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Current Pharmaceutical Biotechnology

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ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

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Research Article

Tocotrienols Activate Nrf2 Nuclear Translocation and Increase the Antioxidant- Related Hepatoprotective Mechanism in Mice Liver

Author(s): Ahmed Atia, Nadia S. Alrawaiq and Azman Abdullah*

Volume 22, Issue 8, 2021

Published on: 28 September, 2020

Page: [1085 - 1098] Pages: 14

DOI: 10.2174/1389201021666200928095950

Price: $65

Abstract

Background: The most common preparation of tocotrienols is the Tocotrienol-Rich Fraction (TRF). This study aimed to investigate whether TRF induced liver Nrf2 nuclear translocation and influenced the expression of Nrf2-regulated genes.

Methods: In the Nrf2 induction study, mice were divided into control, 2000 mg/kg TRF and diethyl maleate treated groups. After acute treatment, mice were sacrificed at specific time points. Liver nuclear extracts were prepared and Nrf2 nuclear translocation was detected through Western blotting. To determine the effect of increasing doses of TRF on the extent of liver nuclear Nrf2 translocation and its implication on the expression levels of several Nrf2-regulated genes, mice were divided into 5 groups (control, 200, 500 and 1000 mg/kg TRF, and butylated hydroxyanisole-treated groups). After 14 days, mice were sacrificed and liver RNA was extracted for qPCR assay.

Results: 2000 mg/kg TRF administration initiated Nrf2 nuclear translocation within 30 min, reached a maximum level of around 1 h and dropped to half-maximal levels by 24 h. Incremental doses of TRF resulted in dose-dependent increases in liver Nrf2 nuclear levels, along with concomitant dosedependent increases in the expressions of Nrf2-regulated genes.

Conclusion: TRF activated the liver Nrf2 pathway resulting in increased expression of Nrf2-regulated cytoprotective genes.

Keywords: Nrf2, TRF, tocotrienols, mice, liver, hepatoprotective.

