Publications by authors named "Irundika H K Dias"

24 Publications

  • Page 1 of 1

Oxidative stress links periodontal inflammation and renal function.

J Clin Periodontol 2021 Mar 28;48(3):357-367. Epub 2021 Jan 28.

Periodontal Research Group, School of Dentistry, University of Birmingham and Birmingham Community Healthcare Trust, Birmingham, UK.

Aims: Patients with chronic kidney disease (CKD) are also susceptible to periodontitis. The causal link between periodontitis and CKD may be mediated via systemic inflammation/oxidative stress. Using structural equation modelling (SEM), this cross-sectional study aimed to explore the causal relationship between periodontal inflammation (PI) and renal function.

Materials And Methods: Baseline data on 770 patients with stage 3-5 (pre-dialysis) CKD from an ongoing cohort study were used. Detailed, bioclinical data on PI and renal function, as well as potential confounders and mediators of the relationship between the two, were collected. SEMs of increasing complexity were created to test the causal assumption that PI affects renal function and vice versa.

Results: Structural equation modelling confirmed the assumption that PI and renal function are causally linked, mediated by systemic oxidative stress. The magnitude of this effect was such that a 10% increase in PI resulted in a 3.0% decrease in renal function and a 10% decrease in renal function resulted in a 25% increase in PI.

Conclusions: Periodontal inflammation represents an occult source of oxidative stress in patients with CKD. Further clinical studies are needed to confirm whether periodontal therapy, as a non-pharmacological approach to reducing systemic inflammatory/oxidative stress burden, can improve outcomes in CKD.
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http://dx.doi.org/10.1111/jcpe.13414DOI Listing
March 2021

Bioenergetic effects of hydrogen sulfide suppress soluble Flt-1 and soluble endoglin in cystathionine gamma-lyase compromised endothelial cells.

Sci Rep 2020 09 25;10(1):15810. Epub 2020 Sep 25.

Aston Medical Research Institute, Aston Medical School, Birmingham, UK.

Endothelial dysfunction is a hallmark of preeclampsia, a life-threatening complication of pregnancy characterised by hypertension and elevated soluble Fms-Like Tyrosine Kinase-1 (sFlt-1). Dysregulation of hydrogen sulfide (HS) by inhibition of cystathionine γ-lyase (CSE) increases sFlt-1 and soluble endoglin (sEng) release. We explored whether compromise in CSE/HS pathway is linked to dysregulation of the mitochondrial bioenergetics and oxidative status. We investigated whether these effects were linked to CSE-induced sFlt-1 and sEng production in endothelial cells. Here, we demonstrate that CSE/HS pathway sustain endothelial mitochondrial bioenergetics and loss of CSE increases the production of mitochondrial-specific superoxide. As a compensatory effect, low CSE environment enhances the reliance on glycolysis. The mitochondrial-targeted HS donor, AP39, suppressed the antiangiogenic response and restored the mitochondrial bioenergetics in endothelial cells. AP39 revealed that upregulation of sFlt-1, but not sEng, is independent of the mitochondrial HS metabolising enzyme, SQR. These data provide new insights into the molecular mechanisms for antiangiogenic upregulation in a mitochondrial-driven environment. Targeting HS to the mitochondria may be of therapeutic benefit in the prevention of endothelial dysfunction associated with preeclampsia.
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http://dx.doi.org/10.1038/s41598-020-72371-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519095PMC
September 2020

Cholesterol and oxysterol sulfates: Pathophysiological roles and analytical challenges.

Br J Pharmacol 2020 Aug 6. Epub 2020 Aug 6.

Aston Medical School, Aston University, Birmingham, UK.

Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked the actions of oxysterol sulfates to their physiological and pathophysiological roles. Overexpression of sulfotransferases confirmed the formation of a range of oxysterol sulfates and their antagonistic effects on liver X receptors (LXRs) prompting further investigations how are the changes to oxysterol/oxysterol sulfate homeostasis can contribute to LXR activity in the physiological milieu. Here, we aim to bring together for novel roles of oxysterol sulfates, the available techniques and the challenges associated with their analysis. Understanding the oxysterol/oxysterol sulfate levels and their pathophysiological mechanisms could lead to new therapeutic targets for metabolic diseases.
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http://dx.doi.org/10.1111/bph.15227DOI Listing
August 2020

Cerebrospinal Fluid 7-Ketocholesterol Level is Associated with Amyloid-β42 and White Matter Microstructure in Cognitively Healthy Adults.

