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1.
Lifestyle-mediated nitric oxide boost to prevent SARS-CoV-2 infection: A perspective.
Kobayashi, J
Nitric oxide : biology and chemistry. 2021;:55-61
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and has seriously threatened public health by causing significant morbidity and mortality. Patients with coronavirus disease (COVID-19) with preexisting endothelial dysfunction caused by aging, diabetes, hypertension, and obesity are at high risk for life-threatening thromboembolic complications. This suggests a possibility that reduced endothelial nitric oxide (NO) production and NO bioavailability could be a common underlying pathology for the progression of COVID-19. Increasingly, evidence from experimental and clinical studies of SARS-CoV-2 infection shows that NO inhibits the pathogenesis of COVID-19, including virus entry into host cells, viral replication, host immune response, and subsequent thromboembolic complications. Restoring NO bioavailability may have the potential to be a preventive or early-treatment option for COVID-19. This review aims to provide in-depth discussion of NO bioavailability to prevent SARS-CoV-2 infection, particularly by focusing on lifestyle factors such as nitrate-rich diets, physical exercise, and nasal breathing, which could be easily performed on a daily basis to boost NO bioavailability.
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2.
Reduction of NO by diiron complexes in relation to flavodiiron nitric oxide reductases.
Pal, N, Jana, M, Majumdar, A
Chemical communications (Cambridge, England). 2021;(70):8682-8698
Abstract
Reduction of nitric oxide (NO) to nitrous oxide (N2O) is associated with immense biological and health implications. Flavodiiron nitric oxide reductases (FNORs) are diiron containing enzymes that catalyze the two electron reduction of NO to N2O and help certain pathogenic bacteria to survive under "nitrosative stress" in anaerobic growth conditions. Consequently, invading bacteria can proliferate inside the body of mammals by bypassing the immune defense mechanism involving NO and may thus lead to harmful infections. Various mechanisms, namely the direct reduction, semireduction, superreduction and hyponitrite mechanisms, have been proposed over time for catalytic NO reduction by FNORs. Model studies in relation to the diiron active site of FNORs have immensely helped to replicate the minimal structure-reactivity relationship and to understand the mechanism of NO reduction. A brief overview of the FNOR activity and the proposed reaction mechanisms followed by a systematic description and detailed analysis of the model studies is presented, which describes the development in the area of NO reduction by diiron complexes and its implications. A great deal of successful modeling chemistry as well as the shortcomings related to the synthesis and reactivity studies is discussed in detail. Finally, future prospects in this particular area of research are proposed, which in due course may bring more clarity in the understanding of this important redox reaction.
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3.
Salicylic acid and nitric oxide signaling in plant heat stress.
Rai, KK, Pandey, N, Rai, SP
Physiologia plantarum. 2020;(2):241-255
Abstract
In agriculture, heat stress (HS) has become one of the eminent abiotic threats to crop growth, productivity and nutritional security because of the continuous increase in global mean temperature. Studies have annotated that the heat stress response (HSR) in plants is highly conserved, involving complex regulatory networks of various signaling and sensor molecules. In this context, the ubiquitous-signaling molecules salicylic acid (SA) and nitric oxide (NO) have diverted the attention of the plant science community because of their putative roles in plant abiotic and biotic stress tolerance. However, their involvement in the transcriptional regulatory networks in plant HS tolerance is still poorly understood. In this review, we have conceptualized current knowledge concerning how SA and NO sense HS in plants and how they trigger the HSR leading to the activation of transcriptional-signaling cascades. Fundamentals of functional components and signaling networks associated with molecular mechanisms involved in SA/NO-mediated HSR in plants have also been discussed. Increasing evidences have suggested the involvement of epigenetic modifications in the development of a 'stress memory', thereby provoking the role of epigenetic mechanisms in the regulation of plant's innate immunity under HS. Thus, we have also explored the recent advancements regarding the biological mechanisms and the underlying significance of epigenetic regulations involved in the activation of HS responsive genes and transcription factors by providing conceptual frameworks for understanding molecular mechanisms behind the 'transcriptional stress memory' as potential memory tools in the regulation of plant HSR.
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4.
Does eNOS derived nitric oxide protect the young from severe COVID-19 complications?
Guan, SP, Seet, RCS, Kennedy, BK
Ageing research reviews. 2020;:101201
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Abstract
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.
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5.
Transcriptional Regulation Contributes to Prioritized Detoxification of Hydrogen Peroxide over Nitric Oxide.
