser H, Ledermann M, Reichen J (2002) Sirolimus, but not losartan, significantly reduces liver fibrosis and mortality in bile duct ligated rats. J Hepatol 36:49–50

    Article  Google Scholar 

  • Fu Y, Zheng S, Lin J, Ryerse J, Chen A (2008) Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol 73:399–409

    Article  PubMed  CAS  Google Scholar 

  • Galli A, Crabb DW, Ceni E, Salzano R, Mello T, Svegliati-Baroni G, Ridolfi F, Trozzi L, Surrenti C, Casini A (2002) Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122:1924–1940

    Article  PubMed  CAS  Google Scholar 

  • Gandhi CR, Kuddus RH, Uemura T, Rao AS (2000) Endothelin stimulates transforming growth factor-beta1 and collagen synthesis in stellate cells from control but not cirrhotic rat liver. Eur J Pharmacol 406:311–318

    Article  PubMed  CAS  Google Scholar 

  • Guo YT, Leng XS, Li T, Peng JR, Song SH, Xiong LF, Qin ZZ (2005) Effect of ligand of peroxisome proliferator-activated receptor γ on the biological characters of hepatic stellate cells. World J Gastroenterol 11:4735–4739

    PubMed  CAS  Google Scholar 

  • Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, Tsukamoto H (2004) Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 279:11392–11401

    Article  PubMed  CAS  Google Scholar 

  • He YJ, Shu JC, Lü X, Fang L, Sheng Y (2006) Prophylactic effect of curcumin on hepatic fibrosis and its relationship with activated hepatic stellate cells. Zhonghua Gan Zang Bing Za Zhi 14:337–340

    PubMed  CAS  Google Scholar 

  • Jin H, Yamamoto N, Uchida K, Terai S, Sakaida I (2007) Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient l-amino acid-defined diet. Biochem Biophys Res Commun 364:801–807

    Article  PubMed  CAS  Google Scholar 

  • Kang HC, Nan JX, Park PH, Kim JM, Lee SH, Woo SW, Zhao YZ, Park EJ, Sohn DH (2002) Curcumin inhibits collagen synthesis and hepatic stellate cell activation in vivo and in vitro. J Pharm Pharmacol 54:119–126

    Article  PubMed  CAS  Google Scholar 

  • Kasdallah-Grissa A, Mornagui B, Aouani E, Hammami M, El May M, Gharbi N, Kamoun A, El-Fazaâ S (2007) Resveratrol, a red wine polyphenol, attenuates ethanol-induced oxidative stress in rat liver. Life Sci 80:1033–1039

    Article  PubMed  CAS  Google Scholar 

  • Kawada N, Seki S, Inoue M, Kuroki T (1998) Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 27:1265–1274

    Article  PubMed  CAS  Google Scholar 

  • Kinnman N, Goria O, Wendum D, Gendron MC, Rey C, Poupon R, Housset C (2001) Hepatic stellate cell proliferation is an early platelet-derived growth factor-mediated cellular event in rat cholestatic liver injury. Lab Invest 81:1709–1716

    Article  PubMed  CAS  Google Scholar 

  • Klion AD, Robyn JA, Akin C, Noel P, Brown MR, Law MA, Metcalfe DD, Dunbar CE, Nutman TB (2003) Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 103:473–478

    Article  PubMed  Google Scholar 

  • Leivas A, Jiménez W, Bruix J, Boix L, Bosch J, Arroyo V, Rivera F, Rodés J (1998) Gene expression of endothelin-1 and ET(A) and ET(B) receptors in human cirrhosis: relationship with hepatic hemodynamics. J Vasc Res 35:186–193

    Article  PubMed  CAS  Google Scholar 

  • Leonard SS, Xia C, Jiang BH, Stinefelt B, Klanforf H, Harris GK, Shi X (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun 309:1017–1026

    Article  PubMed  CAS  Google Scholar 

  • Li X, Meng Y, Wu P, Zhang Z, Yang X (2007) Angiotensin II and Aldosterone stimulating NF-кB and AP-1 activation in hepatic fibrosis of rat. Regul Pept 138:15–25

    Article  PubMed  CAS  Google Scholar 

  • Lüpez-Velez M, Martínez-Martínez F, Del Valle-Ribes C (2003) The study of phenolic compounds as natural antioxidants in wine. Crit Rev Food Sci Nutr 43:233–244

    Google Scholar 

  • Mahmoud MR, El-Abha HS, Saleh S (2002) The effect of Nigella sativa oil against the liver damage induced by Schistosoma mansoni infection in mice. J Ethnopharmacol 79:1–11

    Article  PubMed  CAS  Google Scholar 

  • Manna SK, Mukhopadhyay A, Aggarwal BB (2000) Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-кB, activator protein -1 and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164:6509–6519