J Alzheimers Dis 2020 ;76(2):643-656

Center for Research and Advanced Therapies, CITA-Alzheimer Foundation, Donostia-San Sebastian, Gipuzkoa, Spain.

Background: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer's disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance.

Objective: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals.

Methods: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-OHC), amyloid-β42 (Aβ42), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults.

Results: Higher 7-KC levels were related to lower Aβ42, indicative of greater AD pathology (p = 0.041) .  Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017), genu (B = 68.64, p = 0.000), and fornix (B = 10.97, p = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aβ42 was moderated by 7K-C (p = 0.048).

Conclusion: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process.
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http://dx.doi.org/10.3233/JAD-200105DOI Listing
January 2020

Microvascular function and oxidative stress in adult individuals with early onset of cardiovascular disease.

Sci Rep 2020 03 17;10(1):4881. Epub 2020 Mar 17.

Vascular Research Laboratory, School of Life and Health Sciences, Aston University, Birmingham, UK.

The current study aims to investigate retinal vascular function and its relationship with systemic anti-oxidative defence capacity in normal individuals versus those with early hypertensive changes according to the current ESC/ESH guidelines. Retinal microvascular function was assessed in 201 participants by means of dynamic retinal vessel analysis. Blood pressure, lipid panel, oxidized (GSH) & reduced glutathione (GSSG) were also evaluated for each participant. Individuals classed as grade 1 hypertension demonstrated higher retinal arterial baseline diameter fluctuation (p = 0.0012), maximum dilation percentage (p = 0.0007), time to maximum constriction (p = 0.0003) and lower arterial constriction slope (p = 0.0131). Individuals classed as high normal and grade 1 hypertension also demonstrated higher time to maximum dilation than individuals classed as optimal or normal. GSH levels correlated negatively with SBP, DBP and MBP values in all participants (p = 0.0010; p = 0.0350 and p = 0.0050) as well as with MBP values in high normal and grade 1 hypertension (p = 0.0290). The levels of GSSG correlated positively with SBP, DBP and MBP values in all participants (p = 0.0410; p = 0.0330 and, p = 0.0220). Our results point to the fact that microvascular alterations can be identifiable at BP values still considered within normal values and go in parallel with the changes observed in the level of oxidative stress.
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http://dx.doi.org/10.1038/s41598-020-60766-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078259PMC
March 2020

Inflammation, Lipid (Per)oxidation, and Redox Regulation.

Antioxid Redox Signal 2020 07 28;33(3):166-190. Epub 2020 Feb 28.

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, United Kingdom.

Inflammation increases during the aging process. It is linked to mitochondrial dysfunction and increased reactive oxygen species (ROS) production. Mitochondrial macromolecules are critical targets of oxidative damage; they contribute to respiratory uncoupling with increased ROS production, redox stress, and a cycle of senescence, cytokine production, and impaired oxidative phosphorylation. Targeting the formation or accumulation of oxidized biomolecules, particularly oxidized lipids, in immune cells and mitochondria could be beneficial for age-related inflammation and comorbidities. Inflammation is central to age-related decline in health and exhibits a complex relationship with mitochondrial redox state and metabolic function. Improvements in mass spectrometric methods have led to the identification of families of oxidized phospholipids (OxPLs), cholesterols, and fatty acids that increase during inflammation and which modulate nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPARγ), activator protein 1 (AP1), and NF-κB redox-sensitive transcription factor activity. The kinetic and spatial resolution of the modified lipidome has profound and sometimes opposing effects on inflammation, promoting initiation at high concentration and resolution at low concentration of OxPLs. There is an emerging opportunity to prevent or delay age-related inflammation and vascular comorbidity through a resolving (oxy)lipidome that is dependent on improving mitochondrial quality control and restoring redox homeostasis.
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http://dx.doi.org/10.1089/ars.2020.8022DOI Listing
July 2020

Partial Mitigation of Oxidized Phospholipid-Mediated Mitochondrial Dysfunction in Neuronal Cells by Oxocarotenoids.