Adolfsen, KJ, Chou, WK, Brynildsen, MP
Journal of bacteriology. 2019;(14)
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Abstract
Hydrogen peroxide (H2O2) and nitric oxide (NO·) are toxic metabolites that immune cells use to attack pathogens. These antimicrobials can be present at the same time in phagosomes, and it remains unclear how bacteria deal with these insults when simultaneously present. Here, using Escherichia coli, we observed that simultaneous exposure to H2O2 and NO· leads to prioritized detoxification, where enzymatic removal of NO· is impeded until H2O2 has been eliminated. This phenomenon is reminiscent of carbon catabolite repression (CCR), where preferred carbon sources are catabolized prior to less desirable substrates; however, H2O2 and NO· are toxic, growth-inhibitory compounds rather than growth-promoting nutrients. To understand how NO· detoxification is delayed by H2O2 whereas H2O2 detoxification proceeds unimpeded, we confirmed that the effect depended on Hmp, which is the main NO· detoxification enzyme, and used an approach that integrated computational modeling and experimentation to delineate and test potential mechanisms. Plausible interactions included H2O2-dependent inhibition of hmp transcription and translation, direct inhibition of Hmp catalysis, and competition for reducing equivalents between Hmp and H2O2-degrading enzymes. Experiments illustrated that Hmp catalysis and NAD(P)H supply were not impaired by H2O2, whereas hmp transcription and translation were diminished. A dependence of this phenomenon on transcriptional regulation parallels CCR, and we found it to involve the transcriptional repressor NsrR. Collectively, these data suggest that bacterial regulation of growth inhibitor detoxification has similarities to the regulation of growth substrate consumption, which could have ramifications for infectious disease, bioremediation, and biocatalysis from inhibitor-containing feedstocks.IMPORTANCE Bacteria can be exposed to H2O2 and NO· concurrently within phagosomes. In such multistress situations, bacteria could have evolved to simultaneously degrade both toxic metabolites or preferentially detoxify one over the other. Here, we found that simultaneous exposure to H2O2 and NO· leads to prioritized detoxification, where detoxification of NO· is hampered until H2O2 has been eliminated. This phenomenon resembles CCR, where bacteria consume one substrate over others in carbon source mixtures. Further experimentation revealed a central role for transcriptional regulation in the prioritization of H2O2 over NO·, which is also important to CCR. This study suggests that regulatory scenarios observed in bacterial consumption of growth-promoting compound mixtures can be conserved in bacterial detoxification of toxic metabolite mixtures.
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6.
Functional Nitric Oxide Nutrition to Combat Cardiovascular Disease.
Bryan, NS
Current atherosclerosis reports. 2018;(5):21
Abstract
PURPOSE OF REVIEW To reveal the mechanisms of nitric oxide (NO) production in humans and how lifestyle, drug therapy, and hygienic practices can decrease NO production. Furthermore, to show how functional nitric oxide nutrition can overcome these limitations to restore endogenous NO production and combat cardiovascular disease. RECENT FINDINGS Research over the past decade has revealed that inorganic nitrate and nitrite found naturally in green leafy vegetables and other vegetables such as beets can provide the human body with a source of bioactive nitric oxide. NO is one of the most important molecules produced within the cardiovascular system that maintains normal blood pressure and prevents inflammation, immune dysfunction, and oxidative stress, hallmarks of cardiovascular disease. This pathway is dependent upon the amount of inorganic nitrate and nitrite in the foods we eat, the presence of oral nitrate-reducing bacteria, and sufficient stomach acid production. The concept of food being medicine and medicine being food has lost its place in the practice and implementation of modern medicine over the past century. Certain dietary patterns and specific foods are known to confer very significant protective effects for many human diseases, including cardiovascular disease, the number one killer of men and women in the developed world. However, identification of single or multiple bioactive molecules that are responsible for these effects has escaped scientists and nutritionists for many years. This review will highlight the biochemical, physiological, and epidemiological basis for functional nitric oxide nutrition that can be safely and effectively utilized in patients.
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Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research.
Siervo, M, Scialò, F, Shannon, OM, Stephan, BCM, Ashor, AW
The Proceedings of the Nutrition Society. 2018;(2):112-123
Abstract
CVD are characterised by a multi-factorial pathogenesis. Key pathogenetic steps in the development of CVD are the occurrence of endothelial dysfunction and formation of atherosclerotic lesions. Reduced nitric oxide (NO) bioavailability is a primary event in the initiation of the atherosclerotic cascade. NO is a free radical with multiple physiological functions including the regulation of vascular resistance, coagulation, immunity and oxidative metabolism. The synthesis of NO proceeds via two distinct pathways identified as enzymatic and non-enzymatic. The former involves the conversion of arginine into NO by the NO synthases, whilst the latter comprises a two-step reducing process converting inorganic nitrate into nitrite and subsequently NO.Inorganic is present in water and food, particularly beetroot and green leafy vegetables. Several investigations have therefore used the non-enzymatic NO pathway as a target for nutritional supplementation ( salts) or dietary interventions (high- foods) to increase NO bioavailability and impact on cardiovascular outcomes. Some studies have reported positive effects of dietary on systolic blood pressure and endothelial function in patients with hypertension and chronic heart failure. Nevertheless, results have been inconsistent and the size of the effect appears to be declining in older individuals. Additionally, there is a paucity of studies for disorders such as diabetes, CHD and chronic kidney failure. Thus, whilst dietary supplementation could represent an effective and viable strategy for the primary and secondary prevention of age-related cardiovascular and metabolic diseases, more large-scale, robust studies are awaited to confirm or refute this notion.
