Kleitos Sokratous

Cyprus Institute of Neurology and Genetics

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Kyriacos Kyriacou

Brunel University of London

George M. Spyrou

Cyprus Institute of Neurology and Genetics

Anastasis Oulas

Cyprus Institute of Neurology and Genetics

Andreas Hadjisavvas

Cyprus Institute of Neurology and Genetics

Orthodoxia Nicolaou

Cancer Genetics (United States)

Bernard Lauwerys

UCB Pharma (Belgium)

Marta E. Alarcón‐Riquelme

Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Kyriaki Michailidou

University of Cambridge

Paraskevi Chairta

Cyprus Institute of Neurology and Genetics

Andreas Kousios

Imperial College Healthcare NHS Trust

Cooperative Institutions

Cyprus Institute of Neurology and Genetics

University of Cyprus

University of Oxford

University of Nottingham

University of Nicosia

University of Thessaly

University College London

Academy of Scientific and Innovative Research

Weatherford College

UCLouvain

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Additional file 1 of Comparative analysis of affected and unaffected areas of systemic sclerosis skin biopsies by high-throughput proteomic approaches

Figshare (2020)

Paraskevi Chairta Paschalis Nicolaou Kleitos Sokratous Christine Galant Frédéric Houssiau

Additional file 1. MRM transitions used for the selected proteins analysis. This table shows the selected proteins/peptides for validation and the instrumental parameters used for peptide monitoring. Peptides highlighted in bold were used as the quantitative reference whereas the remaining peptides were used as qualitative references.

10.6084/m9.figshare.12270038

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Omega-3 Fatty Acids Supplementation: Therapeutic Potential in a Mouse Model of Stargardt Disease

Investigative Ophthalmology & Visual Science (2018)

Ekatherine Prokopiou Panagiotis Kolovos Maria Kalogerou Anastasia Neokleous Orthodoxia Nicolaou

To evaluate the therapeutic effects of omega-3 (ω3) fatty acids on retinal degeneration in the ABCA4-/- model of Stargardt disease when the blood level of arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio is between 1 and 1.5.Eight-month-old mice were allocated to three groups: wild type (129S1), ABCA4-/- untreated, and ABCA4-/- ω3 treated. ω3 treatment lasted 3 months and comprised daily gavage administration of EPA and docosahexaenoic acid (DHA). Blood and retinal fatty acid analysis was performed using gas chromatography to adjust the blood AA/EPA ∼1 to 1.5. Eyecups were histologically examined using transmission electron microscopy and confocal microscopy to evaluate lipofuscin granules and the photoreceptor layer. Retinal N-retinylidene-N-retinylethanolamine (A2E), a major component of retinal pigment epithelium lipofuscin, was quantified using liquid chromatography and tandem mass spectrometry, in addition to retinal proteomic analysis to determine changes in inflammatory proteins.EPA levels increased and AA levels decreased in the blood and retinas of the treatment group. Significantly less A2E and lipofuscin granules were observed in the treatment group. The thickness of the outer nuclear layer was significantly greater in the treatment group (75.66 ± 4.80 μm) than in the wild-type (61.40 ± 1.84 μm) or untreated ABCA4-/- (56.50 ± 3.24 μm) groups. Proteomic analysis indicated lower levels of complement component 3 (C3) in the treatment group, indicative of lower complement-induced inflammatory response.Three months of ω3 supplementation (AA/EPA ∼1-1.5) reduces A2E levels, lipofuscin granules, and C3 levels in the ABCA4-/- mouse model of Stargardt disease, consistent with slowing of the disease.

Lipofuscin

ABCA4

Stargardt disease

10.1167/iovs.17-23523

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SP016DYSREGULATION OF PPAR SIGNALING PATHWAY, FOCAL ADHESION PATHWAY AND DECREASED INTEGRIN LINKED KINASE ARE EARLY EVENTS IN COL4A3 −/− MICE MANIFESTING ALPORT SYNDROME

Nephrology Dialysis Transplantation (2017)

Andreas Kousios Orthodoxia Nicolaou Paraskevi Chairta Andreas Hadjisavvas Kyriakos Ioannou

Alport syndrome

10.1093/ndt/gfx138.sp016

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Additional file 3 of Tissue and plasma proteomic profiling indicates AHSG as a potential biomarker for ascending thoracic aortic aneurysms

Figshare (2023)

Rafailia Kazamia Anna Keravnou Areti Moushi Kleitos Sokratous Kyriaki Michailidou

Additional file 3.

Profiling (computer programming)

Thoracic aortic aneurysm

10.6084/m9.figshare.22621399

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Cyclisation of Lys48‐linked diubiquitin in vitro and in vivo

FEBS Letters (2012)

Kleitos Sokratous Joanna Strachan Lucy V. Roach Robert Layfield Neil J. Oldham

Ubiquitin (Ub) is able to form polymeric isopeptide‐linked chains through condensation of any of its seven lysine (Lys) residues with the C‐terminus of an adjacent Ub monomer. Electrospray ionisation mass spectrometry (ESI‐MS) of commercial in vitro‐generated Lys48‐linked di‐Ub (Lys48‐Ub 2 ) revealed a major population of cyclised dimer. The absence of a free C‐terminus in this population was confirmed by an inability to bind the zinc finger ubiquitin‐binding domain (ZnF‐UBP) of USP5/isopeptidase‐T. Endogenous Ub 2 purified from skeletal muscle and cultured mammalian cells was found to contain cyclic Lys48‐Ub 2 , demonstrating that cyclisation of poly‐Ub can also occur in vivo.