J Alzheimers Dis 2020 ;74(1):113-126

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK.

Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer's disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1-20 μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20 μM POVPC. Following delivery of lutein (0.1-1 μM) and zeaxanthin (0.5-5 μM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was > 50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1 μM but not 20 μM POVPC, whereas the increase in ROS production induced by 20 μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20 μM but not 1 μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20 μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids.
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http://dx.doi.org/10.3233/JAD-190923DOI Listing
January 2020

Distribution of plasma oxidised phosphatidylcholines in chronic kidney disease and periodontitis as a co-morbidity.

Free Radic Biol Med 2020 01 20;146:130-138. Epub 2019 Oct 20.

Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, B4 7ET, UK. Electronic address:

Individuals with chronic kidney disease (CKD) and periodontitis as a co-morbidity have a higher mortality rate than individuals with CKD and no periodontitis. The inflammatory burden associated with both diseases contributes to an increased risk of cardiovascular and all-cause mortality. We previously demonstrated that periodontitis is associated with increasing circulating markers of inflammation and oxidative stress. We propose that inflammatory oxidised phosphocholines may contribute to the increased risk of cardiovascular disease in patients with CKD. However, the analysis of oxidised phospholipids has been limited by a lack of authentic standards for absolute quantification. Here, we have developed a comprehensive quantification liquid chromatography-mass spectrometry-based multiple reaction monitoring method for oxidised phospholipids (including some without available authentic species) that enables us to simultaneously measure twelve oxidised phosphatidylcholine species with high levels of sensitivity and specificity. The standard curves for commercial standards 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphatidylcholine (PGPC); 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphatidylcholine (PONPC), 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphatidylcholine (PAzPC) and 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphatidylcholine (POVPC), were linear with a correlation coefficient greater than 0.99 for all analytes. The method is reproducible, with intra- and inter-day precision <15%, and accuracy within ±5% of nominal values for all analytes. This method has been successfully applied to investigate oxidised phosphatidylcholine in plasma from CKD patients with and without chronic periodontitis and the data that was obtained has been compared to plasma from healthy controls. Comparative analysis demonstrates altered chain fragmented phosphatidylcholine profiles in the plasma samples of patients with CKD and periodontitis as a co-morbidity compared to healthy controls.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.10.012DOI Listing
January 2020

Sulfate-based lipids: Analysis of healthy human fluids and cell extracts.

Chem Phys Lipids 2019 07 22;221:53-64. Epub 2019 Mar 22.

LAQV/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007, Porto, Portugal. Electronic address:

Sulfate-based lipids (SL) have been proposed as players in inflammation, immunity and infection. In spite of the many biochemical processes linked to SL, analysis on this class of lipids has only focused on specific SL sub-classes in individual fluids or cells leaving a range of additional SL in other biological samples unaccounted for. This study describes the mass spectrometry screening of SL in lipid extracts of human fluids (saliva, plasma, urine, seminal fluid) and primary human cells (RBC, neutrophils, fibroblasts and skin epidermal) using targeted precursor ion scanning (PIS) approach. The PIS 97 mass spectra reveal a wide diversity of SL including steroid sulfates, sulfoglycolipids and other unidentified SL, as well as metabolites such as taurines, sulfated polyphenols and hypurate conjugates. Semi-quantification of SL revealed that plasma exhibited the highest content of SL whereas seminal fluid and epithelial cells contained the highest sulphur to phosphorous (S/P) ratio. The complexity of biofluids and cells sulfateome presented in this study highlight the importance of expanding the panel of synthetic sulfate-based lipid standards. Also, the heterogenous distribution of SL provides evidence for the interplay of sulfotransferases/sulfatases, opening new avenues for biomarker discovery in oral health, cardiovascular, fertility and dermatology research areas.
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http://dx.doi.org/10.1016/j.chemphyslip.2019.03.009DOI Listing
July 2019

miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients.

