Oxidative Stress, Plant-Derived Antioxidants and Liver Fibrosis

Abstract

There is accumulating evidence that oxidative stress plays a considerable role in the development of liver fibrosis by acting in different cell types and in different signaling pathways. Consequently, antioxidants, particularly those of plant origin, have emerged as potent antifibrotic agents. This review briefly summarizes current views of the mechanisms of fibrogenesis and recent findings on the antifibrotic potential of plant-derived antioxidants.

Key words

Antioxidants - fibrogenesis - flavonoids - hepatic stellate cells - reactive oxygen species

References

• 1 Bissell D M. Hepatic fibrosis as wound repair: a progress report.  J. Gastroenterol. 1998;  33 295-302
• 2 Eickelberg O. Endless healing: TGF-β, SMADs, and fibrosis.  FEBS Lett.. 2001;  506 11-4
• 3 Li D, Friedman S L. Liver fibrogenensis and the role of hepatic stellate cells: New insights and prospects for therapy.  J. Gastroenterol Hepatol. 1999;  14 618-33
• 4 Gressner A M, Bachem M G. Cellular communications and cell-matrix interactions in the pathogenesis of fibroproliferative disease: liver fibrosis as a paradigm.  Ann Biol Clin. 1994;  52 205-26
• 5 Alcolado R, Arthur M J, Iredale J P. Pathogenesis of liver fibrosis.  Clin Sci. 1997;  92 103-12
• 6 Chojkier M, Brenner D A. Therapeutic strategies for hepatic fibrosis.  Hepatology. 1988;  8 176-82
• 7 Wu J, Danielsson A. Inhibition of hepatic fibrogenesis: a review of pharmacologic candidates.  Scand J Gastroenterol. 1994;  29 385-91
• 8 Franklin T J. Current approaches to the therapy of fibrotic diseases.  Biochem Pharmacol. 1995;  49 267-73
• 9 Cales P. Apoptosis and liver fibrosis: antifibrotic strategies.  Biomed Pharmacother. 1998;  52 259-63
• 10 Lieber C S. Prevention and teatment of liver fibrosis based on pathogenesis.  Alcohol Clin Exp Res. 1999;  23 944-9
• 11 Hartmann F, Dölle W. Aetilogy and pathogenesis of liver cirrhosis-chemicals. In: Boyer JL, Binachi L (eds.) Liver Cirrhosis, MTP Press Lancaster; 1987: pp. 139-45
• 12 Arthur M J. Iron, oxidative stress and liver fibrosis.  J Gastroenterol Hepatol. 1996;  11 124-9
• 13 Pietrangelo A. Iron, oxidative stress and liver fibrosis.  J Hepatol. 1998;  28 8-13
• 14 Parola M, Leonarduzzi G, Biasi F, Albano E, Biocca M E, Poli G, Dianzani M U. Vitamin E dietary supplementation protects against carbon tetrachloride-induced chronic liver damage and cirrhosis.  Hepatology. 1992;  16 1014-21
• 15 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress.  Mol Aspects Med. 2000;  21 49-98
• 16 Toyokuni S. Reactive oxygen species-induced molecular damage and its application in pathology.  Pathol Int. 1999;  49 91-102
• 17 Gressner A M. Transdifferentiation of hepatic stellate (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.  Kidney Intern. 1996;  49 39-45
• 18 Gressner A M, Lotfi S, Gressner G, Lahme B. Identification and partial characterization of a hepatocyte-derived factor promoting proliferation of cultured fat storing cells (parasinusoidal lipocytes).  Hepatalogy. 1992;  16 1250-66
• 19 Simpson K J, Lukas N W, Colletti L, Strieter R M, Kunkel S L. Cytokines and the liver.  J Hepatol. 1997;  27 1120-32
• 20 Bedossa P, Paradis V. Transforming growth factor beta (TGF-beta): a key role in liver fibrosis.  J Hepatol. 1995;  22 37-42
• 21 Hellerbrand C, Stefanovic B, Giordano F, Burchardt E R, Brenner D A. The role of TGFbeta1 in initiating hepatic stellate cell acitivation in vivo .  J Hepatol. 1999;  30 77-87
