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Antioxidants
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NO and ROS in Redox Signalling
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NO and ROS in Redox Signalling

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 14095

Special Issue Editors

Prof. Dr. Bulent Mutus

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Guest Editor
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada
Interests: enzymology; protein structure-function; redox signalling; dynamic microscopy; cell biology; intravital fluorescent probes; nanosensors for nitric oxide; thiols and NOx; platelet biochemistry; flow devices; environmental sensor development; the use of biopolymers for the mitigation of environmental phosphate
Special Issues, Collections and Topics in MDPI journals
Dr. Anny Slama-Schwok

E-Mail Website
Guest Editor
Sorbonne Université, INSERM U938, Centre de Recherche Saint Antoine, Biology and Cancer Therapeutics, Saint Antoine Hospital, 75231 Paris, France
Interests: structure-based drug design; NADPH oxidase inhibitors; tumor-associated macrophages; photoactivatable NADPH analogs; antiviral drugs

Special Issue Information

Dear Colleagues,

Nitric oxide (NO) and reactive oxygen species (ROS) superoxide, hydrogen peroxide, and to a lesser extent hydroxyl radical and singlet oxygen regulate a myriad of physiological processes required for the health of organisms.  Our goal in this Special Issue is to present the state of the art on pathways, either physio-pathological or alternative ones, regulating oxidative stress.

NO and ROS can be generated by a variety of oxydoreductases or hemoglobins that, depending on levels of NO or molecular oxygen, can produce either protective or pathological levels of NO or ROS.  Moreover, alternative pathways for producing NO from nitrite or nitrate via various hemoproteins can increase the levels of NO whenever needed under hypoxic conditions. Activators of soluble guanylate cyclase can also improve normal signaling. Additional activities of some hemoproteins to generate ROS by enzymatic decoupling (mitochondrial enzymes, NOS enzymes) or decrease ROS through an increased SOD activity, as recently shown for cytoglobin, will also enhance pathological conditions or reduce oxidative stress.

The goal in redox signaling research is to gain an understanding of the molecular events that underlie the critical point at which the interplay between NO and ROS levels leads to either a physiological or pathological response.  Such studies require the precise and direct measurement of very low levels of NO and ROS during their transient fluxes in vivo.

This Special Issue of Antioxidants invites researchers who are at the forefront of utilizing chemical tools coupled to physical techniques for the intravital determination of NO and/or ROS levels for the elucidation of redox signaling pathways.

Prof. Dr. Bulent Mutus
Dr. Anny Slama-Schwok
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chemical sensors for nitric oxide, peroxide, superoxide and their respective enzymatic sources
  • ROS signaling, nanomaterials, in vivo sensing
  • Redox signaling

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Published Papers (9 papers)

