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Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond

A special issue of Nutrients (ISSN 2072-6643). This special issue belongs to the section "Nutrition and Metabolism".

Deadline for manuscript submissions: closed (15 December 2024) | Viewed by 15586

Special Issue Editor

Dr. Barbora Piknova

E-Mail Website
Guest Editor
Molecular Medicine Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
Interests: nitrate reductive pathway; mammalian nitrate reservoirs; nitric oxide; mammalian nitrate reductase; ageing; diabetes; degenerative eye diseases; cardiovascular disease; exercise; neuromuscular diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce our plans to publish the following Special Issue of Nutrients: “Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond”.

The goal of this Special Issue is to bring together authors from different aspects and corners of the nitric oxide (NO) field to create a fresh view of multiple roles of NO and its metabolites in physiology and to highlight functional transformations of NO.

NO metabolism is dysfunctional in many metabolic, cardiovascular, and neuromuscular diseases, and increasing NO can improve the quality of life of some patients. Even healthy people can benefit from increased NO levels, especially aging people and athletes. The NO precursor, nitrate, is found in many vegetables, which allows everybody “in need of increased NO” to profit from simple dietary intervention. So far, research using dietary nitrate has led to conclusions that it is safe; studies either showed a benefit or no change, with no harm detected. However, more clinical research is needed to understand the basic normal physiology of dietary nitrate transformation into nitric oxide and beyond, as well as sites of its dysfunction in diseases.

We aim to publish the most recent developments within the NO field, hopefully even “beyond” NO itself, such as the role of nitrosothiols (famous “SNO”) and nitro-fatty acids. We also hope that new questions and hypotheses about NO transformations arise in this Special Issue of Nutrients.

Dr. Barbora Piknova
Guest Editor

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Keywords

  • nitrate/nitrite/nitric oxide
  • nitric oxide synthase (NOS)
  • S-nitrosothiols (SNO)
  • nitro-fatty acids
  • nitrate/nitrite transporter (sialin, CLC)
  • nitrate/nitrite reductase
  • oral and gut microbiome
  • diabetes
  • endothelial dysfunction
  • metabolic syndrome
  • cardiovascular diseases
  • ageing
  • athletic performance
  • neuromuscular diseases

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Published Papers (6 papers)

