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Napoli,J.L.,B'C.Pramanik,J'B'Williams,M'I'Dawson'andP'D'Hobbs'1985' ,'Quantification of retinoic acid by gas-liquid chromatography-mass spectrometry: total versus all-trans-retinoic acid in human plasma." J.Lipid Res. 26:387-392' Napoli,J.L. and K.R.Race. 1988. "Biogenesis of retinoic acid from beta-carotene' Differences between the metabolism of beta-carotene and retinal'" J'BioLcheru 263:17372-t7377 . Narula,J., N.Haider, R.virmani, T. G.DiS alvo, F.D.Kolodgie, R. J.Hajj ar, u' S chmidt' M.J.Semigran, G.W.Dec, and B.A.Khaw . tgg6. "Apoptosis in myocytes in endstage heart failure. " N. EngI'J' Med' 33 5 :11 82- 1 1 89' Newcomer,M.E. 1995. "Retinoid-binding proteins: structural determinants important for function." FASEB J. 9 :229 -239' Nicolay,K., N.R.van der, J.J.Fok, and B.de Kruijff. 1985. "Effects of adriamycin on lipid polymorphism in cardiolipin-containing model and mitochondrial membranes'" B iochim. B iophys. Acta. 8 1 9 : 5 5-65' Niedeneither,K., P.McCaffery, U.C.Drager, P.Chambon, and P'Dolle' 1997' "Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase tlpe 2 (RALDH -2) geneduring mouse development '" Mech'Dev' 62:67-78. Nikolaidis,L.A. and T.B.Levine .2004. "Peroxisome proliferator activator receptors (PPAR), insulin resistance, and cardiomyopathy: friends or foes for the diabetic patient with heart failure?" Cardiol'Rev' l2:I58-170' Niles,R.M. 2002. "The use of retinoids in the prevention and treatment of skin cancel'" Exp er t. Op in' P harmacotlt er' 3 :299 -303' Nordberg,J. and E.S.Arn er.200L "Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. " Fr ee Radi c. B iol. M e d. 3 | :1287 -13 12' 158
Notario,B., M.Zamora, O.Vinas, and T.Mampel. 2003' "A1l-trans-retinoic acid binds to and inhibits adenine nucleotide translocase and induces mitochondrial p ermeab ility transiti o n! M o l' P h ar m a col' 63 :224-23 |' O,Brien,M.L., B.T.Spear, and H.P.Glauert. 2005. "Role of oxidative stress in peroxisome proliferator-mediated carcino gen esís." Crit Rev. Toxicol. 3 5 : 6 1 - 8 8' odom,A.L., C.A.Hatwig, J. s. stanley, and A.M.Benso n. 1992. "Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine." B io chem. Pharmacol' 43 : 83 1 -836. O gata,T ., T.Miyauchi, S. S akai, Y.Irukayama-Tomobe, K. Goto, and I'Yamagpchi' 2002' "Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts. " CIin. Sci. (Lond) . 103 Suppl 48 :2845-28 8S' Ogata,Y. and M.Takahashi. 2003. "Bcl-xl as an antiapoptotic molecule for cardiomyocfes. " Drug News P erspect. 16 :446-452' Oliverio,S., A.Amendola, S.F.Di, M.G.Farrace, L.Fesus' Z.Nemes, L'Piredda, A'Spinedi, and M.piacentini. i997. "Tissue transglutaminase-dependent posttranslational modification of the retinoblastoma gene product in promonocytic cells undergoing apoptosis." Mol' CelI BioL lT :6040-6048' Olivetti,G., R.Abbi, F.Quaini, J.Kajstura, W.Cheng, J'A.Nitahara, E'Quaini, C'Di Loreto' C.A.Beltrami, S.Krajewski, J.C.Reed, and P.Anversa' 1997' "Apoptosis in the failing human heart. " N. Engl'J' Med. 33611 3 1 - 1 1 4 1' Olson,H.M. and C.C.C apen. 1977. "Subacute cardiotoxicity of adriamycin in the rat: biochemical and ultrastructural investigatio ns." Lab. Inv es t. 37 :386-39 4. Olson,H.M., D.M.Young, D.J.Prieur, A'F.LeRoy, and R.L'Reagan ' I974' "Electrolyte and morphologic alterations of myocardium in adriamycin- treated rabbits." Am.J. P athol' 7 7 :439 -45 4. 159
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il\VOLVEMENT OF RETII\OIC ACID II{
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Title: AKNOWLEDGMENTS DEDICATION LI
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IV.b.3. The uptake to peripheral ti
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II.a. Total RAR and total RXR recep
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ACKNO\ryLEDGMENTS I must say that m
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DEDICATION To my toughest critic, m
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Figure: LIST OF FIGURES Page: 1. Ch
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30. A and B The expression of anti-
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treated (ADR), trolox treated (TROL
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INTRODUCTION Adriamycin, an anthrac
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apoptosis, which will ultimately pr
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LITERATURE REVIE\il I. Adriamycin i
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Binding and alkylation of DNA Inter
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myocardial inflammation which was s
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1990; Kusuoka et al. l99l; Olson et
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levels of antioxidant enzymes (Odom
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causing the increased leakage of el