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Research

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12 pages, 772 KiB  
Article
Differential Nitric Oxide Responses in Primary Cultured Keratinocytes and Fibroblasts to Visible and Near-Infrared Light
by Augustin C. Barolet, Brice Magne, Daniel Barolet and Lucie Germain
Antioxidants 2024, 13(10), 1176; https://doi.org/10.3390/antiox13101176 - 27 Sep 2024
Cited by 1 | Viewed by 833
Abstract
NO is a crucial signaling molecule involved in skin health, the immune response, and the protection against environmental stressors. This study explores how different wavelengths of light, namely blue (455 nm), red (660 nm), and near infrared (NIR, 850 nm), affect nitric oxide [...] Read more.
NO is a crucial signaling molecule involved in skin health, the immune response, and the protection against environmental stressors. This study explores how different wavelengths of light, namely blue (455 nm), red (660 nm), and near infrared (NIR, 850 nm), affect nitric oxide (NO) production in skin cells. Primary keratinocytes and fibroblasts from three donors were exposed to these wavelengths, and NO production was quantified using a DAF-FM fluorescent probe. The results demonstrated that all three wavelengths stimulated NO release, with blue light showing the most pronounced effect. Specifically, blue light induced a 1.7-fold increase in NO in keratinocytes compared to red and NIR light and a 2.3-fold increase in fibroblasts compared to red light. Notably, fibroblasts exposed to NIR light produced 1.5 times more NO than those exposed to red light, while keratinocytes consistently responded more robustly across all wavelengths. In conclusion, blue light significantly boosts NO production in both keratinocytes and fibroblasts, making it the most effective wavelength. Red and NIR light, while less potent, also promote NO production and could serve as complementary therapeutic options, particularly for minimizing potential photoaging effects. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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15 pages, 1363 KiB  
Article
Perioperative Changes in Plasma Nitrite and IL-6 Levels Predict Postoperative Atrial Fibrillation (POAF) and Acute Kidney Injury (AKI) after Cardiac Surgery
by Matthew A. Fischer, Kimberly Howard-Quijano, Nobel Chenggong Zong, Ji Youn Youn, Norika Mengchia Liu, Jennifer Scovotti, Tristan Grogan, Aman Mahajan and Hua Cai
Antioxidants 2024, 13(8), 971; https://doi.org/10.3390/antiox13080971 - 9 Aug 2024
Cited by 1 | Viewed by 869
Abstract
Background: Postoperative atrial fibrillation (POAF) and acute kidney injury (AKI) are common yet significant complications after cardiac surgery, with incidences of up to 40% for each. Here, we assessed plasma nitrite and serum interleukin-6 (IL-6) levels before and after cardiac surgery to quantify [...] Read more.
Background: Postoperative atrial fibrillation (POAF) and acute kidney injury (AKI) are common yet significant complications after cardiac surgery, with incidences of up to 40% for each. Here, we assessed plasma nitrite and serum interleukin-6 (IL-6) levels before and after cardiac surgery to quantify the extent to which oxidative stress and inflammation contribute to POAF and AKI occurrence. Methods: We prospectively enrolled 206 cardiac surgical patients. Plasma nitrite and serum IL-6 levels were determined preoperatively and at 24 h, 48 h and 72 h postoperatively. The patients had continuous EKG monitoring for occurrence of POAF, while daily serum creatinine was measured for determination of stage 1 + AKI. Results: Postoperatively, 78 (38%) patients experienced AF, and 47 (23%) patients experienced stage 1 + AKI. POAF analysis: Age, ACE-inhibitor use, valve surgery and percent change in baseline plasma nitrite at 24 h postoperatively were associated with POAF in multiple logistic regression analysis. The inclusion of this new biomarker significantly improved the POAF prediction model (AUC 0.77 for clinical risk factors alone, to AUC 0.81). AKI analysis: A history of diabetes mellitus was associated with AKI in multiple logistic regression analysis, and the addition of preoperative IL-6 levels improved the prediction model for AKI occurrence (AUC 0.69 to AUC 0.74). Conclusions: We previously observed selective upregulation of NADPH oxidase isoform 4 (NOX4) in patients with AF, a critical causal role of NOX4 for AF in zebrafish and a robust inhibitory effect of nitric oxide (NO) on NOX4. Our data innovatively demonstrate that a reduction in circulating nitrite levels, likely implicative of elevated NOX4-mediated oxidative stress, independently associates with POAF and improves POAF prediction, whereas the inclusion of circulating IL-6 levels improves the prediction model for AKI. Therefore, therapeutic strategies to mitigate these pathophysiological sequalae of surgical stress may reduce the incidence of severe postoperative complications of POAF and AKI. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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23 pages, 2035 KiB  
