Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Nature Reviews Drug Discovery, Год журнала: 2019, Номер 18(4), С. 295 - 317

Опубликована: Янв. 4, 2019

Язык: Английский

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Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease

Oxidative Medicine and Cellular Longevity, Год журнала: 2019, Номер 2019, С. 1 - 26

Опубликована: Июнь 23, 2019

Cardiovascular disease is a leading cause of death and reduced quality life, proven by the latest data Global Burden Disease Study, only gaining in prevalence worldwide. Clinical trials have identified chronic inflammatory disorders as cardiovascular risks, recent research has revealed contribution various cells to vascular oxidative stress. Atherosclerosis are closely associated with inflammation, probably due close interaction inflammation Classical therapies for demonstrated protective effects models disease; especially established drugs pleiotropic immunomodulatory properties beneficial effects; normalization stress seems be common feature these therapies. The link between redox balance was also supported reports on aggravated phenotype absence antioxidant defense proteins (e.g., superoxide dismutases, heme oxygenase-1, glutathione peroxidases) or overexpression reactive oxygen species producing enzymes NADPH oxidases). value immunomodulation treatment recently large-scale clinical demonstrating mortality patients atherosclerotic when treated highly specific anti-inflammatory using monoclonal antibodies against cytokines). Modern antidiabetic SGLT2 inhibitors, DPP-4 GLP-1 analogs) seem share display potent effects, all which may explain their successful lowering risk.

Язык: Английский

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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Pharmacological Reviews, Год журнала: 2018, Номер 70(2), С. 348 - 383

Опубликована: Март 5, 2018

Systems medicine has a mechanism-based rather than symptom- or organ-based approach to disease and identifies therapeutic targets in nonhypothesis-driven manner. In this work, we apply transcription factor nuclear (erythroid-derived 2)–like 2 (NRF2) by cross-validating its position protein–protein interaction network (the NRF2 interactome) functionally linked cytoprotection low-grade stress, chronic inflammation, metabolic alterations, reactive oxygen species formation. Multiscale analysis of these molecular profiles suggests alterations expression activity as common mechanism subnetwork diseases diseasome). This joins apparently heterogeneous phenotypes such autoimmune, respiratory, digestive, cardiovascular, metabolic, neurodegenerative diseases, along with cancer. Importantly, matches confirms silico several applications for NRF2-modulating drugs validated vivo at different phases clinical development. Pharmacologically, their profile is diverse electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl sulforaphane, DNA–protein inhibitors, even registered metformin statins, which activate may be repurposed indications within the cluster phenotypes. Thus, represents one first fully embraced classic systems approaches facilitate both drug development repurposing focusing on set that appear mechanistically linked. The resulting drugome therefore rapidly advance surprising options subset diseases.

Язык: Английский

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Environmental Noise and the Cardiovascular System

Journal of the American College of Cardiology, Год журнала: 2018, Номер 71(6), С. 688 - 697

Опубликована: Фев. 1, 2018

Noise has been found associated with annoyance, stress, sleep disturbance, and impaired cognitive performance. Furthermore, epidemiological studies have that environmental noise is an increased incidence of arterial hypertension, myocardial infarction, heart failure, stroke. Observational translational indicate especially nighttime increases levels stress hormones vascular oxidative which may lead to endothelial dysfunction hypertension. Novel experimental aircraft be stress–induced damage, mediated by activation the NADPH oxidase, uncoupling nitric oxide synthase, infiltration inflammatory cells. Transcriptome analysis aortic tissues from animals exposed revealed changes in expression genes responsible for regulation function, remodeling, cell death. This review focuses on mechanisms epidemiology noise-induced cardiovascular diseases provides novel insight into underlying damage.

Язык: Английский

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Loneliness, Social Isolation, and Cardiovascular Health

Antioxidants and Redox Signaling, Год журнала: 2017, Номер 28(9), С. 837 - 851

Опубликована: Окт. 23, 2017

Social and demographic changes have led to an increased prevalence of loneliness social isolation in modern society. Recent Advances: Population-based studies demonstrated that both objective the perception (loneliness) are correlated with a higher risk mortality clearly factors for cardiovascular disease (CVD). Lonely individuals peripheral vascular resistance elevated blood pressure. Socially isolated animals develop more atherosclerosis than those housed groups.Molecular mechanisms responsible poorly understood. In recent reports, stress were associated activation hypothalamic-pituitary-adrenocortical axis sympathetic nervous system. Repeated chronic leads glucocorticoid resistance, enhanced myelopoiesis, upregulated proinflammatory gene expression, oxidative stress. However, causal role these development loneliness-associated CVD remains unclear.Elucidation molecular how is induced by requires additional studies. Understanding pathomechanisms essential therapeutic strategies prevent detrimental effects on health. Antioxid. Redox Signal. 28, 837-851.