J Alzheimers Dis 2018 ;64(3):1009-1017

Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.
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http://dx.doi.org/10.3233/JAD-180201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087455PMC
July 2019

Chromatography of oxysterols.

Biochimie 2018 Oct 9;153:3-12. Epub 2018 May 9.

Department of Chemistry, University of Oslo, PO Box 1033, Blindern, NO-0315, Oslo, Norway. Electronic address:

Oxysterols play important roles in development and diseases, but can be highly challenging to analyze. To ensure satisfactory measurements, oxysterols must typically be separated with chromatography prior to detection. Here, we will devote attention to the chromatography of oxysterols, focusing on gas chromatography and liquid chromatography. We will present the role of stationary phases, mobile phases, and dimensions and geometries of particles/columns. We discuss how these parameters may affect the chromatography, regarding factors such as speed and resolution. Finally, we present some less explored avenues for separation of oxysterols.
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http://dx.doi.org/10.1016/j.biochi.2018.05.004DOI Listing
October 2018

Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia.

Redox Biol 2018 06 17;16:139-145. Epub 2018 Feb 17.

Aston Research Centre for Healthy Ageing, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK; Faculty of Health and Medical Sciences, University of Surrey, Stag Hill, Guildford GU2 7XH, UK.

Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date. We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135 pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia. Twenty healthy male volunteers were recruited (aged 41-63 years); ten were asymptomatic with high plasma cholesterol > 6.5 mM and ten were healthy with normal plasma cholesterol (< 6.5 mM). Simvastatin (40 mg/day) was prescribed to those with hypercholesterolaemia. Plasma samples were taken from both groups at baseline and after three months. Simvastatin reduced plasma cholesterol by ~35% (p < 0.05) at the end of three months. Oxysterols generated by autoxidation (but not enzymatically) were elevated up to 45 fold in hypercholesterolaemic midlife men. Plasma oxysterols were restored to those of healthy controls after simvastatin intervention suggesting that autoxidation is either prevented by simvastatin directly or that autoxidation is less prevalent when plasma cholesterol concentrations are within the normal range.
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http://dx.doi.org/10.1016/j.redox.2018.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952874PMC
June 2018

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

Authors:
Javier Egea Isabel Fabregat Yves M Frapart Pietro Ghezzi Agnes Görlach Thomas Kietzmann Kateryna Kubaichuk Ulla G Knaus Manuela G Lopez Gloria Olaso-Gonzalez Andreas Petry Rainer Schulz Jose Vina Paul Winyard Kahina Abbas Opeyemi S Ademowo Catarina B Afonso Ioanna Andreadou Haike Antelmann Fernando Antunes Mutay Aslan Markus M Bachschmid Rui M Barbosa Vsevolod Belousov Carsten Berndt David Bernlohr Esther Bertrán Alberto Bindoli Serge P Bottari Paula M Brito Guia Carrara Ana I Casas Afroditi Chatzi Niki Chondrogianni Marcus Conrad Marcus S Cooke João G Costa Antonio Cuadrado Pham My-Chan Dang Barbara De Smet Bilge Debelec-Butuner Irundika H K Dias Joe Dan Dunn Amanda J Edson Mariam El Assar Jamel El-Benna Péter Ferdinandy Ana S Fernandes Kari E Fladmark Ulrich Förstermann Rashid Giniatullin Zoltán Giricz Anikó Görbe Helen Griffiths Vaclav Hampl Alina Hanf Jan Herget Pablo Hernansanz-Agustín Melanie Hillion Jingjing Huang Serap Ilikay Pidder Jansen-Dürr Vincent Jaquet Jaap A Joles Balaraman Kalyanaraman Danylo Kaminskyy Mahsa Karbaschi Marina Kleanthous Lars-Oliver Klotz Bato Korac Kemal Sami Korkmaz Rafal Koziel Damir Kračun Karl-Heinz Krause Vladimír Křen Thomas Krieg João Laranjinha Antigone Lazou Huige Li Antonio Martínez-Ruiz Reiko Matsui Gethin J McBean Stuart P Meredith Joris Messens Verónica Miguel Yuliya Mikhed Irina Milisav Lidija Milković Antonio Miranda-Vizuete Miloš Mojović María Monsalve Pierre-Alexis Mouthuy John Mulvey Thomas Münzel Vladimir Muzykantov Isabel T N Nguyen Matthias Oelze Nuno G Oliveira Carlos M Palmeira Nikoletta Papaevgeniou Aleksandra Pavićević Brandán Pedre Fabienne Peyrot Marios Phylactides Gratiela G Pircalabioru Andrew R Pitt Henrik E Poulsen Ignacio Prieto Maria Pia Rigobello Natalia Robledinos-Antón Leocadio Rodríguez-Mañas Anabela P Rolo Francis Rousset Tatjana Ruskovska Nuno Saraiva Shlomo Sasson Katrin Schröder Khrystyna Semen Tamara Seredenina Anastasia Shakirzyanova Geoffrey L Smith Thierry Soldati Bebiana C Sousa Corinne M Spickett Ana Stancic Marie José Stasia Holger Steinbrenner Višnja Stepanić Sebastian Steven Kostas Tokatlidis Erkan Tuncay Belma Turan Fulvio Ursini Jan Vacek Olga Vajnerova Kateřina Valentová Frank Van Breusegem Lokman Varisli Elizabeth A Veal A Suha Yalçın Olha Yelisyeyeva Neven Žarković Martina Zatloukalová Jacek Zielonka Rhian M Touyz Andreas Papapetropoulos Tilman Grune Santiago Lamas Harald H H W Schmidt Fabio Di Lisa Andreas Daiber

