Pleiotropic Effects of Nitric Oxide on SARS-CoV-2 Infections

Infection by beta-coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coron-avirus-2) alters the homeostasis of the vascular endothelium, promoting an inflammatory state which causes damage and favors the prothrombotic state. The direct viral cytotoxicity induced by the SARS-CoV-2 leads to endothelial cell death;thus, altering the vessel functions. Moreover, SARS-CoV infection induces endothelial dysfunction (ED) and reduces the levels of nitric oxide (NO);thus, aggravating the vascular injuries, which promotes thrombotic events due to an altera-tion in the homeostasis. NO is a pleiotropic molecule that induces vasodilation, regulates the immune response, inhibits platelet aggregation, and decreases the cellular adhesion to vascular en-dothelium. Moreover, NO acts directly against invasive agents, exhibiting antibacterial, antiviral, and antifungal activity. High levels of NO result in an increase in the ED, causing an inflammatory amplification that aggravates the disease through undesirable positive feedback. The objective of this review was to present and discuss the involvement of NO on ED in SARS-CoV-2 infections. This review may also highlight new perspectives for therapeutic interventions through the supple-mentation of exogenous NO. The maintenance of homeostatic NO levels could represent a useful approach in the prevention of coronavirus-induced ED.Copyright © 2021 Bentham Science Publishers.

Live to die another day: novel insights may explain the pathophysiology behind smoker's paradox in SARS-CoV-2 infection.

The severe acute respiratory coronavirus 2 (SARS-CoV-2) infection demonstrates a highly variable and unpredictable course. Several reports have claimed a smoker's paradox in coronavirus disease 2019 (COVID-19), in line with previous suggestions that smoking is associated with better survival after acute myocardial infarction and appears protective in preeclampsia. Several plausible physiological explanations exist accounting for the paradoxical observation of smoking engendering protection against SARS-CoV-2 infection. In this review, we delineate novel mechanisms whereby smoking habits and smokers' genetic polymorphism status affecting various nitric oxide (NO) pathways (endothelial NO synthase, cytochrome P450 (CYP450), erythropoietin receptor (EPOR); ß-common receptor (ßcR)), along with tobacco smoke modulation of microRNA-155 and aryl-hydrocarbon receptor (AHR) effects, may be important determinators of SARS-CoV-2 infection and COVID-19 course. While transient NO bioavailability increase and beneficial immunoregulatory modulations through the above-mentioned pathways using exogenous, endogenous, genetic and/or therapeutic modalities may have direct and specific, viricidal SARS-CoV-2 effects, employing tobacco smoke inhalation to achieve protection equals self-harm. Tobacco smoking remains the leading cause of death, illness, and impoverishment.

Nitric Oxide in the Management of Respiratory Consequences in COVID-19: A Scoping Review of a Different Treatment Approach.

The severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) virus causing COVID-19 significantly affects the respiratory functions of infected individuals by massively disrupting the pulmonary oxygenation and activating the synthesis of proinflammatory cytokines, inducing severe oxidative stress, enhanced vascular permeability, and endothelial dysfunction which have rendered researchers and clinicians to depend on prophylactic treatment due to the unavailability of proper disease management approaches. Previous studies have indicated that nitric oxide (NO) application appears to be significant concerning the antiviral activities, antioxidant, and anti-inflammatory properties in relieving disease-related symptoms. To identify, explore, and map the literature on the role of nitric oxide in the management of respiratory consequences in COVID-19 through this scoping review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during the search to answer the focal question: "What are the potential uses of nitric oxide in the management of respiratory failure in COVID-19?" Administering exogenous NO in the form of inhaled gas or stimulating the system to produce NO appears to be a suitable option to manage COVID-19-induced pneumonia and respiratory illness. This treatment modality seems to attenuate respiratory distress among patients suffering from severe infections or patients with comorbidities. Exogenous NO at different doses effectively reduces systemic hyperinflammation and oxidative stress, improves arterial oxygenation, and restores pulmonary alveolar cellular integrity to prevent the lungs and other organs from further damage. This therapy could pave the way for better management of COVID-19 before the onset of disease-related complications.

Targeting PSD95/nNOS by ZL006 alleviates social isolation-induced heightened attack behavior in mice.

RATIONALE: Deregulated attack behaviors have devastating social consequences; however, satisfactory clinical management for the behavior is still an unmet need so far. Social isolation (SI) has been common during the COVID-19 pandemic and may have detrimental effects on mental health, including eliciting heightened attack behavior. OBJECTIVES: This study aims to explore whether injection of ZL006 can alleviate SI-induced escalation of attack behavior in mice. METHODS: Pharmacological tools, biochemical methods, and behavioral tests were used to explore the potential therapeutic effects of ZL006 targeting postsynaptic density 95 (PSD95)/neuronal nitric oxide synthase (nNOS) pathway on escalation of attack behavior induced by SI in mice. RESULTS: ZL006 mitigated SI-induced escalated attack behaviors and elevated nitric oxide (NO) level in the cortex of the SI mice. The beneficial effects of ZL006 lasted for at least 72 h after a single injection of ZL006. Potentiation of NO levels by L-arginine blocked the effects of ZL006. Moreover, a sub-effective dose of 7-NI in combination with a sub-effective dose of ZL006 decreased both SI-induced escalated attack behaviors and NO levels in mice subjected to SI. CONCLUSIONS: Our study highlights the importance of the PSD95/nNOS pathway in mediating SI-induced escalation of attack behavior. ZL006 may be a promising therapeutic strategy for treating aggressive behaviors.

