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The 25th Anniversary of NO
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The 25th Anniversary of NO

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (10 October 2024) | Viewed by 14834

Special Issue Editors

Prof. Dr. Michele Samaja

E-Mail Website
Guest Editor
Department of Health Science, University of Milan, Via di Rudinì 8, I-20142 Milan, Italy
Interests: hypoxia; hyperoxia; cardioprotection; brain protection; reoxygenation, molecular mechanisms; apoptosis; autophagy; erythropoietin; nitric oxide; animal models; exercise; high altitude; hemoglobin; oxygen carriers; blood oxygen transport
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Daniele Mancardi

E-Mail Website
Guest Editor
Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, 10154 Turin, Italy
Interests: free radical activity and heart metabolism, protection and development; stem cells and reparation of myocardial injuries; cardioprotection mechanisms of pre-and post-conditioning; effects of hydrogen sulphide and gasotransmitters in cardiovascular diseases; role of hydrogen sulphide in cell biology and physiology

Special Issue Information

Dear Colleagues,

A small molecule with myriad functions, nitric oxide (NO) today represents a nodal point of virtually all bodily functions. Initially identified as a toxic heme-protein ligand mainly derived from industrial chemistry, this small free radical was later recognised to be the most important gaseous signalling molecule and a key component of the endothelium-derived relaxing factor, a strong vasodilator first described as being synthesised in circulatory endothelial cells. The discovery of different isoforms of the enzyme that catalyses endogenous NO formation in various districts of the body, allowed for the deciphering of many functions in the nervous, immune and endocrine systems, in angiogenesis, blood oxygen transport and inflammation, just to name a few. In fact, up to 285,000 manuscripts related to NO have been published between 1815 and 2022, of these more than 220,000 were in the last 20 years only. Although the biological actions of NO were first glimpsed in the early 1990s thanks to Salvador Moncada, the surge of NO in its full potential may be dated to 1998 when the Nobel Prize in Medicine and Physiology was assigned to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad “for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system”. For the 25th anniversary of this worldwide recognition, the purpose of this Special Issue is to celebrate NO by gathering contributions from eminent scientists around the world, aiming at summarizing the various functions of NO in the body’s systems, as well as the biological and pharmacological targets of this pleiotropic molecule that paved the road to similar gaseous transmitters as carbon monoxide and hydrogen sulphide.

Prof. Dr. Michele Samaja
Prof. Dr. Daniele Mancardi
Guest Editors

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Keywords

  • nitric oxide
  • gasotransmitter
  • NO-synthase
  • nitrosation
  • nitrosylation

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Published Papers (6 papers)

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Research

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18 pages, 2789 KiB  
Communication
The Effect of Aging on Nitric Oxide Production during Cerebral Ischemia and Reperfusion in Wistar Rats and Spontaneous Hypertensive Rats: An In Vivo Microdialysis Study
by Yasuo Ito, Harumitsu Nagoya, Masamizu Yamazato, Yoshio Asano, Masahiko Sawada, Tomokazu Shimazu, Makiko Hirayama, Toshimasa Yamamoto and Nobuo Araki
Int. J. Mol. Sci. 2023, 24(16), 12749; https://doi.org/10.3390/ijms241612749 - 13 Aug 2023
Cited by 1 | Viewed by 1381
Abstract
Nitric oxide (NO) is involved in the pathogenesis of cerebral ischemic injury. Here, we investigated the effects of aging on NO production during cerebral ischemia-reperfusion (IR). Male Wister rats (WRs) were assigned to 12-month-old (older; n = 5) and 3-month-old (younger; n = [...] Read more.
Nitric oxide (NO) is involved in the pathogenesis of cerebral ischemic injury. Here, we investigated the effects of aging on NO production during cerebral ischemia-reperfusion (IR). Male Wister rats (WRs) were assigned to 12-month-old (older; n = 5) and 3-month-old (younger; n = 7) groups. Similarly, male spontaneous hypertensive rats (SHRs) were allocated to 12-month-old (older; n = 6) and 3-month-old (younger; n = 8) groups. After anesthesia, their NO production was monitored using in vivo microdialysis probes inserted into the left striatum and hippocampus. Forebrain cerebral IR injuries were produced via ligation of the bilateral common carotid arteries, followed by reperfusion. The change in the NO3− of the older rats in the SHR groups in the striatum was less compared to that of the younger rats before ischemia, during ischemia, and after reperfusion (p < 0.05). In the hippocampus, the change in the NO3− of the older rats in the SHR groups was lower compared to that of the younger rats after reperfusion (p < 0.05). There were no significant differences between the two WR groups. Our findings suggested that aging in SHRs affected NO production, especially in the striatum, before and during cerebral ischemia, and after reperfusion. Hypertension and aging may be important factors impacting NO production in brain IR injury. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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Review

