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Special Issue "Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications"

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 17662

Special Issue Editor

Prof. Dr. Khosrow Kashfi
E-Mail Website
Guest Editor
Department of Molecular, Cellular and Biomedical Sciences Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, USA
Interests: cancer therapeutics; nitric oxide; hydrogen sulfide; cell signaling; resolution
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nitric oxide (NO), a gaseous free radical, is one of the ten smallest molecules found in nature. Although toxic, it is recognized to be a gasotransmitter that plays multiple roles in normal physiology. NO regulates vascular relaxation, controls inflammation, and suppresses expression of pro-inflammatory mediators in mast cells, macrophages, and vascular smooth muscles. NO regulates blood flow and modulates platelet and leukocyte activation, adhesion, and aggregation. The role of NO in cancer biology has been quite perplexing, as both tumor promotion and inflammatory activities as well as anti-tumor and anti-inflammatory properties have been described. This paradox has been explained in terms of a dual or biphasic effect that is dependent on the local flux. In 1992, the journal Science referred to NO as the “Molecule of the Year”. The important role that NO plays in human biology was recognized in 1998 when the Nobel Prize in Physiology and Medicine was awarded to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad for establishing NO as a messenger molecule.

This Special Issue invites state-of-the-art reviews, commentaries, and original research articles to help advance our understanding of the role that NO plays in physiology and pharmacology, which may lead to applications against various diseases.

Prof. Dr. Khosrow Kashfi
Guest Editor

Manuscript Submission Information

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Keywords

  • nitric oxide
  • eNOS, nNOS, iNOS
  • cancer
  • cardiovascular
  • diabetes
  • drug resistance
  • re-sensitization
  • drug design
  • resolution

Published Papers (11 papers)