Article
The Effect of Selected Nitric Oxide Synthase Polymorphisms on the Risk of Developing Diabetic Nephropathy
by Magdalena Król-Kulikowska, Mirosław Banasik and Marta Kepinska
Antioxidants 2024, 13(7), 838; https://doi.org/10.3390/antiox13070838 - 13 Jul 2024
Viewed by 995
Abstract
Background: Nitric oxide synthase (NOS) is an enzyme that catalyzes the formation of nitric oxide (NO), the altered production of which is characteristic of diabetic nephropathy. NOS exists in three isoforms: NOS1, NOS2, and NOS3. Moreover, there are reports about the potential role [...] Read more.
Background: Nitric oxide synthase (NOS) is an enzyme that catalyzes the formation of nitric oxide (NO), the altered production of which is characteristic of diabetic nephropathy. NOS exists in three isoforms: NOS1, NOS2, and NOS3. Moreover, there are reports about the potential role of NOS3 polymorphisms in the development of diabetes complications. The aim of this study was to assess the role of selected NOS polymorphisms—rs3782218 (NOS1), rs1137933 (NOS2), rs1799983, rs2070744, and rs61722009 (NOS3)—in the risk of developing diabetic nephropathy and in the likelihood of renal replacement therapy. Methods: The studied polymorphisms were analyzed in a group of 232 patients divided into three groups. Four polymorphisms (rs3782218, rs1137933, rs1799983, rs2070744) were genotyped using the PCR-RFLP, while the rs61722009 polymorphism was genotyped using the PCR. Results: The C/C genotype and the C allele of the rs3782218 polymorphism (NOS1) were associated with an increased risk of developing diabetic nephropathy and an increased likelihood of renal replacement therapy. In turn, the G allele of the rs1137933 polymorphism (NOS2) reduces the likelihood of renal replacement therapy. Conclusions: The specific genotypes or alleles of the rs3782218 (NOS1) and rs1137933 (NOS2) polymorphisms seem to be potential risk factors for diabetic nephropathy and renal replacement therapy. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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20 pages, 6996 KiB  
Article
CASK Mediates Oxidative Stress-Induced Microglial Apoptosis-Inducing Factor-Independent Parthanatos Cell Death via Promoting PARP-1 Hyperactivation and Mitochondrial Dysfunction
by Keith Jun Hao Cheong, Duen-Yi Huang, Ponarulselvam Sekar, Rou Jhen Chen, Irene Han-Juo Cheng, Chi-Ming Chan, Yuan-Shen Chen and Wan-Wan Lin
Antioxidants 2024, 13(3), 343; https://doi.org/10.3390/antiox13030343 - 13 Mar 2024
Cited by 2 | Viewed by 2452
Abstract
Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein and plays critical roles in neuronal synaptic formation and brain development. Previously, CASK was shown to associate with EGFR to maintain the vulval cell differentiation in C. elegans. In this study, we explored [...] Read more.
Calcium/calmodulin-dependent serine protein kinase (CASK) is a scaffold protein and plays critical roles in neuronal synaptic formation and brain development. Previously, CASK was shown to associate with EGFR to maintain the vulval cell differentiation in C. elegans. In this study, we explored the role of CASK in CHME3 microglial cells. We found that CASK silencing protects cells from H2O2-induced cell death by attenuating PARP-1 activation, mitochondrial membrane potential loss, reactive oxygen species production, and mitochondrial fission, but it increases oxidative phosphorylation. The PARP-1 inhibitor olaparib blocks H2O2-induced cell death, suggesting the death mode of parthanatos. CASK silencing also increases AKT activation but decreases AMPK activation under H2O2 treatment. Pharmacological data further indicate that both signaling changes contribute to cell protection. Different from the canonical parthanatos pathway, we did not observe the AIF translocation from mitochondria into the nucleus, suggesting a non-canonical AIF-independent parthanatos in H2O2-treated CHME3 cells. Moreover, we found that CASK silencing upregulates the EGFR gene and protein expression and increases H2O2-induced EGFR phosphorylation in CHME3 microglia. However, EGFR activation does not contribute to cell protection caused by CASK silencing. In conclusion, CASK plays a crucial role in microglial parthanatos upon H2O2 treatment via stimulation of PARP-1 and AMPK but the inhibition of AKT. These findings suggest that CASK might be an ideal therapeutic target for CNS disorders. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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8 pages, 681 KiB  
