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Imaging Mitochondrial Dynamics in the Adult Heart

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Imaging Mitochondrial Dynamics in the Adult Heart Thesis submitted by Siavash Beikoghli Kalkhoran BSc (First class Hons.), MSc (Distinction) For the degree of Doctor of Philosophy University College London, UK. Institute of Cardiovascular Science The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX. October 2017 Declaration I, Siavash Beikoghli Kalkhoran, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. The assistance and contribution of individuals to the generation of results are acknowledged within the methods sections of each chapter. 2 Dedicated to Soheila & Taher 3 Abstract Background Mitochondrial dynamics, the phenomenon which incorporates inter-mitochondrial communication and changes in mitochondrial morphology is central to cellular homeostasis. Although the phenomenon of mitochondrial dynamics has been comprehensively studied under normal and pathological conditions in non-cardiac cells, and more recently in cardiac cell lines, its relevance to adult cardiomyocytes has not been so well-established and is investigated in this thesis. Methods and Results Using 2D and 3D electron microscopy, we initially evaluated the morphological features of the 3 different mitochondrial subpopulations (interfibrillar, peri-nuclear, subsarcolemmal) in adult rodent cardiomyocytes, and demonstrated that they are morphologically unique. These morphological characteristics were found to be altered under pathological conditions such as ischaemia or the genetic ablation of mitochondrial fusion proteins “mitofusins”. Using mice expressing the Dendra2 fluorescence probe, we then confirmed that mitochondrial fusion events (“the inter- mitochondrial communication”) occur in live adult cardiomyocytes, and the fusion rates differ according to the mitochondrial subpopulation. We next performed high throughput screening of a small molecule library and identified hydralazine (a drug used to treat hypertension and heart failure) to be a novel modulator of mitochondrial dynamics, acting to inhibit mitochondrial fission and protect against the detrimental effects of acute myocardial ischaemia/reperfusion injury by preserving mitochondrial dynamics. 4 Conclusion This thesis has demonstrated that 2D and 3D changes in mitochondrial shape features, as well as alterations in inter-mitochondrial communication, are of high relevance to adult rodent cardiomyocytes. Hydralazine-induced cardioprotection in the setting of IRI demonstrates the significance of distinct aspects of mitochondrial dynamics and reveals the role they play in the normal functioning of adult cardiomyocytes. 5 Acknowledgements My profound appreciation and thanks go to my supervisors Prof Derek Hausenloy and Prof Derek Yellon who were with me every step of the way. Prof Hausenloy, it was an honour to be your student and I am highly grateful for your invaluable support, guidance, directions and kindness for supervising me throughout these years and I hope to work with you again in the near future. Prof Yellon, I am so thankful that you kindly let me take this PhD at the Hatter Institute, and I am proud to be supervised by you. I would like to especially thank my colleagues Dr Sang Bing Ong at Duke-NUS Medical School as well as Dr Sapna Arjun, Dr Jaime Riquelme Melendez, Dr Andrew Hall at the Hatter Cardiovascular Institute for their help with technical aspects of my project including experiment design and assay characterisations. I should also mention and thank my other colleagues, Ms Parisa Samangouei, Dr Jose Miguel Vicencio Bustamante, Dr Niall De Burca and Dr Sean Davidson and Dr David He for all their fruitful discussion and guidance. I would like to also express my deepest gratitude to technical staff from UCL and collaborators who contributed significantly to the publication of this thesis including experts in electron microscopy, Prof Gerald Dorn (For providing the mitofusin mice from Centre for Pharmacogenomics of Washington University), Dr Ian white and Dr Jemima Burden (3D serial section electron tomography, from MRC laboratory of molecular and Cell Biology), Dr Peter Munro (3 view, from Institute of Ophthalmology, UCL), Dr Mark Turmaine (2D EM, from Department of Cell and Developmental Biology) and Dr Rebecca Poh. (FIBSEM, from Carl Zeiss Pte. Ltd, Singapore); the HTS team Dr Janos Kriston-Vizi, Dr. Joana Rodrigues Simoes Da Costa and Robbin Ketteler (HTS, from MRC Laboratory of Molecular and Cell 6 Biology); confocal and Denrda2 related experiments microscopy Michelle Tan Guet Khim (Department of Clinical Translational Research, Singapore