Redox Biol 2017 10 18;13:94-162. Epub 2017 May 18.

Molecular Cardiology, Center for Cardiology, Cardiology 1, University Medical Center Mainz, Mainz, Germany; DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Mainz, Germany. Electronic address:

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
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http://dx.doi.org/10.1016/j.redox.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458069PMC
October 2017

Redox control of protein degradation.

Redox Biol 2015 Dec 9;6:409-420. Epub 2015 Sep 9.

Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPAZ), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Spain. Electronic address:

Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies.
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http://dx.doi.org/10.1016/j.redox.2015.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576413PMC
December 2015

Hypercholesterolaemia-induced oxidative stress at the blood-brain barrier.

Biochem Soc Trans 2014 Aug;42(4):1001-5

*Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Aston Triangle, Birmingham B4 7ET, U.K.

Blood cholesterol levels are not consistently elevated in subjects with age-related cognitive decline, although epidemiological studies suggest that Alzheimer's disease and cardiovascular diseases share common risk factors. These include the presence of an unusual genetic variant, the APOE4 (apolipoprotein E4) allele, which modulates LDL (low-density lipoproteins) metabolism, increases free radical formation and reduces plasma antioxidant concentrations. Together, these risk factors support a mechanism for increased LDL circulation time and free radical modification of LDL. Plasma oxycholesterols, hydroxylated metabolites of cholesterol, are carried by oxidized LDL, and elevated lipids in mid-life are associated with increased long-term risk of dementia. Although brain cholesterol metabolism is segregated from the systemic circulation, during oxidative stress, plasma oxycholesterols could have damaging effects on BBB (blood-brain barrier) function and consequently on neuronal cells. Cholesterol-lowering drugs such as statins may prevent the modifications to LDL in mid-life and might show beneficial effects in later life.
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http://dx.doi.org/10.1042/BST20140164DOI Listing
August 2014

Oxidized LDL lipids increase β-amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation.

Free Radic Biol Med 2014 Oct 15;75:48-59. Epub 2014 Jul 15.

Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, West Midlands B4 7ET, UK. Electronic address:

Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4μg oxLDL and 25µM 27-hydroxycholesterol (27OH-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180009PMC
October 2014

Redox regulation of protein damage in plasma.

Redox Biol 2014 20;2:430-5. Epub 2014 Jan 20.

Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Aston Triangle, Birmingham B4 7ET, UK.

