antioxidants Antioxidants and Second Messengers of Free Radicals Edited by Neven Zarkovic Printed Edition of the Special Issue Published in Antioxidants www.mdpi.com/journal/antioxidants Antioxidants and Second Messengers of Free Radicals Antioxidants and Second Messengers of Free Radicals Special Issue Editor Neven Zarkovic MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Neven Zarkovic Rudjer Boskovic Institute Croatia Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Antioxidants (ISSN 2076-3921) from 2018 (available at: https://www.mdpi.com/journal/ antioxidants/special issues/second messengers free radicals) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-533-5 (Pbk) ISBN 978-3-03897-534-2 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editor ...................................... vii Preface to ”Antioxidants and Second Messengers of Free Radicals” ................ ix Neven Zarkovic Antioxidants and Second Messengers of Free Radicals Reprinted from: Antioxidants 2018, 7, 158, doi:10.3390/antiox7110158 ................ 1 Jessica L. H. Walters, Geoffry N. De Iuliis, Brett Nixon and Elizabeth G. Bromfield Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production Reprinted from: Antioxidants 2018, 7, 132, doi:10.3390/antiox7100132 ................ 5 Giuseppina Barrera, Stefania Pizzimenti, Martina Daga, Chiara Dianzani, Alessia Arcaro, Giovanni Paolo Cetrangolo, Giulio Giordano, Marie Angele Cucci, Maria Graf and Fabrizio Gentile Lipid Peroxidation-Derived Aldehydes, 4-Hydroxynonenal and Malondialdehyde in Aging-Related Disorders Reprinted from: Antioxidants 2018, 7, 102, doi:10.3390/antiox7080102 ................ 20 Bernd Gesslbauer, David Kuerzl, Niko Valpatic and Valery N. Bochkov Unbiased Identification of Proteins Covalently Modified by Complex Mixtures of Peroxidized Lipids Using a Combination of Electrophoretic Mobility Band Shift with Mass Spectrometry Reprinted from: Antioxidants 2018, 7, 116, doi:10.3390/antiox7090116 ................ 37 Andriy Cherkas and Neven Zarkovic 4-Hydroxynonenal in Redox Homeostasis of Gastrointestinal Mucosa: Implications for the Stomach in Health and Diseases Reprinted from: Antioxidants 2018, 7, 158, doi:10.3390/antiox7110158 ................ 55 Cristina Anna Gallelli, Silvio Calcagnini, Adele Romano, Justyna Barbara Koczwara, Marialuisa de Ceglia, Donatella Dante, Rosanna Villani, Anna Maria Giudetti, Tommaso Cassano and Silvana Gaetani Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues Reprinted from: Antioxidants 2018, 7, 158, doi:10.3390/antiox7110158 ................ 69 Magdalena Timoszuk, Katarzyna Bielawska and Elzbieta˙ Skrzydlewska Evening Primrose (Oenothera biennis) Biological Activity Dependent on Chemical Composition Reprinted from: Antioxidants 2018, 7, 108, doi:10.3390/antiox7080108 ................113 Vera Cesar, Iva Jozi´c, Lidija Begovi´c, Tea Vukovi´c, Selma Mlinari´c, Hrvoje Lepeduˇs, Suzana Borovi´c Sunji´ˇ c and Neven Zarkovi´ˇ c Cell-Type-Specific Modulation of Hydrogen Peroxide Cytotoxicity and 4-Hydroxynonenal Binding to Human Cellular Proteins In Vitro by Antioxidant Aloe vera Extract Reprinted from: Antioxidants 2018, 7, 125, doi:10.3390/antiox7100125 ................124 Agnieszka Gegotek, Anna Jastrzab, Iwona Jarocka-Karpowicz, Marta Muszynska ´ and Elzbieta˙ Skrzydlewska The Effect of Sea Buckthorn (Hippophae rhamnoides L.) Seed Oil on UV-Induced Changes in Lipid Metabolism of Human Skin Cells Reprinted from: Antioxidants 2018, 7, 110, doi:10.3390/antiox7090110 ................138 v Lidija Milkovic, Tea Vukovic, Neven Zarkovic, Franz Tatzber, Egils Bisenieks, Zenta Kalme, Imanta Bruvere, Zaiga Ogle, Janis Poikans, Astrida Velena and Gunars Duburs Antioxidative 1,4-Dihydropyridine Derivatives Modulate Oxidative Stress and Growth of Human Osteoblast-Like Cells In Vitro Reprinted from: Antioxidants 2018, 7, 123, doi:10.3390/antiox7090123 ................159 vi About the Special Issue Editor Neven Zarkovic is a Senior Scientist (tenure) and the Head of the Laboratory for Oxidative Stress (LabOS) at the Rudjer Boskovic Institute in Zagreb, Croatia, where he acted as Associate Director for Science and Counsellor for International Affairs. He obtained his MD in 1984 from the Medical Faculty, Zagreb University. Following his MSc in biology in 1986 and PhD in 1989 he undertook a postdoctoral fellowship as a Lise