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Research

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15 pages, 38144 KiB  
Article
Protective Effects of the Food Supplement Flexovital in a Model of Cardiovascular-Kidney-Metabolic Syndrome in Mice
by Lucas Rannier Ribeiro Antonino Carvalho, Maria Tydén, Miho Shimari, Zhengbing Zhuge, Tomas A. Schiffer, Matheus Morais de Oliveira Monteiro, Jon O. Lundberg, Eddie Weitzberg, Daniel C. Andersson, Bengt Fellström and Mattias Carlström
Nutrients 2024, 16(23), 4105; https://doi.org/10.3390/nu16234105 - 28 Nov 2024
Viewed by 3139
Abstract
Background/Objectives: The prevalence of cardiovascular-kidney-metabolic (CKM) syndrome is increasing rapidly, and cardiovascular complications pose significant risks in individuals with kidney disease and metabolic dysfunction. Understanding the mechanisms of CKM disorders is crucial, as is the discovery of novel preventive treatments. This study aimed [...] Read more.
Background/Objectives: The prevalence of cardiovascular-kidney-metabolic (CKM) syndrome is increasing rapidly, and cardiovascular complications pose significant risks in individuals with kidney disease and metabolic dysfunction. Understanding the mechanisms of CKM disorders is crucial, as is the discovery of novel preventive treatments. This study aimed to examine the therapeutic effects of a specially formulated nitric oxide-enhancing food additive in a mouse model of CKM syndrome induced by unilateral nephrectomy (UNX) in combination with chronic Western diet (WD) feeding. Methods: C57BL/6J mice underwent UNX and were fed a WD high in salt, sugar, and fat for 12 weeks, compared to sham-operated mice on standard chow. One group of UNX+WD mice received Flexovital (FLX), a food additive containing extracts of Rhodiola rosea and beetroot, and the amino acids L-arginine and L-citrulline. CKM parameters were assessed both in vivo and ex vivo alongside histological and biochemical analyses. Results: The UNX+WD mice showed an increase in body fat mass, the fat/lean mass ratio, and adipocyte area, of which most were significantly reduced by FLX. Elevated fasting glucose levels were also reduced by FLX, which tended towards improving glucose clearance. Elevated arterial blood pressure and endothelial dysfunction in UNX+WD mice were significantly reduced by FLX. FLX improved GFR and reduced glomerular and tubular injuries in UNX+WD mice. Additionally, FLX increased the P/O ratios of oxidative phosphorylation in the isolated renal mitochondria of UNX+WD mice. Conclusions: In this model of CKM syndrome, FLX effectively prevented the onset and progression of CKM dysfunctions induced by UNX+WD, as well as the associated organ injuries. These promising results highlight the need for validation in upcoming human trials. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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11 pages, 4450 KiB  
Article
Dietary Nitrate Metabolism in Porcine Ocular Tissues Determined Using 15N-Labeled Sodium Nitrate Supplementation
by Ji Won Park, Barbora Piknova, Khalid J. Tunau-Spencer, Samantha M. Thomas, Hongyi Cai, Peter J. Walter, Audrey Jenkins, David Hellinga, Leonard M. Parver and Alan N. Schechter
Nutrients 2024, 16(8), 1154; https://doi.org/10.3390/nu16081154 - 13 Apr 2024
Viewed by 1634
Abstract
Nitrate (NO3−) obtained from the diet is converted to nitrite (NO2−) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar [...] Read more.
Nitrate (NO3−) obtained from the diet is converted to nitrite (NO2−) and subsequently to nitric oxide (NO) within the body. Previously, we showed that porcine eye components contain substantial amounts of nitrate and nitrite that are similar to those in blood. Notably, cornea and sclera exhibited the capability to reduce nitrate to nitrite. To gain deeper insights into nitrate metabolism in porcine eyes, our current study involved feeding pigs either NaCl or Na15NO3 and assessing the levels of total and 15N-labeled NO3−/NO2− in various ocular tissues. Three hours after Na15NO3 ingestion, a marked increase in 15NO3− and 15NO2− was observed in all parts of the eye; in particular, the aqueous and vitreous humor showed a high 15NO3− enrichment (77.5 and 74.5%, respectively), similar to that of plasma (77.1%) and showed an even higher 15NO2− enrichment (39.9 and 35.3%, respectively) than that of plasma (19.8%). The total amounts of NO3− and NO2− exhibited patterns consistent with those observed in 15N analysis. Next, to investigate whether nitrate or nitrite accumulate proportionally after multiple nitrate treatments, we measured nitrate and nitrite contents after supplementing pigs with Na15NO3 for five consecutive days. In both 15N-labeled and total nitrate and nitrite analysis, we did not observe further accumulation of these ions after multiple treatments, compared to a single treatment. These findings suggest that dietary nitrate supplementation exerts a significant influence on nitrate and nitrite levels and potentially NO levels in the eye and opens up the possibility for the therapeutic use of dietary nitrate/nitrite to enhance or restore NO levels in ocular tissues. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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Review

