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Nitric Oxide Synthases: Function and Regulation: 2nd Edition
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Nitric Oxide Synthases: Function and Regulation: 2nd Edition

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

Deadline for manuscript submissions: 20 March 2025 | Viewed by 6045

Special Issue Editor

Prof. Dr. Tzong-Shyuan Lee

E-Mail Website
Guest Editor
Graduate Institute, Department of Physiology, College of Medicine, National Taiwan University, Taipei 10617, Taiwan
Interests: cell culture; cholesterol metabolism; atherosclerosis; reactive oxygen species; signaling; endothelial cell biology; endothelial dysfunction; angiogenesis; vascular biology; vascular diseases; macrophage-foam cells; cardiovascular physiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue “Nitric Oxide Synthases: Function and Regulation”.

Nitric oxide (NO) is a bioactive gas in the body that plays a crucial role in maintaining the homeostasis of the cardiovascular system. It can be synthesized by endothelial nitric oxide synthase (eNOS), neuronal NO synthase (nNOS), and inducible NO synthase (iNOS), which convert arginine into citrulline and produce NO in several types of cell. In addition to its key role in regulating the cardiovascular function, NO has been reported to be involved in the pathological processes of a variety of human diseases, including cardiovascular diseases, metabolic diseases, inflammatory diseases, cancer, and neurological diseases. Given the importance of NOSs in the pathophysiology of human diseases, these enzymes are considered potential therapeutic targets for the treatment of diverse human pathologies. This Special Issue of IJMS aims to provide a research platform to host a collection of the latest review and original research articles covering all aspects of these enzymes.

Prof. Dr. Tzong-Shyuan Lee
Guest Editor

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Keywords

  • nitric oxide synthases
  • isoforms
  • nitric oxide
  • endothelial cell
  • stem cell
  • cellular signaling
  • redox pathway
  • endothelial NOS
  • neuronal NOS
  • disease
  • cancer

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Related Special Issue

Published Papers (5 papers)

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Research

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17 pages, 5807 KiB  
Article
Cinnamaldehyde Protects against P. gingivalis Induced Intestinal Epithelial Barrier Dysfunction in IEC-6 Cells via the PI3K/Akt-Mediated NO/Nrf2 Signaling Pathway
by Chethan Sampath, Sasanka S. Chukkapalli, Abhinav V. Raju, Leela Subhashini C. Alluri, Dollada Srisai and Pandu R. Gangula
Int. J. Mol. Sci. 2024, 25(9), 4734; https://doi.org/10.3390/ijms25094734 - 26 Apr 2024
Viewed by 1216
Abstract
Porphyromonas gingivalis (Pg), a Gram-negative oral pathogen, promotes and accelerates periodontitis-associated gut disorders. Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. In this study, we sought to elucidate the protective role of cinnamaldehyde (CNM, an [...] Read more.
Porphyromonas gingivalis (Pg), a Gram-negative oral pathogen, promotes and accelerates periodontitis-associated gut disorders. Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. In this study, we sought to elucidate the protective role of cinnamaldehyde (CNM, an activator of Nrf2) against P. gingivalis (W83) and Pg-derived lipopolysaccharide (Pg-LPS) induced intestinal epithelial barrier dysfunction via antioxidative mechanisms in IEC-6 cells. IEC-6 (ATCC, CRL-1592) cells were pretreated with or without CNM (100 µM), in the presence or absence of P. gingivalis (strain W83, 109 MOI) or Pg-LPS (1, 10, and 100 µg/mL), respectively, between 0–72 h time points by adopting a co-culture method. Intestinal barrier function, cytokine secretion, and intestinal oxidative stress protein markers were analyzed. P. gingivalis or Pg-LPS significantly (p < 0.05) increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels expressing oxidative stress damage. Pg-LPS, as well as Pg alone, induces inflammatory cytokines via TLR-4 signaling. Furthermore, infection reduced Nrf2 and NAD(P)H quinone dehydrogenase 1 (NQO1). Interestingly, inducible nitric oxide synthase (iNOS) protein expression significantly (p < 0.05) increased with Pg-LPS or Pg infection, with elevated levels of nitric oxide (NO). CNM treatment suppressed both Pg- and Pg-LPS-induced intestinal oxidative stress damage by reducing ROS, MDA, and NO production. Furthermore, CNM treatment significantly upregulated the expression of tight junction proteins via increasing the phosphorylation levels of PI3K/Akt/Nrf2 suppressing inflammatory cytokines. CNM protected against Pg infection-induced intestinal epithelial barrier dysfunction by activating the PI3K/Akt-mediated Nrf2 signaling pathway in IEC-6 cells. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation: 2nd Edition)
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Review