• 22 Kawada N. The hepatic perisinusoidal stellate cell.  Histol Histopathol. 1997;  12 1069-80
• 23 Tsukamoto H. Cytokine regulation of hepatic stellate cells in liver fibrosis.  Alcohol Clin Exp Res. 1999;  23 911-6
• 24 Maher J J. Leukocytes as modulators of stellate cell activation.  Alcohol Clin Exp Res. 1999;  23 917-21
• 25 Bissel D M. Lipocyte activation and hepatic fibrosis.  Gastroenterology. 1992;  102 1803-5
• 26 Casini A, Pinzani M, Milani S, Grappone C, Galli G, Jezequel A M. et al . Regulation of extracellular matrix synthesis by transforming growth factor β1 inhuman fat-storing cells.  Gastroenterology. 1993;  105 245-53
• 27 Bachem M G, Meyer D M, Melchior R, Sell K M, Gressner A M. Activation of rat liver perisinusoidal lipocytes by transforming growth factors derived from myofibroblast-like cells - A potential mechanism of self perpetuation in liver fibrogenesis.  J Clin Invest. 1992;  89 19-27
• 28 Sprenger H, Kaufmann A, Garn H, Lahme B, Gemsa D, Gressner A M. Differential expression of monocyte chemotatic protein-1 (MCP-1) in transforming rat hepatic stellate cells.  J Hepatol. 1999;  30 88-94
• 29 Maher J J, Lozier J S, Scott M K. Rat hepatic stellate cells produce cytokine-induced neutrophil chemoattractant in culture and in vivo .  Am J Physiol. 1998;  275 G847-53
• 30 Gaca M D, Pickering J A, Arthur M J, Benyon R C. Human and rat hepatic stellate cells produce stem cell factor: a possible mechanism for mast cell recruitment in liver fibrosis.  J Hepatol. 1999;  30 850-8
• 31 Gebhardt R, Hartung T. Cokulturen in der in vitro Toxikologie.  Biospektrum. 1996;  2 36-9
• 32 Iredale J P, Benyon R C, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur M J. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.  J Clin Invest. 1998;  102 538-49
• 33 Tilg H. New insights into the mechanisms of interferon alpha.  Gastroenterology. 1997;  112 1017-21
• 34 Saile B, Knittel T, Matthes N, Schott P, Ramadori G. CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair.  Am J Pathol. 1997;  151 265-72
• 35 Rippe R A. Live or death: the fate of the hapatic stellate cell following hepatic injury.  Heaptology. 1998;  27 1447-8
• 36 Gressner A M. The up-and-down of hepatic stellate cells in tissue injury: apoptosis restores cellular homeostasis.  Gastroenterology. 2001;  120 1285-8
• 37 Trim N, Morgan S, Evans M, Issa R, Fine D, Afford S, Wilkins B, Iredale J. Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation.  Am J Pathol. 2000;  156 1235-43
• 38 Fischer R, Schmitt M, Bode J G, Häussinger D. Expression of the peripheral-type bezodiazepine receptor and apoptosis induction in hepatic stellate cells.  Gastroenterology. 2001;  120 1212-26
• 39 Kato R, Kamiya S, Ueki M, Yajima H, Ishii T, Nakamura H, Katayama T, Fukai F. The fibronectin-derived antiadhesive peptides suppress the myofibroblast conversion of rat hepatic stellate cells.  Exp Cell Res. 2001;  265 54-63
• 40 Kim Y, Ratziu V, Choi S G, Lalazar A, Theiss G, Dang Q, Kim S J, Friedman S L. Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury.  J Biol Chem. 1998;  273 33 750-8
• 41 Lee K, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF-alpha and collagen type I is mediated by oxidative stress through c-myb expression.  J Clin Invest. 1995;  96 2461-8
• 42 Iwamoto H, Sakai H, Nawata H. Inhibition of integrin signaling with ARG-Gly-Asp motifs in rat hepatic stellate cells.  J Hepatol. 1998;  29 752-9
