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Molecular Mechanisms of Myricetin Bulk and Nano Forms Mediating Genoprotective and Genotoxic Effects in Lymphocytes from Pre-Cancerous and Myeloma Patients

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Molecular Mechanisms of Myricetin Bulk and Nano Forms Mediating Genoprotective and Genotoxic Effects in Lymphocytes from Pre-Cancerous and Myeloma Patients Molecular mechanisms of myricetin bulk and nano forms mediating genoprotective and genotoxic effects in lymphocytes from pre-cancerous and myeloma patients Item Type Thesis Authors Akhtar, Shabana Publisher University of Bradford Rights <a rel="license" href="http://creativecommons.org/licenses/ by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by- nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http:// creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. Download date 26/09/2021 23:55:28 Link to Item http://hdl.handle.net/10454/17367 Molecular mechanisms of myricetin bulk and nano forms mediating genoprotective and genotoxic effects in lymphocytes from pre-cancerous and myeloma patients Shabana AKHTAR Submitted for the Degree of Doctor of Philosophy School of Medical Sciences Faculty of Life Sciences University of Bradford 2018 Abstract SHABANA AKHTAR Molecular mechanisms of myricetin bulk and nano forms mediating genoprotective and genotoxic effects in lymphocytes from pre-cancerous and myeloma patients Key words: myricetin; bulk and nano forms; genotoxic; genoprotective; human lymphocytes; pre-cancerous blood disorders; myeloma patients; healthy individuals; PhIP and H2O2 Cancer is one of the leading causes of death across the globe which needs appropriate and cost-effective treatment. Several recent studies have suggested that dietary intake of various flavonoids such as myricetin have a protective effect against different types of cancers and cardiovascular diseases. The present study was conducted to investigate the genoprotective and genotoxic effects of myricetin nano and bulk forms on the lymphocytes from pre-cancerous and multiple myeloma cancer patients compared to those from healthy individuals. Also, to investigate the protective potential of myricetin bulk and nano against the oxidative stress produced in vitro by 2- amino-1-methyl-6 phenylimidazo [4, 5-b] pyridine and reactive oxygen species- induced DNA damage using the Comet assay, micronucleus assay, cellular reactive oxygen species and glutathione detection assay, Western blotting, real-time polymerase chain reaction and immunofluorescence. Lymphocytes from the patient groups showed significantly higher levels of basal DNA damage compared to the lymphocytes from healthy individuals which was observed throughout the in vitro treatment. i Myricetin in both forms has not induced any significant DNA damage in all of the investigative groups at selective lower concentrations; in fact, the results demonstrate a reduction in DNA damage upon treating with myricetin nano in lymphocytes from pre-cancerous patients demonstrated by significant reduction in micronuclei formation in mononucleated cells. DNA repair capacity of myricetin bulk and nano was determined by co-treating the drugs with hydrogen peroxide. Myricetin significantly reduced the oxidative stress related damage caused by hydrogen peroxide, where myricetin nano seemed to be more effective employing the Comet assay. In the presence of myricetin bulk and nano, the damaging effects of 2- amino-1-methyl-6 phenylimidazo [4,5-b] pyridine were considerably decreased, where myricetin nano was more effective. This could be because nanoparticles have a larger surface area which could improve their reactivity and also the reduction in size of the particles could improve the anti-cancer properties of this compound. Myricetin has shown genoprotective and anti-oxidant effects by demonstrating the potential to reduce DNA damage caused by over-production of reactive oxygen species and oxidative stress. It has also shown anti-cancer potential in the lymphocytes from multiple myeloma patients by regulating the apoptosis related proteins, dependent on oxidative stress. Therefore, this study suggests that myricetin supplementation in our regular diet with enhanced bioavailability could have potential health beneficial effects and possibly protect against various diseases including cancer. ii Dedication This work is dedicated to my ever-faithful ALLAH (SWT) for keeping me on right path, strong and focused. To the memory of my late father, Major Ali Bahadur, only because of him, I could avail this opportunity to pursue a PhD in UK. To my super-woman mother, Mrs Zeenat Begum, for believing in me since I was a child, for bringing me up like a lioness, for all her love, prayers and emotional support. I could not have had imagined coming this far without her. Most importantly, to my loving husband, Mr Nasir Qayyum, nothing was possible without his backing, love, emotional and financial support. He has served like an angel all these years. To my siblings, Robina Akhtar, for her inspiration, love and physical support throughout my studies and Shabaz Ali, for his love. Last but not least, to my little daughter princess, Abir, for enduring my absences and compromises we had to make all this time. iii Acknowledgements I would like to express my gratitude to my supervisors for their great mentorship. To Professor Diana Anderson (Established Chair of Biomedical Sciences, University of Bradford), thanks to her for the continuous support and motivation. Her immense knowledge, abilities and advice is priceless. To Dr Rajendran C Gopalan, for all the support he provided with different aspects of this research work. Without his guidance and knowledge, my write-up would have been less organised. I am grateful to Dr Mojgan Najafzadeh, who has kindly arranged and provided me with the patient blood samples, taken by the staff from Bradford Royal Infirmary (BRI). To Dr Mohammed Isreb, for the preparation of nanoparticles and Stuart Fox, for the training and assistance he provided with the transmission electron micrography. My sincere thanks also go to Emtiaz Aziz for his technical support on a daily basis. He made my lab life enjoyable. I thank my colleagues (Khaled, Mahmood, Emmanuel, Osama, Azeza and Omera) for the memorable time we have had over the years. My special thanks to Dr Anthony Anene for being always there to provide me with his unconditional support and exchanging wonderful ideas. Last but not least; I would like to thank G-floor technical staff for their help with providing equipment. To, all those volunteers who supported me by donating their blood and made this research possible. iv Declaration I solemnly declare that this work is my own work and where the work of others is used, has been correctly acknowledged. The content of my thesis has not been submitted for the award of PhD elsewhere. v Table of content Abstract…………………………………………………………………………………………………………………………… i Dedication………………………………………………………………………………………………………………………. iii Acknowledgements…………………………………………………………………………………………………………. iv Declaration………………………………………………………………………………………………………………………. v Table content……………………………………………………………………………………………………………….….vi List of figures……………………………………………………………………………………………………………………. xi List of tables……………………………………………………………………………………………………………………xiv Abbreviations……………………………………………………………………………………………………………………..xv Contents IF: Immunofluorescence ................................................................................................... xviii ICC: Immunocytochemistry ............................................................................................... xviii Chapter 1: Introduction ................................................................................................................ 1 1.1 General Introduction ..................................................................................................... 2 1.2 Blood Cancer and its types ............................................................................................ 3 Leukemia ............................................................................................................... 3 Lymphoma ............................................................................................................ 5 Myeloma ............................................................................................................... 5 1.3 Biomarkers of cancer .................................................................................................... 7 1.4 Dietary nutrients and disease prevention .................................................................... 8 1.5 The flavonoids and their role in human nutrition ......................................................... 9 Flavonoids as antioxidant agents ........................................................................ 16 Myricetin and its protective effects against various diseases ............................ 17 1.6 Food derived mutagens and carcinogens ................................................................... 19 PhIP, a potential carcinogen ............................................................................... 21 1.7 Nanotechnology .......................................................................................................... 22 History of nanotechnology .................................................................................. 23 Properties of nanoparticles ................................................................................. 24 Applications of nanotechnology ......................................................................... 25 Toxicity of nanoparticles ..................................................................................... 26 1.8 Genotoxicity produced by ROS induced Oxidative stress
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