Nitric oxide, a gaseous free radical, is one of the ten smallest molecules found in nature. 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. This Entry Collection aims to help advance our understanding of the role that NO plays in physiology and pharmacology, which may lead to applications against various diseases.

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Topic Review
Role of Tumor Microenvironment and EGFR Mutations
Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape.  EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. 
  • 20
  • 01 Jul 2022
Topic Review
Dietary Nitrate and the Maintenance of Oral Health
Nitrate (NO3) is the oxidative product of nitric oxide (NO) and nitrite (NO2). As soil content, NO3 is an essential substrate for all plant growth and provides, among other things, the nitrogen required for the synthesis of nitrogenous amino acids. It is taken up by the plant roots and originates either from the microbial decomposition of organic waste or from the activity of certain soil bacteria utilizing atmospheric nitrogen for the synthesis of ammonia, nitrite and nitrate. Since available nitrate is the limiting factor for plant growth, it is deliberately added to the soil in agricultural crop production in the form of nitrate-containing fertilizers. Although the role of the oral microbiota as a key element in the alternative formation of NO2 and NO from nitrate-rich foods has been known for many years, it is surprisingly only in recent years that the therapeutic and preventive prospects of a nitrate-rich diet have attracted the interest of dental researchers.
  • 37
  • 10 Jun 2022
Topic Review
Nitric Oxide Synthase
Nitric oxide synthase (NOS) plays important roles within the cardiovascular system in physiological states as well as in pathophysiologic and specific cardiovascular (CV) disease states, such as hypertension (HTN), arteriosclerosis, and cerebrovascular accidents.
  • 259
  • 07 May 2022
Topic Review
NO in Viral Infections
Nitric oxide is a ubiquitous signaling radical that influences critical body functions. Its importance in the cardiovascular system and the innate immune response to bacterial and viral infections has been extensively investigated. The overproduction of NO is an early component of viral infections, including those affecting the respiratory tract. The production of high levels of NO is due to the overexpression of NO biosynthesis by inducible NO synthase (iNOS), which is involved in viral clearance. The development of NO-based antiviral therapies, particularly gaseous NO inhalation and NO-donors, has proven to be an excellent antiviral therapeutic strategy. 
  • 86
  • 20 Apr 2022
Topic Review
Redox-Regulation of α-Globin in Vascular Physiology
Interest in the structure, function, and evolutionary relations of circulating and intracellular globins dates back more than 60 years to the first determination of the three-dimensional structure of these proteins. Non-erythrocytic globins have been implicated in circulatory control through reactions that couple nitric oxide (NO) signaling with cellular oxygen availability and redox status. Small artery endothelial cells (ECs) express free α-globin, which causes vasoconstriction by degrading NO. This reaction converts reduced (Fe2+) α-globin to the oxidized (Fe3+) form, which is unstable, cytotoxic, and unable to degrade NO. Therefore, (Fe3+) α-globin must be stabilized and recycled to (Fe2+) α-globin to reinitiate the catalytic cycle. The molecular chaperone α-hemoglobin-stabilizing protein (AHSP) binds (Fe3+) α-globin to inhibit its degradation and facilitate its reduction. The mechanisms that reduce (Fe3+) α-globin in ECs are unknown, although endothelial nitric oxide synthase (eNOS) and cytochrome b5 reductase (CyB5R3) with cytochrome b5 type A (CyB5a) can reduce (Fe3+) α-globin in solution.
  • 75
  • 28 Jan 2022
Topic Review
Therapeutic Approaches Utilizing Macrophage-Derived iNOS/NO in Cancer
Nitric oxide and its production by iNOS is an established mechanism critical to tumor promotion or suppression. Macrophages have important roles in immunity, development, and progression of cancer and have a controversial role in pro-and anti-tumoral effects. The tumor microenvironment consists of tumor-associated macrophages (TAM), among other cell types that influence the fate of the growing tumor. Depending on the microenvironment and various cues, macrophages polarize into a continuum represented by the M1-like pro-inflammatory phenotype or the anti-inflammatory M2-like phenotype; these two are predominant, while there are subsets and intermediates. Manipulating their plasticity through programming or reprogramming of M2-like to M1-like phenotypes presents the opportunity to maximize tumoricidal defenses. The dual role of iNOS derived NO also influences TAM activity by repolarization to tumoricidal M1-type phenotype. Regulatory pathways and immunomodulation achieve this through miRNA that may inhibit the immunosuppressive tumor microenvironment.
  • 71
  • 07 Dec 2021
Topic Review
Endothelial Nitric Oxide Synthase
Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupling” of the enzyme by adverse regulation of well-defined “redox switches” in eNOS itself or up-/down-stream signaling molecules. 
  • 76
  • 01 Dec 2021
Topic Review
NLRP3 and Preeclampsia
Preeclampsia (PE) is a specific syndrome of human pregnancy, being one of the main causes of maternal death. Persistent inflammation in the endothelium stimulates the secretion of several inflammatory mediators, activating different signaling patterns. One of these mechanisms is related to NLRP3 activation, initiated by high levels of danger signals such as cholesterol, urate, and glucose, producing IL-1, IL-18, and cell death by pyroptosis. Furthermore, reactive oxygen species (ROS), act as an intermediate to activate NLRP3, contributing to subsequent inflammatory cascades and cell damage. Moreover, increased production of ROS may elevate nitric oxide (NO) catabolism and consequently decrease NO bioavailability. NO has many roles in immune responses, including the regulation of signaling cascades. At the site of inflammation, vascular endothelium is crucial in the regulation of systemic inflammation with important implications for homeostasis.
  • 70
  • 19 Nov 2021
Topic Review
Sambucus ebulus L. Fruit Extract
Sambucus ebulus L. (SE), also known as dwarf elder or dwarf elderberry, is a widely used as wound-healing, anti-nociceptive, anti-rheumatoid, anti-influenza, antibacterial and diuretic medicinal plant in Bulgaria, Turkey, Iran, Lebanon, Romania and Bosnia–Herzegovina.
  • 56
  • 18 Nov 2021
Topic Review
Applications of Heterocyclic NO-Donors
In a series of known structural classes capable of NO release, heterocyclic NO-donors are of special importance due to their increased hydrolytic stability and low toxicity. It is no wonder that synthetic and biochemical investigations of heterocyclic NO-donors have emerged significantly in recent years. In this review, we summarized recent advances in the synthesis, reactivity and biomedical applications of promising heterocyclic NO-donors (furoxans, sydnone imines, pyridazine dioxides, azasydnones).
  • 85
  • 28 Oct 2021