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[1]
Li, F.; Tan, W.; Kang, Z.; Wong, C.W. Tocotrienol enriched palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferators-activated receptors. Atherosclerosis, 2010, 211(1), 278-282.
[http://dx.doi.org/10.1016/j.atherosclerosis.2010.01.015] [PMID: 20138624]
[2]
Sundram, K.; Sambanthamurthi, R.; Tan, Y.A. Palm fruit chemistry and nutrition. Asia Pac. J. Clin. Nutr., 2003, 12(3), 355-362.
[PMID: 14506001]
[3]
Sundram, K.; Gapor, A. Vitamin E from palm oil. Its extraction and nutritional properties. Lipid Technol., 1992, 4, 137-141.
[4]
Sen, C.K.; Khanna, S.; Roy, S. Tocotrienols: Vitamin E beyond tocopherols. Life Sci., 2006, 78(18), 2088-2098.
[http://dx.doi.org/10.1016/j.lfs.2005.12.001] [PMID: 16458936]
[5]
Meydani, M. Vitamin E modulation of cardiovascular disease. Ann. N. Y. Acad. Sci., 2004, 1031, 271-279.
[http://dx.doi.org/10.1196/annals.1331.027] [PMID: 15753153]
[6]
Koga, T.; Kwan, P.; Zubik, L.; Ameho, C.; Smith, D.; Meydani, M. Vitamin E supplementation suppresses macrophage accumulation and endothelial cell expression of adhesion molecules in the aorta of hypercholesterolemic rabbits. Atherosclerosis, 2004, 176(2), 265-272.
[http://dx.doi.org/10.1016/j.atherosclerosis.2004.05.034] [PMID: 15380448]
[7]
Montiel, T.; Quiroz-Baez, R.; Massieu, L.; Arias, C. Role of oxidative stress on beta-amyloid neurotoxicity elicited during impairment of energy metabolism in the hippocampus: Protection by antioxidants. Exp. Neurol., 2006, 200(2), 496-508.
[http://dx.doi.org/10.1016/j.expneurol.2006.02.126] [PMID: 16626708]
[8]
Butterfield, D.A.; Castegna, A.; Drake, J.; Scapagnini, G.; Calabrese, V. Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr. Neurosci., 2002, 5(4), 229-239.
[http://dx.doi.org/10.1080/10284150290028954] [PMID: 12168685]
[9]
Shay, J.W.; Wright, W.E. Telomerase therapeutics for cancer: challenges and new directions. Nat. Rev. Drug Discov., 2006, 5(7), 577-584.
[http://dx.doi.org/10.1038/nrd2081] [PMID: 16773071]
[10]
Yap, W.N.; Chang, P.N.; Han, H.Y.; Lee, D.T.; Ling, M.T.; Wong, Y.C.; Yap, Y.L. γ-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br. J. Cancer, 2008, 99(11), 1832-1841.
[http://dx.doi.org/10.1038/sj.bjc.6604763] [PMID: 19002171]
[11]
Landes, N.; Pfluger, P.; Kluth, D.; Birringer, M.; Rühl, R.; Böl, G.F.; Glatt, H.; Brigelius-Flohé, R. Vitamin E activates gene expression via the pregnane X receptor. Biochem. Pharmacol., 2003, 65(2), 269-273.
[http://dx.doi.org/10.1016/S0006-2952(02)01520-4] [PMID: 12504802]
[12]
Budin, S.B.; Othman, F.; Louis, S.R.; Bakar, M.A.; Das, S.; Mohamed, J. The effects of palm oil tocotrienol-rich fraction supplementation on biochemical parameters, oxidative stress and the vascular wall of streptozotocin-induced diabetic rats. Clinics (São Paulo), 2009, 64(3), 235-244.
[http://dx.doi.org/10.1590/S1807-59322009000300015] [PMID: 19330251]
[13]
Aleksunes, L.M.; Manautou, J.E. Emerging role of Nrf2 in protecting against hepatic and gastrointestinal disease. Toxicol. Pathol., 2007, 35(4), 459-473.
[http://dx.doi.org/10.1080/01926230701311344] [PMID: 17562481]
[14]
Kitteringham, N.R.; Abdullah, A.; Walsh, J.; Randle, L.; Jenkins, R.E.; Sison, R.; Goldring, C.E.P.; Powell, H.; Sanderson, C.; Williams, S.; Higgins, L.; Yamamoto, M.; Hayes, J.; Park, B.K. Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver. J. Proteomics, 2010, 73(8), 1612-1631.
[http://dx.doi.org/10.1016/j.jprot.2010.03.018] [PMID: 20399915]
[15]
Abdullah, A.; Kitteringham, N.R.; Jenkins, R.E.; Goldring, C.; Higgins, L.; Yamamoto, M.; Hayes, J.; Park, B.K. Analysis of the role of Nrf2 in the expression of liver proteins in mice using two-dimensional gel-based proteomics. Pharmacol. Rep., 2012, 64(3), 680-697.
[http://dx.doi.org/10.1016/S1734-1140(12)70863-0] [PMID: 22814021]
