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13 6 Vol13 No6 200 6 12 Life Science Research Dec 200 1, 2, 3 1, 1 100037 2 214036 3 22500 :,, C E 3, highwire, DAVID GO pathway express GO, 3 14, GO, 3, 3, : ; ; ; GO ; : Q343 : A : 1007-7847(200)06-0487-05 Genes and Common Pathways Related to Three Food Antioxidant Revealed by Combining and Analyzing Candidate Gene Lists from Multiple Technology Platforms HAN Fei 1 SUN Jin 2 ZHOU Meng-liang 3 YU Ting-ting 1 1 Academy of State Administration of Grain Beijing 100037 China 2 School of Food Science and Technology Jiangnan University Wuxi 214036 Jiangsu China 3 College of Bioscience and Biotechnology Yangzhou University Yangzhou 22500 : 200-03-20 : 200-06-15 Jiangsu China Abstract Antioxidants modulate body gene expression and regulate wide biological process Antioxidants related genes are studied using different technology storing in peer reviewed articles Exploring the relationship between these genes is helpful for finding their function mechanism and for development of novel biomarker for new antioxidant screening The gene related to three typical antioxidants retinoic acid vit C and vit E were dig out from articles searching from highwire database The significantly related GO biological terms and gene pathway were analyzed using DAVID tools and pathway express respectively The results showed that 14 genes were commonly related to three antioxidants Similar GO biological and gene pathway were involved in three antioxidants including cell communication immune response apoptosis cell cycle and several typical signaling pathways was the common pathways related three antioxidants implying they modulated cell cycle regulation cytoskeleton assembly adhesion migration motion growth regulation survival and angiogenesis etc They might inhibit tumorigenesis development and invasion targeting to focal adhesion Key words antioxidants gene expression gene pathway GO term focal adhesion Life Science Research 200 13 6 487~41 : 73- Tel 010-5852365 E-mail hf@chinagrainorg

488 200 1 11 [1] highwire http //wwwhighwireorg vitc vite 1 retinoic acid AND review 2 retinoic acid AND gene OR microarray OR proteomics 3 vitc AND review ROS reactive oxygen species 4 vitc AND gene OR microarray OR proteomics 5 ascorbic acid AND review [2,3] 6 ascorbic acid AND gene OR microarray OR proteomics 7 vite AND review 8 vite AND gene OR microarray OR proteomics 80 - [1,4] PCR [4] 12 121 GO DAVID http //davidabccncifcrfgov/ [5~] GO P 122 pathway express http //vortexcswayne [10] edu/ontoexpress / vitc vite [ 11,12] vitc vite IF P 2 21 vitc vite E vite 2 05 C vitc Retinoic acid 3 1 712 542 vitc 3 1 072 501 571 vite 23 3 57 238 1 vitc vite 14

6 : 48 SOD1 SOD2 GPX4 Fos GAS6 TOP2A CDKN1A timp1 clu Table 1 1 vitc vite The common related gene pathway of vitc, vite and retinoic acid Gene symbol Gene name Gene function SOD1 SOD2 Gpx4 CDKN1A Anxa5 Timp1 Clu Fos COL1A1 Pecam1 Mgp Cd44 GAS6 TOP2A Superoxide dismutase 1 Superoxide dismutase 2 Glutathione peroxidase 4 Cyclin-dependent kinase inhibitor 1A Annexin A5 TIMP metallopeptidase inhibitor 1 Clusterin FBJ osteosarcoma oncogene Collagen type I alpha 1 Platelet/ endothelial cell adhesion molecule 1 Matrix Gla protein Cd44 molecule Growth arrest specific 6 Topoisomerase DNA II alpha 170 kda Inhibition of the reactions brought about by dioxygen O 2 or peroxides Catalysis of an oxidation redox reaction Catalysis of an oxidation redox reaction, DNA repair cell apoptosis Negative regulation of coagulation Negative regulation of membrance protein ectodomain proteolysis, response to organic substance, response to peptide hormone stimulus Anti-apoptosis Oxidative stress reaction Leukocyte migration Construction of extracellular matrix Cell metabolism regulation DNA copy 22 vitc vite GO Pathway express GO Gene Ontology Consortium 1 3 GF RTK C PKC Ha- [13] Ras Filamin RhoA vitc vite Actin Rac c-jun JNK UNIGEN id DAVID GO ERK1/2 Elk1 2 Bcl-2 GO 3 vite GO 10 vitc GO S- 4 cell cycle [14] focal adhesion 3 GO ROS 23 vite 3 vitc vite Nrf2 PPAR signaling pathway TGF-beta signaling pathway Pathway express NAD P H NQO1 ARE VE ARE vitc [15] KEAP1 24 vitc vite 14 vitc vite vitc vite SOD1 SOD2

