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Cited by 94Nitric Oxide and Endothelin EffectsNutritional Studies and DietCardiovascular Health and Disease Prevention

NO-Rich Diet for Lifestyle-Related Diseases

Open access
Kobayashi, Jun, Ohtake, Kazuo, Uchida, Hiroyuki·2015·Nutrients
DOI 10.3390/nu7064911PMC PMC4488823
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Abstract

Decreased nitric oxide (NO) availability due to obesity and endothelial dysfunction might be causally related to the development of lifestyle-related diseases such as insulin resistance, ischemic heart disease, and hypertension. In such situations, instead of impaired NO synthase (NOS)-dependent NO generation, the entero-salivary nitrate-nitrite-NO pathway might serve as a backup system for NO generation by transmitting NO activities in the various molecular forms including NO and protein S-nitrosothiols. Recently accumulated evidence has demonstrated that dietary intake of fruits and vegetables rich in nitrate/nitrite is an inexpensive and easily-practicable way to prevent insulin resistance and vascular endothelial dysfunction by increasing the NO availability; a NO-rich diet may also prevent other lifestyle-related diseases, including osteoporosis, chronic obstructive pulmonary disease (COPD), and cancer. This review provides an overview of our current knowledge of NO generation through the entero-salivary pathway and discusses its safety and preventive effects on lifestyle-related diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the entero-salivary nitrate-nitrite-NO pathway and evidence that dietary nitrate/nitrite from fruits and vegetables may prevent lifestyle-related diseases by increasing NO availability. It discusses safety and preventive effects on insulin resistance, hypertension, cardiac ischemia/reperfusion injury, COPD, cancer, and osteoporosis.

Key findings

  • Ingested dietary nitrate is absorbed and peaks in plasma around 30–60 min; approximately 25% is delivered to the salivary gland, 20% of salivary nitrate is reduced to nitrite by oral commensal bacteria, and about 5% of originally ingested nitrate is swallowed into the stomach as nitrite.
  • In healthy volunteers, oral sodium nitrate (10 mg/kg) increased saliva nitrite from 104 ± 21 to 713 ± 150 μM, saliva nitrate from 0.19 ± 0.03 to 8.2 ± 1 mM, plasma nitrite from 123 ± 19 to 229 ± 46 μM, and plasma nitrate from 30 ± 4 to 432 ± 44 mM at 30 min, with no significant change in plasma S-nitrosothiol.
  • The WHO Acceptable Daily Intake is 3.7 mg/kg/day for nitrate and 0.07 mg/kg/day for nitrite; Japanese average nitrate intake is around 200–300 mg/day (1.5–2 times the ADI), and a DASH-style diet can exceed 1,200 mg/day nitrate, with an expected ~45 mg/day nitrite swallowed, exceeding the nitrite ADI.
  • Dietary nitrate/nitrite improved insulin resistance and reduced blood pressure in humans and animals; examples include 250 mL beetroot juice daily for four weeks in hypertensive patients, 0.1 mmol/kg/day sodium nitrate, and 500 mL beetroot juice containing 45.0 ± 2.6 mmol/L nitrate. Protective effects were also reported for cardiac ischemia/reperfusion injury in animal models, while evidence for COPD, cancer, and osteoporosis remains limited or mixed.

Methods

  • Narrative review; no primary experiments or new data collection.
  • Synthesizes published human, animal, and epidemiological studies, including tables of food nitrate/nitrite content and tissue effects of chronic dietary nitrate supplementation in animal models.
  • Main analysis is qualitative, covering the entero-salivary nitrate-nitrite-NO pathway, safety limits, and preventive effects on lifestyle-related diseases.

Limitations

  • Stated: the role of diet-derived NO activity in lifestyle-related diseases is complex and remains to be fully elucidated; the carrier of NO activity and mechanism of transnitrosylation are unresolved; chronic dietary nitrate effects on tissue nitrite are unclear; more long-term and patient studies are needed, especially for hypertension; large-scale epidemiological evidence for COPD is lacking; and few molecular studies address osteoporosis prevention.
  • Evident from the text: as a narrative review, it reports no systematic search strategy, inclusion criteria, quality appraisal, or meta-analysis, and its conclusions rely on heterogeneous animal and human studies, including small or acute interventions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/nu7064911

Cites

169 of 169 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 200 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    A NO-rich diet may prevent other lifestyle-related diseases, including osteoporosis, COPD, and cancer.

    “a NO-rich diet may also prevent other lifestyle-related diseases, including osteoporosis, chronic obstructive pulmonary disease (COPD), and cancer.”
    Quote in the paperNot a substantial claim
  • Interpretationcitation

    Dietary intake of fruits and vegetables rich in nitrate/nitrite prevents insulin resistance and vascular endothelial dysfunction by increasing NO availability.