Therapeutic approaches in COVID-19 followed before arrival of any vaccine.

In present times covid-19 is spreading and is showing very destructive effects. It does not only affected the physical health but mental health as well as the economy of the major affected countries. Corona viruses are group of related RNA viruses. The first case of this virus was observed in China and then this virus got spread in the many countries and different strategies were made to stop the spread of this virus. Since no particular vaccine was available to cure this so different strategies were made. Due to the emergence of pandemic diseases, drug development and control strategies have been re-examined. One of the most important factors that scientists have to consider is the effectiveness of their drugs. This virus causes the respiratory tract infections which can range from mild to lethal. COVID-19 is a major cause of death in advanced countries. It is due to the absence of any particular vaccine that can effectively treat this condition. So in this review we will discuss about the therapeutic approaches followed to combat this deadly virus. Ayurveda, nitric oxide, nanoparticles and enzymes played a very important role in boosting the immunity and treatment of corona. Many herbs and some tips of using a combination of herbs proved to be very efficient while facing problems in breathing. Giving the dose of nitric oxide at some particular level and chloroquine the drug showed the antiviral activity against the virus. Developing methods to identify and contain COVID-19 is essential to successfully manage the virus. Various strains of the SARS-COV-2 were detected and were found more dangerous. The therapeutic approaches followed actually were efficient and can be used to combat the other variants also. This review focuses on the latest developments in the field of therapeutics and the strategies which were followed before any vaccine.

The Functional Diversity of Nitric Oxide Synthase Isoforms in Human Nose and Paranasal Sinuses: Contrasting Pathophysiological Aspects in Nasal Allergy and Chronic Rhinosinusitis.

The human paranasal sinuses are the major source of intrinsic nitric oxide (NO) production in the human airway. NO plays several roles in the maintenance of physiological homeostasis and the regulation of airway inflammation through the expression of three NO synthase (NOS) isoforms. Measuring NO levels can contribute to the diagnosis and assessment of allergic rhinitis (AR) and chronic rhinosinusitis (CRS). In symptomatic AR patients, pro-inflammatory cytokines upregulate the expression of inducible NOS (iNOS) in the inferior turbinate. Excessive amounts of NO cause oxidative damage to cellular components, leading to the deposition of cytotoxic substances. CRS phenotype and endotype classifications have provided insights into modern treatment strategies. Analyses of the production of sinus NO and its metabolites revealed pathobiological diversity that can be exploited for useful biomarkers. Measuring nasal NO based on different NOS activities is a potent tool for specific interventions targeting molecular pathways underlying CRS endotype-specific inflammation. We provide a comprehensive review of the functional diversity of NOS isoforms in the human sinonasal system in relation to these two major nasal disorders' pathologies. The regulatory mechanisms of NOS expression associated with the substrate bioavailability indicate the involvement of both type 1 and type 2 immune responses.

Assessment of nitric oxide (NO) potential to mitigate COVID-19 severity.

Novel coronavirus disease by SARS-CoV-2 virus (also known as COVID-19) has emerged as major health concern worldwide. While, there is no specific drugs for treating this infection till date, SARS-CoV-2 had spread to most countries around the globe. Nitric oxide (NO) gas serves as an important signaling molecule having vasodilatory effects as well as anti-microbial properties. Previous studies from the 2004 SARS-CoV infection demonstrated that NO may also help to reduce respiratory tract infection by inactivating viruses and inhibiting their replication cycle and is an effective supportive measure for treating infection in patients with pulmonary complications. NO gas inhalation is being suggested as potential therapy for managing severe acute respiratory distress syndrome in COVID-19 patients. In view of COVID-19 pandemic, several clinical trials are underway to examine the effects of NO inhalation on infected patients. Previously published reports on beneficial effects of endogenous NO and NO inhalation therapy were thoroughly searched to assess the potential of NO therapy for treating COVID-19 patients. Present report summarized the therapeutic importance of NO to reverse pulmonary hypertension, restore normal endothelial activity and produce anti-thrombotic effects. In addition to this, NO also reduces viral infection by inhibiting its replication and entry into the host cell. In absence of vaccine and effective treatment strategies, we suggest that NO inhalation therapy and NO releasing foods/compounds could be considered as an alternative measure to combat COVID-19 infection.

Does eNOS derived nitric oxide protect the young from severe COVID-19 complications?

The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications.