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singal,P.K., N.Iliskovic, T.Li, and D.Kumat.1997. "Adriamycin cardiomyopathy: pathophysioiogy and prevention'" FASEB J' 11:93I-936' Singal,P.K. and L.A.Kirshenbaum. 1990. ''A relative deficit in antioxidant reserve may contributeincardiacfailure'''Can'J,Cardiol.6:47-49. singal,P.K. and G.N.Pierce. 1986. "Adriamycin stimulates low-affinity caT+ binding and lipid peroxidation but depresses myocardial function ." Am'J'Physiol' 250:H419- H425. Singal,P.K', R'J.Segstro, R.P.Singh, and M'J.Kutryk. 1985. ''Changes in lysosomal morphology and eîzqeactivities during the development of adriamycin-induced cardiomyopathy." Can.J. Cardiol' 1:139-147' Singal,P.K. and J.G.Tong. 1988. "Vitamin E deficiency accentuates adriamycin-induced cardiomyopathy and cell surface changes." Mot.ceu Biochem' 84:I63-I7L siveski-Itiskovic,N., M.Hill, D.A.Chow, and P.K.singal' 1995' "Probucol protects against adriamycin cardiomyopathy without interfering with its antitumor effect'" Circulation 91:10-15' siveski-Iliskovic,N., N.Kaul, and p.K.sin gal. 1994. "Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats' " Circulation. 89 :2829 -2835' Siwik,D.A., J.D.Tzortzis, D.R.Pimental, D.L.Chang, P.J.Pagano, K.Singh, D.B.Sawyer, andW.S.Colucci.1999.''Inhibitionofcopper-zincsuperoxidedismutaseinduces cell growth, hypertrophic phenotype, and apoptosis in neonatai rat cardiac myocytes in vitro." Circ'Res' 85:141-I53' Slezak,J., N.Tribulova, J.Pristacova, B.llhrik, T.Thomas, N'Khaper, N'Kaul, and P.K.Singal . lgg5."Hydrogen peroxide changes in ischemic and reperfused heart' Cytochemistry and biochemical and X-ray microanaiysis'" Am'J'Pathol' I47:772- 781. t66
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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
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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
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Page 163 and 164: Herman,E., R.Young, and S.Krop . Ig
Page 165 and 166: morphogenetic protein-2 inhibits se
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Page 169 and 170: Kusuoka,H., S.Futaki, Y.Koretsune,
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Page 175 and 176: Morriss-Kay,G.M. and s.J.ward. 1999
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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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