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Forman,B.M., J.Chen, and R.M.Evans. 1997. "Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta." Pro c.Natl.Acad. sci.u. s.A' 9 4:4312-43 l7' Freeman,B.A. and J.D.Crapo. Ig82. "Biology of disease: free radicals and tissue injury'" Lab Invest. 47 :412-426. Friedman,M.A., M.J.Bo zdech,M.E.Billingham, and A.K.Rider. 1978' "Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals'" JAMA' 240:1603-1606. Fruchart,J.c., B.Staels, and P.Duriez.200l. "PPARS, metabolic disease and atherosclerosis. " P harma co I. Res' 44 :3 45 -3 52' Fujimura,s., J.Suzumiya, Y.Yamada, M.Kuroki, and J'ono. 2003. "Downregulation of Bcl-xl and activation of caspases during retinoic acid-induced apoptosis in an adult T-cell leukemia cell line'" Hematol'J' 4:328-335' Gaetano,c., A.catalano, B.I11i, A.Felici, s.Minucci, R.Palumbo, F.Facchiano, A.Mangoni, s.Mancarella, J.Muhlhauser, andM'c.capogrossi. 2001' "Retinoids induce fibroblast growth factor-Zproduction in endothelial cells via retinoic acid receptor alpha activation and stimulate angiogenesis in vitro and in vivo." Circ.Res' 88:E38-E47. Galvez,A., M.P.Morales, J.M.Eltit, P.Ocaranza,L.CarcascO, X.Campos, M.Sapag-Hagar, G.Diaz-Araya, and S.Lavandero. 2001. "A rapid and strong apoptotic process is triggered by hyperosmotic stress in cultured rat cardiac myocytes'" cell Tissue Res. 304:279-285. Gardner,D.G. and s.chen. 1999. "Retinoids and cell growth in the cardiovascular system." Life Sci. 65:1607 -1613' G*g, S., Narula, J. and y. Chandrashekhar. 2005. "Apoptosis and heart failure: ciinical relevance and therapeutic target." J MoI Cell cardiol.3S:73-79. 142
Ghione M. Development of Adriamycin. Cancer ChemotherapyReports 89.197s. Ref TYPe: Generic Part 3 6121,83- Gianni,M., LPonzanelli, L.Mologni, u.Reichert, A.Rambaldi, M'Terao, and E'Garattini' 2000. ',Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases '" cell Death.Dffir. 7:447-460. Gille,L. and H.Nohl.lgg7. "Analyses of the molecular mechanism of adriamycininduced cardiotoxic ity." Free Radic. BioL Med' 23 :7 7 5 -7 82' Goodall,A.H., D.Fisher, and J.A.Lucy. 1980' "Cellfusion, haemolysis and mitochondrial swelling induced by retinol and derivatives." Biochim.Biophys.Acta. 595:9-t4' Gordon,N. 1995. "Apoptosis þrogrammed cell death) and other reasons for elimination of neurons and axons." Brain Dev. 17:73-77 ' Gottlieb,J.A. and E.A.Lefrak. Fatal adriamycin cardiomyopathy (CMY): prevention and dose limitation. Proc.Am.Assoc.cancer Res. 14, 88. 1973. RefTyPe: Generic Gottlieb,R.A., K.O.Burleson, R.A.Kloner, B.M.Babior, and R.L.Engler ' 1994. ,'Reperfusion injury induces apoptosis in rabbit cardiomyocytes." J.Clin'Invest' 94:1621-1628. Green,S. and P.Chambon. 1988. "Nuclear receptors enhance our understanding of transcription regulatio n." Tr ends G enet' 4:309 -3 I 4' Grignani,F., M.S.De, C'Nervi, L.Tomassoni, V'Gelmetti, M'Cioce' M'Fanelli' M.Ruthardt, F.F.Ferrar a,LZamit,c.seiser, F.Grignani ,M.A'Lazar, S'Minucci, and p.G.pelicci. i998. "Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. " N atur e' %19 ;39 1: 8 1 5 - 8 1 8' 143
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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
Page 113 and 114: significantly decreased when compar
Page 116: IL b.7. RAR alPha recePtor levels T
Page 120: ILb. 3. RAR sammø recEtor levels F
Page 124: 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: Evans,R.M. 1988. "The steroid and t
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,
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Page 173 and 174: Mehta,J.L., B.Hu, J.Chen, and D.Li.
Page 175 and 176: Morriss-Kay,G.M. and s.J.ward. 1999
Page 177 and 178: Notario,B., M.Zamora, O.Vinas, and
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Page 181 and 182: Ruberte,E., P.Dolle, P.Chambon, and
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Page 187 and 188: Teebor,G.w., R.J.Boorstein, and J.c
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Page 191 and 192: wi1liams,J.B. and J.L.Napoli. 1985.
Page 193 and 194: peroxisome proliferator-activated r
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