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Research

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Article
Contributions of Nitric Oxide to AHR-Ligand-Mediated Keratinocyte Differentiation
Int. J. Mol. Sci. 2020, 21(16), 5680; https://doi.org/10.3390/ijms21165680 - 08 Aug 2020
Cited by 2 | Viewed by 1383
Abstract
Activation of the aryl hydrocarbon receptor (AHR) in normal human epidermal keratinocytes (NHEKs) accelerates keratinocyte terminal differentiation through metabolic reprogramming and reactive oxygen species (ROS) production. Of the three NOS isoforms, NOS3 is significantly increased at both the RNA and protein levels by [...] Read more.
Activation of the aryl hydrocarbon receptor (AHR) in normal human epidermal keratinocytes (NHEKs) accelerates keratinocyte terminal differentiation through metabolic reprogramming and reactive oxygen species (ROS) production. Of the three NOS isoforms, NOS3 is significantly increased at both the RNA and protein levels by exposure to the very potent and selective ligand of the AHR, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Inhibition of NOS with the chemical N-nitro-l-arginine methyl ester (l-NAME) reversed TCDD-induced cornified envelope formation, an endpoint of terminal differentiation, as well as the expression of filaggrin (FLG), a marker of differentiation. Conversely, exposure to the NO-donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), increased the number of cornified envelopes above control levels and augmented the levels of cornified envelopes formed in response to TCDD treatment and increased the expression of FLG. This indicates that nitric oxide signaling can increase keratinocyte differentiation and that it is involved in the AHR-mediated acceleration of differentiation. As the nitrosylation of cysteines is a mechanism by which NO affects the structure and functions of proteins, the S-nitrosylation biotin switch technique was used to measure protein S-nitrosylation. Activation of the AHR increased the S-nitrosylation of two detected proteins of about 72 and 20 kD in size. These results provide new insights into the role of NO and protein nitrosylation in the process of epithelial cell differentiation, suggesting a role of NOS in metabolic reprogramming and the regulation of epithelial cell fate. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Article
The T2 Toxin Produced by Fusarium spp. Impacts Porcine Duodenal Nitric Oxide Synthase (nNOS)-Positive Nervous Structures—The Preliminary Study
Int. J. Mol. Sci. 2020, 21(14), 5118; https://doi.org/10.3390/ijms21145118 - 20 Jul 2020
Cited by 3 | Viewed by 812
Abstract
T2 toxin synthetized by Fusarium spp. negatively affects various internal organs and systems, including the digestive tract and the immune, endocrine, and nervous systems. However, knowledge about the effects of T2 on the enteric nervous system (ENS) is still incomplete. Therefore, during the [...] Read more.
T2 toxin synthetized by Fusarium spp. negatively affects various internal organs and systems, including the digestive tract and the immune, endocrine, and nervous systems. However, knowledge about the effects of T2 on the enteric nervous system (ENS) is still incomplete. Therefore, during the present experiment, the influence of T2 toxin with a dose of 12 µg/kg body weight (b.w.)/per day on the number of enteric nervous structures immunoreactive to neuronal isoform nitric oxide synthase (nNOS—used here as a marker of nitrergic neurons) in the porcine duodenum was studied using the double immunofluorescence method. Under physiological conditions, nNOS-positive neurons amounted to 38.28 ± 1.147%, 38.39 ± 1.244%, and 35.34 ± 1.151 of all enteric neurons in the myenteric (MP), outer submucous (OSP), and inner submucous (ISP) plexuses, respectively. After administration of T2 toxin, an increase in the number of these neurons was observed in all types of the enteric plexuses and nNOS-positive cells reached 46.20 ± 1.453% in the MP, 45.39 ± 0.488% in the OSP, and 44.07 ± 0.308% in the ISP. However, in the present study, the influence of T2 toxin on the intramucosal and intramuscular nNOS-positive nerves was not observed. The results obtained in the present study indicate that even low doses of T2 toxin are not neutral for living organisms because they may change the neurochemical characterization of the enteric neurons. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Article
The Influence of Bisphenol a on the Nitrergic Nervous Structures in the Domestic Porcine Uterus
Int. J. Mol. Sci. 2020, 21(12), 4543; https://doi.org/10.3390/ijms21124543 - 26 Jun 2020
Cited by 4 | Viewed by 1133
Abstract
Bisphenol A (BPA) is one of the most common environmental pollutants among endocrine disruptors. Due to its similarity to estrogen, BPA may affect estrogen receptors and show adverse effects on many internal organs. The reproductive system is particularly vulnerable to the impact of [...] Read more.
Bisphenol A (BPA) is one of the most common environmental pollutants among endocrine disruptors. Due to its similarity to estrogen, BPA may affect estrogen receptors and show adverse effects on many internal organs. The reproductive system is particularly vulnerable to the impact of BPA, but knowledge about BPA-induced changes in the innervation of the uterus is relatively scarce. Therefore, this study aimed to investigate the influence of various doses of BPA on nitrergic nerves supplying the uterus with the double immunofluorescence method. It has been shown that even low doses of BPA caused an increase in the number of nitrergic nerves in the uterine wall and changed their neurochemical characterization. During the present study, changes in the number of nitrergic nerves simultaneously immunoreactive to substance P, vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating peptide, and/or cocaine- and amphetamine-regulated transcript were found under the influence of BPA. The obtained results strongly suggest that nitrergic nerves in the uterine wall participate in adaptive and/or protective processes aimed at homeostasis maintenance in the uterine activity under the impact of BPA. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Article
Dose-Dependent Effects of Long-Term Administration of Hydrogen Sulfide on Myocardial Ischemia–Reperfusion Injury in Male Wistar Rats: Modulation of RKIP, NF-κB, and Oxidative Stress
Int. J. Mol. Sci. 2020, 21(4), 1415; https://doi.org/10.3390/ijms21041415 - 19 Feb 2020
Cited by 18 | Viewed by 1518
Abstract
Decreased circulating levels of hydrogen sulfide (H2S) are associated with higher mortality following myocardial ischemia. This study aimed at determining the long-term dose-dependent effects of sodium hydrosulfide (NaSH) administration on myocardial ischemia-reperfusion (IR) injury. Male rats were divided into control and [...] Read more.
Decreased circulating levels of hydrogen sulfide (H2S) are associated with higher mortality following myocardial ischemia. This study aimed at determining the long-term dose-dependent effects of sodium hydrosulfide (NaSH) administration on myocardial ischemia-reperfusion (IR) injury. Male rats were divided into control and NaSH groups that were treated for 9 weeks with daily intraperitoneal injections of normal saline or NaSH (0.28, 0.56, 1.6, 2.8, and 5.6 mg/kg), respectively. At the end of the study, hearts from all rats were isolated and hemodynamic parameters were recorded during baseline and following IR. In isolated hearts, infarct size, oxidative stress indices as well as mRNA expression of H2S-, nitric oxide (NO)-producing enzymes, and inflammatory markers were measured. In heart tissue following IR, low doses of NaSH (0.28 and 0.56 mg/kg) had no effect, whereas an intermediate dose (1.6 mg/kg), improved recovery of hemodynamic parameters, decreased infarct size, and decreased oxidative stress. It also increased expression of cystathionine γ-lyase (CSE), Raf kinase inhibitor protein (RKIP), endothelial NO synthase (eNOS), and neuronal NOS (nNOS), as well as decreased expression of inducible NOS (iNOS) and nuclear factor kappa-B (NF-κB). At the high dose of 5.6 mg/kg, NaSH administration was associated with worse recovery of hemodynamic parameters and increased infarct size as well as increased oxidative stress. This dose also decreased expression of CSE, RKIP, and eNOS and increased expression of iNOS and NF-κB. In conclusion, chronic treatment with NaSH has a U-shaped concentration effect on IR injury in heart tissue. An intermediate dose was associated with higher CSE-derived H2S, lower iNOS-derived NO, lower oxidative stress, and inflammation in heart tissue following IR. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review