General Hospital), Miss Kwek Xiu Yi and Mrs Khairunnisa Binte Katwadi, statistical assistance Dr Qiao Fan, Dr Bibhas Chakraborty (from Centre for Quantitative Medicine, DUKE-NUS) and Miss Jackie Cooper (from Institute of Cardiovascular Science, UCL) and surface plasmon resonance and computational docking Dr Jessica Holien, Dr Shiang Yong Lim, Miss Naomi XY Ling and Dr Jonathan S Oakhill (from O'Brien Institute Department, St Vincent's Institute of Medical Research). I have dedicated this work to my mother, Soheila, who has been always there for me and helped me reach this level, and my father, Taher, who will be absent when I graduate but is always in my heart and will be always remembered. I owe my deepest gratitude to my brother and sister, Kaveh and Sara, and the rest of my family and friends in Iran and the United Kingdom, whose moral support were of high importance in the completion of this project. 7 List of Publications Original Research and Review Articles 1. Beikoghli Kalkhoran S, Hall AR, White IJ, Cooper J, Fan Q, Ong S, Hernández‐Reséndiz S, Cabrera‐Fuentes H, Chinda K, Chakraborty B, Dorn GW, Yellon DM, Hausenloy DJ. Assessing the effects of mitofusin 2 deficiency in the adult heart using 3D electron tomography. Physiol. Rep. 2017 Sep;5(17):e13437. 2. Beikoghli Kalkhoran S, Munro P, Qiao F, Ong S-B, Hall AR, Cabrera-Fuentes H, Chakraborty B, Boisvert WA, Yellon DM, Hausenloy DJ. Unique morphological characteristics of mitochondrial subtypes in the heart: the effect of ischemia and ischaemic preconditioning. Discoveries 2017 Mar;5(1):e71. 3. Ong S-B, Beikoghli Kalkhoran S, Hernández-Reséndiz S, Samangouei P, Ong S-G, Hausenloy DJ. Mitochondrial-Shaping Proteins in Cardiac Health and Disease – the Long and the Short of It!. Cardiovasc. Drugs Ther. 2017 Feb;31(1):87–107. 4. Cabrera-Fuentes HA, Aragones J, Bernhagen J, Boening A, Boisvert WA, Bøtker HE, Bulluck H, Cook S, Di Lisa F, Engel FB, Engelmann B, Ferrazzi F, Ferdinandy P, Fong A, Fleming I, Gnaiger E, Hernández-Reséndiz S, Beikoghli Kalkhoran S, Kim MH, Lecour S, Liehn EA, Marber MS, Mayr M, Miura T, Ong S-B, Peter K, Sedding D, Singh MK, Suleiman MS, Schnittler HJ, Schulz R, Shim W, Tello D, Vogel C-W, Walker M, Li QOY, Yellon DM, Hausenloy DJ, Preissner KT. From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on “New frontiers in cardiovascular research”. Basic Res. Cardiol. 2016 Nov;111(6):69. 5. Hall AR, Burke N, Dongworth RK, Beikoghli Kalkhoran S, Dyson A, Vicencio JM, Dorn Ii GW, Yellon DM, Hausenloy DJ. Hearts deficient in both Mfn1 and Mfn2 are protected against acute myocardial infarction. Cell Death Dis. 2016;7(5):e2238. 6. Ong S-B, Samangouei P, Beikoghli Kalkhoran S, Hausenloy DJ. The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J. Mol. Cell. Cardiol. 2015;78:23–34. 7. Ong S-B, Hall AR, Dongworth RK, Beikoghli Kalkhoran S, Pyakurel A, Scorrano L, Hausenloy DJ. Akt protects the heart against ischaemia- reperfusion injury by modulating mitochondrial morphology. Thromb. Haemost. 2014 Sep;113(3):513–521. 8. Hussain A, Ghosh S, Beikoghli Kalkhoran S, Hausenloy DJ, Hanssen E, Vijay Rajagopal V. An Automated Workflow for Segmenting Single Adult Cardiac Cells from Large-Volume Serial Block-Face Scanning Electron Microscopy Data. J. of Struc. Biol. 2018; 202(3). 9. Beikoghli Kalkhoran S, Kriston-Visi J, Simoes Da Costa JR, Binte Katwadi K, Holien J, Ong SB, Y Lim S, Guet Khim MT, Arjun S, Chinda K, Samangouei P, Kwek X, Ketteler R, Yellon DM, Hausenloy DJ. A new pathway for Hydralazine induced Cardioprotection: The involvement of Mitochondrial Dynamics. (Unpublished). 8 Oral Presentations 1. Morphological Characteristics of Mitochondria in the Heart: The Effect of Ischaemic Preconditioning. Siavash Beikoghli Kalkhoran, Peter Munro, Fan Qiao, Sang-Bing Ong, Izzah Alfasihin, Andrew R.Hall, Bibhas Chakraborty, Derek M. Yellon, Derek J. Hausenloy. Singapore Cardiac Society, 2017. 2. Quantification of Mitochondrial Morphology and Its Interaction With Junctional Sarcoplasmic Reticulum in MFN2-KO Mice Using a 3 Dimensional Approach. Siavash Beikoghli Kalkhoran, Andrew R. Hall, Ian J. White, Jackie Cooper, Derek M. Yellon, Derek J. Hausenloy., ISHR, Bordeaux 2015. Abstracts Presentations 1. S Beikoghli Kalkhoran, A R Hall, H Whittington, S M Davidson, D M Yellon, D J Hausenloy. Characterisation of Mitochondrial Morphology in the Adult Rodent Heart. Heart 2014;100:A2-A3. 2. S Kalkhoran, AR Hall, A Cole, White, DM Yellon, DJ Hausenloy. 3d Electron Microscopy Tomography to Assess Mitochondrial Morphology in the Adult Heart. Heart 2014;100:A10. 9 Table of Contents Declaration .................................................................................................................
