Nitric Oxide: From Research to Therapeutics

Preface
Contents
1 Translating Nitric Oxide Research to Therapeutics: A Critical Appraisal
Introduction
NO Formation
Factors Affecting NO Production
Nitric Oxide Dynamics
Sources of Nitric Oxide
Therapeutic Potential of NO
Conclusion
References
2 Nitric Oxide and Cardiovascular Health
Introduction
Nitric Oxide Synthesis
Regulation of Intracellular Levels of Nitric Oxide
Cross-Talk Between Oxidative Stress and Nitrosative Stress
Nitric Oxide Signaling
Nitric Oxide and Cardiovascular Diseases
Conclusions
References
3 Nitric Oxide and Cardiovascular Diseases: Cardioprotection, Complications and Therapeutics
Introduction
Nitric Oxide (NO) and NO Synthases (NOS)
Neuronal Nitric Oxide Synthase (nNOS)
Inducible Nitric Oxide Synthase (iNOS)
Endothelial Nitric Oxide Synthase (eNOS)
NO Synthesis and Distribution
NO and Vaso-Modulation
The Link Between NO and Hydrogen Sulfide (H2S) Signaling
Cardiovascular Homeostasis Maintenance by NO-NOS
Homeostasis in Blood Vessels
Homeostasis in Perivascular Adipose Tissue (PVAT)
Homeostasis in Cardiac Myocytes
Homeostasis in Cardiovascular Nerve Cells
NOS, NO and Cardiovascular Disease
Endothelial Dysfunction
NOS and NO in Cardiac Remodeling
Contribution of NOS and NO in Common CVDs
Hypertension
Diabetes
Heart Failure and Ventricular Hypertrophy
Coronary Artery Disease (CAD)
Atherosclerosis
NO Signaling and Therapeutics and Pitfalls
SGC Stimulators or Activators
BH4 or Folate Supplementation
Nitroxyl (HNO)
Nitrate and Nitrite Supplementation
PDE Inhibitors
Experiences Form Clinical Studies
Conclusion and Future Perspectives
References
4 Nitric Oxide and the Heart Autonomic Nervous System
Nitric Oxide in the Heart
Nitric Oxide and Neuronal Nitric Oxide Synthase in the Intrinsic Cardiac Nervous System
Role of Nitric Oxide as a Mediator of Cardiac Parasympathetic Effects
Role of Nitric Oxide as a Modulator of Cardiac Sympathetic Effects
NO as a Mediator in Autonomic Regulation of the Cardiac Conduction System
NO as a Mediator in Autonomic Regulation of Coronary Flow
Conclusion
References
5 Exercise Induced NO Modulation in Prevention and Treatment of Cardiovascular Diseases
Nitric Oxide and Exercise
Nitric Oxide Synthases
Nitric Oxide—Mechanism of Action
Nitric Oxide and Cardiovascular System
Erythrocyte Derived NO and Exercise
Neuronal Nitric Oxide Synthase in Cardiovascular System and Physical Activity
NO, Exercise and Cardiovascular Diseases
Hypertension
Atherosclerosis, Coronary Artery Disease, Stroke
Heart Failure
Concluding Remarks
References
6 Nitric Oxide-cGMP-PKG Signaling in the Cardioprotective Effects of Phosphodiesterase 5 Inhibitors
Introduction
Nitric Oxide (NO)—A Key Signaling Molecule in Cardioprotection
Cyclic Nucleotide Phosphodiesterases
PDE5 as Therapeutic Target for Cardiac Protection
Cardioprotection in Diabetes and Metabolic Syndrome
Conclusions
References
7 Role of Nitric Oxide Synthases in Doxorubicin-Induced Cardiomyopathy
Introduction
Dox-Induced Cardiac Effects
Mitigation of Dox-Induced Cardiac Effects
The Challenge
Nitrosative Stress
Peroxynitrite (ONOO−)
Nitric Oxide (NO)
Nitric Oxide Synthases (NOS)
Endothelial Nitric Oxide Synthase (eNOS)
Neuronal Nitric Oxide Synthase (nNOS)
Inducible Nitric Oxide Synthase (iNOS)
Nitric Oxide Signaling
Nitrosative Stress
Modulation of NOS
Inflammatory Responses
Conclusions
References
8 Role of Nitric Oxide Synthase and Nitric Oxide Signaling in the Neutrophil Ontogeny and Functions
Neutrophil Ontogeny
NOS/NO Signaling
NOS/NO and Granulopoiesis
Molecular Mechanisms in NOS/NO Driven Granulopoiesis
NO/NOSs in Neutrophils
Pathological Conditions
Nitric Oxide-Mediated Modulation of PMNs Functions
Conclusion and Future Perspective
References
