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Non-enzymatic nitric oxide (NO) generation via the reduction of nitrate and nitrite ions, along with remarkably high levels of nitrate ions in skeletal muscle, have been recently described. Skeletal muscle nitrate storage may be critical for maintenance of NO homeostasis in healthy ageing and nitrate supplementation may be useful for treatment of specific pathophysiologies as well as enhancing normal functions.

The production of the redox-active signaling molecule, NO, has long been associated with interactions between microbes and their host plants. Emerging evidence now suggests that specific NO signatures and cognate patterns of PHYTOGLOBIN1 (PHYTOGB1) expression, a key regulator of cellular NO homeostasis, may help determine either symbiosis or pathogenicity.

Nitric oxide (NO) is an important signaling molecule implicated in numerous physiological and pathological conditions. NO homeostasis is crucial to its proper functions and misregulation of NO production is implicated in a large number of pathologies. The effect of NO depends on the cell microenvironment as well as its concentration, spatial, and temporal constraints. Thus, the visualization and monitoring of NO in living systems would be valuable for understanding the origin, activities, and biological effects of NO. This review focuses on organic small-molecule fluorescent probes for selective detection and imaging of endogenous NO in vitro and in vivo. The progress suggests that fluorescence imaging is a vital and rapidly technology for real-time detection of NO in biological system.

[EN] After 30 years of intensive work, nitric oxide (NO) has just started to be characterized as a relevant regulatory molecule on plant development and responses to stress. Its reactivity as a free radical determines its mode of action as an inducer of posttranslational modifications of key target proteins through cysteine S-nitrosylation and tyrosine nitration. Many of the NO-triggered regulatory actions are exerted in tight coordination with phytohormone signaling. This review not only summarizes and updates the information accumulated on how NO is synthesized, sensed, and transduced in plants but also makes emphasis on controversies, deficiencies, and misconceptions that are hampering our present knowledge on the biology of NO in plants. The development of noninvasive accurate tools for the endogenous NO quantitation as well as the implementation of genetic approaches that overcome misleading pharmacological experiments will be critical for getting significant advances in better knowledge of NO homeostasis and regulatory actions in plants., Ministerio de Ciencia e Innovacion, Grant/Award Numbers: BIO2014-56067-P and BIO2017-82945-P; Government of Spain MINECO, Grant/Award Numbers: BIO2017-82945-P and BIO2014-56067-P

Background: There are now indisputable health benefits of nitrite when administered in a clinical setting for specific diseases. Most of the published reports identify the production of nitric oxide (NO) as the mechanism of action for nitrite. Basic science as well as clinical studies demonstrates nitrite and/or nitrate can restore NO homeostasis as an endothelium independent source of NO that may be a redundant system for endogenous NO production. Nitrate must first be reduced to nitrite by oral commensal bacteria and then nitrite further reduced to NO along the physiological oxygen gradient. Despite decades of rigorous research on its safety and efficacy as a curing agent, sodium nitrite is still regarded by many as a toxic undesirable food additive. However, research within the biomedical science community has revealed enormous therapeutic benefits of nitrite that is currently being developed as novel therapies for conditions associated with nitric oxide insufficiency. This review will highlight the fundamental biochemistry of nitrite and nitrate in human physiology and provide evidence that nitrite and nitrate be considered essential nutrients. Foods or diets enriched with nitrite can have profound positive health benefits. Keywords: nitrite, nitrate, nitric oxide, curing, nutrition, epidemiology, cardiovascular, cancer, diet, nitrosamines, antioxidants

