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Cellular Mechanisms of Resveratrol's Interaction with Mitochondrial Reactive Oxygen Species Metabolism Ellen Louise Robb © 2013

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Cellular Mechanisms of Resveratrol's Interaction with Mitochondrial Reactive Oxygen Species Metabolism Ellen Louise Robb © 2013 Cellular Mechanisms of Resveratrol's Interaction with Mitochondrial Reactive Oxygen Species Metabolism Ellen Louise Robb A thesis submitted to the Department of Biological Sciences In partial fulfillment of the requirements for the degree PhD of Biological Sciences Faculty of Mathematics and Science Biological Sciences, Brock University St. Catharines, Ontario © 2013 Abstract Resveratrol, a polyphenol found naturally in red wines, has attracted great interest in both the scientific community and the general public for its reported ability to protect against many of the diseases facing Western society today. While the purported health effects of resveratrol are well characterized, details of the cellular mechanisms that give rise to these observations are unclear. Here, the mitochondrial antioxidant enzyme Mn superoxide dismutase (MnSOD) was identified as a proximal target of resveratrol in vitro and in vivo . MnSOD protein and activity levels increase significantly in cultured cells treated with resveratrol, and in the brain tissue of mice given resveratrol in a high fat diet. Preventing the increase in MnSOD levels eliminates two of resveratrol’s more interesting effects in the context of human health: inhibition of proliferative cell growth and cytoprotection. Thus, the induction of MnSOD is a critical step in the molecular mechanism of resveratrol. Mitochondrial morphology is a malleable property that is capable of impeding cell cycle progression and conferring resistance against stress induced cell death. Using confocal microscopy and a novel ‘cell free’ fusion assay it was determined that concurrent with changes in MnSOD protein levels, resveratrol treatment leads to a more fused mitochondrial reticulum. This observation may be important to resveratrol’s ability to slow proliferative cell growth and confer cytoprotection. Resveratrol's biological activities, including the ability to increase MnSOD levels, are strikingly similar to what is observed with estrogen treatment. Resveratrol fails to increase MnSOD levels, slow proliferative cell growth and confer cytoprotection in the presence of an estrogen receptor antagonist. Resveratrol's effects can be replicated with 2 the specific estrogen receptor beta agonist diarylpropionitrile, and are absent in myoblasts lacking estrogen receptor beta. Four compounds that are structurally similar to resveratrol and seven phytoestrogens predicted to bind to estrogen receptor beta were screened for their effects on MnSOD, proliferative growth rates and stress resistance in cultured mammalian cells. Several of these compounds were able to mimic the effects of resveratrol on MnSOD levels, proliferative cell growth and stress resistance in vitro . Thus, I hypothesize that resveratrol interacts with estrogen receptor beta to induce the upregulation of MnSOD, which in turn affects cell cycle progression and stress resistance. These results have important implications for the understanding of RES’s biological activities and potential applications to human health. 3 Acknowledgements I am extremely grateful to the wonderful community of colleagues, friends and family that have provided me with unlimited encouragement and support over the past five years. Thank you to the members of my thesis advisory committee: Dr. Jeff Stuart, Dr. Debbie Inglis and Dr. Gary Pickering, for your insight, patience and mentorship throughout my graduate career. A special thanks to Jeff for your unwavering support, your optimism, and for sharing your passion for research and teaching with me. I have been lucky to work with many fabulous people who helped to make life in the lab fun. I am thankful for their constructive criticisms, moral support and for the many laughs we shared. Thank you to Melissa Page and Amanda Rochon for being great mentors and friends, and to Casey Christoff and Lucas Maddalena for helping me through the last leg of this journey. My time at Brock has been shared with many family members and friends (who are really family) outside the lab. Thank you to my husband David for never asking me why, for accompanying me on late night lab-trips, and for believing in me (even when I did not); to Lisa Neville for always making me laugh and for supporting me in my (sometimes questionable) decisions; and to Mark Frampton for always being there when needed. 4 Table of Contents Chapter 1. Literature Review ........................................................................................ 14 1.1 Introduction........................................................................................................... 14 1.2 The Health Effects of Resveratrol ....................................................................... 16 1.2.1 Anticancer Effects............................................................................................ 17 1.2.2 Neuroprotection ............................................................................................... 18 1.2.3 Cardiovascular Disease and Metabolic Disorders ........................................... 19 1.3 Are Resveratrol’s Health Effects Unique? ......................................................... 21 1.4 Molecular Mechanisms of Resveratrol in Mammals......................................... 21 1.4.1 Oxidative Stress and Antioxidant Enzymes..................................................... 22 1.4.2 Induction of Antioxidant Enzymes by Resveratrol.......................................... 24 1.4.3 The Activation of Sirtuins as a Molecular Mechanism of Resveratrol............ 27 1.4.4 Resveratrol as a Phytoestrogen ........................................................................ 29 1.4.5 Estrogen Receptors Alpha and Beta ................................................................ 30 1.5 Bioavailability of Resveratrol .............................................................................. 31 1.5.1 Resveratrol Delivery and the Need for a High Fat Diet................................... 33 1.6 Hypotheses and Proposed Approach .................................................................. 35 Chapter 2. MnSOD is an Essential Target of Resveratrol that is Required for its Effects on Cell Proliferation and Stress Resistance..................................................... 38 Hypothesis.................................................................................................................... 38 Objectives..................................................................................................................... 38 Publication of results .................................................................................................. 38 Contributions............................................................................................................... 38 2.1 Introduction........................................................................................................... 39 2.2 Experimental Procedures..................................................................................... 41 2.2.1 Materials: ......................................................................................................... 41 2.2.2 Cell Lines and Culture Conditions................................................................... 42 2.2.3 siRNA Treatment............................................................................................. 42 2.2.4 Stress Resistance and Death Experiments ....................................................... 43 2.2.5 Lactate Dehydrogenase Activity...................................................................... 43 2.2.6 Preparation of Whole Cell Lysates .................................................................. 43 2.2.7 Western Blots................................................................................................... 44 2.2.8 Hydrogen Peroxide Detection.......................................................................... 44 2.2.9 Glutathione Peroxidase Activity...................................................................... 45 2.2.10 Citrate Synthase Activity............................................................................... 45 2.2.11 Statistical Analysis:........................................................................................ 45 2.3 Results:................................................................................................................... 46 5 2.4 Discussion: ............................................................................................................. 57 Chapter 3: Resveratrol and Estrogen Receptor Beta Agonist DPN Affect Mitochondrial Morphology............................................................................................ 63 Hypothesis: .................................................................................................................. 63 Objectives: ................................................................................................................... 63 Contributions: ............................................................................................................. 63 3.1 Introduction........................................................................................................... 64 3.2 Experimental Procedures..................................................................................... 68 3.2.1 Materials: ......................................................................................................... 68 3.2.2 Cell Lines and Culture Conditions..................................................................
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