9 Cell Death-NO-Today: Effect of NO and RNS on Non-apoptotic Regulated Cell Death
Introduction
Sources of Nitric Oxide
Reactive Nitrogen Species (RNS) and Nitrosative Stress
Protein Modification in NO Signalling
Defence Against Nitrosative Stress
Programmed Cell Death
NO in Autophagy Induction
NO Mediated Inhibition of Autophagy
Positive Interaction Between Nitric Oxide and Inflammasome
NO as Inflammasome Inhibitor
Inflammasome and S-nitrosylation
Ferroptosis and Nitric Oxide
Lipid Oxidation, Iron and Nitrosative Stress
Peroxynitrite Mediated DNA Modifications
NO Mediated Parthanatos
NO and RNS as Necroptosis Inducers
Role of RNS in NETs Formation
Conclusion and Further Perspective
References
10 Involvement of Nitric Oxide in Insulin Secretion to Carbohydrate Metabolism
Introduction
NO in Insulin Secretion
NO in Insulin Sensing
NO in Glucose Metabolism
Conclusion
References
11 Nitric Oxide as a Diagnostic and Therapeutic Tool in Respiratory Diseases
Introduction
Source and Biosynthesis of NO
Nitric Oxide—Cytotoxicity Versus Cytoprotection: A Question of Balance
Role of NO in the Physiology of the Lungs
NO and Bronchodilation
NO and Bronchoprotection
NO and Pulmonary Vasculature
NO and Airway Secretions
Exhaled NO as a Non-invasive Biomarker for a Variety of Respiratory Conditions
FeNO and Asthma
FeNO and Chronic Obstructive Pulmonary Disease
FeNO and Cystic Fibrosis
FeNO and Bronchiectasis
FeNO and Rhinitis
FeNO and Interstitial Lung Diseases
FeNO and Pulmonary Hypertension
FeNO and Infections
NO Inhalation: A Therapeutic Tool in Respiratory Diseases
Inhaled NO in Lung Transplantation
Inhaled NO In Respiratory Distress Syndrome
Inhaled NO in Chronic Obstructive Pulmonary Disease (COPD)
Inhaled NO in Severe Acute Respiratory Syndrome in Response to COVID-19
Conclusions
References
12 Therapeutic Potential of Nitric Oxide in the Management of COVID-19 Induced Acute Respiratory Distress Syndrome (ARDS)
Introduction
SARS-CoV2 or COVID-19 Induced Pathological Changes
Classification of Drugs for COVID-19 Treatment
Nitric Oxide and its Impact on the Pulmonary System
NO and it’s Potential in COVID-19 Induced Lung Injury
Conclusion
References
13 Emerging Novel Therapies for COVID-19: Implications for the Use of Nitric Oxide as an Anti-COVID-19 Therapy
Introduction
COVID-19 Problems and Challenges in the Treatment
Failures of Repurposed Drugs in Treatment of COVID-19
Emerging Anti-COVID-19 Therapies
Antivirals
Immunosuppressants
ACE Inhibitors
Vitamins
Add on Therapies
Nitric Oxide
Respiratory Tract Pathology During COVID-19 Infection
Rationale for Nitric Oxide Use in COVID-19
Preclinical Evidences on Role of NO/iNOS Inhibitors in Viral Infections
NO in Physiology and Pathology of Viral Infection
Clinical Studies on NO in Treatment of Viral Infections
NO in COVID-19/Viral Infections
Conclusion
References
14 Sex Differences in Stress and Stress Related Neuropsychiatric Disorders: Focus on Nitric Oxide
Introduction
NO Signaling in the CNS: An Overview
NO Signaling in the Brain and Gonadal Hormones
NO and Sex Differences in Brain and Behavioral Responses to Stress
NO and Sex Differences in Neuropsychiatric Disorders
Targeting NO and NO-Mediated Signaling as a Treatment for Stress and Mood Disorders
Conclusion and Perspectives
References
15 Nitric Oxide in Major Depressive Disorder
Introduction
General Aspects of Nitric Oxide in the Brain
No and Mental Health Disorders
Clinical Evidence
Preclinical Evidence
Conclusion
References
16 Nitric Oxide in Parkinson’s Disease: Insights into Research and Therapeutics
Introduction
Molecular Targets of Nitric Oxide in PD
Nitric Oxide and Nitrosative Stress in PD
Clinical Evidence for the Involvement of Nitric Oxide in PD
Pharmacological Agents Targeting Nitric Oxide in Preclinical PD Models