• 43 Sato M, Kojima N, Miura M, Imai K, Senoo H. Induction of cellular processes containing collagenase and retinoid by integrin-binding to interstitial collagen in hepatic stellate cell culture.  Cell Biol Int. 1998;  22 115-25
• 44 Doooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressen A M. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts.  Hepatology. 2000;  31 1094-106
• 45 Nakano M, Worner T M, Lieber C S. Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression.  Gastroenterology. 1982;  83 777-85
• 46 Friedman S L. Stellate cell activation in alcoholic fibrosis - an overview.  Alcohol Clin Exp Res. 1999;  23 904-10
• 47 Albano E, French S W, Ingelman-Sundberg M. Hydroxyethyl radicals in ethanol hepatoxicity.  Front Biosci. 1999;  4 D533-40
• 48 Mari M, Wu D, Nieto N, Cederbaum A l. CYP2E1-dependent toxicity and up-regulation of antioxidant genes.  J Biomed Sci. 2001;  8 52-8
• 49 Crabb D W. Pathogenesis of alcoholic liver disease: newer mechanisms of injury.  Keio J Med. 1999;  48 184-8
• 50 Svegliati-Baroni G, Jezequel A M, Orlandi F. Wine: risk factors for liver disease and antifibrotic compounds.  Drugs Exp Clin Res. 1999;  25 143-5
• 51 Baroni G S, Pastorelli A, Manzin A, Benedetti A, Marucci L, Solforosi L, Di Sario A, Brunelli E, Orlandi F, Clementi M, Macarri G. Hepatic stellate cell activation and liver fibrosis are associated with necroinflammatory injury and Th1-like response in chronic hepatitis C.  Liver. 1999;  19 212-9
• 52 Sakaida I, Nagatomi A, Hironaka K, Uchida K, Okita K. Quantitative analysis of liver fibrosis and stellate cell changes in patients with chronic hepatitis C after interferon therapy.  Am J Gastroenterol. 1999;  94 489-96
• 53 Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C.  Gastroenterology. 1997;  113 1069-73
• 54 Gebhardt R. Metabolic zonation of the liver: regulation and implications for liver function.  Pharmac Ther. 1992;  53 275-354
• 55 Inoue M. Protective mechanisms against reactive oxygen species. In: Arias IM, Bojer JL, Fausto N, Jacoby WB, Schachter D, Shafritz DA, editors The Liver. Biology and Pathobiology New York; Raven Press 1994: pp. 443-59
• 56 Comporti M. Biology of disease. Lipid peroxidation and cellular damage in toxic liver injury.  Lab Invest. 1985;  53 599-25
• 57 Dalton T P, Shertzer H G, Puga A. Regulation of gene expression by reactive oxygen.  Annu Rev Pharmacol Toxicol. 1999;  39 67-101
• 58 Kowaltowski A J, Vercesi A E. Mitochondrial damage induced by conditions of oxidative stress.  Free Radic Biol Med. 1999;  26 463-71
• 59 Hernandez-Munos R, Diaz-Munos M, Lopez V, Lopez-Barrera F, Yanez L, Vidrio S, Aranda-Fraustro A, de Sanchez V. Balance between oxidative damage and proliferative potential in an experimental rat model of CCl₄-induced cirrhosis: protective role of adenosine administration.  Hepatology. 1997;  26 1100-10
• 60 Parola M, Robino G, Dianzani M U. 4-Hydroxy-2,3-alkenals as molecular mediators of oxidative stress in the pathogenesis of liver fibrosis.  Int J Mol Med. 1999;  4 425-32
• 61 Houglum K, Filip M, Witztum J L, Chojkier M. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.  J Clin Invest. 1990;  86 1991-8
• 62 Casini A, Cunningham M, Rojkind M, Liber C S. Acetaldehyde increases procollagen type I and fibronectin gene transcription in cultured rat fat-storing cells through a protein synthesis-dependent mechanisms.  Hepatology. 1991;  13 758-65