[16]
Almazroo, O.A.; Miah, M.K.; Venkataramanan, R. Drug metabolism in the liver. Clin. Liver Dis., 2017, 21(1), 1-20.
[http://dx.doi.org/10.1016/j.cld.2016.08.001] [PMID: 27842765]
[17]
Vomund, S.; Schäfer, A.; Parnham, M.J.; Brüne, B.; von Knethen, A. Nrf2, the master regulator of anti-oxidative responses. Int. J. Mol. Sci., 2017, 18(12), E2772.
[http://dx.doi.org/10.3390/ijms18122772] [PMID: 29261130]
[18]
Ngah, W.Z.; Jarien, Z.; San, M.M.; Marzuki, A.; Top, G.M.; Shamaan, N.A.; Kadir, K.A. Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats. Am. J. Clin. Nutr., 1991, 53(4)(Suppl.), 1076S-1081S.
[http://dx.doi.org/10.1093/ajcn/53.4.1076S] [PMID: 1672785]
[19]
Iqbal, J.; Minhajuddin, M.; Beg, Z.H. Suppression of diethylnitrosamine and 2-acetylaminofluorene-induced hepatocarcinogenesis in rats by tocotrienol-rich fraction isolated from rice bran oil. Eur. J. Cancer Prev., 2004, 13(6), 515-520.
[http://dx.doi.org/10.1097/00008469-200412000-00009] [PMID: 15548946]
[20]
Goldring, C.E.; Kitteringham, N.R.; Elsby, R.; Randle, L.E.; Clement, Y.N.; Williams, D.P.; McMahon, M.; Hayes, J.D.; Itoh, K.; Yamamoto, M.; Park, B.K. Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology, 2004, 39(5), 1267-1276.
[http://dx.doi.org/10.1002/hep.20183] [PMID: 15122755]
[21]
Oo, S.L.; Chang, P.; Chan, K.E. Toxicological and pharmacological studies on palm vitee. Nutr. Res., 1992, 12, S217-S222.
[http://dx.doi.org/10.1016/S0271-5317(05)80465-8]
[22]
Dignam, J.D.; Lebovitz, R.M.; Roeder, R.G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res., 1983, 11(5), 1475-1489.
[http://dx.doi.org/10.1093/nar/11.5.1475] [PMID: 6828386]
[23]
Livak, K.J.; Schmittgen, T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods, 2001, 25, 402-408.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[24]
Kong, L.; Tanito, M.; Huang, Z.; Li, F.; Zhou, X.; Zaharia, A.; Yodoi, J.; McGinnis, J.F.; Cao, W. Delay of photoreceptor degeneration in tubby mouse by sulforaphane. J. Neurochem., 2007, 101(4), 1041-1052.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04481.x] [PMID: 17394579]
[25]
Seta, F.; Rahmani, M.; Turner, P.V.; Funk, C.D. Pulmonary oxidative stress is increased in cyclooxygenase-2 knockdown mice with mild pulmonary hypertension induced by monocrotaline. PLoS One, 2011, 6(8), e23439.
[http://dx.doi.org/10.1371/journal.pone.0023439] [PMID: 21850273]
[26]
Lu, H.; Koshkin, V.; Allister, E.M.; Gyulkhandanyan, A.V.; Wheeler, M.B. Molecular and metabolic evidence for mitochondrial defects associated with beta-cell dysfunction in a mouse model of type 2 diabetes. Diabetes, 2010, 59(2), 448-459.
[http://dx.doi.org/10.2337/db09-0129] [PMID: 19903739]
[27]
Nakamura, B.N.; Lawson, G.; Chan, J.Y.; Banuelos, J.; Cortés, M.M.; Hoang, Y.D.; Ortiz, L.; Rau, B.A.; Luderer, U. Knockout of the transcription factor NRF2 disrupts spermatogenesis in an age-dependent manner. Free Radic. Biol. Med., 2010, 49(9), 1368-1379.
[http://dx.doi.org/10.1016/j.freeradbiomed.2010.07.019] [PMID: 20692336]
[28]
Nair, S.; Xu, C.; Shen, G.; Hebbar, V.; Gopalakrishnan, A.; Hu, R.; Jain, M.R.; Lin, W.; Keum, Y.S.; Liew, C.; Chan, J.Y.; Kong, A.N. Pharmacogenomics of phenolic antioxidant Butylated Hydroxyanisole (BHA) in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Pharm. Res., 2006, 23(11), 2621-2637.
[http://dx.doi.org/10.1007/s11095-006-9099-x] [PMID: 16969697]
[29]
Feng, Z.; Liu, Z.; Li, X.; Jia, H.; Sun, L.; Tian, C.; Jia, L.; Liu, J. α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J. Nutr. Biochem., 2010, 21(12), 1222-1231.
[http://dx.doi.org/10.1016/j.jnutbio.2009.10.010] [PMID: 20153624]
[30]
Varady, J.; Gessner, D.K.; Most, E.; Eder, K.; Ringseis, R. Dietary moderately oxidized oil activates the Nrf2 signaling pathway in the liver of pigs. Lipids Health Dis., 2012, 11, 31.