Meitner awardee at the Institute of Biochemistry of the Karl Franz University of Graz, working mostly with Jorg¨ Schaur and Hermann Esterbauer. His research focuses on oxidative stress and lipid peroxidation and the role of 4-hydroxynonenal (HNE) in the pathophysiology of stress and age-associated disorders. Currently he is coordinating the international offset project on metabolomics in cancer and PTSD patients supported by the Government of Croatia and the Finnish company Patria. He was a founding member of the International HNE-Club (SFRR-I) and now chairs its Steering Committee. Prof. Zarkovic was the proposer and co-ordinator of the European COST Action B35 on lipid peroxidation-associated disorders and was a member of the CMST Domain of COST and of the Board of Governors of EARTO, while he acts now as Study Director of the Interdisciplinary PhD Study Program in Molecular Biosciences and as visiting professor of the Medical University in Bialystok. He is a college professor of economy/management and holds university professorships in biology and in medicine. Professor Zarkovic has (co)authored more than 250 publications, which have been cited more than six thousand times (GS). In 1985, he received the national award for research in pathology, while in 2007 he received the national award for scientific achievements. He is a fellow of the Royal Society of Medicine (RSM, London) and a member of the European Order of St. Georg Knights. vii Preface to ”Antioxidants and Second Messengers of Free Radicals” For decades, chemical species with unpaired electrons known as free radicals, in particular, oxygen free radicals, have been considered to act as enemies of living cells, damaging major bioactive molecules and thus causing degenerative and malignant diseases. Despite this, free radicals are live for very short periods and are highly reactive molecules that also play and important roles in the cellular metabolism. This paradox is further stressed by the fact that some products of the oxidative metabolism of lipids, especially reactive aldehydes, can mimic the bioactivity of free radicals, while living much longer and even acting on long distance. Therefore, there is a lack of general understanding of pathophysiological roles played by reactive aldehydes like malondialdehyde, 4-hydroxynoenal, 4-hydroxyhexenal, acrolein, etc., which are also considered to be “second messengers of free radicals”. Being generated mostly by non-enzymatic lipid peroxidation, they often form bioactive adducts with macromolecules important for the pathophysiology of living cells, even in the absence of severe oxidative stress. This book is based on the Special Issue of Antioxidants comprising original research papers and reviews on complex aspects of reactive aldehydes and their macromolecular adducts (especially with proteins) generated during lipid peroxidation and their interference with natural and synthetic antioxidants in the physiology of cells and in the pathophysiology of various diseases studied by modern bioanalytical methods applied in translational and clinical medicine. Taken together, these scientific papers suggest that understanding the pathophysiology of reactive aldehydes might indeed be crucial to a better understanding of major human diseases, while monitoring their production and controlling them by using efficient antioxidants might help the development of the modern, interdisciplinary life sciences and integrative biomedicine. Neven Zarkovic Special Issue Editor ix antioxidants Editorial Antioxidants and Second Messengers of Free Radicals Neven Zarkovic Laboratory for Oxidative Stress (LabOS), Institute “Rudjer Boskovic”, HR-10000 Zagreb, Croatia; [email protected] Received: 1 November 2018; Accepted: 1 November 2018; Published: 6 November 2018 In the recent years, numerous research on the pathology of oxidative stress has been completed by intense studies on redox signaling implementing various experimental models and clinical trials. Nonetheless, there is still a lack of general understanding of pathophysiological roles played by reactive aldehydes like malondialdehyde, 4-hydroxynonenal, 4-hydroxyhexenal, acrolein, etc., which are considered as “second messengers of free radicals” [1,2]. Mostly being generated by lipid peroxidation, reactive aldehydes often form bioactive adducts with macromolecules