• 63 Casini A, Galli G, Solzeno R, Ceni E, Franceschelli F, Rotella C M, Surrenti C. Acetaldehyde induces c-fos and c-jun proto-onogenesis in fat-storing cell cultures through protein kinase c activation.  Alcohol Alcohol. 1994;  29 303-14
• 64 Holstege A, Bedossa P, Poynard T, Kollinger M, Chaput J C, Houglum K, Chojkier M. Acetaldehyde-modified epitopes in liver biopsy specimens of alcoholic and nonalcoholic patients; localization and association with progression of liver fibrosis.  Hepatology. 1994;  19 367-74
• 65 Svegliati Baroni G, Ridolfi F, Di Sario A, Saccomanno S, Bendia E, Benedetti A, Greenwel P. Intracellular signaling pathways involved in acetaldehyde-induced collagen and fibronectin gene expression in human hepatic stellate cells.  Hepatology. 2001;  33 1130-40
• 66 Brenner D A, Chojkier M. Acetaldehyde stimulates collagen and noncollagen protein production by human fibroblasts.  J Biol Chem. 1987;  262 17 690-5
• 67 Casini A, Ceni E, Salzano R, Biondi P, Parola M, Galli A, Foschi M, Caligiuri A, Pinzani M, Surrenti C. Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: role of nitric oxide.  Hepatology. 1997;  25 361-7
• 68 Svegliati Baroni G, Saccomanno S, van Goor H, Jansen P, Benedetti A, Moshage H. Involvement of reactive oxygen species and nitric oxide radicals in activation and proliferation of rat hepatic stellate cells.  Liver. 2001;  21 1-12
• 69 Svegliati Baroni G, D’Ambrosio L, Ferretti G, Casini A, Di Sario A, Salzano R, Ridolfi F, Saccomanno S, Jezequel A M, Benedetti A. Fibrogenic effect of oxidative stress on rat hepatic stellate cells.  Hepatology. 1998;  27 720-6
• 70 Britton R S, Bacon B R. Intracellular signaling pathways in stellate cell activation.  Alcohol Clin Exp Res. 1999;  23 922-5
• 71 Lang A, Brenner D A. Gene regulation in hepatic stellate cell.  Ital J Gastroenterol Hepatol. 1999;  31 173-9
• 72 Xu Y, Rojkind M, Czaja M J. Regulation of monocyte chemoattractant protein 1 by cytokines and oxygen free radicals in rat hepatic fat storing cells.  Gastroenterology. 1996;  110 1870-7
• 73 Park S K, Kim J, Seomun Y, Choi J, Kim D H, Han I O, Lee E H, Chung S K, Joo C K. Hydrogen peroxide is a novel inducer of connective tissue growth factor.  Biochem Biophys Res Commun. 2001;  284 966-71
• 74 Svegliati-Baroni G, Di Sario A, Casini A, Feretti G, D’Ambrosio L, Ridolfi F, Bolognini L, Salzano R, Orlandi F, Benedetti A. The Na⁺/H⁺ exchanger modulates the fibrogenic effect of oxidative stress in rat hepatic stellate cells.  J Hepatol. 1999;  30 868-75
• 75 Di Sario A, Svegliati Baroni G, Bendia E, Ridolfi F, Saccomanno S, Ugili L, Trozzi L, Marzioni M, Jezequel A M, Macarri G, Benedetti A. Intracellular pH regulation and Na⁺/H⁺ exchange activity in human hepatic stellate cells: effect of platelet-derived growth factor, insulin-like growth factor 1 and insulin.  J Hepatol. 2001;  34 378-85
• 76 Benedetti A, Di Sario A, Casinin A, Ridolfi F, Bendia E, Pigini P, Tonnini C, D’Ambrosio L, Feliciangeli G, Macarri G, Svegliati Baroni G. Inhibition of the Na⁺/H⁺ exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study.  Gastroenterology. 2001;  120 545-56
• 77 Lee K S, Cottam H B, Houglum K, Wasson D B, Carson D, Chojkier M. Pentoxifylline blocks hepatic stellate cells activation independently of phosphodiesterase inhibitory activity.  Am J Physiol. 1997;  273 G1094-100
• 78 Wu J, Zern M A. NF-kappa B, lipososomes and pathogenesis of hepatic injury and fibrosis.  Front Biosci. 1999;  4 D520-7
• 79 Lee K S, Lee S J, Park H J, Chung J P, Han K H, Chon C Y, Lee S I, Moon Y M. Oxidative stress effect on the activation of hepatic stellate cells.  Yonsei Med J. 2001;  42 1-8