Язык: Английский

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Effects of gaseous and solid constituents of air pollution on endothelial function

European Heart Journal, Год журнала: 2018, Номер 39(38), С. 3543 - 3550

Опубликована: Июль 25, 2018

Ambient air pollution is a leading cause of non-communicable disease globally. The largest proportion deaths and morbidity due to now known be cardiovascular disorders. Several particulate gaseous pollutants can trigger acute events (e.g. myocardial infarction, stroke, heart failure). While the mechanisms by which undergoing continual refinement, preponderant evidence support rapid effects diversity including all course, fine, ultrafine particles) such as ozone, on vascular function. Indeed alterations in endothelial function seem critically important transducing signals eventually promoting disorders hypertension, diabetes, atherosclerosis. Here, we provide an updated overview impact from human animal studies. for causal mechanistic pathways both studies that various hypothesized general their individual collective highlighted. We also discuss current gaps knowledge trials evaluating personal-level strategies reduce exposure fine matter (PM2.5) function, given lack definitive randomized using hard endpoints. conclude exhortation formal inclusion major risk factor societal guidelines provision recommendations prevent adverse attributable pollution.

Язык: Английский

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

Redox Biology, Год журнала: 2017, Номер 13, С. 94 - 162

Опубликована: Май 18, 2017

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 providing new insights tools for better understanding redox biology medicine and, the long run, finding therapeutic strategies target dysregulated processes various diseases. This report highlights major achievements EU-ROS as well updates perspectives arising its members. comprised more than 140 active members worked together four years on topics briefly described below. formation reactive oxygen nitrogen species (RONS) is established hallmark our aerobic environment metabolism but RONS also act messengers via regulation essential cellular processes. fact that many diseases have been found be associated with oxidative stress theory trigger can corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical still generate controversial results, due complex pathophysiology humans. For future improvement therapy redox-associated disease progression detailed knowledge sources targets discrimination their detrimental or beneficial roles required. In order advance important area medicine, highly synergistic approaches combining variety diverse contrasting needed.

Язык: Английский

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Plants as Sources of Anti-Inflammatory Agents

Molecules, Год журнала: 2020, Номер 25(16), С. 3726 - 3726

Опубликована: Авг. 15, 2020

Plants represent the main source of molecules for development new drugs, which intensifies interest transnational industries in searching substances obtained from plant sources, especially since vast majority species have not yet been studied chemically or biologically, particularly concerning anti-inflammatory action. Anti-inflammatory drugs can interfere pathophysiological process inflammation, to minimize tissue damage and provide greater comfort patient. Therefore, it is important note that due existence a large number available research, successful naturally occurring depends mainly on multidisciplinary effort find molecules. Although many review articles published this regard, presented subject limited regional perspective. Thus, current article presents highlights literature plants as sources agents.

Язык: Английский

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ROS and RNS signalling: adaptive redox switches through oxidative/nitrosative protein modifications

Free Radical Research, Год журнала: 2018, Номер 52(5), С. 507 - 543

Опубликована: Март 28, 2018

Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body evidence indicates that under physiological conditions, low concentrations reactive oxygen and nitrogen species (RONS) maintained by activity endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications key redox-sensitive residues in regulatory proteins. The reversibility redox such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation disulphide bond formation, or Tyr nitration, which occur through electrophilic attack RONS nucleophilic groups amino acid provides switches activities signalling Key requirement for involvement including ROS-MAPK, ROS-PI3K/Akt, RNS-TNF-α/NF-kB is their specificity provided residue microenvironment reaction kinetics. Glutathione, glutathione peroxidases, peroxiredoxins, thioredoxin, reductases, glutaredoxins modulate level signalling, while some modulators (glutathione, peroxidases peroxiredoxins) are themselves targets modifications. Additionally, gene expression, transcription factors, epigenetic pathways also regulation. present review focuses on sources (NADPH-oxidases, mitochondrial electron-transportation chain (ETC), nitric oxide synthase (NOS), etc.), cross-talks, influence proteins phenomenon attained living cells during evolution control oxygen-enriched environment. We discussed recent advances investigation mechanisms protein adaptive MAPK/PI3K/PTEN, Nrf2/Keap1, NF-κB/IκB, powerful regulators numerous processes, implicated various diseases.

Язык: Английский

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New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(1), С. 187 - 187

Опубликована: Янв. 7, 2019

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most these stressors, an early (subclinical) marker/predictor atherosclerosis. Oxidative stress trigger endothelial it hall-mark diseases the factors/stressors are responsible for their initiation. function largely based on nitric oxide synthase (eNOS) activity. Likewise, oxidative can lead to loss eNOS activity or even “uncoupling” enzyme by adverse regulation well-defined “redox switches” in itself up-/down-stream signaling molecules. Of note, not only endothelium essential vascular integrity homeostasis, but also perivascular adipose tissue plays important role processes. Accordingly, protein attractive therapeutic target that, so far, was pharmacologically exploited. With our present work, we want provide overview recent advances future strategies could be used (and other) diseases, including style changes epigenetic modulations. We highlight redox-regulatory mechanisms up- down-stream pathways (e.g., tetrahydrobiopterin metabolism soluble guanylyl cyclase/cGMP pathway) potential pharmacological exploitation.

Язык: Английский

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