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mechanisms which are involved in th
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to protect against adriamycin-induc
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The usage of Probucol.' Most promis
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II. Oxidative stress II.a. Introduc
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of a large array of cellular abnorm
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menstruation (Kokawa et al. 1996),
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DNA(Cohen 1997; Saikumar et al. 199
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pathogenesis of heart failure. A nu
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elonging to spontaneous hlpertensiv
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AlþTrsns Retlnolc Acld fAfRAl g€
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dehydrogenase (SDR), alcohol dehydr
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(Bavik et a|. 1991). Soon after its
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et al. 1994; Napoli 1996). The func
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is achieved through its binding to
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Retinoic acid signaling pathwaybegi
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(Bavik et al. 1997). One of the mos
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cells (Gaetano et ai. ZOot¡. The s
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neuroblastoma, genn cell tumors and
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presence of two distinctive pathway
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cytochrome C release from mitochond
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peroxidation (Sultana et a|.2004).
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adipose tissue and to a lesser exte
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such as; increased generation of re
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physiological and pathological proc
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Protective effects of PPAR y agonis
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IIYPOTHESIS This study tests the hy
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I.c.Collection of Tissues Hearts we
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thoracotomy was performed and heart
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Il.c.Western Blot Analvsis Western
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green were counted as dead cells. T
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RESULTS I.In Vivo Studies I.a.Gener
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Lc. Retinoic acid receptors Three w
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The RAR o and PPAR-õ receptors RNA
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significantly decreased when compar
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IL b.7. RAR alPha recePtor levels T
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ILb. 3. RAR sammø recEtor levels F
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ILb. 5. RXR baa recEúor levels The
Page 129: visible staining were accounted as
Page 137 and 138: DISSCUSION I. Adriamvcin CardiomvoP
Page 139 and 140: Treatment with adriamycin has been
Page 141 and 142: High RA 1 Adriamycin I oxidative st
Page 143 and 144: study as well as in others (Kumar e
Page 145 and 146: It is reported that PPAR y receptor
Page 147 and 148: expression. These effects of trolox
Page 149 and 150: REFERENCES Abdul Hamied,T.A., D.Par
Page 151 and 152: Bashor,M.M., D.O.Toft, and F.Chytll
Page 153 and 154: distribution of PPAR-alpha, -beta,
Page 155 and 156: colbert,M.C., D.G.Hall, T.R.Kimball
Page 157 and 158: Diep,Q.N., M'El Mabrouk, J.S.Cohn,
Page 159 and 160: Evans,R.M. 1988. "The steroid and t
Page 161 and 162: Ghione M. Development of Adriamycin
Page 163 and 164: Herman,E., R.Young, and S.Krop . Ig
Page 165 and 166: morphogenetic protein-2 inhibits se
Page 167 and 168: Khandoudi,N., P.Delerive, I.Berrebi
Page 169 and 170: Kusuoka,H., S.Futaki, Y.Koretsune,
Page 171 and 172: and myosin heavy chain gene express
Page 173 and 174: Mehta,J.L., B.Hu, J.Chen, and D.Li.
Page 175: Morriss-Kay,G.M. and s.J.ward. 1999
Page 179 and 180: petkovich,M., N.J.Brand, A.Krust, a
Page 181 and 182: Ruberte,E., P.Dolle, P.Chambon, and
Page 183 and 184: Sharov,V.G., H.N.Sabbah, H.Shimoyam
Page 185 and 186: spiegelman,B.M. and J.s.Flier .1996
Page 187 and 188: Teebor,G.w., R.J.Boorstein, and J.c
Page 189 and 190: vanVeen,T.A.,H.V.vanRijen,R.F.V/ieg
Page 191 and 192: wi1liams,J.B. and J.L.Napoli. 1985.
Page 193 and 194: peroxisome proliferator-activated r
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