Communication
In Vivo Analysis of Tissue S-Nitrosothiols in Pediatric Sepsis
by Daniel T. Cater, Charles Clem, Nadzeya Marozkina and Benjamin Gaston
Antioxidants 2024, 13(3), 263; https://doi.org/10.3390/antiox13030263 - 21 Feb 2024
Viewed by 1259
Abstract
S-nitrosothiols are endogenous, bioactive molecules. S-nitrosothiols are implicated in many diseases, including sepsis. It is currently cumbersome to measure S-nitrosothiols clinically. We have previously developed an instrument to measure tissue S-nitrosothiols non-invasively using ultraviolet light. We have performed a prospective case control study [...] Read more.
S-nitrosothiols are endogenous, bioactive molecules. S-nitrosothiols are implicated in many diseases, including sepsis. It is currently cumbersome to measure S-nitrosothiols clinically. We have previously developed an instrument to measure tissue S-nitrosothiols non-invasively using ultraviolet light. We have performed a prospective case control study of controls and children with sepsis admitted to the PICU. We hypothesized that tissue S-nitrosothiols would be higher in septic patients than controls. Controls were patients with no cardiopulmonary instability. Cases were patients with septic shock. We measured S-nitrosothiols, both at diagnosis and after resolution of shock. A total of 44 patients were enrolled: 21 controls and 23 with sepsis. At baseline, the controls were younger [median age 5 years (IQR 0, 9) versus 11 years (IQR: 6, 16), p-value = 0.012], had fewer comorbidities [7 (33.3%) vs. 20 (87.0%), p-value < 0.001], and had lower PELOD scores [0 (IQR: 0, 0) vs. 12 (IQR: 11, 21), p-value < 0.001]. S-nitrosothiol levels were higher in sepsis cohort (1.1 ppb vs. 0.8 ppb, p = 0.004). Five patients with sepsis had longitudinal measures and had a downtrend after resolution of shock (1.3 ppb vs. 0.9 ppb, p = 0.04). We dichotomized patients based on S-nitrosothiol levels and found an association with worse clinical outcomes, but further work will be needed to validate these findings. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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16 pages, 5634 KiB  
Article
Targeting M2 Macrophages with a Novel NADPH Oxidase Inhibitor
by Sébastien Dilly, Miguel Romero, Stéphanie Solier, Olivier Feron, Chantal Dessy and Anny Slama Schwok
Antioxidants 2023, 12(2), 440; https://doi.org/10.3390/antiox12020440 - 10 Feb 2023
Cited by 5 | Viewed by 2377
Abstract
ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell [...] Read more.
ROS in cancer cells play a key role in pathways regulating cell death, stemness maintenance, and metabolic reprogramming, all of which have been implicated in resistance to chemo/ immunotherapy. Adjusting ROS levels to reverse the resistance of cancer cells without impairing normal cell functions is a new therapeutic avenue. In this paper, we describe new inhibitors of NADPH oxidase (NOX), a key enzyme in many cells of the tumor microenvironment. The first inhibitor, called Nanoshutter-1, NS1, decreased the level of tumor-promoting “M2” macrophages differentiated from human blood monocytes. NS1 disrupted the active NADPH oxidase-2 (NOX2) complex at the membrane and in the mitochondria of the macrophages, as shown by confocal microscopy. As one of the characteristics of tumor invasion is hypoxia, we tested whether NS1 would affect vascular reactivity by reducing ROS or NO levels in wire and pressure myograph experiments on isolated blood vessels. The results show that NS1 vasodilated blood vessels and would likely reduce hypoxia. Finally, as both NOX2 and NOX4 are key proteins in tumors and their microenvironment, we investigated whether NS1 would probe these proteins differently. Models of NOX2 and NOX4 were generated by homology modeling, showing structural differences at their C-terminal NADPH site, in particular in their last Phe. Thus, the NADPH site presents an unexploited chemical space for addressing ligand specificity, which we exploited to design a novel NOX2-specific inhibitor targeting variable NOX2 residues. With the proper smart vehicle to target specific cells of the microenvironment as TAMs, NOX2-specific inhibitors could open the way to new precision therapies. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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Review

