Oxidative Stress: Biochemical and Pharmacological aspects
Most diseases are defined by a symptom, not a mechanism. Consequently, therapies remain symptomatic. In reverse, many potential disease mechanisms remain in arbitrary search for clinical relevance. Reactive oxygen species (ROS) are such an example. It is an attractive hypothesis that dysregulation of ROS can become a disease trigger. Indeed, elevated ROS levels of various biomarkers have been correlated with almost every disease, yet after decades of research without any therapeutic application. We here present a first systematic, non-hypothesis-based approach to transform this field as a proof of concept for biomedical research in general. We selected as seed proteins 9 families with 42 members of clinically researched ROS-generating enzymes, ROS-metabolizing enzymes or ROS targets. Applying an unbiased network medicine approach, their first neighbours were connected, and, based on a stringent subnet participation degree (SPD) of 0.4, hub nodes excluded. This resulted in 12 distinct human interactome-based ROS signalling modules, while 8 proteins remaining unconnected. This ROSome is in sharp contrast to commonly used highly curated and integrated KEGG, HMDB or WikiPathways. These latter serve more as mind maps of possible ROS signalling events but may lack important interactions and often do not take different cellular and subcellular localization into account. Moreover, novel non-ROS-related proteins were part of these forming functional hybrids, such as the NOX5/sGC, NOX1,2/NOS2, NRF2/ENC-1 and MPO/SP-A modules. Thus, ROS sources are not interchangeable but associated with distinct disease processes or not at all. Module members represent leads for precision diagnostics to stratify patients with specific ROSopathies for precision intervention. The upper panel shows the classical approach to generate hypotheses for a role of ROS in a given disease by focusing on ROS levels and to some degree the ROS type or metabolite. Low levels are considered physiological; higher amounts are thought to cause a redox imbalance, oxidative stress and eventually disease. The source of ROS is less relevant; there is also ROS-induced ROS formation, i.e. by secondary sources (see upwards arrow). The non-hypothesis-based network medicine approach uses genetically or otherwise validated risk genes to construct disease-relevant signalling modules, which will contain also ROS targets. Not all ROS sources will be relevant for a given disease; some may not be disease relevant at all. The three examples show (from left to right) the disease-relevant appearance of an unphysiological ROS modifier/toxifier protein, ROS target or ROS source.
Harald Schmidt Dr. med. Harald H.H.W. Schmidt is a medical doctor and pharmacist and Professor and Chair of Pharmacology & Personalised Medicine at Maastricht University’s Faculty of Health, Medicine and Life Sciences. He led a research program as European Research Council (ERC) Advanced Investigator, which translated into a current ERC Proof-of-Concept grant to develop a first-in-class neuroprotective therapy for ischemic stroke. He co-led a EUROSTAR programme which led to the development and commercialisation of a NOX4 inhibitor. As a science leader, he founded/led two European Science Foundation COST actions, one on reactive oxygen (EUROS), one on Systems Medicine. He now co-coordinates the EU-funded Horizon 2020 programme REPO-TRIAL on Systems Medicine and the Horizon Europe platform project, REPO4EU, on drug repurposing. Before Maastricht, prof. Schmidt had worked in Australia, Germany and USA in different academic and business leadership positions. These include chair of Monash University’s Centre for Vascular Health, Australia, Maastricht University Faculty of Medicine innovation platform, the Netherlands, different chairs in pharmacology and director of a drug discovery CRO at TransMIT, Giessen, Germany. He also co-founded and for two years led as CEO Vasopharm GmbH, a drug discovery company now entering into phase III clinical development. His research focuses on cardiovascular and neurological disease mechanisms, target validation, drug and biomarker discovery, personalised and network medicine. Professor Schmidt has published over 200 peer-reviewed papers, reviews, books and patents (Hirsch-index of 99) and co-founded and is co-editor-in-chief of the journal Network Medicine. He has been awarded the Roche Molecular Biochemicals Research Prize for Cell Biology, the Phoenix Research Prize in Pharmacy, and the Pro Scientia Prize.
Molecular interaction network models describe how different molecules – proteins, small RNAs, any molecules we wish to study – interact with each other. Collecting this interaction information helps scientific communities by serving as a knowledge base of all known interactions, and at the same time driving research forward by making it possible to predict interactions which were previously unknown. Molecular interactions can occur in different “layers”, depending on the qualities of the molecules at hand: for example protein – protein interaction layers describe the direct, physical interactions of proteins, while the transcriptional regulatory layer describes the relationships between transcription factors and their regulated genes. While both of these layers represent interactions in the same organism or cell, they occupy a different lane of information flow, and rarely meet. Multi-layered network models aim to connect them, by finding the points where the layers do cross over – such links, referred to as intralayer interactions help us describe molecular interactions networks in a more realistic way, by giving us a more complete picture of the studied system, for example by highlighting how a specific protein – protein interaction is regulated upstream.
NRF2 is the master transcriptional regulator of oxidative and xenobiotic stress responses. Using the above described concept, we developed an online resource, NRF2-ome, to provide an integrated and systems-level database for NRF2. The database contains manually curated and predicted interactions of NRF2 as well as data from external interaction databases. We integrated NRF2 interactome with NRF2 target genes, NRF2 regulating TFs, and miRNAs. We connected NRF2-ome to signaling pathways to allow mapping upstream NRF2 regulatory components that could directly or indirectly influence NRF2 activity totaling 35,967 protein-protein and signaling interactions. The user-friendly website, available at http://nrf2ome.org, allows researchers without computational background to search, browse, and download the database.