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8.
Intravascular hemolysis and the pathophysiology of sickle cell disease.
Kato, GJ, Steinberg, MH, Gladwin, MT
The Journal of clinical investigation. 2017;(3):750-760
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Abstract
Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. Decompartmentalized hemoglobin, arginase 1, asymmetric dimethylarginine, and adenine nucleotides are all products of hemolysis that promote vasomotor dysfunction, proliferative vasculopathy, and a multitude of clinical complications of pulmonary and systemic vasculopathy, including pulmonary hypertension, leg ulcers, priapism, chronic kidney disease, and large-artery ischemic stroke. Nitric oxide (NO) is inactivated by cell-free hemoglobin in a dioxygenation reaction that also oxidizes hemoglobin to methemoglobin, a non-oxygen-binding form of hemoglobin that readily loses heme. Circulating hemoglobin and heme represent erythrocytic danger-associated molecular pattern (eDAMP) molecules, which activate the innate immune system and endothelium to an inflammatory, proadhesive state that promotes sickle vaso-occlusion and acute lung injury in murine models of sickle cell disease. Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. These pathological responses promote regional vasoconstriction and subsequent blood vessel remodeling. Thus, intravascular hemolysis represents an intrinsic mechanism for human vascular disease that manifests clinical complications in sickle cell disease and other chronic hereditary or acquired hemolytic anemias.
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9.
Immunoregulatory and Effector Activities of Nitric Oxide and Reactive Nitrogen Species in Cancer.
Fionda, C, Abruzzese, MP, Santoni, A, Cippitelli, M
Current medicinal chemistry. 2016;(24):2618-2636
Abstract
Nitric Oxide (NO) is a signaling radical, highly diffusible pleiotropic regulator of a large set of different molecular and biological pathways, including, neurotransmission, vasodilatation and macrophagemediated responses against infections. It is produced from the amino acid L-Arginine and oxygen by the enzymatic action of three isoforms of the Nitric Oxide Synthase (NOS), differently expressed and regulated in tissues. Increasing evidence highlights the wide spectrum of action of NO in different pathologic conditions, including cancer. In this regard, a dual role for this molecule as a pro- and anti-tumorigenic mediator has been described, in a context and concentration-dependent manner. Moreover, NO exerts numerous immunologic effects, by operating as an effector molecule in innate immune responses as well as a regulator of adaptive immune components. Here, we will review recent advances in the field of biology of this pleiotropic signaling molecule in cancer, also providing a concise description of the immunoregulatory and effector activities of NO and Reactive Nitrogen Species (RNS). In particular, we will summarize recent knowledge of the molecular mechanisms underlying the complex functions of NO in cancer pathogenesis. We will also address emerging immune-mediated mechanisms regulated by NO to provide a comprehensive view of the complex cellular interactions which control cancer progression and that can be influenced by NO at multiple levels. In the light of different immunologic effects of this molecule, the potential therapeutic implications of novel drugs targeting NO to treat cancer and to improve anti-tumor immune responses will be discussed.
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10.
The defence elicitor AsES causes a rapid and transient membrane depolarization, a triphasic oxidative burst and the accumulation of nitric oxide.
Martos, GG, Terán, Mdel M, Díaz Ricci, JC
Plant physiology and biochemistry : PPB. 2015;:443-50
Abstract
The newly characterized elicitor AsES obtained from Acremonium strictum induces a strong defence response in strawberry plants and confers plants resistance against the fungal pathogen Colletotricum acutatum the casual agent of anthracnose disease. Previous studies showed that AsES causes the accumulation of reactive oxygen species (ROS) that peaked 4 h post treatment (hpt), but due to the experimental approach used it was not clear whether the accumulation of ROS observed was intracellular or extracellular or took place as a single peak. By using a different experimental setup, a more complex early events associated to the activation of the innate immunity were observed. In this paper we report that strawberry plant cells treated with AsES exhibits a triphasic production of H2O2 and a rapid intracellular accumulation of NO. The first phase consists in a progressive extracellular accumulation of H2O2 that starts immediately after the treatment with AsES and is preceded by a rapid and transient cell membrane depolarization. During this phase takes place also a rapid intracellular accumulation of NO. Microscopic observations of mesophyll cells treated with AsES reveals that NO accumulates at the chloroplast. After the first extracellular H2O2 production phase, two intracellular H2O2 accumulation events occur, the first 2 hpt, and the second 7 hpt. Cells treated with AsES also show a transient increase of ion leakage, and a progressive alkalinization of the extracellular medium.