[http://dx.doi.org/10.1186/1476-511X-11-31] [PMID: 22364167]
[31]
Su, L.; Li, P.; Lu, T.; Mao, C.; Ji, D.; Hao, M.; Huang, Z. Protective effect of Schisandra chinensis total lignans on acute alcoholic-induced liver injury related to inhibiting CYP2E1 activation and activating the Nrf2/ARE signaling pathway. Rev. Bras. Farmacogn., 2019, 2, 198-205.
[http://dx.doi.org/10.1016/j.bjp.2019.01.008]
[32]
Schemitt, E.G.; Hartmann, R.M.; Colares, J.R.; Licks, F.; Salvi, J.O.; Marroni, C.A.; Marroni, N.P. Protective action of glutamine in rats with severe acute liver failure. World J. Hepatol., 2019, 11(3), 273-286.
[http://dx.doi.org/10.4254/wjh.v11.i3.273] [PMID: 30967905]
[33]
Khor, S.C.; Wan Ngah, W.Z.; Mohd Yusof, Y.A.; Abdul Karim, N.; Makpol, S. Tocotrienol-rich fraction ameliorates antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in human myoblasts. Oxid. Med. Cell. Longev., 2017, 2017, 3868305.
[http://dx.doi.org/10.1155/2017/3868305] [PMID: 28243354]
[34]
Mukherjee, S.; Mitra, A. health effects of palm oil. J. Hum. Ecol., 2009, 26, 197-203.
[http://dx.doi.org/10.1080/09709274.2009.11906182]
[35]
Muharis, S.P.; Top, A.G.; Murugan, D.; Mustafa, M.R. Palm oil tocotrienol fractions restore endothelium dependent relaxation in aortic rings of streptozotocin-induced diabetic and spontaneously hypertensive rats. Nutr. Res., 2010, 30(3), 209-216.
[http://dx.doi.org/10.1016/j.nutres.2010.03.005] [PMID: 20417882]
[36]
Kwak, M.K.; Itoh, K.; Yamamoto, M.; Sutter, T.R.; Kensler, T.W. Role of transcription factor Nrf2 in the induction of hepatic phase 2 and antioxidative enzymes in vivo by the cancer chemoprotective agent, 3H-1, 2-dimethiole-3-thione. Mol. Med., 2001, 7(2), 135-145.
[http://dx.doi.org/10.1007/BF03401947] [PMID: 11471548]
[37]
Ramos-Gomez, M.; Kwak, M.K.; Dolan, P.M.; Itoh, K.; Yamamoto, M.; Talalay, P.; Kensler, T.W. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl. Acad. Sci. USA, 2001, 98(6), 3410-3415.
[http://dx.doi.org/10.1073/pnas.051618798] [PMID: 11248092]
[38]
Krajka-Kuźniak, V.; Paluszczak, J.; Baer-Dubowska, W. The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol. Rep., 2017, 69, 393-402.
[http://dx.doi.org/10.1016/j.pharep.2016.12.011]
[39]
Niture, S.K.; Khatri, R.; Jaiswal, A.K. Regulation of Nrf2-an update. Free Radic. Biol. Med., 2014, 66, 36-44.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.008] [PMID: 23434765]
[40]
Randle, L.E.; Goldring, C.E.; Benson, C.A.; Metcalfe, P.N.; Kitteringham, N.R.; Park, B.K.; Williams, D.P. Investigation of the effect of a panel of model hepatotoxins on the Nrf2-Keap1 defence response pathway in CD-1 mice. Toxicology, 2008, 243(3), 249-260.
[http://dx.doi.org/10.1016/j.tox.2007.10.011] [PMID: 18078705]
[41]
Hsieh, T.C.; Elangovan, S.; Wu, J.M. Differential suppression of proliferation in MCF-7 and MDA-MB-231 breast cancer cells exposed to alpha-, gamma- and delta-tocotrienols is accompanied by altered expression of oxidative stress modulatory enzymes. Anticancer Res., 2010, 30(10), 4169-4176.
[PMID: 21036737]
[42]
Peh, H.Y.; Ho, W.E.; Cheng, C.; Chan, T.K.; Seow, A.C.; Lim, A.Y.; Fong, C.W.; Seng, K.Y.; Ong, C.N.; Wong, W.S. Vitamin E isoform γ-tocotrienol downregulates house dust mite-induced asthma. J. Immunol., 2015, 195(2), 437-444.
[http://dx.doi.org/10.4049/jimmunol.1500362] [PMID: 26041537]
[43]
Peh, H.Y.; Tan, W.S.D.; Chan, T.K.; Pow, C.W.; Foster, P.S.; Wong, W.S.F. Vitamin E isoform γ-tocotrienol protects against emphysema in cigarette smoke-induced COPD. Free Radic. Biol. Med., 2017, 110, 332-344.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.06.023] [PMID: 28684161]
[44]
Peh, H.Y.; Tan, W.S.D.; Liao, W.; Wong, W.S.F. Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol. Pharmacol. Ther., 2016, 162, 152-169.
[http://dx.doi.org/10.1016/j.pharmthera.2015.12.003] [PMID: 26706242]
[45]