Tamas Korcsmaros. As a PhD student, Tamas developed a signalling network database, SignaLink, which filled a vital niche in the landscape of bioinformatics tools, and by now it has become one of the most used signalling network resources for human and model organism studies. It also forms the core of OmniPath, a more general human signaling network resource Tamas co-developed with the group of Julio Saez-Rodriguez. In 2014, Tamas received a special 5-year BBSRC fellowship to work in the computational biology and sequencing focused Earlham Institute and in the gut microbiome centred Quadram Institute at the Norwich Research Park in the UK. This fellowship allowed him to establish a multi-disciplinary group that combines computational and experimental approaches, including gut organoids. In 2019, he was appointed as a Tenure-track group leader at the Earlham and the Quadram Institutes, and between 2017 and 2021 he led the Systems Genomics workpackage of the Earlham Institute’s strategic programme. His group has carried out multiple projects to predict, analyse and validate host-microbe interactions in the gut, especially in relation to the regulation of autophagy by microbes and upon disease conditions such as inflammatory bowel disease (IBD) and cancer. He had multiple innovation and industrial partnership projects to develop new computational tools and platforms to analyse multi-omics data. End of 2021, Tamas moved to Imperial College as a Senior Lecturer, and currently leads both a research group that focuses on improving our understanding on the pathomechanisms of IBD and the NIHR Imperial BRC Organoid Facility to establish patient-specific multi-omics studies for various complex diseases.
In the first part of the talk, network-based methods and tools for mechanism understanding and drug repurposing developed by the Bioinformatics Department at CING will be presented. In the second part, a recent work on drug repurposing on Alzheimer’s Disease (AD) through modulation of NRF2 neighborhood will be presented. NRF2 has a critical role in the inflammation response and in the cellular redox hemeostasis and provides cytoprotection in several diseases including those in the neurodegeneration spectrum. These roles suggest that NRF2 and the directly associated proteins could be novel attractive therapeutic targets in the fight against for AD. By applying a systemics perspective, we propose an in silico drug repurposing approach for AD, based on the NRF2 interactome and regulome, aiming to highlight possible repurposed drugs for AD. Using publicly available information based on differential expressions of the NRF2-neighborhood in AD and through a computational drug repurposing pipeline, we derived to a finest group of candidate repurposed drugs and small molecules that affect the expression levels of the majority of NRF2-partners. The relevance of these findings was assessed in a four-steps computational meta-analysis including i) structural similarity comparisons with currently ongoing NRF2-related drugs ii) evaluation based on the NRF2-diseasome iii) comparison of relevance between targeted pathways of finest drugs and ongoing NRF2-related drugs and iv) further comparison with existing knowledge on AD and ongoing NRF2-related drugs based on their known modes of action. Overall, our analysis yielded in 5 candidate repurposed drugs for AD. We expect that our proposed candidate repurposed drugs will be useful for further research and clinical translation for AD.
George Spyrou: Prof. George M. Spyrou is the Bioinformatics European Research Area Chair Holder and the Head of the Bioinformatics Department (C-BIG) at the Cyprus Institute of Neurology and Genetics (CING). He holds a BSc on Physics, an MSc on Medical Physics and an MSc on Bioinformatics as well. During his PhD he worked on algorithms and simulations focusing on breast imaging. At the very beginning of the Biomedical Research Foundation of the Academy of Athens (BRFAA), Dr. Spyrou was selected to drive and supervise the design and development of the whole informatics infrastructure at BRFAA, being appointed as a Staff Research Scientist of level B and promoted to Staff Research Scientist of Level A at BRFAA in 2007 after successful evaluation. Since 2001 and for over 10 years he worked on the strategic plan and implementation of IT development at BRFAA, holding also the position of the Head of the Department of Informatics and New Technologies of BRFAA. In parallel, he was organizing his research group and was running his own research on bioinformatics and medical informatics. For the years 2009-2016 he was coordinating a full semester course (Simulation Methods in Medicine and Biology) in the Postgraduate Program “Information Technologies in Medicine and Biology” (in both directions: Bioinformatics and Medical Informatics) at the Department of Informatics and Telecommunications, University of Athens. In 2016 he accepted the offer for the position of the Bioinformatics European Research Area Chair Holder at CING. Since 2017, Dr. Spyrou is the Bioinformatics Course Coordinator at the Postgraduates School of CING where he has been elected as full Professor in 2019. He is also a visiting instructor on thematic areas including Systems Bioinformatics, Biological Network Analysis and Biomedical Informatics in other graduate and postgraduate courses. Dr. Spyrou is a Senior IEEE Member and a Member of the Steering Committee for the creation of the European Bioinformatics Infrastructure ELIXIR-Cyprus Node. He serves as member of the Editorial Board in the journals Briefings in Bioinformatics, BMC Bioinformatics and Frontiers in Bioinformatics. His work is focusing on the design and development of computational methods for the discovery of complex patterns of biomarkers, the understanding of underlying molecular mechanisms and drug repurposing though network-based analytics and systems bioinformatics.