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24 pages, 1625 KiB  
Review
Nitric Oxide in Parkinson’s Disease: The Potential Role of Dietary Nitrate in Enhancing Cognitive and Motor Health via the Nitrate–Nitrite–Nitric Oxide Pathway
by Gianluca Tripodi, Mauro Lombardo, Sercan Kerav, Gilda Aiello and Sara Baldelli
Nutrients 2025, 17(3), 393; https://doi.org/10.3390/nu17030393 - 22 Jan 2025
Cited by 1 | Viewed by 1803
Abstract
Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremor, rigidity, and bradykinesia. The pathological hallmarks of PD include Lewy bodies and mechanisms [...] Read more.
Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms such as tremor, rigidity, and bradykinesia. The pathological hallmarks of PD include Lewy bodies and mechanisms like oxidative/nitrosative stress, chronic inflammation, and mitochondrial dysfunction. Nitric oxide (NO), produced by nitric oxide synthase (NOS) isoforms, plays a dual role in neuroprotection and neurodegeneration. Excessive NO production exacerbates neuroinflammation and oxidative/nitrosative damage, contributing to dopaminergic cell death. This review explores NO’s role in PD pathogenesis and investigates dietary nitrate as a therapeutic strategy to regulate NO levels. Methods: A literature review of studies addressing the role of NO in PD was conducted using major scientific databases, including PubMed, Scopus, and Web of Science, using keywords such as “nitric oxide”, “NOSs”, “Parkinson’s disease”, and “nitrate neuroprotection in PD”. Studies on nitrate metabolism via the nitrate–nitrite–NO pathway and its effects on PD hallmarks were analyzed. Studies regarding the role of nitrosamine formation in PD, which are mainly formed during the nitrification process of amines (nitrogen-containing compounds), often due to chemical reactions in the presence of nitrite or nitrate, were also examined. In particular, nitrate has been shown to induce oxidative stress, affect the mitochondrial function, and contribute to inflammatory phenomena in the brain, another factor closely related to the pathogenesis of PD. Results: Excessive NO production, particularly from iNOS and nNOS, was strongly associated with neuroinflammation and oxidative/nitrosative stress, amplifying neuronal damage in PD. Dietary nitrate was shown to enhance NO bioavailability through the nitrate–nitrite–NO pathway, mitigating inflammation and oxidative/nitrosative damage. Conclusions: Dysregulated NO production contributes significantly to PD progression via inflammatory and oxidative/nitrosative pathways. Dietary nitrate, by modulating NO levels, offers a promising therapeutic strategy to counteract these pathological mechanisms. Further clinical trials are warranted to establish its efficacy and optimize its use in PD management. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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13 pages, 423 KiB  
Review
Associations between Vegetable Nitrate Intake and Cardiovascular Disease Risk and Mortality: A Systematic Review
by Loucas Tan, Libby Stagg, Emily Hanlon, Toby Li, Andrea M. Fairley, Mario Siervo, Jamie Matu, Alex Griffiths and Oliver M. Shannon
Nutrients 2024, 16(10), 1511; https://doi.org/10.3390/nu16101511 - 17 May 2024
Cited by 4 | Viewed by 3700
Abstract
Consumption of nitrate-rich vegetables increases nitric oxide bioavailability, lowers blood pressure, and improves endothelial function. These effects could also translate into reduced cardiovascular disease (CVD) risk and mortality. This systematic review aimed to investigate the associations between habitual vegetable nitrate intake and CVD [...] Read more.
Consumption of nitrate-rich vegetables increases nitric oxide bioavailability, lowers blood pressure, and improves endothelial function. These effects could also translate into reduced cardiovascular disease (CVD) risk and mortality. This systematic review aimed to investigate the associations between habitual vegetable nitrate intake and CVD incidence and mortality. A secondary aim was to identify factors that moderate the relationship between vegetable nitrate intake and CVD incidence/mortality. Seven databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, CINAHL, and APA PsycINFO) were searched from inception to 13 February 2023. Observational studies quantifying vegetable nitrate intake in participants aged 18+ years through self-reported dietary exposure and assessing incidence or mortality from CVD overall, or individual CVD subtypes, were eligible. Five studies including a total of 63,155 participants were included. There was an inverse association between vegetable nitrate intake and most reported CVD outcomes. Reported risk reductions tended to plateau at moderate intake, suggesting a possible ceiling effect. The risk of bias across all studies was low. The results of this systematic review suggest a potential role for vegetable nitrate in reducing CVD risk and mortality. Further randomised controlled trials are now required to corroborate these findings. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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16 pages, 931 KiB  
Review
The Nitrate-Nitrite-Nitric Oxide Pathway: Potential Role in Mitigating Oxidative Stress in Hypertensive Disorders of Pregnancy
by Priscila Oliveira Barbosa, José E. Tanus-Santos, Ricardo de Carvalho Cavalli, Tore Bengtsson, Marcelo F. Montenegro and Valéria Cristina Sandrim
Nutrients 2024, 16(10), 1475; https://doi.org/10.3390/nu16101475 - 14 May 2024
Cited by 6 | Viewed by 3016
Abstract
Hypertensive diseases of pregnancy (HDPs) represent a global clinical challenge, affecting 5–10% of women and leading to complications for both maternal well-being and fetal development. At the heart of these complications is endothelial dysfunction, with oxidative stress emerging as a pivotal causative factor. [...] Read more.
Hypertensive diseases of pregnancy (HDPs) represent a global clinical challenge, affecting 5–10% of women and leading to complications for both maternal well-being and fetal development. At the heart of these complications is endothelial dysfunction, with oxidative stress emerging as a pivotal causative factor. The reduction in nitric oxide (NO) bioavailability is a vital indicator of this dysfunction, culminating in blood pressure dysregulation. In the therapeutic context, although antihypertensive medications are commonly used, they come with inherent concerns related to maternal–fetal safety, and a percentage of women do not respond to these therapies. Therefore, alternative strategies that directly address the pathophysiology of HDPs are required. This article focuses on the potential of the nitrate-nitrite-NO pathway, abundantly present in dark leafy greens and beetroot, as an alternative approach to treating HDPs. The objective of this review is to discuss the prospective antioxidant role of nitrate. We hope our discussion paves the way for using nitrate to improve endothelial dysfunction and control oxidative stress, offering a potential therapy for managing HDPs. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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Other

