A bioinformatic and mechanistic study elicits the antifibrotic effect of ursolic acid through the attenuation of oxidative stress with the involvement of ERK, PI3K/Akt, and p38 MAPK signaling pathways in human hepatic stellate cells and rat liver

Drug Design, Development and Therapy

Volumn 9, Issue , 2015, Pages 3989-4104

  He, Wenhua ^a   Shi, Feng ^a   Zhou, Zhi Wei ^b   Li, Bimin ^a   Zhang, Kunhe ^a   Zhang, Xinhua ^a   Ouyang, Canhui ^a   Zhou, Shu Feng ^b   Zhu, Xuan ^a  

^a NANCHANG UNIVERSITY   (China)

^b UNIVERSITY OF SOUTH FLORIDA   (United States)

Author keywords

DAVID; DDI CPI; Liver fibrosis; NADPH oxidase; ROS; Ursolic acid

Indexed keywords

COLLAGEN TYPE 1; GLYCOPROTEIN GP 91; MALONALDEHYDE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN P22; PROTEIN P67; RAC1 PROTEIN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; SUPEROXIDE DISMUTASE; TISSUE INHIBITOR OF METALLOPROTEINASE 1; URSOLIC ACID; ANTIOXIDANT; DIMETHYLNITROSAMINE; INTERSTITIAL COLLAGENASE; MMP1 PROTEIN, RAT; NOX4 PROTEIN, HUMAN; NOX4 PROTEIN, RAT; PROTEIN KINASE INHIBITOR; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; TISSUE INHIBITOR OF METALLOPROTEINASE-1 PROTEIN, RAT; TRITERPENE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIFIBROTIC ACTIVITY; ARTICLE; BIOINFORMATICS; CONTROLLED STUDY; DOSE RESPONSE; DRUG ACTIVITY; DRUG DOSE COMPARISON; DRUG PROTEIN BINDING; ENZYME BLOOD LEVEL; ENZYME INHIBITION; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; LIVER CELL; LIVER FIBROSIS; MALE; NONHUMAN; OXIDATIVE STRESS; PREDICTION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN TARGETING; QUALITY CONTROL; RAT; SIGNAL TRANSDUCTION; STELLATE CELL; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOLOGY; CELL LINE; CELL PROLIFERATION; CHEMICALLY INDUCED; DRUG EFFECTS; ENZYMOLOGY; GENETICS; HEPATIC STELLATE CELL; LIVER; LIVER CIRRHOSIS, EXPERIMENTAL; METABOLISM; PATHOLOGY; PROTEIN PROTEIN INTERACTION; SPRAGUE DAWLEY RAT; TIME FACTOR;

ANIMALS; ANTIOXIDANTS; CELL LINE; CELL PROLIFERATION; COLLAGEN TYPE I; COMPUTATIONAL BIOLOGY; DIMETHYLNITROSAMINE; DOSE-RESPONSE RELATIONSHIP, DRUG; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; GENE EXPRESSION REGULATION; HEPATIC STELLATE CELLS; HUMANS; LIVER; LIVER CIRRHOSIS, EXPERIMENTAL; MALE; MATRIX METALLOPROTEINASE 1; NADPH OXIDASE; OXIDATIVE STRESS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN INTERACTION MAPS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RATS, SPRAGUE-DAWLEY; SIGNAL TRANSDUCTION; TIME FACTORS; TISSUE INHIBITOR OF METALLOPROTEINASE-1; TRITERPENES;

EID: 84939824477     PISSN: None     EISSN: 11778881     Source Type: Journal    
DOI: 10.2147/DDDT.S85426     Document Type: Article

References (69)

1. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep. 2013;61(4):1–117.
2. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–218.
3. Mitchell AE, Colvin HM, Palmer Beasley R. Institute of Medicine recommendations for the prevention and control of hepatitis B and C. Hepatology. 2010;51(3):729–733.
4. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138(2):e1–e6.
5. Liu J, Fan D. Hepatitis B in China. Lancet. 2007;369(9573):1582–1583.
6. Zhang F, Zhu H, Wu Y, et al. HIV, hepatitis B virus, and hepatitis C virus co-infection in patients in the China national free antiretroviral treatment program, 2010–2012: a retrospective observational cohort study. Lancet Infect Dis. 2014;14(11):1065–1072.
7. Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis. 2007;11(1):75–104,ix.
8. Brenner DA. Molecular pathogenesis of liver fibrosis. Trans Am Clin Climatol Assoc. 2009;120:361–368.
9. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–1669.
10. Novo E, Cannito S, Paternostro C, Bocca C, Miglietta A, Parola M. Cellular and molecular mechanisms in liver fibrogenesis. Arch Biochem Biophys. 2014;548:20–37.
11. De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys. 2007;462(2):266–272.
12. Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol. 2011;4(6):391–417.
13. Rosenbloom J, Mendoza FA, Jimenez SA. Strategies for anti-fibrotic therapies. Biochim Biophys Acta. 2013;1832(7):1088–1103.
14. Dufour D, Pichette A, Mshvildadze V, et al. Antioxidant, anti-inflammatory and anticancer activities of methanolic extracts from Ledum groenlandicum Retzius. J Ethnopharmacol. 2007;111(1):22–28.
15. Saravanan R, Viswanathan P, Pugalendi KV. Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats. Life Sci. 2006;78(7):713–718.
16. Saraswat B, Visen PK, Agarwal DP. Ursolic acid isolated from Eucalyptus tereticornis protects against ethanol toxicity in isolated rat hepatocytes. Phytother Res. 2000;14(3):163–166.
17. Shen YM, Zhu X, Zhang KH, et al. [Effect of ursolic acid on proliferation and apoptosis of hepatic stellate cells in vitro]. Zhonghua Gan Zang Bing Za Zhi. 2008;16(4):298–301.
18. Steinkamp-Fenske K, Bollinger L, Völler N, et al. Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells. Atherosclerosis. 2007;195(1):e104–e111.
19. Huang da W, Shermann BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.
20. Luo H, Chen J, Shi L, et al. DRAR-CPI: a server for identifying drug repositioning potential and adverse drug reactions via the chemical-protein interactome. Nucleic Acids Res. 2011;39(Web Server issue): W492–W498.
21. Luo H, Zhang P, Huang H, et al. DDI-CPI, a server that predicts drug-drug interactions through implementing the chemical-protein interactome. Nucleic Acids Res. 2014;42(Web Server issue): W46–W52.
22. Wang R, Fang X, Lu Y, Wang S. The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. J Med Chem. 2004;47(12):2977–2980.
23. Yang L, Luo H, Chen J, Xing Q, He L. SePreSA: a server for the prediction of populations susceptible to serious adverse drug reactions implementing the methodology of a chemical-protein interactome. Nucleic Acids Res. 2009;37(Web Server issue):W406–W412.
24. Yang L, Chen J, Shi L, Hudock MP, Wang K, He L. Identifying unexpected therapeutic targets via chemical-protein interactome. PLoS One. 2010;5(3):e9568.
25. Vogel S, Piantedosi R, Frank J, et al. An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro. J Lipid Res. 2000;41(6):882–893.
26. Bataller R, Schwabe RF, Choi YH, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112(9):1383–1394.
27. Herrera B, Murillo MM, Alvarez-Barrientos A, Beltrán J, Fernández M, Fabregat I. Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-β in fetal rat hepatocytes. Free Radic Biol Med. 2004;36(1):16–26.
28. Wang H, Joseph JA. Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader. Free Radic Biol Med. 1999;27(5–6):612–616.
29. LeBel CP, Ischiropoulos H, Bondy SC. Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol. 1992;5(2):227–231.
30. Proell V, Carmona-Cuenca I, Murillo MM, Huber H, Fabregat I, Mikulits W. TGF-β dependent regulation of oxygen radicals during transdifferentiation of activated hepatic stellate cells to myofibroblastoid cells. Comp Hepatol. 2007;6:1.
31. Zhou ZW, Xie XL, Zhou SF, Li CG. Mechanism of reversal of high glucose-induced endothelial nitric oxide synthase uncoupling by tanshinone IIA in human endothelial cell line EA.hy926. Eur J Pharmacol. 2012;697(1–3):97–105.
32. Sanchez-Valle V, Chavez-Tapia NC, Uribe M, Mendez-Sanchez N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem. 2012;19(28):4850–4860.
33. Van Raamsdonk JM, Hekimi S. Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci U S A. 2012;109(15):5785–5790.
34. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425–456.
35. Galli F, Battistoni A, Gambari R, et al; Working Group on Inflammation in Cystic Fibrosis. Oxidative stress and antioxidant therapy in cystic fibrosis. Biochim Biophys Acta. 2012;1822(5):690–713.
36. Paik YH, Kim J, Aoyama T, De Minicis S, Bataller R, Brenner DA. Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal. 2014;20(17):2854–2872.
37. Maraldi T. Natural compounds as modulators of NADPH oxidases. Oxid Med Cell Longev. 2013;2013:271602.
38. Ikeda Y, Murakami A, Ohigashi H. Ursolic acid: an anti- and pro-inflammatory triterpenoid. Mol Nutr Food Res. 2008;52(1):26–42.
39. Mazumder K, Tanaka K, Fukase K. Cytotoxic activity of ursolic acid derivatives obtained by isolation and oxidative derivatization. Molecules. 2013;18(8):8929–8944.
40. Yang L, Wang KJ, Wang LS, et al. Chemical-protein interactome and its application in off-target identification. Interdiscip Sci. 2011;3(1):22–30.
41. Yang L, Wang K, Chen J, et al. Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome–clozapine-induced agranulocytosis as a case study. PLoS Comput Biol. 2011;7(3):e1002016.
42. Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. Redox Biol. 2014;2:267–272.
43. Babior BM, Lambeth JD, Nauseef W. The neutrophil NADPH oxidase. Arch Biochem Biophys. 2002;397(2):342–344.
44. Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973;52(3):741–744.
45. Babior BM. The NADPH oxidase of endothelial cells. IUBMB Life. 2000;50(4–5):267–269.
46. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313.
47. Katsuyama M, Matsuno K, Yabe-Nishimura C. Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme. J Clin Biochem Nutr. 2012;50(1):9–22.
48. Lassegue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol. 2010;30(4):653–661.
49. Nauseef WM. Biological roles for the NOX family NADPH oxidases. J Biol Chem. 2008;283(25):16961–16965.
50. Adachi T, Togashi H, Suzuki A, et al. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology. 2005;41(6):1272–1281.
51. Ris-Stalpers C. Physiology and pathophysiology of the DUOXes. Antioxid Redox Signal. 2006;8(9–10):1563–1572.
52. Kawahara T, Quinn MT, Lambeth JD. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol Biol. 2007;7:109.
53. Kawahara T, Lambeth JD. Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes. BMC Evol Biol. 2007;7:178.
54. Lambeth JD, Kawahara T, Diebold B. Regulation of Nox and Duox enzymatic activity and expression. Free Radic Biol Med. 2007;43(3):319–331.
55. Cave AC, Brewer AC, Narayanapanicker A, et al. NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal. 2006;8(5–6):691–728.
56. Streeter J, Thiel W, Brieger K, Miller FJ Jr. Opportunity Nox: the future of NADPH oxidases as therapeutic targets in cardiovascular disease. Cardiovasc Ther. 2012;31(3):125–137.
57. Drummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov. 2011;10(6):453–471.
58. Sancho P, Mainez J, Crosas-Molist E, et al. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS One. 2012;7(9):e45285.
59. Hordijk PL. Regulation of NADPH oxidases: the role of Rac proteins. Circ Res. 2006;98(4):453–462.
60. Katsuyama M. NOX/NADPH oxidase, the superoxide-generating enzyme: its transcriptional regulation and physiological roles. J Pharmacol Sci. 2010;114(2):134–146.
61. Choi SS, Sicklick JK, Ma Q, et al. Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. Hepatology. 2006;44(5):1267–1277.
62. Mehal W, Imaeda A. Cell death and fibrogenesis. Semin Liver Dis. 2010;30(3):226–231.
63. Yamamori T, Inanami O, Nagahata H, Kuwabara M. Phosphoinositide 3-kinase regulates the phosphorylation of NADPH oxidase component p47(phox) by controlling cPKC/PKCdelta but not Akt. Biochem Biophys Res Commun. 2004;316(3):720–730.
64. Kilpatrick LE, Sun S, Li H, Vary TC, Korchak HM. Regulation of TNF-induced oxygen radical production in human neutrophils: role of delta-PKC. J Leukoc Biol. 2010;87(1):153–164.
65. De Minicis S, Seki E, Oesterreicher C, Schnabl B, Schwabe RF, Brenner DA. Reduced nicotinamide adenine dinucleotide phosphate oxidase mediates fibrotic and inflammatory effects of leptin on hepatic stellate cells. Hepatology. 2008;48(6):2016–2026.
66. Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest. 2013;123(5):1887–1901.
67. Jiang JX, Chen X, Serizawa N, et al. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med. 2012;53(2):289–296.
68. Babalola O, Mamalis A, Lev-Tov H, Jagdeo J. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents. Arch Dermatol Res. 2014;306(4):313–330.
69. Guy J, Peters MG. Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y). 2013;9(10):633–639.