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Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 6092

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Special Issue Editor

Prof. Dr. Jun Kobayashi

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Guest Editor

Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Science, Josai University, 1-1 Keyakidai, Sakado 350-0295, Japan
Interests: nitric oxide; nitrate/nitrite; crush syndrome; ischemia/reperfusion injury; reactive oxygen species
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nitric oxide (NO) was identified as an endothelium-derived relaxing factor in 1987. Recent pharmacological and clinical evidence has advanced our knowledge on NO biosynthesis and NO signaling in health and disease. NO plays important roles in a wide range of physiological and pathological processes in cardiovascular, neurotransmission, gastrointestinal, and host defense systems by regulating transcription activity and posttranscriptional modification of their downstream effector proteins. Research is now focused on the pharmacological and clinical significance of canonical (NO synthase-mediated oxidation of _L-arginine) and noncanonical (sequential reduction of nitrate/nitrite to NO) NO generation pathways, and on enhancing NO bioavailability in health and disease. NO, a free radical, is a double-edged sword; its role depends on the sites and amounts of generation. Therefore, this theme welcomes studies dealing with controversial findings. I look forward to fruitful discussions in this Special Issue and call for both original articles and reviews, which would provide the readers of IJMS with new findings and comprehensive elucidation about the NO biosynthesis pathway and NO signaling in health and disease, necessary for developing novel research approaches, particularly leading to therapeutic strategies.

Dr. Jun Kobayashi
Guest Editor

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Keywords

nitric oxide
nitrite
nitrate
nitric oxide synthase
redox
oxidative stress
signaling
vascular endothelial cell
enterosalivary
ischemia/reperfusion

Published Papers (5 papers)

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Research

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21 pages, 2275 KiB

Open AccessArticle

Spin Trapping of Nitric Oxide by Hemoglobin and Ferrous Diethyldithiocarbamate in Model Tumors Differing in Vascularization

by Dariusz Szczygieł, Małgorzata Szczygieł, Anna Łaś, Martyna Elas, Roxana Zuziak, Beata K. Płonka and Przemysław M. Płonka

Int. J. Mol. Sci. 2024, 25(8), 4172; https://doi.org/10.3390/ijms25084172 - 10 Apr 2024

Viewed by 648

Abstract

Animal tumors serve as reasonable models for human cancers. Both human and animal tumors often reveal triplet EPR signals of nitrosylhemoglobin (HbNO) as an effect of nitric oxide formation in tumor tissue, where NO is complexed by Hb. In search of factors determining the appearance of nitrosylhemoglobin (HbNO) in solid tumors, we compared the intensities of electron paramagnetic resonance (EPR) signals of various iron–nitrosyl complexes detectable in tumor tissues, in the presence and absence of excess exogenous iron(II) and diethyldithiocarbamate (DETC). Three types of murine tumors, namely, L5178Y lymphoma, amelanotic Cloudman S91 melanoma, and Ehrlich carcinoma (EC) growing in DBA/2 or Swiss mice, were used. The results were analyzed in the context of vascularization determined histochemically using antibodies to CD31. Strong HbNO EPR signals were found in melanoma, i.e., in the tumor with a vast amount of a hemorrhagic necrosis core. Strong Fe(DETC)₂NO signals could be induced in poorly vascularized EC. In L5178Y, there was a correlation between both types of signals, and in addition, Fe(RS)₂(NO)₂ signals of non-heme iron–nitrosyl complexes could be detected. We postulate that HbNO EPR signals appear during active destruction of well-vascularized tumor tissue due to hemorrhagic necrosis. The presence of iron–nitrosyl complexes in tumor tissue is biologically meaningful and defines the evolution of complicated tumor–host interactions. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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15 pages, 1148 KiB

Open AccessArticle

Nitrite Attenuates the In Vitro Inflammatory Response of Immune Cells to the SARS-CoV-2 S Protein without Interfering in the Antioxidant Enzyme Activation

by Miguel D. Ferrer, Clara Reynés, Laura Jiménez, Gianluca Malagraba, Margalida Monserrat-Mesquida, Cristina Bouzas, Antoni Sureda, Josep A. Tur and Antoni Pons

Int. J. Mol. Sci. 2024, 25(5), 3001; https://doi.org/10.3390/ijms25053001 - 5 Mar 2024

Viewed by 639

Abstract

SARS-CoV-2 induces a hyperinflammatory reaction due to the excessive release of cytokines during the immune response. The bacterial endotoxin lipopolysaccharide (LPS) contributes to the low-grade inflammation associated with the metabolic syndrome, enhancing the hyperinflammatory reaction induced by the SARS-CoV-2 infection. The intake of sodium nitrate, a precursor of nitrite and nitric oxide, influences the antioxidant and pro-inflammatory gene expression profile after immune stimulation with LPS in peripheral blood mononuclear cells from metabolic syndrome patients. We aimed to assess the inflammatory and antioxidant responses of immune cells from metabolic syndrome patients to exposure to the SARS-CoV-2 spike protein (S protein) together with LPS and the effect of nitrite in these responses. Whole blood samples obtained from six metabolic syndrome patients were cultured for 16 h at 37 °C with four different media: control medium, control medium plus LPS (100 ng/mL), control medium plus LPS (100 ng/mL) plus S protein (10 ng/mL), and control medium plus LPS (100 ng/mL) plus S protein (10 ng/mL) plus nitrite (5 µM). Immune stimulation with the LPS/S protein enhanced nitrate biosynthesis from nitrite oxidation and probably from additional organic precursors. In vitro incubations with the LPS/S protein enhanced the expression and/or release of pro-inflammatory TNFα, IL-6, IL-1β, and TLR4, as well as the expression of the anti-inflammatory IL-1ra and IL-10 and antioxidant enzymes. Nitrite attenuated the pro- and anti-inflammatory response induced by the S protein without interfering with the activation of TLR4 and antioxidant enzyme expression, raising the possibility that nitrite could have potential as a coadjutant in the treatment of COVID-19. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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17 pages, 2407 KiB