Deubiquitinating enzyme

10.1016/j.febslet.2012.10.011

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Computational Drug Repurposing for Neurodegenerative Diseases

Elsevier eBooks (2019)

Kyriaki Savva Margarita Zachariou Anastasis Oulas George Minadakis Kleitos Sokratous

Drug repositioning

Repurposing

10.1016/b978-0-12-816125-8.00004-3

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Systems Bioinformatics: increasing precision of computational diagnostics and therapeutics through network-based approaches

Briefings in Bioinformatics (2017)

Anastasis Oulas George Minadakis Margarita Zachariou Kleitos Sokratous Marilena M. Bourdakou

Systems Bioinformatics is a relatively new approach, which lies in the intersection of systems biology and classical bioinformatics. It focuses on integrating information across different levels using a bottom-up approach as in systems biology with a data-driven top-down approach as in bioinformatics. The advent of omics technologies has provided the stepping-stone for the emergence of Systems Bioinformatics. These technologies provide a spectrum of information ranging from genomics, transcriptomics and proteomics to epigenomics, pharmacogenomics, metagenomics and metabolomics. Systems Bioinformatics is the framework in which systems approaches are applied to such data, setting the level of resolution as well as the boundary of the system of interest and studying the emerging properties of the system as a whole rather than the sum of the properties derived from the system's individual components. A key approach in Systems Bioinformatics is the construction of multiple networks representing each level of the omics spectrum and their integration in a layered network that exchanges information within and between layers. Here, we provide evidence on how Systems Bioinformatics enhances computational therapeutics and diagnostics, hence paving the way to precision medicine. The aim of this review is to familiarize the reader with the emerging field of Systems Bioinformatics and to provide a comprehensive overview of its current state-of-the-art methods and technologies. Moreover, we provide examples of success stories and case studies that utilize such methods and tools to significantly advance research in the fields of systems biology and systems medicine.

Systems medicine

Modelling biological systems

Pharmacogenomics

Translational bioinformatics

10.1093/bib/bbx151

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Systemic Evaluation of Chimeric LNA/2′-O-Methyl Steric Blockers for Myotonic Dystrophy Type 1 Therapy

Nucleic Acid Therapeutics (2019)

Melina Christou Jesper Wengel Kleitos Sokratous Kyriacos Kyriacou Γεώργιος Νικολάου

Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystemic disorder characterized clinically by delayed muscle relaxation and weakness. The disease is caused by a CTG repeat expansion in the 3′ untranslated region (3′ UTR) of the DMPK gene, which leads to the expression of a toxic gain-of-function mRNA. The expanded CUG repeat mRNA sequesters the MBNL1 splicing regulator in nuclear-retained foci structures, resulting in loss of protein function and disruption of alternative splicing homeostasis. In this study, we used CAG repeat antisense oligonucleotides (ASOs), composed of locked nucleic acid (LNA)- and 2′-O-methyl (2′OMe)-modified bases in a chimeric design, to alleviate CUGexpanded-mediated toxicity. Chimeric 14–18mer LNA/2′OMe oligonucleotides, exhibiting an LNA incorporation of ∼33%, significantly ameliorated the misregulated alternative splicing of Mbnl1-dependent exons in primary DM1 mouse myoblasts and tibialis anterior muscles of DM1 mice. Subcutaneous delivery of 14mer and 18mer LNA/2′OMe chimeras in DM1 mice resulted in high levels of accumulation in all tested skeletal muscles, as well as in the diaphragm and heart tissue. Despite the efficient delivery, chimeric LNA/2′OMe oligonucleotides were not able, even at a high-dosage regimen (400 mg/kg/week), to correct the misregulated splicing of Serca1 exon 22 in skeletal muscles. Nevertheless, oligonucleotide doses were well-tolerated as determined by histological and plasma biochemistry analyses. Our results provide proof of concept that inhibition of MBNL1 sequestration by systemic delivery of a steric-blocking ASO is extremely challenging, considering the large number of target sites that need to be occupied per RNA molecule. Although not suitable for DM1 therapy, chimeric LNA/2′OMe oligonucleotides could prove to be highly beneficial for other diseases, such as Duchenne muscular dystrophy, that require inhibition of a single target site per RNA molecule.

Exon skipping

10.1089/nat.2019.0811

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The effects of cation adduction upon the conformation of three-helix bundle protein domains

International Journal for Ion Mobility Spectrometry (2012)

Kleitos Sokratous Robert Layfield Neil J. Oldham

Ion-mobility spectrometry

Helix bundle

Helix (gastropod)

10.1007/s12127-012-0114-0

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