• 80 Li N, Karin M. Is NF-kappaB the sensor of oxidative stress?.  FASEB J. 1999;  13 1137-43
• 81 Lang A, Schoonhoven R, Tuvia S, Brenner D A, Rippe R A. Nuclear factor kB in proliferation, activation and apoptosis in rat hepatic stellate cells.  J Hepatol. 2000;  33 49-58
• 82 Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G. The bcl, NF-κB and p53/p21^WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-β or TNF-alpha on activated hepatic stellate cells.  Eur J Cell Biol. 2001;  80 554-61
• 83 Saliou C, Rihn B, Cillard J, Okamoto T, Packer L. Selective inhibition of NF-κB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence of different activating pathways.  FEBS Lett. 1998;  440 8-12
• 84 Foo S Y, Nolan G P. NF-κB to the rescue. RELs, apoptosis and cellular transformation.  Trends Genet. 1999;  15 229-35
• 85 Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, Dargel R, Poli G. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor betal expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis.  FASEB J. 1997;  11 851-7
• 86 Reichard J F, Vasiliou V, Petersen D R. Characterization of 4-hydroxy-2-nonenal metabolism in stellate cell lines d from normal and cirrhotic rat liver.  Biochim Biophys Acta. 2000;  27 222-32
• 87 Whalen R, Rockey D C, Friedman S L, Boyer T D. Activation of rat heaptic stellate cells leads to loss of glutathione S-transfer and their enzymatic activity against products of oxidative stress.  Hepatology. 1999;  30 927-33
• 88 Maher J J, Saito J M, Neuschwander-Tetri B A. Glutathione regulation in rat hepatic stellate cells. Comparative studies in primary culture and in liver injury in vivo .  Biochem Pharmacol. 1997;  53 637-41
• 89 Montosi G, Garuti C, Iannone A, Pietrangelo A. Spatial and temporal dynamics of hepatic stellate cell acitivation during oxidant-stress-induced fibrogenesis.  Am J Pathol. 1998;  152 1319-26
• 90 Maher J J, Neuschwander-Tetri B A. Manipulation of glutathione stores in rat hepatic stellate cells does not alter collagen synthesis.  Hepatology. 1997;  26 618-23
• 91 Kim K Y, Choi I, Kim S S. Progression of hepatic stellate cell activation is associated with the level of oxidative stress rather than cytokines during CC14-induced fibrogenesis.  Mol Cells. 2000;  10 289-300
• 92 De Bleser P J, Xu G, Rombouts K, Rogiers V, Geerts A. Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells.  J Biol Chem. 1999;  274 3881-7
• 93 Schuppan D, Koda M, Bauer M, Hahn E G. Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets?.  Acta Gastro-Enterol Belgica. 2000;  63 366-70
• 94 Windmeier C, Gressner A M. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis.  Gen Pharmacol. 1997;  29 181-96
• 95 Ferency P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B. Randomized controlled trial of silymarin-treatment in patients with cirrhosis of the liver.  J Hepatol. 1989;  9 105-13
• 96 Held C h. Silymarin bei Hepatopathien. Fibrose-Hemmung unter Praxisbedingungen.  Therapiewoche. 1992;  42 1696-701
• 97 Boigk G, Stroedter L, Herbst H, Waldschmidt J, Riecken E, Schuppan D. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats.  Hepatology. 1997;  26 643-9
• 98 Jia J D, Bauer M, Cho J J, Ruehl M, Milani S, Boigk G, Riecken E O, Schuppan D. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha 1(I) and TIMP-1.  J Hepatol. 2001;  35 392-8