Open AccessArticle

NO Deficiency Compromises Inter- and Intrahemispheric Blood Flow Adaptation to Unilateral Carotid Artery Occlusion

by László Hricisák, Éva Pál, Dorina Nagy, Max Delank, Andreas Polycarpou, Ágnes Fülöp, Péter Sándor, Péter Sótonyi, Zoltán Ungvári and Zoltán Benyó

Int. J. Mol. Sci. 2024, 25(2), 697; https://doi.org/10.3390/ijms25020697 - 5 Jan 2024

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Abstract

Carotid artery stenosis (CAS) affects approximately 5–7.5% of older adults and is recognized as a significant risk factor for vascular cognitive impairment (VCI). The impact of CAS on cerebral blood flow (CBF) within the ipsilateral hemisphere relies on the adaptive capabilities of the cerebral microcirculation. In this study, we aimed to test the hypothesis that the impaired availability of nitric oxide (NO) compromises CBF homeostasis after unilateral carotid artery occlusion (CAO). To investigate this, three mouse models exhibiting compromised production of NO were tested: NOS1 knockout, NOS1/3 double knockout, and mice treated with the NO synthesis inhibitor L-NAME. Regional CBF changes following CAO were evaluated using laser-speckle contrast imaging (LSCI). Our findings demonstrated that NOS1 knockout, NOS1/3 double knockout, and L-NAME-treated mice exhibited impaired CBF adaptation to CAO. Furthermore, genetic deficiency of one or two NO synthase isoforms increased the tortuosity of pial collaterals connecting the frontoparietal and temporal regions. In conclusion, our study highlights the significant contribution of NO production to the functional adaptation of cerebrocortical microcirculation to unilateral CAO. We propose that impaired bioavailability of NO contributes to the impaired CBF homeostasis by altering inter- and intrahemispheric blood flow redistribution after unilateral disruption of carotid artery flow. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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Review

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27 pages, 3044 KiB

Open AccessReview

Roles of Oxidative Injury and Nitric Oxide System Derangements in Kawasaki Disease Pathogenesis: A Systematic Review

by Mitsuru Tsuge, Kazuhiro Uda, Takahiro Eitoku, Naomi Matsumoto, Takashi Yorifuji and Hirokazu Tsukahara

Int. J. Mol. Sci. 2023, 24(20), 15450; https://doi.org/10.3390/ijms242015450 - 22 Oct 2023

Cited by 2 | Viewed by 1976

Abstract

Kawasaki disease (KD) is an acute febrile vasculitis that occurs mostly in children younger than five years. KD involves multiple intricately connected inflammatory reactions activated by a cytokine cascade. Despite therapeutic advances, coronary artery damage may develop in some patients, who will be at risk of clinical cardiovascular events and even sudden death. The etiology of KD remains unclear; however, it may involve both genetic and environmental factors leading to aberrant inflammatory responses. Given the young age of onset, prenatal or perinatal exposure may be etiologically relevant. Multisystem inflammatory syndrome in children, a post-infectious hyper-inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2, has features that overlap with those of KD. Available evidence indicates that vascular endothelial dysfunction is a critical step in the sequence of events leading to the development of cardiovascular lesions in KD. Oxidative stress and the dysregulation of the nitric oxide (NO) system contribute to the pathogenesis of inflammatory responses related to this disease. This review provides current evidence and concepts highlighting the adverse effects of oxidative injury and NO system derangements on the initiation and progression of KD and potential therapeutic strategies for cardiovascular pathologies in affected children. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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15 pages, 2138 KiB

Open AccessReview

Pro-Tumor Activity of Endogenous Nitric Oxide in Anti-Tumor Photodynamic Therapy: Recently Recognized Bystander Effects

by Albert W. Girotti, Jerzy Bazak and Witold Korytowski

Int. J. Mol. Sci. 2023, 24(14), 11559; https://doi.org/10.3390/ijms241411559 - 17 Jul 2023

Cited by 1 | Viewed by 932

Abstract

Various studies have revealed that several cancer cell types can upregulate inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) after moderate photodynamic treatment (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin-IX. As will be discussed, the NO signaled cell resistance to photokilling as well as greater growth and migratory aggressiveness of surviving cells. On this basis, it was predicted that diffusible NO from PDT-targeted cells in a tumor might enhance the growth, migration, and invasiveness of non- or poorly PDT-targeted bystander cells. This was tested using a novel approach in which ALA-PDT-targeted cancer cells on a culture dish were initially segregated from non-targeted bystander cells of the same type via impermeable silicone-rimmed rings. Several hours after LED irradiation, the rings were removed, and both cell populations were analyzed in the dark for various responses. After a moderate extent of targeted cell killing (~25%), bystander proliferation and migration were evaluated, and both were found to be significantly enhanced. Enhancement correlated with iNOS/NO upregulation in surviving PDT-targeted cancer cells in the following cell type order: PC3 > MDA-MB-231 > U87 > BLM. If occurring in an actual PDT-challenged tumor, such bystander effects might compromise treatment efficacy by stimulating tumor growth and/or metastatic dissemination. Mitigation of these and other negative NO effects using pharmacologic adjuvants that either inhibit iNOS transcription or enzymatic activity will be discussed. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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