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Nitric Oxide Modulators in Health and Disease
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Nitric Oxide Modulators in Health and Disease

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 30761

Special Issue Editors

Dr. Cristina Maccallini

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Guest Editor
Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini, 30, 66100 Chieti, Italy
Interests: medicinal chemistry; synthesis and biological evaluation of new small molecules for the therapy of cancer; inflammatory diseases and infections; extraction of bioactive compounds from natural sources
Special Issues, Collections and Topics in MDPI journals
Dr. Rosa Amoroso

E-Mail Website
Guest Editor
Department of Pharmacy, University of G. d\'Annunzio of Chieti and Pescara, Chieti, Italy
Interests: medicinal chemistry; organic synthesis; nitric oxide; nitric oxide synthase; PPAR receptors; metabolic syndrome; aromatase inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

About 40 years ago, the first paper on the endothelium-dependent relaxation factor (EDRF) opened the research field of the later discovered molecule nitric oxide (NO). To date, more than 71,000 papers have been published with NO in the title, and more than 260,000 refer to it in some way.

In medicinal chemistry, NO is a very important molecule, since it is involved in several diseases, and many efforts have been made to understand its cellular biosynthesis details and roles. Considering the numerous and continuous achievements over the years, the identification of NO modulators, both synthetic or naturally occurring, represents an attractive and valuable tool for the development of potential new therapeutic agents, useful to preserve health state or control different disease progression.

This Special Issue aims to focus its attention on the most recent advances in the design and synthesis of small molecules, as well as on the discovery of naturally occurring compounds, able to modulate NO bioavailability, and useful as potential therapeutics or nutraceuticals. 

This Special Issue will accept original research papers and high-quality reviews in the field of NO donors, as well as of NO biosynthesis inhibitors and activators, with particular regard to:

  • Their design, synthesis, and structure–activity relationship study;
  • Their isolation and identification from natural sources;
  • Their evaluation as protective and therapeutic agents.

Dr. Cristina Maccallini
Prof. Dr. Rosa Amoroso
Guest Editors

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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

  • Activators
  • Inhibitors
  • Nitric oxide donors
  • Nitric oxide synthases
  • Nitrosative stress
  • Nutraceuticals
  • Synthesis
  • Structure–activity relationships
  • Therapeutics

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Related Special Issue

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

3 pages, 188 KiB  
Editorial
Preface to Nitric Oxide Modulators in Health and Disease I
by Cristina Maccallini and Rosa Amoroso
Molecules 2022, 27(20), 6820; https://doi.org/10.3390/molecules27206820 - 12 Oct 2022
Cited by 1 | Viewed by 1208
Abstract
Nitric oxide (NO) is a small free radical molecule biosynthesized by nitric oxide synthases (NOS), a family of oxidoreductases responsible for the conversion of the natural substrate L-arginine into L-citrulline and NO [...] Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)