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    TITLE: Trimebutine Maleate and Pinaverium Bromide for Irritable Bowel Syndrome: A Review of the Clinical Effectiveness, Safety and Guidelines DATE: 30 November 2015 CONTEXT AND POLICY ISSUES Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain or discomfort and altered bowel movement consistency and frequency resulting in constipation or diarrhea.1,2 It is a functional disorder and not an organic disease.2 According to the Rome III diagnostic criteria, IBS is defined as recurrent abdominal pain or discomfort for at least three days per month in the last three months and with two or more of the following: improvement with defecation, onset associated with a change in frequency of stool, or onset associated with a change in form (appearance) of stool.2,3 There are three main subtypes of IBS: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed IBS (IBS-M).2 Hard or lumpy stool with ≥25% of bowel movements and loose or watery stool with < 25% of bowel movements is indicative of IBS-C. Loose or watery stool with ≥25% of bowel movements and hard or lumpy stool with < 25% of bowel movements is indicative of IBS-D. Hard or lumpy stool with ≥25% of bowel movements and loose or watery stool with ≥ 25% of bowel movements is indicative IBS-M. 2 The reported prevalence estimates of IBS vary widely. Some of this variation may result from differences in the clinical setting and the criteria used for diagnosis.1 There is no gold standard for diagnosing IBS.1 Criteria for diagnosing IBS
  • Product Monograph

    Product Monograph

    PRODUCT MONOGRAPH Sitcom LD Cream Each g contains : Euphorbia Prostrata Extract 1.0% w/w 10 mg (containing 0.315–0.825 mg total flavonoids calculated as apigenin-7-glucoside and 1.26–4.4 mg total phenolics calculated as gallic acid) and Lidocaine 3 % w/w 30 mg cream base. Cream Treatment of Haemorrhoids Manufactured By: Date of Preparation: The Madras Pharmaceuticals (05/07/2019) Old Mahabalipuram Road Karapakkam, Chennai Marketed By: Panacea Biotec Ltd. New Delhi 1 PART I: HEALTH PROFESSIONAL Page No. INFORMATION SUMMARY PRODUCT INFORMATION 4 INDICATIONS AND CLINICAL USE 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 DOSAGE AND ADMINISTRATION 8 OVERDOSAGE 9 ACTION AND CLINICAL PHARMACOLOGY 9 STORAGE AND STABILITY 9 DOSAGE FORMS, COMPOSITION AND PACKAGING 9 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION 10 PART III: PATIENT INFORMATION 11 2 Sitcom LD Cream Each g contains : Euphorbia Prostrata Extract 1.0% w/w 10 mg (containing 0.315–0.825 mg total flavonoids calculated as apigenin-7-glucoside and 1.26–4.4 mg total phenolics calculated as gallic acid) and Lidocaine 3 % w/w 30 mg cream base. Cream Treatment of Haemorrhoids 3 PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form / Approved Indications Administration Strength Topical Sitcom LD Cream Euphorbia Prostrata is Euphorbia Prostrata indicated for: Extract 1.0% w/w 10 mg (containing 0.315–0.825 - Treatment of Bleeding mg total flavonoids Haemorrhoids calculated as apigenin- - In post- 7-glucoside and 1.26–4.4 haemorrhoidectomy. mg total phenolics calculated as gallic acid) and Lidocaine 3 % w/w 30 mg cream base.
  • WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T

    WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61K 31/5513 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/045 (2006.01) A61K 31/5517 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/522 (2006.01) A61P 31/22 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/551 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/NL20 14/050781 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 13 November 2014 (13.1 1.2014) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/903,433 13 November 2013 (13.