Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

American Journal of Nephrology, Год журнала: 2017, Номер 45(6), С. 473 - 483

Опубликована: Янв. 1, 2017

<b><i>Background:</i></b> Nuclear factor erythroid 2-related 2 (NRF2) is a critical transcription for the antioxidative stress response and it activates variety of cytoprotective genes related to redox detoxification. NRF2 activity regulated by oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation through ubiquitinating under unstressed conditions. Because oxidative major pathogenic aggravating kidney diseases, KEAP1-NRF2 system has been proposed be therapeutic target renal protection. <b><i>Summary:</i></b> Oxidative-stress molecules, such as reactive oxygen species, accumulate in kidneys animal models acute injury (AKI), which transiently slightly activated. Genetic or pharmacological enhancement tubules significantly ameliorates damage AKI prevents progression chronic disease (CKD) reducing stress. These beneficial effects activation highlight an important treatment. However, phase-3 clinical trial KEAP1 inhibitor patients with stage 4 CKD type-2 diabetes mellitus (T2DM) was terminated due occurrence cardiovascular events. recent basic studies have accumulated positive inhibitors moderate stages CKD, phase-2 trials restarted. The data from ongoing projects demonstrate improves glomerular filtration rate 3 T2DM without safety concerns. <b><i>Key Message:</i></b> one most promising targets disease, could part therapies disease.

Язык: Английский

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Oxidative stress, aging, and diseases

Clinical Interventions in Aging, Год журнала: 2018, Номер Volume 13, С. 757 - 772

Опубликована: Апрель 1, 2018

Oxidative stress, aging and diseases Ilaria Liguori,1 Gennaro Russo,1 Francesco Curcio,1 Giulia Bulli,1 Luisa Aran,1 David Della-Morte,2,3 Gaetano Gargiulo,4 Gianluca Testa,1,5 Cacciatore,1,6 Domenico Bonaduce,1 Pasquale Abete1 1Department of Translational Medical Sciences, University Naples “Federico II”, Naples, Italy; 2Department Systems Medicine, Rome Tor Vergata, Rome, 3San Raffaele Roma Open University, 4Division Internal AOU San Giovanni di Dio e Ruggi Aragona, Salerno, 5Department Medicine Health Molise, Campobasso, 6Azienda Ospedaliera dei Colli, Monaldi Hospital, Heart Transplantation Unit, Italy Abstract: Reactive oxygen nitrogen species (RONS) are produced by several endogenous exogenous processes, their negative effects neutralized antioxidant defenses. stress occurs from the imbalance between RONS production these Aging is a process characterized progressive loss tissue organ function. The oxidative theory based on hypothesis that age-associated functional losses due to accumulation RONS-induced damages. At same time, involved in age-related conditions (ie, cardiovascular [CVDs], chronic obstructive pulmonary disease, kidney neurodegenerative diseases, cancer), including sarcopenia frailty. Different types biomarkers have been identified may provide important information about efficacy treatment, guiding selection most effective drugs/dose regimens for patients and, if particularly relevant pathophysiological point view, acting specific therapeutic target. Given role pathogenesis many clinical aging, therapy could positively affect natural history but further investigation needed evaluate real interventions. purpose this paper review literature complex topic ever increasing interest. Keywords: elderly, reactive species, antioxidants

Язык: Английский

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Oxidative Stress

Annual Review of Biochemistry, Год журнала: 2017, Номер 86(1), С. 715 - 748

Опубликована: Апрель 25, 2017

Oxidative stress is two sided: Whereas excessive oxidant challenge causes damage to biomolecules, maintenance of a physiological level challenge, termed oxidative eustress, essential for governing life processes through redox signaling. Recent interest has focused on the intricate ways by which signaling integrates these converse properties. Redox balance maintained prevention, interception, and repair, concomitantly regulatory potential molecular thiol-driven master switches such as Nrf2/Keap1 or NF-κB/IκB used system-wide response. Nonradical species hydrogen peroxide (H2O2) singlet oxygen, rather than free-radical species, perform major second messenger functions. Chemokine-controlled NADPH oxidases metabolically controlled mitochondrial sources H2O2 well glutathione- thioredoxin-related pathways, with powerful enzymatic back-up systems, are responsible fine-tuning This makes rich research field spanning from biochemistry cell biology into nutritional sciences, environmental medicine, knowledge-based medicine.

Язык: Английский

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Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 23(7), С. 499 - 515

Опубликована: Фев. 21, 2022

Язык: Английский

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Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

Archives of Toxicology, Год журнала: 2023, Номер 97(10), С. 2499 - 2574

Опубликована: Авг. 19, 2023

Abstract A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or “good stress” characterized by low to mild levels oxidants involved in the regulation various biochemical transformations such carboxylation, hydroxylation, peroxidation, modulation signal transduction pathways Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2–related 2 (Nrf2) other processes. Increased ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result a harmful condition stress (“bad stress”). Although it widely accepted, that many chronic diseases are multifactorial origin, they share common denominator. Here we review importance mechanisms through which contributes pathological states an organism. Attention focused on chemistry ROS RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl nitric oxide, peroxynitrite), their role damage DNA, proteins, membrane lipids. Quantitative qualitative assessment biomarkers also discussed. Oxidative pathology cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer’s Parkinson’s Down syndrome), psychiatric (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, cancer), aging. The concerted action antioxidants ameliorate effect achieved antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), small molecular weight (vitamins C E, flavonoids, carotenoids, melatonin, ergothioneine, others). Perhaps one most effective vitamin first line defense against peroxidation promising approach appears be use flavonoids), showing weak prooxidant properties may boost cellular systems thus act preventive anticancer agents. Redox metal-based enzyme mimetic compounds potential pharmaceutical interventions sirtuins therapeutic targets for age-related anti-aging strategies

Язык: Английский

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Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo

Nature Metabolism, Год журнала: 2022, Номер 4(6), С. 651 - 662

Опубликована: Июнь 27, 2022

Язык: Английский

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Measurement and Clinical Significance of Biomarkers of Oxidative Stress in Humans

Oxidative Medicine and Cellular Longevity, Год журнала: 2017, Номер 2017(1)

Опубликована: Янв. 1, 2017

Oxidative stress is the result of imbalance between reactive oxygen species (ROS) formation and enzymatic nonenzymatic antioxidants. Biomarkers oxidative are relevant in evaluation disease status health‐enhancing effects We aim to discuss major methodological bias methods used for humans. There a lack consensus concerning validation, standardization, reproducibility measurement following: (1) ROS leukocytes platelets by flow cytometry, (2) markers based on ROS‐induced modifications lipids, DNA, proteins, (3) players redox status, (4) total antioxidant capacity human body fluids. It has been suggested that each method could be overcome using indexes include more than one marker. However, choice considered global index should dictated study its design, as well clinical relevance selected subjects. In conclusion, significance biomarkers humans must come from critical analysis give an overall particular conditions.

Язык: Английский

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Network pharmacology: curing causal mechanisms instead of treating symptoms

Trends in Pharmacological Sciences, Год журнала: 2021, Номер 43(2), С. 136 - 150

Опубликована: Дек. 9, 2021

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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Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer

Mutation Research/Reviews in Mutation Research, Год журнала: 2021, Номер 787, С. 108365 - 108365

Опубликована: Янв. 1, 2021

Язык: Английский

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