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23 pages, 4525 KiB  
Review
Potential Opportunities for Pharmacogenetic-Based Therapeutic Exploitation of Xanthine Dehydrogenase in Cardiovascular Disease
by Gianmichele Massimo, Nicki Dyson, Fisayo Olotu, Rayomand S. Khambata and Amrita Ahluwalia
Antioxidants 2024, 13(12), 1439; https://doi.org/10.3390/antiox13121439 - 22 Nov 2024
Abstract
The majority of naturally occurring mutations of the human gene XDH, are associated with reduced or completely absent xanthine oxidoreductase (XOR) activity, leading to a disease known as classical xanthinuria, which is due to the accumulation and excretion of xanthine in urine. [...] Read more.
The majority of naturally occurring mutations of the human gene XDH, are associated with reduced or completely absent xanthine oxidoreductase (XOR) activity, leading to a disease known as classical xanthinuria, which is due to the accumulation and excretion of xanthine in urine. Three types of classical xanthinuria have been identified: type I, characterised by XOR deficiency, type II, caused by XOR and aldehyde oxidase (AO) deficiency, and type III due to XOR, AO, and sulphite oxidase (SO) deficiency. Type I and II are considered rare autosomal recessive disorders, a condition where two copies of the mutated gene must be present to develop the disease or trait. In most cases, xanthinuria type I and II result to be asymptomatic, and only occasionally lead to renal failure due to urolithiasis caused by xanthine deposition. However, in the last 10–15 years, new observations have been made about the link between naturally occurring mutations and pathological phenotypes particularly pertinent to cardiovascular diseases (CVD). These links have been attributed to a genetically driven increase of XOR expression and activity that is responsible for what is thought to be damaging uric acid (UA) and reactive oxygen species (ROS) accumulation, nitric oxide (·NO) depletion and endothelial dysfunction. In this review, we discuss the importance of genetics for interindividual variability of XOR expression and activity while focusing mainly on those variants thought to be relevant for CVD. In addition, we discuss the potential exploitation of the genetically driven increase of XOR activity to deliver more beneficial bioavailable ·NO. Finally, we examine the effect that non-synonymous mutations have on the tertiary structure of the protein and consequently on its capacity to interact with glycosaminoglycans (GAGs) localised on the outer surface of endothelial cells. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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41 pages, 4602 KiB  
Review
Nitric Oxide Signaling and Sensing in Age-Related Diseases
by Olga Mazuryk, Ilona Gurgul, Maria Oszajca, Justyna Polaczek, Konrad Kieca, Ewelina Bieszczad-Żak, Tobiasz Martyka and Grażyna Stochel
Antioxidants 2024, 13(10), 1213; https://doi.org/10.3390/antiox13101213 - 9 Oct 2024
Viewed by 913
Abstract
Nitric oxide (NO) is a key signaling molecule involved in numerous physiological and pathological processes within the human body. This review specifically examines the involvement of NO in age-related diseases, focusing on the cardiovascular, nervous, and immune systems. The discussion delves into the [...] Read more.
Nitric oxide (NO) is a key signaling molecule involved in numerous physiological and pathological processes within the human body. This review specifically examines the involvement of NO in age-related diseases, focusing on the cardiovascular, nervous, and immune systems. The discussion delves into the mechanisms of NO signaling in these diseases, emphasizing the post-translational modifications of involved proteins, such as S-nitrosation and nitration. The review also covers the dual nature of NO, highlighting both its protective and harmful effects, determined by concentration, location, and timing. Additionally, potential therapies that modulate NO signaling, including the use of NO donors and nitric oxide synthases (NOSs) inhibitors in the treatment of cardiovascular, neurodegenerative, and oncological diseases, are analyzed. Particular attention is paid to the methods for the determination of NO and its derivatives in the context of illness diagnosis and monitoring. The review underscores the complexity and dual role of NO in maintaining cellular balance and suggests areas for future research in developing new therapeutic strategies. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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22 pages, 2515 KiB  
Review
Determination of Nitric Oxide and Its Metabolites in Biological Tissues Using Ozone-Based Chemiluminescence Detection: A State-of-the-Art Review
by Junjie Li, Anthea LoBue, Sophia K. Heuser and Miriam M. Cortese-Krott
Antioxidants 2024, 13(2), 179; https://doi.org/10.3390/antiox13020179 - 31 Jan 2024
Cited by 4 | Viewed by 3050
Abstract
Ozone-based chemiluminescence detection (CLD) has been widely applied for determining nitric oxide (•NO) and its derived species in many different fields, such as environmental monitoring and biomedical research. In humans and animals, CLD has been applied to determine exhaled •NO [...] Read more.
Ozone-based chemiluminescence detection (CLD) has been widely applied for determining nitric oxide (•NO) and its derived species in many different fields, such as environmental monitoring and biomedical research. In humans and animals, CLD has been applied to determine exhaled •NO and •NO metabolites in plasma and tissues. The main advantages of CLD are high sensitivity and selectivity for quantitative analysis in a wide dynamic range. Combining CLD with analytical separation techniques like chromatography allows for the analytes to be quantified with less disturbance from matrix components or impurities. Sampling techniques like microdialysis and flow injection analysis may be coupled to CLD with the possibility of real-time monitoring of •NO. However, details and precautions in experimental practice need to be addressed and clarified to avoid wrong estimations. Therefore, using CLD as a detection tool requires a deep understanding of the sample preparation procedure and chemical reactions used for liberating •NO from its derived species. In this review, we discuss the advantages and pitfalls of CLD for determining •NO species, list the different applications and combinations with other analytical techniques, and provide general practical notes for sample preparation. These guidelines are designed to assist researchers in comprehending CLD data and in selecting the most appropriate method for measuring •NO species. Full article
(This article belongs to the Special Issue NO and ROS in Redox Signalling)
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