Nitric Oxide Synthase Inhibitors
Potential of Antioxidants Acting Through Nitric Oxide Pathway in PD
Concluding Remarks and Future Directions
References
17 Stable Gastric Pentadecapeptide BPC 157 and NO-System
Stable Gastric Pentadecapeptide BPC 157
Stable Gastric Pentadecapeptide BPC 157 and NO
Particular Relationships Between the NO-System as a Follow Up of the NO-Agents Effects
Triple Relationships L-NAME Versus L-Arginine Versus L-NAME + L-Arginine, All Together, as an Indicator How NO-System May be Involved
Both L-NAME and L-Arginine in the Similar Disease Condition
L-NAME and L-Arginine May Have Both Opposite and Parallel Effect; BPC 157 Effect
Delineation of Both Opposite and Parallel of Effects of L-NAME and L-Arginine
Conclusion
References
18 Exploring the Gastroprotective, Ulcer Healing and Chemopreventive Properties of Nitric Oxide-Releasing Nonsteroidal Anti-inflammatory Drugs
A New Class of Anti-inflammatory Drugs Containing the NO Moiety and Stomach Protection. Evidence from Preclinical Studies
NO-Releasing NSAIDs Versus Conventional NSAIDs in the Mechanism of Gastric Ulcer Healing
The Importance of NO-NSAIDs in Protecting the Stomach Against Experimental Ethanol Damage, Stress, and Ischemia–Reperfusion
Anticarcinogenic and Chemopreventive Potential of NO-Releasing NSAIDs
References
19 The Role of Nitric Oxide in the Etiopathogenesis of Preeclampsia
Introduction
Role of Nitric Oxide in Preeclampsia
Nitric Oxide Basics
Oxidative/Nitrosative Stress
Oxidative Stress in Preeclampsia
Role of Nitric Oxide in Normal Pregnancy
Role of NO in the Pathogenesis of Preeclampsia
ADMA and Preeclampsia
Antioxidant Defense System in Preeclampsia
Vitamins (Vitamin C, E)
Superoxide Dismutase (Mn-SOD, CuZn-SOD, EC-SOD)
Catalase
Glutathione Peroxidase (GPx)
Oxidative Stress Biomarkers for Preeclampsia
Conclusion
References
20 Therapeutic Prospects of Nitric Oxide as an Anti-teratogen
Introduction
Cadmium as an Environmental Teratogen
Thalidomide as a Drug Teratogen
Prevention of Birth Defects
Nitric Oxide and Teratogenicity
Scope of Nitric Oxide as an Anti-teratogen
Methodology
Drug Administration to the Chicken Embryos
Morphological Analysis
Histopathology Study of Eye
Transcriptome Sequencing and Analysis
Results
To Study the Anti-teratogenic Effect of NO Against Teratogens
Nitric Oxide Recovers the Eye Structural Integrity Affected by Thalidomide
Enrichment of Pathways Based on Transcriptome Sequencing Modulated by Thalidomide and Thalidomide-Nitric Oxide Combination
Discussion
Summary
References
21 Ruthenium Nitrosyl Complexes: Photoinduced Delivery of NO to Different Biological Targets
Introduction
Synthesis of NO in the Biosystem
Biological Significance of NO
Cardiovascular Function of NO
Function of NO in CNS
NO Function in Programmed Cell Death (Apoptosis)
Exogenous Organic NO Carriers
Exogenous Inorganic NO Carriers
Ruthenium Nitrosyl (Ru–NO) Complexes
Porphyrin Based Ruthenium Nitrosyl Complexes
Polypyridyl Ligands Based Ruthenium Nitrosyl Complexes
Imine and Carboxamido Ligand-Based Ruthenium Nitrosyl Complexes
Organometallic Ru–NO Complexes
Conclusions
References
22 Nitric Oxide Regulation in Microparticles
Introduction
Endothelial Microparticles
Nitric Oxide and Endothelial Microparticles
NOS in EMP Mediated Inflammation
NO in EMP Mediated Vascular Function
EMP in Cardiovascular Diseases
EMP in Hepatic Diseases
EMP as Double Edge Sword
Potential Action of NO During Diseases
Role of NO Mediated Cellular EMP Generation and Functions
Cell Migration
Angiogenesis
Inflammation
Oxygen Radical (O2−)
Cytotoxicity
NO Formation in EMP
Targets and Physiological Function of NO in EMP
NOS Inhibitors in EMP and Therapeutic Implications
Drug Mediated Effect
Conclusion
References