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Antioxidants
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NO(NOx) and H2S
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NO(NOx) and H2S

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

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 27893

Special Issue Editor

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

Special Issue Information

Dear Colleagues,

As we are aware, nitric oxide (NO) (its redox-related products-NOx) and hydrogen sulfide (H2S) are important signaling molecules produced in the body, playing major roles in the function as well as dysfunction of the nervous system, immune system, and circulatory system. In the cellular milieu, NO and H2S react with each other as well as with oxygen and other biomolecules to form both stable and unstable derivatives that help mediate their physiological and pathological effects. However, the identity of the protein molecular target(s) of H2S as well as the structure of the protein-modulating H2S derivative(s) remains largely unknown. In addition, the crosstalk between NO- or H2S-mediated cellular processes is poorly understood.

We welcome original contributions to this Special Issue covering all aspects of NO(NOx) and H2S signaling and on the in vivo detection of NO(NOx), H2S and its derivatives; protein targets implicated in signaling; and the metabolism of NO(NOx) and H2S. Studies examining the use of H2S and related compounds in alleviating NO(NOx)-induced pathologies are especially welcome.

Prof. Dr. Bulent Mutus
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Published Papers (6 papers)

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Research

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22 pages, 6069 KiB  
Article
Design of Light-Sensitive Triggers for Endothelial NO-Synthase Activation
by Sébastien Dilly, Linda J. Roman, Nicolas Bogliotti, Juan Xie, Eric Deprez and Anny Slama-Schwok
Antioxidants 2020, 9(2), 89; https://doi.org/10.3390/antiox9020089 - 21 Jan 2020
Cited by 2 | Viewed by 2042
Abstract
A specific light trigger for activating endothelial Nitric Oxide-Synthase (eNOS) in real time would be of unique value to decipher cellular events associated with eNOS activation or to generate on demand cytotoxic levels of NO at specific sites for cancer research. We previously [...] Read more.
A specific light trigger for activating endothelial Nitric Oxide-Synthase (eNOS) in real time would be of unique value to decipher cellular events associated with eNOS activation or to generate on demand cytotoxic levels of NO at specific sites for cancer research. We previously developed novel tools called nanotriggers (NT), which recognized constitutive NO-synthase, eNOS or neuronal NOS (nNOS), mainly via their 2’ phosphate group which is also present in NADPH in its binding site. Laser excitation of NT1 bound to eNOS triggered recombinant NOS activity and released NO. We recently generated new NTs carrying a 2’ or 3’ carboxylate group or two 2’ and 3’ carboxylate moieties replacing the 2’ phosphate group of NADPH. Among these new NT, only the 3’ carboxylate derivative released NO from endothelial cells upon laser activation. Here, Molecular Dynamics (MD) simulations showed that the 3’ carboxylate NT formed a folded structure with a hydrophobic hub, inducing a good stacking on FAD that likely drove efficient activation of nNOS. This NT also carried an additional small charged group which increased binding to e/nNOS; fluorescence measurements determined a 20-fold improved affinity upon binding to nNOS as compared to NT1 affinity. To gain in specificity for eNOS, we augmented a previous NT with a “hook” targeting variable residues in the NADPH site of eNOS. We discuss the potential of exploiting the chemical diversity within the NADPH site of eNOS for reversal of endothelial dysfunction in cells and for controlled generation of cytotoxic NO-derived species in cancer tissues. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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12 pages, 5126 KiB  
Article
Evidence for an Allosteric S-Nitrosoglutathione Binding Site in S-Nitrosoglutathione Reductase (GSNOR)
by Kathleen Fontana, Nneamaka Onukwue, Bei-Lei Sun, Cristina Lento, Leslie Ventimiglia, Sahar Nikoo, James W. Gauld, Derek J. Wilson and Bulent Mutus
Antioxidants 2019, 8(11), 545; https://doi.org/10.3390/antiox8110545 - 13 Nov 2019
Cited by 3 | Viewed by 2907
Abstract
Current research has identified S-nitrosoglutathione reductase (GSNOR) as the central enzyme for regulating protein S-nitrosylation. In addition, the dysregulation of GSNOR expression is implicated in several organ system pathologies including respiratory, cardiovascular, hematologic, and neurologic, making GSNOR a primary target for [...] Read more.
Current research has identified S-nitrosoglutathione reductase (GSNOR) as the central enzyme for regulating protein S-nitrosylation. In addition, the dysregulation of GSNOR expression is implicated in several organ system pathologies including respiratory, cardiovascular, hematologic, and neurologic, making GSNOR a primary target for pharmacological intervention. This study demonstrates the kinetic activation of GSNOR by its substrate S-nitrosoglutathione (GSNO). GSNOR kinetic analysis data resulted in nonhyperbolic behavior that was successfully accommodated by the Hill–Langmuir equation with a Hill coefficient of +1.75, indicating that the substrate, GSNO, was acting as a positive allosteric affector. Docking and molecular dynamics simulations were used to predict the location of the GSNO allosteric domain comprising the residues Asn185, Lys188, Gly321, and Lys323 in the vicinity of the structural Zn2+-binding site. GSNO binding to Lys188, Gly321, and Lys323 was further supported by hydrogen–deuterium exchange mass spectroscopy (HDXMS), as deuterium exchange significantly decreased at these residues in the presence of GSNO. The site-directed mutagenesis of Lys188Ala and Lys323Ala resulted in the loss of allosteric behavior. Ultimately, this work unambiguously demonstrates that GSNO at large concentrations activates GSNOR by binding to an allosteric site comprised of the residues Asn185, Lys188, Gly321, and Lys323. The identification of an allosteric GSNO-binding domain on GSNOR is significant, as it provides a platform for pharmacological intervention to modulate the activity of this essential enzyme. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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Review