Nitrate reductase produces nitric oxide (NO) as an early response to nitrate, and the coordinated induction of ns-haemoglobins finely modulates NO level. The control of NO homeostasis regulates root elongation and represents a novel key component of nitrate signaling in maize, Crop plant development is strongly dependent on nitrogen availability in the soil and on the efficiency of its recruitment by roots. For this reason, the understanding of the molecular events underlying root adaptation to nitrogen fluctuations is a primary goal to develop biotechnological tools for sustainable agriculture. However, knowledge about molecular responses to nitrogen availability is derived mainly from the study of model species. Nitric oxide (NO) has been recently proposed to be implicated in plant responses to environmental stresses, but its exact role in the response of plants to nutritional stress is still under evaluation. In this work, the role of NO production by maize roots after nitrate perception was investigated by focusing on the regulation of transcription of genes involved in NO homeostasis and by measuring NO production in roots. Moreover, its involvement in the root growth response to nitrate was also investigated. The results provide evidence that NO is produced by nitrate reductase as an early response to nitrate supply and that the coordinated induction of non-symbiotic haemoglobins (nsHbs) could finely regulate the NO steady state. This mechanism seems to be implicated on the modulation of the root elongation in response to nitrate perception. Moreover, an improved agar-plate system for growing maize seedlings was developed. This system, which allows localized treatments to be performed on specific root portions, gave the opportunity to discern between localized and systemic effects of nitrate supply to roots.

Beyond an inert oxidation product of nitric oxide (NO) metabolism, current thinking posits a key role for nitrite as a mediator of NO-signaling, especially during hypoxia. This concept has been discussed both in the context of nitrite serving a role as an endogenous modulator of NO-homeostasis, but also from a novel clinical perspective whereby nitrite therapy may replete NO-signaling and prevent ischemic tissue injury. Indeed, the relatively rapid translation of studies delineating mechanisms of action to ongoing and planned clinical trials has been critical in fuelling interest in nitrite biology and several excellent reviews have been written on this topic. In this article we limit our discussions to current concepts, and what we feel are questions that remain unanswered within the paradigm of nitrite being a mediator of NO biology.

Traditional Chinese medicine (TCM) has been used for centuries to treat and prevent certain ailments and diseases. Although TCM has served as mainstream medical care throughout Asia for many generations, it is considered an alternative medical system in much of the Western world. Because many TCMs are used primarily for cardiovascular indications characterized by a nitric oxide (NO) insufficiency, we hypothesized that some, if not all, of these TCMs have a robust NO bioactivity that may act to restore NO homeostasis. We tested a group of convenience samples of TCMs obtained in the United States for endogenous nitrite, nitrate, nitroso, and nitrite reductase activity as well as their ability to relax isolated aortic rings. The results from this study reveal that all of the TCMs tested reveal NO bioactivity through their inherent nitrite and nitrate content and their ability to reduce nitrite to NO. Many of the TCM extracts contain a nitrite reductase activity greater by 1000 times that of biological tissues. Repletion of biological nitrite and nitrate by these extracts and providing a natural system for NO generation in both endothelium-dependent and -independent mechanisms may account for some of the therapeutic effects of TCMs.

It is becoming increasingly clear that many diseases are characterized or associated with perturbations in nitric oxide (NO) production/signaling. Therapeutics or strategies designed to restore normal NO homeostasis will likely have broad application and utility. This highly complex and multistep pathway for NO production and subsequent target activation provides many steps in the endogenous pathway that may be useful targets for drug development for cardiovascular disease, antimicrobial, cancer, wound healing, etc. This article will summarize known strategies that are currently available or in development for enhancing NO production or availability in the human body. Each strategy will be discussed including exogenous sources of NO, use of precursors to promote NO production and downstream pathways affected by NO production with advantages and disadvantages highlighted for each. Development of NO-based therapeutics is and will continue to be a major focus of biotech, academia as well as pharmaceutical companies. Application of safe and effective strategies will certainly transform health and disease.

We read with interest the article by Ghebremariam et al1 demonstrating that proton pump inhibitors (PPIs) reduce endogenous formation of nitric oxide (NO) and impair vascular reactivity.1 This deleterious effect of PPIs occurred through inhibition of the enzyme dimethylarginine dimethylaminohydrolase, which degrades asymmetrical diemethylarginine, an endogenous NO synthase inhibitor.1 The authors discuss this as a possible mechanism explaining the increased risk of adverse cardiovascular events with prolonged PPI treatment.2 We bring up another mechanism by which PPIs may alter vascular NO homeostasis, with possible added deleterious effects …

It is becoming increasingly clear that many diseases are characterized or associated with perturbations in nitric oxide (NO) production/signaling. Therapeutics or strategies designed to restore normal NO homeostasis will likely have broad application and utility in human health. This highly complex and multi-step pathway for NO production and subsequent target activation provides many steps in the endogenous pathway that may be useful targets for drug development. Important therapeutic areas for NO-based therapies are inflammatory disorders, cardiovascular diseases, erectile dysfunction and metabolic disorders.The following review will discuss the endogenous NO pathway, highlight the current market and indications for NO-based therapeutics, as well as identify pathway targets currently under drug development. Each step along the NO pathway will be discussed including exogenous sources of NO, use of precursors to promote NO production and downstream pathways affected by NO production with advantages and disadvantages highlighted for each.Development of NO-based therapeutics is and will continue to be a major focus of biotech and pharmaceutical companies. Understanding and utilizing dietary and nutritional strategies to restore NO homeostasis could allow for safer, quicker marketing of products that may be just as efficacious as drugs designed against specific targets.

The association of NOS with the Golgi-complex has been shown in various mammalian cell types such as neurons (Brain Res Bull 34:301–308, 1994; Exp Cell Res 211:183–188, 1994; J Neurocytol 24:271–281, 1995; Nitric Oxide 4:483–495, 2000), astrocytes (Brain Res Bull 34:301–308, 1994), microglia (Histochem Cell Biol 105:81–89, 1996), retinal cells (Brain Res 690:231–235, 1995), pancreatic islet cells (Histochemistry 101:209–214, 1994), cardiomyocytes (Mol Cell Biochem 217:73–82, 2001), endothelial cells (J Neurosci Res 36:272–279, 1993; Histochem Cell Biol 103:221–225, 1995; J Biol Chem 270:17641–17644, 1995; J Biol Chem 277:4277–4284, 2002; Pflugers Arch 460:965–974, 2010), muscle fibers (J Clin Invest 120:816–826, 2010), lymphocytes (Immunity 24:753–765, 2006) and macrophages (Histochem Cell Biol 105:81–89, 1996). Acrosome, a specialized form of the Golgi-complex in vertebrate spermatocytes, also contains NOS (Anat Histol Embryol 32:321–325, 2003). Comparative studies show that NOS is anchored to the Golgi-complex in the neurons of invertebrates (J Comp Neurol 448:165–185, 2002; J Comp Neurol 501:381–399, 2007) and NO-induced morphological changes of dictyosomes, the functional equivalents of the Golgi-system, from alga cells have also been reported (J Plant Physiol 166:117–127, 2009).

The use of complementary and alternative medicine (CAM) as a therapy and preventative care measure for cardiovascular diseases (CVD) may prove to be beneficial when used in conjunction with or in place of conventional medicine. However, the lack of understanding of a mechanism of action of many CAMs limits their use and acceptance in western medicine. We have recently recognized and characterized specific nitric oxide (NO) activity of select alternative and herbal medicines that may account for many of their reported health benefits. The ability of certain CAM to restore NO homeostasis both through enhancing endothelial production of NO and by providing a system for reducing nitrate and nitrite to NO as a compensatory pathway for repleting NO bioavailability may prove to be a safe and cost-effective strategy for combating CVD. We will review the current state of science behind NO activity of herbal medicines and their effects on CVD.

“There is no homeostasis whatever. We are involved in the business cycles of boom and failure, in the successions of dictatorship and revolution, in the wars which everyone loses, which are so real a feature of modern times,” writes Norbert Wiener in Cybernetics (The MIT press, Cambridge 1961, p. 159).