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Review
Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment
Int. J. Mol. Sci. 2021, 22(13), 7068; https://doi.org/10.3390/ijms22137068 - 30 Jun 2021
Cited by 6 | Viewed by 1247
Abstract
The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A [...] Read more.
The metabolic requirements and functions of cancer and normal tissues are vastly different. Due to the rapid growth of cancer cells in the tumor microenvironment, distorted vasculature is commonly observed, which creates harsh environments that require rigorous and constantly evolving cellular adaption. A common hallmark of aggressive and therapeutically resistant tumors is hypoxia and hypoxia-induced stress markers. However, recent studies have identified alterations in a wide spectrum of metabolic pathways that dictate tumor behavior and response to therapy. Accordingly, it is becoming clear that metabolic processes are not uniform throughout the tumor microenvironment. Metabolic processes differ and are cell type specific where various factors promote metabolic heterogeneity within the tumor microenvironment. Furthermore, within the tumor, these metabolically distinct cell types can organize to form cellular neighborhoods that serve to establish a pro-tumor milieu in which distant and spatially distinct cellular neighborhoods can communicate via signaling metabolites from stroma, immune and tumor cells. In this review, we will discuss how biochemical interactions of various metabolic pathways influence cancer and immune microenvironments, as well as associated mechanisms that lead to good or poor clinical outcomes. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review
Role of Nitric Oxide in Gene Expression Regulation during Cancer: Epigenetic Modifications and Non-Coding RNAs
Int. J. Mol. Sci. 2021, 22(12), 6264; https://doi.org/10.3390/ijms22126264 - 10 Jun 2021
Cited by 3 | Viewed by 1252
Abstract
Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate [...] Read more.
Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs). Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review
Lost-in-Translation of Metabolic Effects of Inorganic Nitrate in Type 2 Diabetes: Is Ascorbic Acid the Answer?
Int. J. Mol. Sci. 2021, 22(9), 4735; https://doi.org/10.3390/ijms22094735 - 29 Apr 2021
Cited by 3 | Viewed by 1058
Abstract
Beneficial metabolic effects of inorganic nitrate (NO3) and nitrite (NO2) in type 2 diabetes mellitus (T2DM) have been documented in animal experiments; however, this is not the case for humans. Although it has remained an open question, [...] Read more.
Beneficial metabolic effects of inorganic nitrate (NO3) and nitrite (NO2) in type 2 diabetes mellitus (T2DM) have been documented in animal experiments; however, this is not the case for humans. Although it has remained an open question, the redox environment affecting the conversion of NO3 to NO2 and then to NO is suggested as a potential reason for this lost-in-translation. Ascorbic acid (AA) has a critical role in the gastric conversion of NO2 to NO following ingestion of NO3. In contrast to AA-synthesizing species like rats, the lack of ability to synthesize AA and a lower AA body pool and plasma concentrations may partly explain why humans with T2DM do not benefit from NO3/NO2 supplementation. Rats also have higher AA concentrations in their stomach tissue and gastric juice that can significantly potentiate gastric NO2-to-NO conversion. Here, we hypothesized that the lack of beneficial metabolic effects of inorganic NO3 in patients with T2DM may be at least in part attributed to species differences in AA metabolism and also abnormal metabolism of AA in patients with T2DM. If this hypothesis is proved to be correct, then patients with T2DM may need supplementation of AA to attain the beneficial metabolic effects of inorganic NO3 therapy. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review
Human Nitric Oxide Synthase—Its Functions, Polymorphisms, and Inhibitors in the Context of Inflammation, Diabetes and Cardiovascular Diseases
Int. J. Mol. Sci. 2021, 22(1), 56; https://doi.org/10.3390/ijms22010056 - 23 Dec 2020
Cited by 26 | Viewed by 2165
Abstract
In various diseases, there is an increased production of the free radicals needed to carry out certain physiological processes but their excessive amounts can cause oxidative stress and cell damage. Enzymes play a major role in the transformations associated with free radicals. One [...] Read more.
In various diseases, there is an increased production of the free radicals needed to carry out certain physiological processes but their excessive amounts can cause oxidative stress and cell damage. Enzymes play a major role in the transformations associated with free radicals. One of them is nitric oxide synthase (NOS), which catalyzes the formation of nitric oxide (NO). This enzyme exists in three forms (NOS1, NOS2, NOS3), each encoded by a different gene. The following work presents the most important information on the NOS isoforms and their role in the human body, including NO synthesis in various tissues and cells, intercellular signaling and activities supporting the immune system and regulating blood vessel functions. The role of NOS in pathological conditions such as obesity, diabetes and heart disease is considered. Attention is also paid to the influence of the polymorphisms of these genes, encoding particular isoforms, on the development of these pathologies and the role of NOS inhibitors in the treatment of patients. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review