• 99 Campos R, Garrido A, Guerra R, Valenzuela A. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver.  Planta Med. 1989;  55 417-9
• 100 Pietrangelo A, Borella F, Casalgrandi G, Montosi G, Ceccarelli D, Gallesi D. , et al . Antioxidant activity of silybin in vivo during chronic iron overload in rats.  Gastroenterology. 1995;  109 1941-9
• 101 Nan J X, Park E J, Lee S H, Park P H, Kim J Y, Ko G, Sohn D H. Antifibrotic effect of Stephania tetrandra on experimental liver fibrosis induced by bile duct ligation and scission in rats.  Arch Pharm Res. 2000;  23 501-6
• 102 Nan J X, Park E J, Kim H J, Ko G, Sohn D H. Antifibrotic effects of the methanol extract of Polygonum aviculare in bibrotic rats induced by bile duct ligation and scission.  Biol Pharm Bull. 2000;  23 240-3
• 103 Peres W, Tunon M J, Collado P S, Herrmann S, Marroni N, Gonzales-Gallego J. The flavonoid quercetin ameliorates liver damage in rats with biliary obstruction.  J Hepatol. 2000;  33 742-50
• 104 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
• 105 Shimizu I, Ma Y -R, Mizobuchi X, Miura T, Nakai Y, Yasuda M, Shiba M, Horie T, Amagaya S, Kawada N, Hori H, Ito S. Effects of Sho-saiko-to, a Jananese herbal medicine, on hepatic fibrosis in rats.  Hepatology. 1999;  29 149-60
• 106 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
• 107 Hirayama C, Okumura M, Tanikawa K, Yano M, Mizuta M, Ogawa N. A multicenter randomized controlled clinical trial of Sho-saiko-to in chronic active hepatitis.  Gastroenterol Jpn. 1989;  24 715-9
• 108 Shimizu I. Sho-siako-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma.  J Gastroenterol Hepatol. 2000;  15 84-90
• 109 Lieber C, Leo M, Aleynik S, Aleynik M, DiCarli L. Polyenylphosphatidyl-choline decreases alcohol-induced oxidative stress in the baboon.  Alcohol Clin Exp Res. 1997;  21 375-9
• 110 Turkdogan M K, Agaoglu Z, Yener Z, Sekeroglu R, Akkan H A, Avci M E. The role of antioxidant vitamins (C and E), selenium and Nigella sativa in the prevention of liver fibrosis and cirrhosis in rabbits: new hopes.  Dtsch Tierarztl Wochenschr. 2001;  108 71-3
• 111 Jose J K, Kuttan R. Hepatoprotective activity of Emblica officinalis and Chyavanaprash.  J Ethnopharmacol. 2000;  72 135-40
• 112 Park E J, Nan J X, Kim J Y, Kang H C, Choi J H, Lee S J, Lee B H, Kim S J, Lee J H, Kim Y C, Sohn D H. The ethanol-soluble part of a hot-water extract from Artemisia iwayomogi inhibits liver fibrosis induced by carbon tetrachloride in rats.  J Pharm Pharmacol. 2000;  52 875-81
• 113 Szende B, Timar F, Hargitai B. Olive oil decreases liver damage in rats caused by carbon tetrachloride (CCl₄).  Exp Toxicol Pathol. 1994;  46 355-9
• 114 Kawada N, Seki S, Inoue M, Kuroki T. Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells.  Hepatology. 1998;  27 1265-74
• 115 Rice-Evans C. Plant polyphenols: free radical scavengers or chain-breaking antioxidants.  Biochem Soc Symp. 1995;  61 103-16
• 116 Osawa T. Protective role of dietary polyphenols in oxidative stress.  Mech Ageing Dev. 1999;  111 133-9
• 117 Gebhardt R. Antioxidative and protective properties of extracts from leaves of the artischoke (Cynara scolymus L.) against hydroperoxide-induced oxidative stress in cultured rat hepatocytes.  Toxicol Appl Pharmacol. 1997;  144 279-86
• 118 Fuchs E C, Weyhenmeyer R, Weiner O H. Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts.  Arzneimittelforschung. 1997;  47 1383-7
• 119 Godichaud S, Krisa S, Couronne B, Dubuisson L, Merillon J M, Desmouliere A, Rosenbaum J. Deactivation of cultured human liver myofibroblasts by trans-resveratrol, a grapevine-derived polyphenol.  Hepatology. 2000;  31 922-31