The presence and concentrations of modified proteins circulating in plasma depend on rates of protein synthesis, modification and clearance. In early studies, the proteins most frequently analysed for damage were those which were more abundant in plasma (e.g. albumin and immunoglobulins) which exist at up to 10 orders of magnitude higher concentrations than other plasma proteins e.g. cytokines. However, advances in analytical techniques using mass spectrometry and immuno-affinity purification methods, have facilitated analysis of less abundant, modified proteins and the nature of modifications at specific sites is now being characterised. The damaging reactive species that cause protein modifications in plasma principally arise from reactive oxygen species (ROS) produced by NADPH oxidases (NOX), nitric oxide synthases (NOS) and oxygenase activities; reactive nitrogen species (RNS) from myeloperoxidase (MPO) and NOS activities; and hypochlorous acid from MPO. Secondary damage to proteins may be caused by oxidized lipids and glucose autooxidation. In this review, we focus on redox regulatory control of those enzymes and processes which control protein maturation during synthesis, produce reactive species, repair and remove damaged plasma proteins. We have highlighted the potential for alterations in the extracellular redox compartment to regulate intracellular redox state and, conversely, for intracellular oxidative stress to alter the cellular secretome and composition of extracellular vesicles. Through secreted, redox-active regulatory molecules, changes in redox state may be transmitted to distant sites.
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http://dx.doi.org/10.1016/j.redox.2014.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949090PMC
March 2015

Plasma levels of HDL and carotenoids are lower in dementia patients with vascular comorbidities.

J Alzheimers Dis 2014 ;40(2):399-408

Life and Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Birmingham, UK.

Elevated serum cholesterol concentrations in mid-life increase risk for Alzheimer's disease (AD) in later life. However, lower concentrations of cholesterol-carrying high density lipoprotein (HDL) and its principal apolipoprotein A1 (ApoA1) correlate with increased risk for AD. As HDL transports oxocarotenoids, which are scavengers of peroxynitrite, we have investigated the hypothesis that lower HDL and oxocarotenoid concentrations during AD may render HDL susceptible to nitration and oxidation and in turn reduce the efficiency of reverse cholesterol transport (RCT) from lipid-laden cells. Fasting blood samples were obtained from subjects with (1) AD without cardiovascular comorbidities and risk factors (AD); (2) AD with cardiovascular comorbidities and risk factors (AD Plus); (3) normal cognitive function; for carotenoid determination by HPLC, analysis of HDL nitration and oxidation by ELISA, and 3H-cholesterol export to isolated HDL. HDL concentration in the plasma from AD Plus patients was significantly lower compared to AD or control subject HDL levels. Similarly, lutein, lycopene, and zeaxanthin concentrations were significantly lower in AD Plus patients compared to those in control subjects or AD patients, and oxocarotenoid concentrations correlated with Mini-Mental State Examination scores. At equivalent concentrations of ApoA1, HDL isolated from all subjects irrespective of diagnosis was equally effective at mediating RCT. HDL concentration is lower in AD Plus patients' plasma and thus capacity for RCT is compromised. In contrast, HDL from patients with AD-only was not different in concentration, modifications, or function from HDL of healthy age-matched donors. The relative importance of elevating HDL alone compared with elevating carotenoids alone or elevating both to reduce risk for dementia should be investigated in patients with early signs of dementia.
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http://dx.doi.org/10.3233/JAD-131964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230763PMC
January 2015

Nrf2 activation supports cell survival during hypoxia and hypoxia/reoxygenation in cardiomyoblasts; the roles of reactive oxygen and nitrogen species.

Redox Biol 2013 22;1:418-26. Epub 2013 Aug 22.

Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK ; Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK.