40 200 Gpx4 3 [16] VitC 3 GO Cip1 / p21 [17] cell cycle IF 2 3 GO Table 2 The significantly related GO biological terms of three antioxidants Gene ontology Gene number Ratio/ % P-value Retinoic acid Cell communication Adipocyte signaling pathway Regulation of action cytoskeleton B cell receptor signaling pathway Hematopoietic cell lineage Complement and coagulation cascade Adherens junction Cell adhesion molecule TGF-β signaling pathway Dorso-ventral axis formation WNT signaling pathway Apoptosis Cytokine-cytokine receptor interaction MAPK signaling pathway vitc Cell communication vite Toll-like receptor signaling pathway MAPK signaling pathway Glutathione metabolism TGF-β signaling pathway Fc epsilon ri signaling pathway T cell receptor signaling pathway Hematopoietic cell lineage 47 21 54 30 23 32 30 68 36 11 38 25 40 65 75 11 15 10 18 5 8 7 20 8 251 112 288 101 160 101 123 171 160 362 2 05 203 133 213 346 400 207 282 188 357 320 641 178 320 676 285 24 712 285 320 0000 001 0034 128 0013 114 0083 261 0000 641 0083 261 0035 162 0085 87 0002 127 0000 007 0000 002 0051 484 0045 66 0056 81 0000 044 0006 74 0000 510 0070 33 0000 087 0085 44 0013 473 0021 436 0020 311 0067 52 0016 7 0000 678 0034 23 0067 0 0000 000 01 005 213 0011 51 3 3 Table 3 The significantly related gene pathway of three antioxidants Pathway name Impact factor P-value Corrected gamma P-value Retinoic acid PPAR signaling pathway ErbB signaling pathway TGF-beta signaling pathway B cell receptor signaling pathway VitE PPAR signaling pathway TGF-beta signaling pathway 1244 5078 8718 678 6174 575 14027 4484 4472 4347 3345 375E-06 0006 231 164E-04 0001 116 0002 083 0003 043 80E-07 0011 286 0011 42 0012 42 0035 252 0000 05 0037 88 0001 5 0008 703 0014 43 0020 675 0000 012 0061 04 0062 515 006 22 0153 206

6 : 41 RhoGAP mdia1 ECM ECM-receptor interaction ITGA ITGB PKC Src RhoGEF Calpain Actinin Filamin Talin Paxillin PTEN Zyxin VASP Vinculin Parvin ILK RhoA ROCK PIPSK MLCP PIP2 PDK1 Akt/PKB Cdc42 MLCK MLC Actin Regulation of actin cytoskeleton Actin polymerization GSK-3β β-catenin wnt signaling pathway Cell motility Stress fiber /FA formation Filopodia Lamellipodia formation FA turnover Cytokinecytokine receptor interaction Caveolin Fyn FAK GF RTK Shc Grb2 Sos Ha-Ras Raf-1 PI3K p130cas Phosphatidyl inositol signaling system Crk PIP3 GRF2 C3G Vav Rac PAK DOCK1 Rap1 B-Raf MEK1 Apoptosis JNK c-jun ERK1/2 Bad MAPK signaling pathway Bcl-2 E1K1 Cell proliferation CycD DNA Cell survival ciaps DNA 1 3 - Fig1 The common responsive gene pathway of vitc, vite and retinoic acid- focal adhesion [8] BLOCK G PATTERSON B SUBAR A Fruit vegetables and cancer prevention a review of the epidemiological evidence[j] Nutr Cancer 2 18 1-2 [] LIU R H Health benefits of fruits and vegetables are from additive and synergistic combinayion of phytochemicals[j] 3 GO Am J Clin Nutr 2003 78 517S-520S [10] BLUMBERG J Use of biomarkers of oxidative stress in research studies[j] J Nutr 2004 134 11 3188-318 [11] STOREY J D TIBSHIRANI R Statistical significance for genomewide studies[j] Proc Natl Acad Sci USA 2003 100 [18] 3 16 440-445 [12] DRAGHICI S KHATRI P TARCA A L et al A systems biology approach for pathway level analysis[j] Genome Res 3 2007 3 32-41 [13] ASHBURNER M BALL C A BLAKE J A et al Gene ontology tool for the unification of biology[j] Nat Genet (References): 2000 25 1 25-2 [14] TANAKA H MAKINO Y OKAMOTO K et al Redox [1] VALKO M LEIBFRITZ D MONCOL J et al Free radicals regulation of the nuclear receptor[j] Oncology 2000 5 and antioxidants in normal physiological functions and human Suppl 1 13-18 disease[j] The International Journal of Biochemistry & Cell [15] CHEN X L DODD G THOMAS S et al Activation of Biology 2007 3 1 44-84 Nrf2/ARE pathway protects endothelial cells from oxidant [2] AMES B N GOLD L S Endogenous mutagens and the injury and inhibits inflammatory gene expression[j] Am J causes of aging and cancer[j] Mutat Res 1 250 1-2 Physiol Heart Circ Physiol 2006 20 5 1862-1870 3-16 [16] NAHUM A HIRSH K DANILENKO M et al Lycopene [3] HALLIWELL B GUTTERIDGE J M C Free Radicals in inhibition of cell cycle progression in breast and endometrial Biology and Medicine[M] New York Oxford University Press cancer cells is associated with reduction in cyclin D levels 138-16 and retention of p27 Kip1 in the cyclin E-cdk2 complexes [4] MAYNE S T Antioxidant nutrients and chronic disease use [J] Oncogene 2001 20 26 3428-3436 of biomarkers of exposure and oxidative stress status in [17] THOMAS C G VEZYRAKI P E KALFAKAKOU V P et al epidemiologic research [J] J Nutr 2003 133 Suppl 3 Vitamin C transiently arrests cancer cell cycle progression in 33-40 S phase and G2/M boundary by modulating the kinetics of [5] TEMPLE N J Antioxidants and disease More questions than activation and the subcellular localization of Cdc25C answers[j] Nutr Res 2000 20 44-45 phosphatase[j] J Cell Physiol 2005 205 2 310-318 [6] WILLETT W C Diet and health what should we eat [J] [18] ROMER L H BIRUKOV K G GARCIA J G Focal Science 4 254 532-537 adhesions paradigm for a signaling nexus [J] Circ Res [7] WILLETT W C Balancing life-style and genomics research 2006 8 5 606-616 for disease prevention[j] Science 2002 26 65-68