Research

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10 pages, 1352 KiB  
Article
Photolytic Measurement of Tissue S-Nitrosothiols in Rats and Humans In Vivo
by Noah Neidigh, Alyssa Alexander, Parker van Emmerik, Allison Higgs, Logan Plack, Charles Clem, Daniel Cater, Nadzeya Marozkina and Benjamin Gaston
Molecules 2022, 27(4), 1294; https://doi.org/10.3390/molecules27041294 - 15 Feb 2022
Cited by 3 | Viewed by 2269
Abstract
S-nitrosothiols are labile thiol-NO adducts formed in vivo primarily by metalloproteins such as NO synthase, ceruloplasmin, and hemoglobin. Abnormal S-nitrosothiol synthesis and catabolism contribute to many diseases, ranging from asthma to septic shock. Current methods for quantifying S-nitrosothiols in vivo [...] Read more.
S-nitrosothiols are labile thiol-NO adducts formed in vivo primarily by metalloproteins such as NO synthase, ceruloplasmin, and hemoglobin. Abnormal S-nitrosothiol synthesis and catabolism contribute to many diseases, ranging from asthma to septic shock. Current methods for quantifying S-nitrosothiols in vivo are suboptimal. Samples need to be removed from the body for analysis, and the S-nitrosothiols can be broken down during ex vivo processing. Here, we have developed a noninvasive device to measure mammalian tissue S-nitrosothiols in situ non-invasively using ultraviolet (UV) light, which causes NO release in proportion to the S-nitrosothiol concentration. We validated the assay in vitro; then, we applied it to measure S-nitrosothiols in vivo in rats and in humans. The method was sensitive to 0.5 µM, specific (did not detect other nitrogen oxides), and was reproducible in rats and in humans. This noninvasive approach to S-nitrosothiol measurements may be applicable for use in human diseases. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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12 pages, 1873 KiB  
Article
Selective Inhibitors of the Inducible Nitric Oxide Synthase as Modulators of Cell Responses in LPS-Stimulated Human Monocytes
by Marialucia Gallorini, Monica Rapino, Helmut Schweikl, Amelia Cataldi, Rosa Amoroso and Cristina Maccallini
Molecules 2021, 26(15), 4419; https://doi.org/10.3390/molecules26154419 - 22 Jul 2021
Cited by 12 | Viewed by 3161
Abstract
Inducible nitric oxide synthase (iNOS) is a crucial enzyme involved in monocyte cell response towards inflammation, and it is responsible for the production of sustained amounts of nitric oxide. This free radical molecule is involved in the defense against pathogens; nevertheless, its continuous [...] Read more.
Inducible nitric oxide synthase (iNOS) is a crucial enzyme involved in monocyte cell response towards inflammation, and it is responsible for the production of sustained amounts of nitric oxide. This free radical molecule is involved in the defense against pathogens; nevertheless, its continuous and dysregulated production contributes to the development of several pathological conditions, including inflammatory and autoimmune diseases. In the present study, we investigated the effects of two new iNOS inhibitors, i.e., 4-(ethanimidoylamino)-N-(4-fluorophenyl)benzamide hydrobromide (FAB1020) and N-{3-[(ethanimidoylamino)methyl]benzyl}-l-prolinamidedihydrochloride (CM554), on human LPS-stimulated monocytes, using the 1400 W compound as a comparison. Our results show that CM544 and FAB1020 are selective and decrease cytotoxicity, IL-6 secretion and LPS-stimulated monocyte migration. Furthermore, the modulation of iNOS, nitrotyrosine and Nrf2 were analyzed at the protein level. Based on the collected preliminary results, the promising therapeutic value of the investigated compounds emerges, as they appear able to modulate the pro-inflammatory LPS-stimulated response in the low micromolar range in human monocytes. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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14 pages, 1736 KiB  
Article
Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione
by Santiago Andrés Plano, Fernando Martín Baidanoff, Laura Lucía Trebucq, Sebastián Ángel Suarez, Fabio Doctorovich, Diego Andrés Golombek and Juan José Chiesa
Molecules 2021, 26(9), 2514; https://doi.org/10.3390/molecules26092514 - 26 Apr 2021
Cited by 9 | Viewed by 2485
Abstract
The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase [...] Read more.
The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli’s salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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16 pages, 1745 KiB  
Article
In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug
by Ksenia M. Shestakova, Natalia E. Moskaleva, Natalia V. Mesonzhnik, Alexey V. Kukharenko, Igor V. Serkov, Igor I. Lyubimov, Elena V. Fomina-Ageeva, Vladimir V. Bezuglov, Mikhail G. Akimov and Svetlana A. Appolonova
Molecules 2020, 25(24), 5896; https://doi.org/10.3390/molecules25245896 - 13 Dec 2020
Cited by 2 | Viewed by 2675
Abstract
Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic [...] Read more.
Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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Review

