Nitric Oxide restricts iron availability and induces quorum sensing in Streptococcus pyogenes.

Nitric oxide (NO) is a free radical signaling molecule with multiple biological functions. As part of the innate immune system, NO has antimicrobial properties playing an important role in host defense. Mechanisms of NO cytotoxicity result from its ability to bind metals and inhibit enzyme function or by increasing nitrosative and oxidative stress within cells.

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.

DNA methylation at cytosine bases (5-methylcytosine, 5mC) is a heritable epigenetic mark regulating gene expression. While enzymes that metabolize 5mC are well-characterized, endogenous signaling molecules that regulate DNA methylation machinery have not been described. We report that physiological nitric oxide (NO) concentrations reversibly inhibit the DNA demethylases TET and ALKBH2 by binding to the mononuclear non-heme iron atom forming a dinitrosyliron complex (DNIC) and preventing cosubstrates from binding.

Nitric oxide inhibits FTO demethylase activity to regulate N-methyladenosine mRNA methylation.

N-methyladenosine (mA) is the most abundant internal modification on eukaryotic mRNAs. Demethylation of mA on mRNA is catalyzed by the enzyme fat mass and obesity-associated protein (FTO), a member of the nonheme Fe(II) and 2-oxoglutarate (2-OG)-dependent family of dioxygenases. FTO activity and mA-mRNA are dysregulated in multiple diseases including cancers, yet endogenous signaling molecules that modulate FTO activity have not been identified.

Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment.

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.

Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation.

Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation.

Nitric oxide and hydrogen sulfide: Sibling rivalry in the family of epigenetic regulators.

Nitric oxide (NO) and hydrogen sulfide (HS) were previously only known for their toxic properties. Now they are regarded as potent gaseous messenger molecules (gasotransmitters) that rapidly transverse cell membranes and transduce cellular signals through their chemical reactions and modifications to protein targets. Both are known to regulate numerous physiological functions including angiogenesis, vascular tone, and immune response, to name a few.

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1.

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI).

The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.

Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize Pseudomonas aeruginosa (PA), which can contribute to the compromised innate immunity in VAP.

Nitric oxide reduces oxidative stress in cancer cells by forming dinitrosyliron complexes.

The chelatable iron pool (CIP) is a small but chemically significant fraction of total cellular iron. While this dynamic population of iron is limited, it is redox active and capable of generating reactive oxygen species (ROS) that can lead to oxidative stress which is associated with various pathologies. Nitric oxide (•NO), is a free radical signalling molecule that regulates numerous physiological and pathological conditions.

Differential mitochondrial dinitrosyliron complex formation by nitrite and nitric oxide.

Nitrite represents an endocrine reserve of bioavailable nitric oxide (NO) that mediates a number of physiological responses including conferral of cytoprotection after ischemia/reperfusion (I/R). It has long been known that nitrite can react with non-heme iron to form dinitrosyliron complexes (DNIC). However, it remains unclear how quickly nitrite-dependent DNIC form in vivo, whether formation kinetics differ from that of NO-dependent DNIC, and whether DNIC play a role in the cytoprotective effects of nitrite.

NOS2 as an Emergent Player in Progression of Cancer.

Although the inducible form of nitric oxide synthase (NOS2) was initially shown to be a major player as an antitumor component of the immune response, more recent data have shown that NOS2 expression in cancer cells often predicts poor outcome. Unlike growth factors associated with a single oncogenic pathway, nitric oxide (NO) has a ubiquitous nature wherein it simultaneously mediates major oncogenic pathways from Akt/PI3K and RAS/ERK to HIF1a and TGFb. These interactive loops perpetuate oncogenic mechanism that leads to increased cancer stemness, proliferation metastasis, chemoresistance, angiogenesis, and immunosuppression.

Epigenetics: The third pillar of nitric oxide signaling.