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15 pages, 1882 KiB  
Review
The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow
by Giorgia Scarpellino, Valentina Brunetti, Roberto Berra-Romani, Giovambattista De Sarro, Germano Guerra, Teresa Soda and Francesco Moccia
Int. J. Mol. Sci. 2024, 25(16), 9071; https://doi.org/10.3390/ijms25169071 - 21 Aug 2024
Viewed by 1026
Abstract
Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then to exert tight control over a much broader range of processes, including neurotransmitter release, neuronal excitability, and synaptic plasticity. Endothelial NO synthase (eNOS) is [...] Read more.
Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then to exert tight control over a much broader range of processes, including neurotransmitter release, neuronal excitability, and synaptic plasticity. Endothelial NO synthase (eNOS) is usually far from the mind of synaptic neurophysiologists, who have focused most of their attention on neuronal NO synthase (nNOS) as the primary source of NO at the neurovascular unit (NVU). Nevertheless, the available evidence suggests that eNOS could also contribute to generating the burst of NO that, serving as volume intercellular messenger, is produced in response to neuronal activity in the brain parenchyma. Herein, we review the role of eNOS in both the regulation of cerebral blood flow and of synaptic plasticity and discuss the mechanisms by which cerebrovascular endothelial cells may transduce synaptic inputs into a NO signal. We further suggest that eNOS could play a critical role in vascular-to-neuronal communication by integrating signals converging onto cerebrovascular endothelial cells from both the streaming blood and active neurons. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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24 pages, 2970 KiB  
Review
NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer
by Leandro L. Coutinho, Elise L. Femino, Ana L. Gonzalez, Rebecca L. Moffat, William F. Heinz, Robert Y. S. Cheng, Stephen J. Lockett, M. Cristina Rangel, Lisa A. Ridnour and David A. Wink
Int. J. Mol. Sci. 2024, 25(11), 6103; https://doi.org/10.3390/ijms25116103 - 1 Jun 2024
Viewed by 1685
Abstract
Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, [...] Read more.
Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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12 pages, 820 KiB  
Review
Role of Nasal Nitric Oxide in Primary Ciliary Dyskinesia and Other Respiratory Conditions in Children
by Salvatore Paternò, Laura Pisani, Stefania Zanconato, Valentina Agnese Ferraro and Silvia Carraro
Int. J. Mol. Sci. 2023, 24(22), 16159; https://doi.org/10.3390/ijms242216159 - 10 Nov 2023
Cited by 3 | Viewed by 1915
Abstract
Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of [...] Read more.
Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of the literature to examine the relationship between nNO and some respiratory diseases with a particular focus on primary ciliary dyskinesia (PCD). A total of 115 papers were assessed, and 50 were eventually included in the review. nNO in PCD is low (below 77 nL/min), and its measurement has a clear diagnostic value when evaluated in a clinically suggestive phenotype. Many studies have evaluated the role of NO as a molecular mediator as well as the association between nNO values and genotype or ciliary function. As far as other respiratory diseases are concerned, nNO is low in chronic rhinosinusitis and cystic fibrosis, while increased values have been found in allergic rhinitis. Nonetheless, the role in the diagnosis and prognosis of these conditions has not been fully clarified. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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22 pages, 1055 KiB  
Review
How Nitric Oxide Hindered the Search for Hemoglobin-Based Oxygen Carriers as Human Blood Substitutes
by Michele Samaja, Ashok Malavalli and Kim D. Vandegriff
Int. J. Mol. Sci. 2023, 24(19), 14902; https://doi.org/10.3390/ijms241914902 - 4 Oct 2023
Cited by 1 | Viewed by 2083
Abstract
The search for a clinically affordable substitute of human blood for transfusion is still an unmet need of modern society. More than 50 years of research on acellular hemoglobin (Hb)-based oxygen carriers (HBOC) have not yet produced a single formulation able to carry [...] Read more.
The search for a clinically affordable substitute of human blood for transfusion is still an unmet need of modern society. More than 50 years of research on acellular hemoglobin (Hb)-based oxygen carriers (HBOC) have not yet produced a single formulation able to carry oxygen to hemorrhage-challenged tissues without compromising the body’s functions. Of the several bottlenecks encountered, the high reactivity of acellular Hb with circulating nitric oxide (NO) is particularly arduous to overcome because of the NO-scavenging effect, which causes life-threatening side effects as vasoconstriction, inflammation, coagulopathies, and redox imbalance. The purpose of this manuscript is not to add a review of candidate HBOC formulations but to focus on the biochemical and physiological events that underly NO scavenging by acellular Hb. To this purpose, we examine the differential chemistry of the reaction of NO with erythrocyte and acellular Hb, the NO signaling paths in physiological and HBOC-challenged situations, and the protein engineering tools that are predicted to modulate the NO-scavenging effect. A better understanding of two mechanisms linked to the NO reactivity of acellular Hb, the nitrosylated Hb and the nitrite reductase hypotheses, may become essential to focus HBOC research toward clinical targets. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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15 pages, 1841 KiB  
Review
Nitric Oxide as a Determinant of Human Longevity and Health Span
by Burkhard Poeggeler, Sandeep Kumar Singh, Kumar Sambamurti and Miguel A. Pappolla
Int. J. Mol. Sci. 2023, 24(19), 14533; https://doi.org/10.3390/ijms241914533 - 26 Sep 2023
Cited by 3 | Viewed by 5856
Abstract
The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy [...] Read more.
The master molecular regulators and mechanisms determining longevity and health span include nitric oxide (NO) and superoxide anion radicals (SOR). L-arginine, the NO synthase (NOS) substrate, can restore a healthy ratio between the dangerous SOR and the protective NO radical to promote healthy aging. Antioxidant supplementation orchestrates protection against oxidative stress and damage—L-arginine and antioxidants such as vitamin C increase NO production and bioavailability. Uncoupling of NO generation with the appearance of SOR can be induced by asymmetric dimethylarginine (ADMA). L-arginine can displace ADMA from the site of NO formation if sufficient amounts of the amino acid are available. Antioxidants such as ascorbic acids can scavenge SOR and increase the bioavailability of NO. The topics of this review are the complex interactions of antioxidant agents with L-arginine, which determine NO bioactivity and protection against age-related degeneration. Full article
(This article belongs to the Special Issue The 25th Anniversary of NO)
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