• 120 Kayano K, Sakaida I, Uchida K, Okita K. Inhibitory effects of the herbal medicine Shosaiko-to (TJ-9) on cell proliferation and procollagen gene expressions in cultured rat hepatic stellate cells.  J Hepatol. 1998;  29 642-9
• 121 Ricupero D A, Polkis C F, Risihikof D C, Kuang P P, Goldstein R H. Apigenin decreases expression of the myofibroblast phenotype.  FEBS Lett. 2001;  506 15-21
• 122 Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases.  J Biol Chem. 1987;  262 5592-5
• 123 Ferriola P C, Cody V, Middleton E J r. Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.  Biochem Pharmacol. 1989;  38 1617-24
• 124 Jinsart W, Ternai B, Polya G M. Inhibition of rat liver cyclic AMP-dependent protein kinase by flavonoids.  Biol Chem Hoppe Seyler. 1992;  373 205-11
• 125 Walker E H, Pacold M E, Perisic O, Stephens L, Hawkins P T, Wymann M P, Williams R L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY29002, quercetin, myricetin, and staurosporine.  Mol Cell. 2000;  6 909-19
• 126 Gebhardt R. Inhibition of cholesterol biosynthesis in primary cultured rat hepatocytes by artichoke (Cynara scolymus L.) extracts.  J Pharmacol Exp Therap. 1998;  86 1-7
• 127 Yoshida M, Sakai T, Hosokawa N, Marui N, Matsumoto K, Fujioka A, Nishino H, Aoike A. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells.  FEBS Lett. 1990;  260 10-3
• 128 Kuo M L, Yang N C. Reversion of v-H-ras-transformed NIH 3T3 cells by apigenin through inhibiting mitogen activated protein kinase and its downstream oncogens.  Biochim Biophys Res Commun. 1995;  212 767-75
• 129 Inoue T, Jackson E K. Strong antiproliferative effects of baicalein in cultured rat hepatic stellate cells.  Eur J Pharmacol. 1999;  378 129-35
• 130 Reeves H L, Dack C L, Peak M, Burt A D, Day C P. Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture.  J Hepatol. 2000;  32 465-72
• 131 Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T. Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells.  Mol Pharmacol. 2001;  60 656-65
• 132 Morazzoni P, Montalbetti A, Malandrino S, Pifferi G. Comparative pharmacokinetics of silipide and silymarin in rats.  Eur J Drug Metab Pharmacokinet. 1993;  18 289-97
• 133 Schandalik R, Perucca E. Pharmacokinetics of silybin following oral administration of silipide in patients with extrahepatic biliary obstruction.  Drugs Exp Clin Res. 1994;  20 37-42
• 134 Schulz H U, Schurer M, Krumbiegel G, Wachter W, Weyhenmeyer R, Seidel G. The solubility and bioequivalence of silymarin preparations.  Arzneimittelforschung. 1995;  45 61-4
• 135 Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients.  Arzneimittelforschung. 1992;  42 964-8
• 136 Akao T, Kawabata K, Yanagisawa E, Ishihara K, Mizuhara Y, Wakui Y, Sakashita Y, Kobashi K. Baicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form.  J Pharm Pharmacol. 2000;  52 1563-8
• 137 Li C, Homma M, Oka K. Characteristics of delayed excretion of flavonoids in human urine after administration of Sho-saiko-to, a herbal medicine.  Biol Pharm Bull. 1998;  21 1251-7
• 138 Gläßer G, Graefe E U, Struck F, Veit M, Gebhardt R. Comparison of antioxidative capacities and inhibitory effects on cholesterol biosynthesis of quercetin and potential metabolites.  Phytomedicine. 2002;  9 33-40
• 139 Casley-Smith J R. The pathophysiology of lymphedema and the action of benzopyrones in reducing it.  Lymphology. 1988;  21 190-4