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14 pages, 2160 KiB  
Systematic Review
Ergogenic Effect of Nitrate Supplementation in Clinical Populations: A Systematic Review and Meta-Analysis
by Cassandra C. Derella, Kara C. Anderson, Mary N. Woessner, Craig Paterson and Jason D. Allen
Nutrients 2024, 16(22), 3832; https://doi.org/10.3390/nu16223832 - 8 Nov 2024
Viewed by 1521
Abstract
Background/Objectives: Inorganic nitrate (NO3−) supplementation, via its conversion to nitric oxide (NO), has been purported to be ergogenic in healthy individuals. Many disease states are characterized by reduced NO bioavailability and are expected to derive a benefit from NO3 [...] Read more.
Background/Objectives: Inorganic nitrate (NO3−) supplementation, via its conversion to nitric oxide (NO), has been purported to be ergogenic in healthy individuals. Many disease states are characterized by reduced NO bioavailability and are expected to derive a benefit from NO3−. This systematic review and meta-analysis evaluate the current literature on the ergogenic effect of NO3− supplementation in individuals with cardiopulmonary and metabolic diseases (CPMD). Methods: Relevant databases were searched up to December 2023 for randomized, placebo-controlled crossover trials for aerobic exercise outcome variables with CPMD. Results: Twenty-two studies were included, and 46% reported ergogenic benefits of inorganic nitrate supplementation. NO3− supplementation had no effect on aerobic performance with respect to maximal (SMD = 0.11, 95% CI: −0.12 to 0.34, p = 0.34) and submaximal (SMD = 0.16, 95% CI: −0.13 to 0.46, p = 0.27) TTE, VO2peak (SMD = 0.002, 95% CI: −0.37 to 0.38, p = 0.99), or 6MW (SMD = 0.01, 95% CI: −0.29 to 0.28, p = 0.96). When the studies were limited to only cardiovascular disease conditions, NO3− supplementation had trivial effects on aerobic performance with respect to Timed Trials (SMD = 0.14, 95% CI: −0.04 to 0.33, p = 0.13), VO2 (SMD = −0.02, 95% CI: −0.32 to 0.27, p = 0.87), and small effects on Distance Trials (SMD = 0.25, 95% CI: −0.18 to 0.69, p = 0.25). Sunset funnel plots revealed low statistical power in all trials. Conclusions: The results of this systematic review revealed that 46% of the individual studies showed a positive benefit from inorganic nitrate supplementation. However, the meta-analysis revealed a trivial effect on physical function in CPMD populations. This is likely due to the large heterogeneity and small sample sizes in the current literature. Full article
(This article belongs to the Special Issue Dietary Nitrate in Health and Diseases: Pathways from Nitrate and NOS to Nitric Oxide and Beyond)
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