Genetic Factors of Nitric Oxide’s System in Psychoneurologic Disorders
Int. J. Mol. Sci. 2020, 21(5), 1604; https://doi.org/10.3390/ijms21051604 - 26 Feb 2020
Cited by 9 | Viewed by 1369
Abstract
According to the recent data, nitric oxide (NO) is a chemical messenger that mediates functions such as vasodilation and neurotransmission, as well as displaying antimicrobial and antitumoral activities. NO has been implicated in the neurotoxicity associated with stroke and neurodegenerative diseases; neural regulation [...] Read more.
According to the recent data, nitric oxide (NO) is a chemical messenger that mediates functions such as vasodilation and neurotransmission, as well as displaying antimicrobial and antitumoral activities. NO has been implicated in the neurotoxicity associated with stroke and neurodegenerative diseases; neural regulation of smooth muscle, including peristalsis; and penile erections. We searched for full-text English publications from the past 15 years in Pubmed and SNPedia databases using keywords and combined word searches (nitric oxide, single nucleotide variants, single nucleotide polymorphisms, genes). In addition, earlier publications of historical interest were included in the review. In our review, we have summarized information regarding all NOS1, NOS2, NOS3, and NOS1AP single nucleotide variants (SNVs) involved in the development of mental disorders and neurological diseases/conditions. The results of the studies we have discussed in this review are contradictory, which might be due to different designs of the studies, small sample sizes in some of them, and different social and geographical characteristics. However, the contribution of genetic and environmental factors has been understudied, which makes this issue increasingly important for researchers as the understanding of these mechanisms can support a search for new approaches to pathogenetic and disease-modifying treatment. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Review
Modulation of AMPA Receptors by Nitric Oxide in Nerve Cells
Int. J. Mol. Sci. 2020, 21(3), 981; https://doi.org/10.3390/ijms21030981 - 01 Feb 2020
Cited by 11 | Viewed by 3072
Abstract
Nitric oxide (NO) is a gaseous molecule with a large number of functions in living tissue. In the brain, NO participates in numerous intracellular mechanisms, including synaptic plasticity and cell homeostasis. NO elicits synaptic changes both through various multi-chain cascades and through direct [...] Read more.
Nitric oxide (NO) is a gaseous molecule with a large number of functions in living tissue. In the brain, NO participates in numerous intracellular mechanisms, including synaptic plasticity and cell homeostasis. NO elicits synaptic changes both through various multi-chain cascades and through direct nitrosylation of targeted proteins. Along with the N-methyl-d-aspartate (NMDA) glutamate receptors, one of the key components in synaptic functioning are α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors—the main target for long-term modifications of synaptic effectivity. AMPA receptors have been shown to participate in most of the functions important for neuronal activity, including memory formation. Interactions of NO and AMPA receptors were observed in important phenomena, such as glutamatergic excitotoxicity in retinal cells, synaptic plasticity, and neuropathologies. This review focuses on existing findings that concern pathways by which NO interacts with AMPA receptors, influences properties of different subunits of AMPA receptors, and regulates the receptors’ surface expression. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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Other

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Opinion
A New Perspective on Cancer Therapy: Changing the Treaded Path?
Int. J. Mol. Sci. 2021, 22(18), 9836; https://doi.org/10.3390/ijms22189836 - 11 Sep 2021
Cited by 3 | Viewed by 1255
Abstract
During the last decade, we have persistently addressed the question, “how can the innate immune system be used as a therapeutic tool to eliminate cancer?” A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state [...] Read more.
During the last decade, we have persistently addressed the question, “how can the innate immune system be used as a therapeutic tool to eliminate cancer?” A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways. Full article
(This article belongs to the Special Issue Nitric Oxide: Physiology, Pharmacology, and Therapeutic Applications)
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