On the Clinical Pharmacology of Reactive Oxygen Species

Casas, Ana I.; Nogales, Cristian; Mucke, Hermann Am; Petraina, Alexandra; Cuadrado, Antonio; Rojo, Ana I.; Ghezzi, Pietro; Jaquet, Vincent; Augsburger, Fiona; Dufrasne, François; Soubhye, Jalal; Deshwal, Soni; Sante, Moises Di; Kaludercic, Nina; Lisa, Fabio Di; Schmidt, Harald

doi:10.1124/pr.120.019422

Cited by 87 publications

(100 citation statements)

References 325 publications

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“…Although NADPH oxidases are already investigated for therapeutic targeting since more than a decade, there are still no NOX inhibitors in clinical use for the therapy of CVD [ 161 , 162 ]. So far, there are several promising drug candidates for NOX inhibition in clinical phase II and III trials, although not directly for the therapy of CVD but associated comorbidities [ 27 , 163 ].…”

Section: Advanced Redox Biomarkersmentioning

confidence: 99%

“…[ 161 , 191 ]). The importance of MPO as a redox biomarker is supported by several pharmacological MPO inhibitors that are currently investigated within phase II trials [ 27 ].…”

Section: Advanced Redox Biomarkersmentioning

confidence: 99%

“…This fact is also well supported by phenotypic changes in animal models of CVD with genetic deletion or overexpression of enzymes involved in the synthesis or degradation of ROS and RNS [ 18 , 19 , 24 , 25 ]. Further support for the oxidative stress concept comes from modern approaches using systems biology to identify therapeutic targets based on redox processes within a specific disease and systematic overviews of redox drug candidates in advanced clinical phase II-III trials [ 26 , 27 ]. Overall the discrepancy between the rather disappointing outcome of antioxidant trials and the established presence of redox biomarkers as well as drugable redox targets in CVD highlights the need of better knowledge on sources of ROS and RNS, their interaction, discrimination between beneficial (physiological) redox signaling and detrimental (pathophysiological) oxidative damage pathways [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

et al. 2021

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Global epidemiological studies show that chronic non-communicable diseases such as atherosclerosis and metabolic disorders represent the leading cause of premature mortality and morbidity. Cardiovascular disease such as ischemic heart disease is a major contributor to the global burden of disease and the socioeconomic health costs. Clinical and epidemiological data show an association of typical oxidative stress markers such as lipid peroxidation products, 3-nitrotyrosine or oxidized DNA/RNA bases with all major cardiovascular diseases. This supports the concept that the formation of reactive oxygen and nitrogen species by various sources (NADPH oxidases, xanthine oxidase and mitochondrial respiratory chain) represents a hallmark of the leading cardiovascular comorbidities such as hyperlipidemia, hypertension and diabetes. These reactive oxygen and nitrogen species can lead to oxidative damage but also adverse redox signaling at the level of kinases, calcium handling, inflammation, epigenetic control, circadian clock and proteasomal system. The in vivo footprints of these adverse processes (redox biomarkers) are discussed in the present review with focus on their clinical relevance, whereas the details of their mechanisms of formation and technical aspects of their detection are only briefly mentioned. The major categories of redox biomarkers are summarized and explained on the basis of suitable examples. Also the potential prognostic value of redox biomarkers is critically discussed to understand what kind of information they can provide but also what they cannot achieve.

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Section: Advanced Redox Biomarkersmentioning

confidence: 99%

“…[ 161 , 191 ]). The importance of MPO as a redox biomarker is supported by several pharmacological MPO inhibitors that are currently investigated within phase II trials [ 27 ].…”

Section: Advanced Redox Biomarkersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

et al. 2021

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“…The argument that similar treatments would be effective in human diseases may thus not be compelling, given that most humans have a functional Nnt gene. Perhaps noteworthy is that many pre-clinical studies showing effective disease amelioration with MitoTEMPO treatments were conducted in 6J mice (Aoyama et al, 2012;Li et al, 2018;Vincent et al, 2020;Wu et al, 2020), whereas anti-oxidants have not shown clear benefits in human clinical trials (Casas et al, 2020;Jiang et al, 2020;Kovacic, 2020;Steinhubl, 2008).…”

Section: Discussionmentioning

confidence: 99%

An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Rawle

Dumenil

et al. 2021

Preprint

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Granzyme A (GzmA) is a serine protease secreted by cytotoxic lymphocytes, with GzmA-/- mouse studies informing our understanding of GzmAs physiological function. We show herein that GzmA-/- mice have a mixed C57BL/6J and C57BL/6N background and retain the full length Nicotinamide Nucleotide Transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in GzmA-/- mice; however, the presence of Nnt, rather than loss of GzmA, was responsible for this phenotype by constraining lymphocyte infiltration. A new CRISPR active site mutant C57BL/6J GzmAS211A mouse provided the first insights into GzmAs bioactivity free of background issues, with circulating proteolytically active GzmA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ~27% of Run Accessions and ~38% of Bioprojects listing C57BL/6J as the mouse strain, had Nnt sequencing reads inconsistent with a C57BL/6J background. The Nnt issue has clearly complicated our understanding of GzmA and may similarly have influenced studies across a broad range of fields.

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“…The normal range more than likely varies in different cells at different times. Therefore, specific NADPH oxidase isoform or mitochondria-site antioxidants with cell- or tissue-specific drug delivery at a specific time is a promising therapeutic approach ( Casas et al, 2020 ).…”

Section: Reactive Oxygen Species-targeted Therapeutic Implicationsmentioning

confidence: 99%

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

Lee

José

2021

Front. Pharmacol.

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Metabolic syndrome (MetS), a complex of interrelated risk factors for cardiovascular disease and diabetes, is comprised of central obesity (increased waist circumference), hyperglycemia, dyslipidemia (high triglyceride blood levels, low high-density lipoprotein blood levels), and increased blood pressure. Oxidative stress, caused by the imbalance between pro-oxidant and endogenous antioxidant systems, is the primary pathological basis of MetS. The major sources of reactive oxygen species (ROS) associated with MetS are nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases and mitochondria. In this review, we summarize the current knowledge regarding the generation of ROS from NADPH oxidases and mitochondria, discuss the NADPH oxidase- and mitochondria-derived ROS signaling and pathophysiological effects, and the interplay between these two major sources of ROS, which leads to chronic inflammation, adipocyte proliferation, insulin resistance, and other metabolic abnormalities. The mechanisms linking MetS and chronic kidney disease are not well known. The role of NADPH oxidases and mitochondria in renal injury in the setting of MetS, particularly the influence of the pyruvate dehydrogenase complex in oxidative stress, inflammation, and subsequent renal injury, is highlighted. Understanding the molecular mechanism(s) underlying MetS may lead to novel therapeutic approaches by targeting the pyruvate dehydrogenase complex in MetS and prevent its sequelae of chronic cardiovascular and renal diseases.

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On the Clinical Pharmacology of Reactive Oxygen Species

Cited by 87 publications

References 325 publications

Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Coordinated Contribution of NADPH Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Metabolic Syndrome and Its Implication in Renal Dysfunction

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