https://staff.blog.ui.ac.id/hsuryadi/files/2012/02/ROS_RNS.pdf

Free radicals and antioxidants in normal physiological functions and human disease

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

The metabolic syndrome

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Heart mtNOS, a key mediator of oxidative injury in ischemia/reperfusion.

Response : Cytidylate Cyclase: Possible Artifacts in the Methodology

Publisher Summary Carcinogenesis is a multistep process. It starts with accumulation of mutations caused by environmental or hereditary factors that lead to malignant cell transformation, local invasion, and metastasis to distant sites. The main targets of mutagenesis are genes that promote or inhibit cell growth and genes that control DNA repair and apoptosis. The role of nitric oxide (NO) in carcinogenesis, tumor progression, and cancer therapy is multifaceted and dependent on a variety of conditions that exist in the cell milieu. NO has been shown to have both tumoricidal and tumorigenic effects, and modulation of NO levels in tumor microcirculation can affect tumor hemodynamics and cancer therapy. Tumor survival depends on adequate blood flow to supply nutrients and oxygen. NO produced by tumor cells maintains these optimal conditions, but it also reduces their ability to grow and metastasize by inhibiting DNA synthesis and mitochondrial respiration. High NO levels are generally tumoricidal and this is a therapeutical approach that can be used for tumor cells that are susceptible to NO-mediated apoptosis. The antitumor activity of NO includes inhibition of tumor-cell proliferation, promotion, and differentiation. It includes reduction of the metastatic spread in certain types of cancers. The antimetastatic effect of NO occurs either by apoptosis or by alterations in the genes that regulate metastasis. Angiogenesis and apoptosis can also be regulated by NO, which has been shown to be both an inhibitor and stimulant of these processes.

Nitric Oxide and Cancer

Studiesin vivo in fetal sheep have shown that bradykinin is released following oxygenation of the lungs and is at least partly responsible for normal pulmonary vasodilatation in the transition from fetal to extrauterine life. Part of this action involves secondary release of prostaglandin I2 (PGI2). In various adult vessels, bradykinin also stimulates the release of a powerful endothelium-derived relaxing factor (EDRF). Studiesin vitro were designed (using a modification of the bioassay cascade superfusion technique) to determine whether non-PGI2-related perinatal pulmonary vasodilatation is mediated by an EDRF. Superfused, precontracted, endothelium-denuded strips of fetal sheep thoracic aorta and the maternal sheep main pulmonary artery served as detectors of an EDRF released from isolated, perfused fetal sheep pulmonary arteries. Bradykinin, in the presence of indomethacin to block PGI2 synthesis, caused perfused fetal pulmonary arteries to release an EDRF, which generated a dose-dependent relaxation (24% for 1·0 µM,16·8% for 0·1 µM, and 10% for 0·01 µM bradykinin). Thus, bradykinin can produce perinatal pulmonary vasodilatation via a mechanism involving the endothelium-dependent synthesis of an EDRF.

Endothelium-derived relaxing factor as a mediator of bradykinin-induced perinatal pulmonary vasodilatation in fetal sheep

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of nitric oxide (•NO) by inflammatory superoxide (O2•−), pulmonary •NO concentration ceases, resulting in uncontrolled platelet aggregation and massive thrombosis, which kills the patients. Introducing •NO by inhalation (INO) may replace the loss of endothelium-derived •NO. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. An ongoing phase III study is expected to confirm the method’s efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of •NO by deoxyhemoglobin to nitrate, pulmonary administration of •NO will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O2•−-driven destruction of •NO by neutralizing inflammatory O2•−. By making use of low molecular weight compounds that mimic the action of the enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called porphyrin type (e.g., AEOL 10150), salen type (e.g., EUK-8) and cyclic polyamine type (e.g., M40419, today known as GC4419 and avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of chronic obstructive pulmonary disease. The Manganese diPyridoxyL EthylDiamine (MnPLED)-type mangafodipir (manganese dipyridoxyl diphosphate—MnDPDP), a magnetic resonance imaging (MRI) contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of inflammation, in preclinical as well as clinical settings. Intravenously administration of mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors’ viewpoint, it appears logical to test mangafodipr in COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with GC4419 for COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.

https://www.mdpi.com/2076-3921/9/10/971/pdf

Louis J. Ignarro

Papers

Heart mtNOS, a key mediator of oxidative injury in ischemia/reperfusion.

Response : Cytidylate Cyclase: Possible Artifacts in the Methodology

Nitric Oxide and Cancer

Endothelium-derived relaxing factor as a mediator of bradykinin-induced perinatal pulmonary vasodilatation in fetal sheep

May Mangafodipir or Other SOD Mimetics Contribute to Better Care in COVID-19 Patients?