Adaptive mechanisms involving upregulation of cytoprotective genes under the control of transcription factors such as Nrf2 exist to protect cells from permanent damage and dysfunction under stress conditions. Here we explore of the hypothesis that Nrf2 activation by reactive oxygen and nitrogen species modulates cytotoxicity during hypoxia (H) with and without reoxygenation (H/R) in H9C2 cardiomyoblasts. Using MnTBap as a cell permeable superoxide dismutase (SOD) mimetic and peroxynitrite scavenger and L-NAME as an inhibitor of nitric oxide synthase (NOS), we have shown that MnTBap inhibited the cytotoxic effects of hypoxic stress with and without reoxygenation. However, L-NAME only afforded protection during H. Under reoxygenation, conditions, cytotoxicity was increased by the presence of L-NAME. Nrf2 activation was inhibited independently by MnTBap and L-NAME under H and H/R. The increased cytotoxicity and inhibition of Nrf2 activation by the presence of L-NAME during reoxygenation suggests that NOS activity plays an important role in cell survival at least in part via Nrf2-independent pathways. In contrast, O2 (-•) scavenging by MnTBap prevented both toxicity and Nrf2 activation during H and H/R implying that toxicity is largely dependent on O2 (-•).To confirm the importance of Nrf2 for myoblast metabolism, Nrf2 knockdown with siRNA reduced cell survival by 50% during 4 h hypoxia with and without 2 h of reoxygenation and although cellular glutathione (GSH) was depleted during H and H/R, GSH loss was not exacerbated by Nrf2 knockdown. These data support distinctive roles for ROS and RNS during H and H/R for Nrf2 induction which are important for survival independently of GSH salvage.
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http://dx.doi.org/10.1016/j.redox.2013.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814985PMC
May 2015

Oxidative stress in diabetes - circulating advanced glycation end products, lipid oxidation and vascular disease.

Ann Clin Biochem 2014 Mar 21;51(Pt 2):125-7. Epub 2013 Oct 21.

Life and Health Sciences, Aston Research Centre for Healthy Ageing, Aston University, Birmingham, UK.

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http://dx.doi.org/10.1177/0004563213508747DOI Listing
March 2014

Sulforaphane restores cellular glutathione levels and reduces chronic periodontitis neutrophil hyperactivity in vitro.

PLoS One 2013 24;8(6):e66407. Epub 2013 Jun 24.

Life and Health Sciences, Aston Research Centre for Healthy Ageing, Aston University, Birmingham, United Kingdom.

The production of high levels of reactive oxygen species by neutrophils is associated with the local and systemic destructive phenotype found in the chronic inflammatory disease periodontitis. In the present study, we investigated the ability of sulforaphane (SFN) to restore cellular glutathione levels and reduce the hyperactivity of circulating neutrophils associated with chronic periodontitis. Using differentiated HL60 cells as a neutrophil model, here we show that generation of extracellular O2 (. -) by the nicotinamide adenine dinucleotide (NADPH) oxidase complex is increased by intracellular glutathione depletion. This may be attributed to the upregulation of thiol regulated acid sphingomyelinase driven lipid raft formation. Intracellular glutathione was also lower in primary neutrophils from periodontitis patients and, consistent with our previous findings, patients neutrophils were hyper-reactive to stimuli. The activity of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, is impaired in circulating neutrophils from chronic periodontitis patients. Although patients' neutrophils exhibit a low reduced glutathione (GSH)/oxidised glutathione (GSSG) ratio and a higher total Nrf2 level, the DNA-binding activity of nuclear Nrf2 remained unchanged relative to healthy controls and had reduced expression of glutamate cysteine ligase catalytic (GCLC), and modifier (GCLM) subunit mRNAs, compared to periodontally healthy subjects neutrophils. Pre-treatment with SFN increased expression of GCLC and GCM, improved intracellular GSH/GSSG ratios and reduced agonist-activated extracellular O2 (. -) production in both dHL60 and primary neutrophils from patients with periodontitis and controls. These findings suggest that a deficiency in Nrf2-dependent pathways may underpin susceptibility to hyper-reactivity in circulating primary neutrophils during chronic periodontitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691189PMC
March 2014

Stabilising cysteinyl thiol oxidation and nitrosation for proteomic analysis.

J Proteomics 2013 Oct 21;92:160-70. Epub 2013 Jun 21.

Life and Health Sciences, Aston University, United Kingdom; Aston Research Centre for Healthy Ageing, Aston University, United Kingdom.