Li, G.; Lee, M.J.; Liu, A.B.; Yang, Z.; Lin, Y.; Shih, W.J.; Yang, C.S. The antioxidant and anti-inflammatory activities of tocopherols are independent of Nrf2 in mice. Free Radic. Biol. Med., 2012, 52(7), 1151-1158.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.12.005] [PMID: 22226829]
[46]
Singh, B.; Bhat, H.K. Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer. Carcinogenesis, 2012, 33(12), 2601-2610.
[http://dx.doi.org/10.1093/carcin/bgs300] [PMID: 23027624]
[47]
Li, N.; Alam, J.; Venkatesan, M.I.; Eiguren-Fernandez, A.; Schmitz, D.; Di Stefano, E.; Slaughter, N.; Killeen, E.; Wang, X.; Huang, A.; Wang, M.; Miguel, A.H.; Cho, A.; Sioutas, C. Nel, A.E. Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. J. Immunol., 2004, 173(5), 3467-3481.
[http://dx.doi.org/10.4049/jimmunol.173.5.3467] [PMID: 15322212]
[48]
Dong, J.; Sulik, K.K.; Chen, S.Y. Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: Implications for the prevention of fetal alcohol spectrum disorders. Antioxid. Redox Signal., 2008, 10(12), 2023-2033.
[http://dx.doi.org/10.1089/ars.2007.2019] [PMID: 18759561]
[49]
Sugiura, H.; Ichinose, M. Oxidative and nitrative stress in bronchial asthma. Antioxid. Redox Signal., 2008, 10(4), 785-797.
[http://dx.doi.org/10.1089/ars.2007.1937] [PMID: 18177234]
[50]
Prawan, A.; Kundu, J.K.; Surh, Y.J. Molecular basis of heme oxygenase-1 induction: Implications for chemoprevention and chemoprotection. Antioxid. Redox Signal., 2005, 7(11-12), 1688-1703.
[http://dx.doi.org/10.1089/ars.2005.7.1688] [PMID: 16356130]
[51]
Lavrovsky, Y.; Schwartzman, M.L.; Levere, R.D.; Kappas, A.; Abraham, N.G. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc. Natl. Acad. Sci. USA, 1994, 91(13), 5987-5991.
[http://dx.doi.org/10.1073/pnas.91.13.5987] [PMID: 8016102]
[52]
Zhou, L.Z.; Johnson, A.P.; Rando, T.A. NF κ B and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic. Biol. Med., 2001, 31(11), 1405-1416.
[http://dx.doi.org/10.1016/S0891-5849(01)00719-5] [PMID: 11728812]
[53]
Ahn, K.S.; Sethi, G.; Krishnan, K.; Aggarwal, B.B. Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J. Biol. Chem., 2007, 282(1), 809-820.
[http://dx.doi.org/10.1074/jbc.M610028200] [PMID: 17114179]
[54]
Yap, W.N.; Zaiden, N.; Luk, S.Y.; Lee, D.T.; Ling, M.T.; Wong, Y.C.; Yap, Y.L. In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormone-refractory prostate cancer. Pharmacology, 2010, 85(4), 248-258.
[http://dx.doi.org/10.1159/000278205] [PMID: 20375535]
[55]
Wu, S.J.; Liu, P.L.; Ng, L.T. Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol. Nutr. Food Res., 2008, 52(8), 921-929.
[http://dx.doi.org/10.1002/mnfr.200700418] [PMID: 18481320]
[56]
Bruno, R.S.; Traber, M.G. Vitamin E biokinetics, oxidative stress and cigarette smoking. Pathophysiology, 2006, 13(3), 143-149.
[http://dx.doi.org/10.1016/j.pathophys.2006.05.003] [PMID: 16814530]
[57]
Gao, L.; Wang, J.; Sekhar, K.R.; Yin, H.; Yared, N.F.; Schneider, S.N.; Sasi, S.; Dalton, T.P.; Anderson, M.E.; Chan, J.Y.; Morrow, J.D.; Freeman, M.L. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J. Biol. Chem., 2007, 282(4), 2529-2537.
[http://dx.doi.org/10.1074/jbc.M607622200] [PMID: 17127771]
[58]
Serbinova, E.; Kagan, V.; Han, D.; Packer, L. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Free Radic. Biol. Med., 1991, 10(5), 263-275.
[http://dx.doi.org/10.1016/0891-5849(91)90033-Y] [PMID: 1649783]
[59]
Numakawa, Y.; Numakawa, T.; Matsumoto, T.; Yagasaki, Y.; Kumamaru, E.; Kunugi, H.; Taguchi, T.; Niki, E. Vitamin E protected cultured cortical neurons from oxidative stress-induced cell death through the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. J. Neurochem., 2006, 97(4), 1191-1202.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03827.x] [PMID: 16686696]

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