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15 pages, 11086 KiB  
Review
Role of Nitric Oxide Synthases in Respiratory Health and Disease: Insights from Triple Nitric Oxide Synthases Knockout Mice
by Takaaki Ogoshi, Kazuhiro Yatera, Hiroshi Mukae and Masato Tsutsui
Int. J. Mol. Sci. 2024, 25(17), 9317; https://doi.org/10.3390/ijms25179317 - 28 Aug 2024
Viewed by 705
Abstract
The system of nitric oxide synthases (NOSs) is comprised of three isoforms: nNOS, iNOS, and eNOS. The roles of NOSs in respiratory diseases in vivo have been studied by using inhibitors of NOSs and NOS-knockout mice. Their exact roles remain uncertain, however, because [...] Read more.
The system of nitric oxide synthases (NOSs) is comprised of three isoforms: nNOS, iNOS, and eNOS. The roles of NOSs in respiratory diseases in vivo have been studied by using inhibitors of NOSs and NOS-knockout mice. Their exact roles remain uncertain, however, because of the non-specificity of inhibitors of NOSs and compensatory up-regulation of other NOSs in NOS-KO mice. We addressed this point in our triple-n/i/eNOSs-KO mice. Triple-n/i/eNOSs-KO mice spontaneously developed pulmonary emphysema and displayed exacerbation of bleomycin-induced pulmonary fibrosis as compared with wild-type (WT) mice. Triple-n/i/eNOSs-KO mice exhibited worsening of hypoxic pulmonary hypertension (PH), which was reversed by treatment with sodium nitrate, and WT mice that underwent triple-n/i/eNOSs-KO bone marrow transplantation (BMT) also showed aggravation of hypoxic PH compared with those that underwent WT BMT. Conversely, ovalbumin-evoked asthma was milder in triple-n/i/eNOSs-KO than WT mice. These results suggest that the roles of NOSs are different in different pathologic states, even in the same respiratory diseases, indicating the diversity of the roles of NOSs. In this review, we describe these previous studies and discuss the roles of NOSs in respiratory health and disease. We also explain the current state of development of inorganic nitrate as a new drug for respiratory diseases. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation: 2nd Edition)
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16 pages, 7553 KiB  
Review
Advancements in the Research of New Modulators of Nitric Oxide Synthases Activity
by Cristina Maccallini, Roberta Budriesi, Barbara De Filippis and Rosa Amoroso
Int. J. Mol. Sci. 2024, 25(15), 8486; https://doi.org/10.3390/ijms25158486 - 3 Aug 2024
Cited by 1 | Viewed by 825
Abstract
Nitric oxide (NO) has been defined as the “miracle molecule” due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for [...] Read more.
Nitric oxide (NO) has been defined as the “miracle molecule” due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation: 2nd Edition)
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14 pages, 2091 KiB  
Review
Upregulation of iNOS/NO in Cancer Cells That Survive a Photodynamic Challenge: Role of No in Accelerated Cell Migration and Invasion
by Albert W. Girotti and Witold Korytowski
Int. J. Mol. Sci. 2024, 25(11), 5697; https://doi.org/10.3390/ijms25115697 - 23 May 2024
Viewed by 781
Abstract
Anti-tumor photodynamic therapy (PDT) is a unique modality that employs a photosensitizer (PS), PS-exciting light, and O2 to generate cytotoxic oxidants. For various reasons, not all malignant cells in any given tumor will succumb to a PDT challenge. Previous studies by the [...] Read more.
Anti-tumor photodynamic therapy (PDT) is a unique modality that employs a photosensitizer (PS), PS-exciting light, and O2 to generate cytotoxic oxidants. For various reasons, not all malignant cells in any given tumor will succumb to a PDT challenge. Previous studies by the authors revealed that nitric oxide (NO) from inducible NO synthase (iNOS/NOS2) plays a key role in tumor cell resistance and also stimulation of migratory/invasive aggressiveness of surviving cells. iNOS was the only NOS isoform implicated in these effects. Significantly, NO from stress-upregulated iNOS was much more important in this regard than NO from preexisting enzymes. Greater NO-dependent resistance, migration, and invasion was observed with at least three different cancer cell lines, and this was attenuated by iNOS activity inhibitors, NO scavengers, or an iNOS transcriptional inhibitor. NO diffusing from PDT-targeted cells also stimulated migration/invasion potency of non-targeted bystander cells. Unless counteracted by appropriate measures, all these effects could seriously compromise clinical PDT efficacy. Here, we will review specific examples of these negative side effects of PDT and how they might be suppressed by adjuvants such as NO scavengers or inhibitors of iNOS activity or expression. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation: 2nd Edition)
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15 pages, 1553 KiB  
Review
The Physiological Function of nNOS-Associated CAPON Proteins and the Roles of CAPON in Diseases
by Wenshuo Xie, Nianhong Xing, Jicheng Qu, Dongwu Liu and Qiuxiang Pang
Int. J. Mol. Sci. 2023, 24(21), 15808; https://doi.org/10.3390/ijms242115808 - 31 Oct 2023
Cited by 1 | Viewed by 1662
Abstract
In this review, the structure, isoform, and physiological role of the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) are summarized. There are three isoforms of CAPON in humans, including long CAPON protein (CAPON-L), short CAPON protein (CAPON-S), and CAPON-S’ protein. CAPON-L [...] Read more.
In this review, the structure, isoform, and physiological role of the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) are summarized. There are three isoforms of CAPON in humans, including long CAPON protein (CAPON-L), short CAPON protein (CAPON-S), and CAPON-S’ protein. CAPON-L includes three functional regions: a C-terminal PDZ-binding motif, carboxypeptidase (CPE)-binding region, and N-terminal phosphotyrosine (PTB) structural domain. Both CAPON-S and CAPON-S’ only contain the C-terminal PDZ-binding motif. The C-terminal PDZ-binding motif of CAPON can bind with neuronal nitric oxide synthase (nNOS) and participates in regulating NO production and neuronal development. An overview is given on the relationship between CAPON and heart diseases, diabetes, psychiatric disorders, and tumors. This review will clarify future research directions on the signal pathways related to CAPON, which will be helpful for studying the regulatory mechanism of CAPON. CAPON may be used as a drug target, which will provide new ideas and solutions for treating human diseases. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation: 2nd Edition)
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