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46 pages, 5362 KiB  
Review
An Overview of NO Signaling Pathways in Aging
by Ali Mohammad Pourbagher-Shahri, Tahereh Farkhondeh, Marjan Talebi, Dalia M. Kopustinskiene, Saeed Samarghandian and Jurga Bernatoniene
Molecules 2021, 26(15), 4533; https://doi.org/10.3390/molecules26154533 - 27 Jul 2021
Cited by 51 | Viewed by 5483
Abstract
Nitric Oxide (NO) is a potent signaling molecule involved in the regulation of various cellular mechanisms and pathways under normal and pathological conditions. NO production, its effects, and its efficacy, are extremely sensitive to aging-related changes in the cells. Herein, we review the [...] Read more.
Nitric Oxide (NO) is a potent signaling molecule involved in the regulation of various cellular mechanisms and pathways under normal and pathological conditions. NO production, its effects, and its efficacy, are extremely sensitive to aging-related changes in the cells. Herein, we review the mechanisms of NO signaling in the cardiovascular system, central nervous system (CNS), reproduction system, as well as its effects on skin, kidneys, thyroid, muscles, and on the immune system during aging. The aging-related decline in NO levels and bioavailability is also discussed in this review. The decreased NO production by endothelial nitric oxide synthase (eNOS) was revealed in the aged cardiovascular system. In the CNS, the decline of the neuronal (n)NOS production of NO was related to the impairment of memory, sleep, and cognition. NO played an important role in the aging of oocytes and aged-induced erectile dysfunction. Aging downregulated NO signaling pathways in endothelial cells resulting in skin, kidney, thyroid, and muscle disorders. Putative therapeutic agents (natural/synthetic) affecting NO signaling mechanisms in the aging process are discussed in the present study. In summary, all of the studies reviewed demonstrate that NO plays a crucial role in the cellular aging processes. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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12 pages, 1573 KiB  
Review
The Nitric Oxide (NO) Donor Sodium Nitroprusside (SNP) and Its Potential for the Schizophrenia Therapy: Lights and Shadows
by Elli Zoupa and Nikolaos Pitsikas
Molecules 2021, 26(11), 3196; https://doi.org/10.3390/molecules26113196 - 26 May 2021
Cited by 29 | Viewed by 4551
Abstract
Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, [...] Read more.
Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, to develop novel neuroleptics with higher efficacy and safety. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, appears to be implicated in the pathogenesis of schizophrenia. In particular, underproduction of this gaseous molecule is associated to this mental disease. The latter suggests that increment of nitrergic activity might be of utility for the medication of schizophrenia. Based on the above, molecules able to enhance NO production, as are NO donors, might represent a class of compounds candidates. Sodium nitroprusside (SNP) is a NO donor and is proposed as a promising novel compound for the treatment of schizophrenia. In the present review, we intended to critically assess advances in research of SNP for the therapy of schizophrenia and discuss its potential superiority over currently used neuroleptics. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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18 pages, 2660 KiB  
Review
Prospects for the Personalized Multimodal Therapy Approach to Pain Management via Action on NO and NOS
by Natalia A. Shnayder, Marina M. Petrova, Tatiana E. Popova, Tatiana K. Davidova, Olga P. Bobrova, Vera V. Trefilova, Polina S. Goncharova, Olga V. Balberova, Kirill V. Petrov, Oksana A. Gavrilyuk, Irina A. Soloveva, German V. Medvedev and Regina F. Nasyrova
Molecules 2021, 26(9), 2431; https://doi.org/10.3390/molecules26092431 - 22 Apr 2021
Cited by 15 | Viewed by 3479
Abstract
Chronic pain syndromes are an important medical problem generated by various molecular, genetic, and pathophysiologic mechanisms. Back pain, neuropathic pain, and posttraumatic pain are the most important pathological processes associated with chronic pain in adults. Standard approaches to the treatment of them do [...] Read more.
Chronic pain syndromes are an important medical problem generated by various molecular, genetic, and pathophysiologic mechanisms. Back pain, neuropathic pain, and posttraumatic pain are the most important pathological processes associated with chronic pain in adults. Standard approaches to the treatment of them do not solve the problem of pain chronicity. This is the reason for the search for new personalized strategies for the prevention and treatment of chronic pain. The nitric oxide (NO) system can play one of the key roles in the development of peripheral pain and its chronicity. The purpose of the study is to review publications devoted to changes in the NO system in patients with peripheral chronical pain syndromes. We have carried out a search for the articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier, and Google Scholar databases. The search was carried out using keywords and their combinations. The role of NO and NO synthases (NOS) isoforms in peripheral pain development and chronicity was demonstrated primarily from animal models to humans. The most studied is the neuronal NOS (nNOS). The role of inducible NOS (iNOS) and endothelial NOS (eNOS) is still under investigation. Associative genetic studies have shown that single nucleotide variants (SNVs) of NOS1, NOS2, and NOS3 genes encoding nNOS, iNOS, and eNOS may be associated with acute and chronic peripheral pain. Prospects for the use of NOS inhibitors to modulate the effect of drugs used to treat peripheral pain syndrome are discussed. Associative genetic studies of SNVs NOS1, NOS2, and NOS3 genes are important for understanding genetic predictors of peripheral pain chronicity and development of new personalized pharmacotherapy strategies. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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15 pages, 1079 KiB  
Review
The Role of Single-Nucleotide Variants of NOS1, NOS2, and NOS3 Genes in the Comorbidity of Arterial Hypertension and Tension-Type Headache
by Natalia A. Shnayder, Marina M. Petrova, Polina V. Moskaleva, Pavel A. Shesternya, Elena A. Pozhilenkova and Regina F. Nasyrova
Molecules 2021, 26(6), 1556; https://doi.org/10.3390/molecules26061556 - 12 Mar 2021
Cited by 18 | Viewed by 3504
Abstract
Patients with tension-type headache (TTH) have an increased risk of developing arterial hypertension (AH), while hypertensive subjects do seem to have an increased risk of TTH. We searched for full-text English publications in databases using keywords and combined word searches over the past [...] Read more.
Patients with tension-type headache (TTH) have an increased risk of developing arterial hypertension (AH), while hypertensive subjects do seem to have an increased risk of TTH. We searched for full-text English publications in databases using keywords and combined word searches over the past 15 years. In addition, earlier publications of historical interest were included in the review. In our review, we summed up the single nucleotide variants (SNVs) of Nitric Oxide Synthases (NOSs) genes involved in the development of essential AH and TTH. The results of studies we discussed in this review are contradictory. This might be due to different designs of the studies, small sample sizes in some of them, as well as different social and geographical characteristics. However, the contribution of genetic and environmental factors remains understudied. This makes the issue interesting for researchers, as understanding these mechanisms can contribute to a search for new approaches to pathogenetic and disease-modifying treatment of the AH and TTH phenotype. New drugs against AH and TTH can be based on inhibition of nitric oxide (NO) production, blockade of steps in the NO-cGMP pathway, or NO scavenging. Indeed, selective neuronal NOS (n-NOS) and inducible NOS (i-NOS) inhibitors are already in early clinical development. Full article
(This article belongs to the Special Issue Nitric Oxide Modulators in Health and Disease)
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