    “Recently accumulated evidence has demonstrated that dietary intake of fruits and vegetables rich in nitrate/nitrite is an inexpensive and easily-practicable way to prevent insulin resistance and vascular endothelial dysfunction by increasing the NO availability”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Hord, 2009, Food sources of nitrates and nitrites: The physiologic context for potential health benefits, Am. J. Clin. Nutr. source

      Not checked in the free run.

  • Interpretationnone given

    When NOS-dependent NO generation is impaired, the entero-salivary nitrate-nitrite-NO pathway might serve as a backup system for NO generation by transmitting NO activities in various molecular forms including NO and protein S-nitrosothiols.

    “In such situations, instead of impaired NO synthase (NOS)-dependent NO generation, the entero-salivary nitrate-nitrite-NO pathway might serve as a backup system for NO generation by transmitting NO activities in the various molecular forms including NO and protein S-nitrosothiols.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The beneficial effects of nitrate-rich foods on diseases resulting from circulatory disturbances are attributed to cGMP-dependent actions of NO, including vasodilation and vascular endothelial protection from platelet aggregation and leukocyte adhesion.

    “The beneficial effects of these foods on the diseases resulting from circulatory disturbances are attributed to the cyclic guanosine monophosphate (cGMP)-dependent actions of NO, including vasodilation and vascular endothelial protection from platelet aggregation and leukocyte adhesion [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Davignon, 2004, Role of endothelial dysfunction in atherosclerosis, Circulation source

      Not checked in the free run.

  • Premisecitation

    NO has novel functions through cGMP-independent and protein S-nitrosylation-dependent intracellular signaling pathways.

    “recent studies have indicated novel functions for NO through cGMP-independent and protein S-nitrosylation-dependent intracellular signaling pathways [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Hess, 2005, Protein S-nitrosylation: Purview and parameters, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • May combine two claims. 55
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Premisecitation

    Green leafy vegetables are protective against coronary heart disease, hypertension, and ischemic stroke.

    “Recent prospective and epidemiologic studies have shown that among the various foods, green leafy vegetables are undoubtedly protective against coronary heart disease, hypertension [3,4,5,6], and ischemic stroke [7].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [3] Liu, 2000, Fruit and vegetable intake and risk of cardiovascular disease: The women’s health study, Am. J. Cin. Nutr. source

      Not checked in the free run.

    • cites [4] Joshipura, 2001, The effect of fruit and vegetable intake on risk for coronary heart disease, Ann. Intern. Med. source

      Not checked in the free run.

    • cites [5] Bazzano, 2002, Fruit and vegerable intake and risk of cardiovascular disease in US adults: The first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, Am. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [6] Daucher, 2006, Fruit and vegetable consumption and risk of coronary heart disease: A meta-analysis of cohort studies, J. Nutr. source

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    • cites [7] Joshipura, 1999, Fruit and vegetable intake in relation to risk of ischemic stroke, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S-nitrosylation is associated with activation of transcription factors, regulation of signal transduction molecules, redox protein modification, mitochondrial functions, and cell apoptosis.

    “S-nitrosylation is associated with the activation of transcription factors, the regulation of a number of signal transduction molecules [10] and redox protein modification [11], mitochondrial functions [12,13], and cell apoptosis [14]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [10] Bryan, 2005, Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues, Nat. Chem. Biol. source

      Not checked in the free run.

    • cites [11] West, 2006, Protein glutathiolation by nitric oxide: An intracellular mechanism regulating redox protein modification, FASEB J. source

      Not checked in the free run.

    • cites [12] Larsen, 2011, Dietary inorganic nitrate improves mitochondrial efficiency in humans, Cell Metab. source

      Not checked in the free run.

    • cites [13] Nair, 2011, Can dietary nitrates enhance the efficiency of mitochondria?, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some nitrite escapes protonation in the stomach, enters systemic circulation, and reaches peripheral organs including skeletal muscles, where it acts in an endocrine manner to exert NO-like activity.

    “some of the nitrite escapes the protonation in the acidic milieu of the stomach and enters the systemic circulation, and then reaches the peripheral organs, including skeletal muscles, where it acts in an endocrine manner to exert NO-like activity [18]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Lundberg, 2008, The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics, Nat. Rev. Drug Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ingested dietary nitrate is absorbed in the upper gastrointestinal tract and reaches peak plasma level around 30-60 min after ingestion.