Oxidation and S-nitrosylation of cysteinyl thiols (Cys-SH) to sulfenic (Cys-SOH), sulfinic (Cys-SO2H), sulfonic acids (Cys-SO3H), disulphides and S-nitrosothiols are suggested as important post-translational modifications that can activate or deactivate the function of many proteins. Non-enzymatic post-translational modifications to cysteinyl thiols have been implicated in a wide variety of physiological and pathophysiological states but have been difficult to monitor in a physiological setting because of a lack of experimental tools. The purpose of this review is to bring together the approaches that have been developed for stably trapping cysteine either in its reduced or oxidised forms for enrichment and or subsequent mass spectrometric analysis. These tools are providing insight into potential targets for post-translational modifications to cysteine modification in vivo. This article is part of a Special Issue entitled: Special Issue: Posttranslational Protein modifications in biology and Medicine.
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http://dx.doi.org/10.1016/j.jprot.2013.06.019DOI Listing
October 2013

Activation of the neutrophil respiratory burst by plasma from periodontitis patients is mediated by pro-inflammatory cytokines.

J Clin Periodontol 2011 Jan 21;38(1):1-7. Epub 2010 Oct 21.

School of Life and Health Sciences, Aston University, Birmingham, UK.

Aim: To determine the effect of periodontitis patients' plasma on the neutrophil oxidative burst and the role of albumin, immunoglobulins (Igs) and cytokines.

Materials And Methods: Plasma was collected from chronic periodontitis patients (n=11) and periodontally healthy controls (n=11) and used with/without depletion of albumin and Ig or antibody neutralization of IL-8, GM-CSF or IFN-α to prime/stimulate peripheral blood neutrophils, isolated from healthy volunteers. The respiratory burst was measured by lucigenin-dependent chemiluminescence. Plasma cytokine levels were determined by ELISA.

Results: Plasmas from patients were significantly more effective in both directly stimulating neutrophil superoxide production and priming for subsequent formyl-met-leu-phe (fMLP)-stimulated superoxide production than plasmas from healthy controls (p<0.05). This difference was maintained after depletion of albumin and Ig. Plasma from patients contained higher mean levels of IL-8, GM-CSF and IFN-α. Individual neutralizing antibodies against IL-8, GM-CSF or IFN-α inhibited the direct stimulatory effect of patients' plasma, whereas the ability to prime for fMLP-stimulated superoxide production was only inhibited by neutralization of IFN-α. The stimulating and priming effects of control plasma were unaffected by antibody neutralization.

Conclusions: This study demonstrates that plasma cytokines may have a role in inducing the hyperactive (IL-8, GM-CSF, IFN-α) and hyper-reactive (IFN-α) neutrophil phenotype seen in periodontitis patients.
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http://dx.doi.org/10.1111/j.1600-051X.2010.01628.xDOI Listing
January 2011

Gingipains from Porphyromonas gingivalis increase the chemotactic and respiratory burst-priming properties of the 77-amino-acid interleukin-8 variant.

Infect Immun 2008 Jan 19;76(1):317-23. Epub 2007 Nov 19.

School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.

Porphyromonas gingivalis, a gram-negative anaerobe which is implicated in the etiology of active periodontitis, secretes degradative enzymes (gingipains) and sheds proinflammatory mediators (e.g., lipopolysaccharides [LPS]). LPS triggers the secretion of interleukin-8 (IL-8) from immune (72-amino-acid [aa] variant [IL-8(72aa)]) and nonimmune (IL-8(77aa)) cells. IL-8(77aa) has low chemotactic and respiratory burst-inducing activity but is susceptible to cleavage by gingipains. This study shows that both R- and K-gingipain treatments of IL-8(77aa) significantly enhance burst activation by fMLP and chemotactic activity (P < 0.05) but decrease burst activation and chemotactic activity of IL-8(72aa) toward neutrophil-like HL60 cells and primary neutrophils (P < 0.05). Using tandem mass spectrometry, we have demonstrated that R-gingipain cleaves 5- and 11-aa peptides from the N-terminal portion of IL-8(77aa) and the resultant peptides are biologically active, while K-gingipain removes an 8-aa N-terminal peptide yielding a 69-aa isoform of IL-8 that shows enhanced biological activity. During periodontitis, secreted gingipains may differentially affect neutrophil chemotaxis and activation in response to IL-8 according to the cellular source of the chemokine.
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http://dx.doi.org/10.1128/IAI.00618-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223636PMC
January 2008