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11 pages, 483 KiB  
Review
An Update on Thiol Signaling: S-Nitrosothiols, Hydrogen Sulfide and a Putative Role for Thionitrous Acid
by Nadzeya Marozkina and Benjamin Gaston
Antioxidants 2020, 9(3), 225; https://doi.org/10.3390/antiox9030225 - 10 Mar 2020
Cited by 19 | Viewed by 3399
Abstract
Long considered vital to antioxidant defenses, thiol chemistry has more recently been recognized to be of fundamental importance to cell signaling. S-nitrosothiols—such as S-nitrosoglutathione (GSNO)—and hydrogen sulfide (H2S) are physiologic signaling thiols that are regulated enzymatically. Current evidence suggests that they [...] Read more.
Long considered vital to antioxidant defenses, thiol chemistry has more recently been recognized to be of fundamental importance to cell signaling. S-nitrosothiols—such as S-nitrosoglutathione (GSNO)—and hydrogen sulfide (H2S) are physiologic signaling thiols that are regulated enzymatically. Current evidence suggests that they modify target protein function primarily through post-translational modifications. GSNO is made by NOS and other metalloproteins; H2S by metabolism of cysteine, homocysteine and cystathionine precursors. GSNO generally acts independently of NO generation and has a variety of gene regulatory, immune modulator, vascular, respiratory and neuronal effects. Some of this physiology is shared with H2S, though the mechanisms differ. Recent evidence also suggests that molecules resulting from reactions between GSNO and H2S, such as thionitrous acid (HSNO), could also have a role in physiology. Taken together, these data suggest important new potential targets for thiol-based drug development. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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26 pages, 1353 KiB  
Review
Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes
by Anish Engineer, Tana Saiyin, Elizabeth R. Greco and Qingping Feng
Antioxidants 2019, 8(10), 436; https://doi.org/10.3390/antiox8100436 - 01 Oct 2019
Cited by 28 | Viewed by 4880
Abstract
Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child by more than four-fold. As [...] Read more.
Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. In experimental animal models of pregestational diabetes induced-CHDs, upwards of 50% of offspring display congenital malformations of the heart, including septal, valvular, and outflow tract defects. Specifically, the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) signaling is a major driver of the development of CHDs in offspring of mice with pregestational diabetes. NO from endothelial nitric oxide synthase (eNOS) is crucial to cardiogenesis, regulating various cellular and molecular processes. In fact, deficiency in eNOS results in CHDs and coronary artery malformation. Embryonic hearts from diabetic dams exhibit eNOS uncoupling and oxidative stress. Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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23 pages, 575 KiB  
Review
Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies
by Emily Hays and Benjamin Bonavida
Antioxidants 2019, 8(9), 407; https://doi.org/10.3390/antiox8090407 - 17 Sep 2019
Cited by 40 | Viewed by 4241
Abstract
In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in [...] Read more.
In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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32 pages, 2225 KiB  
Review
S-Nitrosylation: An Emerging Paradigm of Redox Signaling
by Veani Fernando, Xunzhen Zheng, Yashna Walia, Vandana Sharma, Joshua Letson and Saori Furuta
Antioxidants 2019, 8(9), 404; https://doi.org/10.3390/antiox8090404 - 17 Sep 2019
Cited by 115 | Viewed by 9633
Abstract
Nitric oxide (NO) is a highly reactive molecule, generated through metabolism of L-arginine by NO synthase (NOS). Abnormal NO levels in mammalian cells are associated with multiple human diseases, including cancer. Recent studies have uncovered that the NO signaling is compartmentalized, owing to [...] Read more.
Nitric oxide (NO) is a highly reactive molecule, generated through metabolism of L-arginine by NO synthase (NOS). Abnormal NO levels in mammalian cells are associated with multiple human diseases, including cancer. Recent studies have uncovered that the NO signaling is compartmentalized, owing to the localization of NOS and the nature of biochemical reactions of NO, including S-nitrosylation. S-nitrosylation is a selective covalent post-translational modification adding a nitrosyl group to the reactive thiol group of a cysteine to form S-nitrosothiol (SNO), which is a key mechanism in transferring NO-mediated signals. While S-nitrosylation occurs only at select cysteine thiols, such a spatial constraint is partially resolved by transnitrosylation, where the nitrosyl moiety is transferred between two interacting proteins to successively transfer the NO signal to a distant location. As NOS is present in various subcellular locales, a stress could trigger concerted S-nitrosylation and transnitrosylation of a large number of proteins involved in divergent signaling cascades. S-nitrosylation is an emerging paradigm of redox signaling by which cells confer protection against oxidative stress. Full article
(This article belongs to the Special Issue NO(NOx) and H2S)
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