    “the ingested dietary nitrate is absorbed in the upper gastrointestinal tract and reaches the peak plasma level around 30–60 min after ingestion [20]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Lundberg, 2004, Inorganic nitrate is a possible source for systemic generation of nitric oxide, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Released NO in the stomach locally contributes to increasing gastric mucosal blood flow and mucous thickness and serves as first-line host defense against swallowed pathogens.

    “the released NO in the stomach is thought to locally contribute to increasing the gastric mucosal blood flow and mucous thickness to ensure the normal gastric physiology, and serves as the first-line host defense against swallowed pathogens [25,26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Peterson, 2004, Nitrite in saliva increases gastric mucosal blood flow and mucus thickness, J. Clin. Investig. source

      Not checked in the free run.

    • cites [26] Petersson, 2007, Dietary nitrate increases gastric mucosal blood flow and mucosal defence, Am. J. Physiol. Gastrointest. Liver Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increase in plasma nitrite within the physiological range of 0.2-2 μM after nitrite administration enhanced S-nitrosothiol in organs and modulated signaling and gene expressions of cGMP, cytochrome P-450, heat shock protein 70, and heme oxygenase-1.

    “Bryan et al., also showed that the increase in plasma nitrite within the physiological concentration rage of 0.2–2 μM after nitrite administration (plasma concentration of nitrite far lower than those required for vasodilation) enhanced S-nitrosothiol in the organs (heart, kidney, liver, lung, and aorta) with the subsequent modulation of signaling and gene expressions of cGMP, cytochrome P-450, he”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Bryan, 2005, Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A switch to a low nitrate/nitrite diet for two days in rats decreased nitrite levels substantially in all tissues and changed signaling and gene expressions in a direction opposite to nitrite administration.

    “they also showed that a switch of the standard chow to the low nitrate/nitrite diet for two days in rats decreased nitrite levels substantially in all tissues and represented changes of the signaling and gene expressions in a direction opposite to those found with nitrite administration [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Bryan, 2005, Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral intake of sodium nitrate (10 mg/kg) in healthy volunteers significantly increased plasma nitrite but did not increase S-nitrosothiol in plasma.

    “Lundberg et al., showed that oral intake of sodium nitrate (10 mg/kg) in healthy volunteers significantly increased plasma levels of nitrite, but did not increase S-nitrosothiol in plasma [20]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Lundberg, 2004, Inorganic nitrate is a possible source for systemic generation of nitric oxide, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Nitrite reduction to NO is enhanced under hypoxic and acidic conditions, unlike NOS-dependent NO production which requires molecular oxygen.

    “In contrast to NOS-dependent NO production, which requires molecular oxygen, this nitrite reduction to NO is enhanced under hypoxic and acidic conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Chronic dietary nitrate intake does not always increase plasma and tissue levels of nitrite, but increases tissue levels of nitrate and S-nitrosylated products.

    “chronic dietary nitrate intake does not always increase the plasma and tissue levels of nitrite, but increases the tissue levels of nitrate and S-nitrosylated products (Table 3).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    It is unlikely that nitrate causes methemoglobinemia without bacterial contamination, and the 40-50 mg/L limit on nitrate in drinking water is not necessary.

    “A recent report by Avery has argued that it is unlikely that nitrate causes methemoglobinemia without bacterial contamination, and also that the 40–50 mg/L limit on nitrate in drinking water is not necessary [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Avery, 1999, Infantile methemoglobinemia: Reexamining the role of drinking water nitrates, Environ. Health Perspect. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Nitrite-induced transnitrosylation in organs might be an alternative in vivo nitrite signaling for mammalian biology, including protection of protein thiols from irreversible oxidation, transcriptional modulation, and posttranslational regulation of proteins.

    “These observations indicate that the nitrite-induced transnitrosylation in organs might be an alternative in vivo nitrite signaling for the mammalian biology including protection of protein thiols from irreversible oxidation, transcriptional modulation, and posttranslational regulation of most classes of proteins present in all cells [9]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Hess, 2005, Protein S-nitrosylation: Purview and parameters, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

    • Rests on an assumption: The mechanisms and effects of dietary nitrate/nitrite observed in animal and in vitro studies are applicable to humans.

  • May combine two claims.

    Premisecitation

    The average intake of nitrate in Japanese populations is around 200-300 mg/day, one and a half to two times the ADI.

    “the average intake of nitrate in the Japanese populations is around 200–300 mg/day, which is one and a half times to two times the ADI.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A DASH diet containing 1200 mg nitrate exceeds the WHO ADI by more than five-fold and the US EPA level for a 60 kg individual by more than two-fold.