Nitric oxide (NO), the endogenously produced free radical signaling molecule, is generally thought to function via its interactions with heme-containing proteins, such as soluble guanylyl cyclase (sGC), or by the formation of protein adducts containing nitrogen oxide functional groups (such as S-nitrosothiols, 3-nitrotyrosine, and dinitrosyliron complexes). These two types of interactions result in a multitude of down-stream effects that regulate numerous functions in physiology and disease. Of the numerous purported NO signaling mechanisms, epigenetic regulation has gained considerable interest in recent years.

Nitric oxide, the new architect of epigenetic landscapes.

Nitric oxide (NO) is an endogenously produced signaling molecule with multiple regulatory functions in physiology and disease. The most studied molecular mechanisms underlying the biological functions of NO include its reaction with heme proteins and regulation of protein activity via modification of thiol residues. A significant number of transcriptional responses and phenotypes observed in NO microenvironments, however, still lack mechanistic understanding.

Ascorbic Acid Attenuates Hyperoxia-Compromised Host Defense against Pulmonary Bacterial Infection.

Supraphysiological concentrations of oxygen (hyperoxia) can compromise host defense and increase susceptibility to bacterial infections, causing ventilator-associated pneumonia. The phagocytic activity of macrophages is impaired by hyperoxia-induced increases in the levels of reactive oxygen species (ROS) and extracellular high-mobility group box protein B1 (HMGB1). Ascorbic acid (AA), an essential nutrient and antioxidant, has been shown to be beneficial in various animal models of ROS-mediated diseases.

Nitric Oxide Regulates Gene Expression in Cancers by Controlling Histone Posttranslational Modifications.

Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis.

Signaling and stress: The redox landscape in NOS2 biology.

Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. However, deleterious as well as beneficial roles of NO have been reported. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints.

Breathing new life into nitric oxide signaling: A brief overview of the interplay between oxygen and nitric oxide.

Nitric oxide ((•)NO, nitrogen monoxide) is one of the most unique biological signaling molecules associated with a multitude of physiologic and pathological conditions. In order to fully appreciate its numerous roles, it is essential to understand its basic biochemical properties. Most signaling effector molecules such as steroids or proteins have a significant life-span and function through classical receptor-ligand interactions.

Insights into the diverse effects of nitric oxide on tumor biology.

Among its many roles in cellular biology, nitric oxide (·NO) has long been associated with cancers both as a protumorigenic and as an antitumorigenic agent. The dual nature of this signaling molecule in varied settings is attributable to its temporal and concentration-dependent effects that produce different phenotypes. The steady-state ·NO concentration within the cell is a balance between its rate of enzymatic synthesis from the three nitric oxide synthase (NOS) isoforms and consumption via numerous metabolic pathways and demonstrates strong dependence on the tissue oxygen concentration.

The compromise of macrophage functions by hyperoxia is attenuated by ethacrynic acid via inhibition of NF-κB-mediated release of high-mobility group box-1.

The prolonged exposure to hyperoxia can compromise macrophage functions and contribute to the development of ventilator-associated pneumonia. High levels of extracellular high-mobility group box-1 (HMGB1) in the airways of mice exposed to hyperoxia can directly cause macrophage dysfunction. Hence, inhibition of the release of nuclear HMGB1 into the extracellular milieu may help to maintain macrophage functions under hyperoxic conditions.

Oxygen dependence of nitric oxide-mediated signaling.

Nitric oxide (•NO) is a biologically important short-lived free radical signaling molecule. Both the enzymatic synthesis and the predominant forms of cellular metabolism of •NO are oxygen-dependent. For these reasons, changes in local oxygen concentrations can have a profound influence on steady-state •NO concentrations.

S-nitrosation: current concepts and new developments.

The S-nitrosation (also referred to as S-nitrosylation) of cysteine residues is an important post-translational protein modification that regulates protein function and cell signaling. The original research articles and reviews in this Forum cover important concepts in protein S-nitrosation and identify key developments and opportunities for progress in this area. Defining the mechanisms by which S-nitrosothiols (RSNOs) may be formed and decomposed in cells and tissues, the integration of the biological chemistry associated with nitric oxide (NO) and other derivatives such as nitrite, and the development of new methodologies merging proteomics and direct quantitation are all key issues that we believe would require detailed attention.