    PubMed  CAS  Google Scholar 

  • Neef M, Ledermann M, Saegesser H, Schneider V, Widmer N, Decosterd LA, Rochat B, Reichen J (2006) Oral imatinib treatment reduces early fibrogenesis but does not prevent progression in the long term. J Hepatol 44:167–175

    Article  PubMed  CAS  Google Scholar 

  • Rainsford KD (1985) Pharmacological manipulation of the chronic granulomatous reactions in the livers of mice infected with schistosomiasis. Int J Tissue React 7:35–39

    PubMed  CAS  Google Scholar 

  • Reyes-Gordillo K, Segovia J, Shibayama M, Vergara P, Moreno MG, Muriel P (2007) Curcumin protects against acute liver damage in the rat by inhibiting NF-кB, proinflammatory cytokines production and oxidative stress. Biochim Biophys Acta 1770:989–996

    Article  PubMed  CAS  Google Scholar 

  • Rockey DC, Chung JJ (1996) Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 98:1381–1388

    Article  PubMed  CAS  Google Scholar 

  • Savage DG, Antman KH (2002) Imatinib mesylate: a new oral targeted therapy. N Engl J Med 346:683–693

    Article  PubMed  CAS  Google Scholar 

  • Shishodia S, Potdar P, Gairola CG, Aggarwal BB (2003) Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NFkappaB activation through inhibition of IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis 24:1269–1279

    Article  PubMed  CAS  Google Scholar 

  • Singh KP, Gerard HC, Hudson AP, Boros DL (2004) Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice. Immunology 111:343–352

    Article  PubMed  CAS  Google Scholar 

  • Thirunavukkarasu C, Yang Y, Subbotin VM, Harvey SA, Fung J, Gandhi CR (2004) Endothelin receptor antagonist TAK-044 arrests and reverses the development of carbon tetrachloride induced cirrhosis in rats. Gut 53:1010–1019

    Article  PubMed  CAS  Google Scholar 

  • Uto H, Nakanishi C, Ido A, Hasuike S, Kusumoto K, Abe H, Numata M, Nagata K, Hayashi K, Tsubouchi H (2005) The peroxisome proliferator-activated receptor-γ agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet. Hepatol Res 32:235–242

    PubMed  CAS  Google Scholar 

  • Weber WM, Hunsaker LA, Roybal CN, Bobrovnikova-Marjon EV, Abcouwer SF, Royer RE, Deck LM, Vander Jagt DL (2006) Activation of NFкB is inhibited by curcumin and related enones. Bioorg Med Chem 14:2450–2461

    Article  PubMed  CAS  Google Scholar 

  • Wolf AM, Wolf D, Rumpold H, Ludwiczek S, Enrich B, Gastl G, Weiss G, Tilg H (2005) The kinase inhibitor imatinib mesylate inhibits TNF-α production in vitro and prevents TNF-dependent acute hepatic inflammation. PNAS 102:13622–13627

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Fu Y, Chen A (2003) Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am J Physiol 285:G20–G30

    CAS  Google Scholar 

  • Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H (2001) Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34:745–750

    Article  PubMed  CAS  Google Scholar 

  • Yoshiji H, Noguchi R, Kuriyama S, Ikenaka Y, Yoshii J, Yanase K, Namisaki T, Kitade M, Masaki T, Fukui H (2005) Imatinib mesylate (STI571) attenuates liver fibrosis development in rats. Am J Physiol 288:G907–G913

    CAS  Google Scholar 

  • Yoshiji H, Kuriyama S, Noguchi R, Ikenaka Y, Yoshii J, Yanase K, Namisaki T, Kitade M, Yamazaki M, Asada K, Akahane T, Tsujimoto T, Uemura M, Fukui H (2006) Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-β with a combination of imatinib mesylate and ACE inhibitor in rats. Int J Mol Med 17:899–904

    PubMed  CAS  Google Scholar 

  • Zheng S, Chen A (2007) Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells. Am J Physiol 292:G113–G123

    CAS  Google Scholar 

  • Zheng S, Yumei F, Chen A (2007) de novo synthesis of glutathione is a prerequisite for curcumin to inhibit HSC activation. Free Radic Biol Med 43:444–453

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Dina S. El-Agamy & Shehta A. Said

  2. Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt

    Abdelhadi M. Shebl

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  1. Dina S. El-Agamy
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  2. Abdelhadi M. Shebl
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  3. Shehta A. Said
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Correspondence to Dina S. El-Agamy.

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El-Agamy, D.S., Shebl, A.M. & Said, S.A. Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice. Inflammopharmacol 19, 307–316 (2011). https://doi.org/10.1007/s10787-011-0092-6

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  • DOI: https://doi.org/10.1007/s10787-011-0092-6

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