    “This is more than five-fold higher than the WHO’s ADI of 3.7 mg nitrate/kg body weight/day, and more than two-fold the US Environmental Protection Agency’s level of 7.0 mg nitrate/kg body weight/day for a 60 kg individual [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Hord, 2009, Food sources of nitrates and nitrites: The physiologic context for potential health benefits, Am. J. Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The WHO Acceptable Daily Intake for humans for nitrate and nitrite are 3.7 and 0.07 mg/kg body weight/day, respectively.

    “The WHO showed that the Acceptable Daily Intake for humans (ADI) for nitrate and nitrite were 3.7 and 0.07 mg/kg body weight/day, respectively”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    International estimates of nitrate intake from food are 31-185 mg/day in Europe and 40-100 mg/day in the United States.

    “The international estimates of nitrate intake from food are 31–185 mg/day in Europe and 40–100 mg/day in the United States [44,45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Mensinga, 2003, Health implications of exposure to environmental nitrogenous compounds, Toxicol. Rev. source

      Not checked in the free run.

    • cites [45] Gangolli, 1994, Nitrate, nitrite and N-nitroso compounds, Eur. J. Pharmacol.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    For a DASH diet containing 1200 mg nitrate, an individual would swallow approximately 45 mg of nitrite a day, exceeding the ADI of nitrite.

    “for a DASH diet containing 1200 mg nitrate, an individual would be expected to swallow approximately 45 mg of nitrite a day, which easily exceeds the ADI of nitrite.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Insulin resistance is always associated with impaired NO availability, suggesting a reciprocal relationship between insulin activation and endothelial function.

    “insulin resistance is always associated with impaired NO availability, suggesting that a reciprocal relationship exists between insulin activation and endothelial function [50,53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Kim, 2006, Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathphysiological mechanismns, Circulation source

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    • cites [53] Kim, 2008, Vascular inflammation, insulin resistance and reduced nitric oxide production precede the onset of peripheral insulin resistance, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Nitrite formed from dietary nitrate might react with dietary amines to form carcinogenic nitrosoamines.

    “nitrite which is formed from dietary nitrate might react with dietary amines to form carcinogenic nitrosoamines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NO mediates S-nitrosylation of PTPB1 and enhances the effects of insulin.

    “Wang et al., indicated that NO mediates the S-nitrosylation of protein-tyrosine phosphatase 1B (PTPB1) and enhances the effects of insulin [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Wang, 2013, Nitric oxide directly promotes vascular endothelial insulin transport, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO-dependent nitrosylation of GLUT4 facilitates GLUT4 translocation to the membrane for glucose uptake and improves insulin resistance.

    “Jiang recently reported that NO-dependent nitrosylation of GLUT4 facilitates GLUT4 translocation to the membrane for glucose uptake, and improves insulin resistance [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Jiang, 2014, Dietary nitrite improves insulin signaling through GLUT4 translocation, Free Rad. Biol. Med. source

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  • May combine two claims.

    Premisecitation

    On reperfusion, cardiac muscle cells are further injured because mitochondria produce large quantities of ROS due to massive electron leaks and superoxide formation with resupplied oxygen, which denatures cytosolic enzymes and destroys cell membranes by lipid peroxidation.

    “On reperfusion, the cardiac muscle cells are further injured, because in the mitochondria, ROS are produced in large quantities due to massive electron leaks and the formation of superoxide with the resupplied oxygen, which denatures cytosolic enzymes and destroys cell membranes by lipid peroxidation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Leist, 1997, Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis, J. Exp. Med. source

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    • cites [94] Eguchi, 1997, Intracellular ATP levels determine cell death fate by apoptosis or necrosis, Cancer Res.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bhushan et al. reported that dietary nitrite supplementation in drinking water (50 mg/L sodium nitrite, for nine weeks) increased cardiac nitrite, nitrosothiol, and cGMP levels, which improved left ventricular function during heart failure in mice with hypertension produced by transverse aortic constriction.

    “Bhushan et al., reported that dietary nitrite supplementation in drinking water (50 mg/L sodium nitrite, for nine weeks) increased the cardiac nitrite, nitrosothiol, and cGMP levels, which improved the left ventricular function during heart failure in mice with hypertension produced by transverse aortic constriction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Bhushan, 2014, Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling, Circ. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Consuming 250 mL beetroot juice (5.5 mmol nitrate) enhances plasma nitrite and cGMP and decreases blood pressure in healthy volunteers.

    “Kapil et al., also showed a similar finding that consuming 250 mL of beetroot juice (5.5 mmol nitrate) enhanced the plasma levels of nitrite and cGMP with a consequent decrease in blood pressure in healthy volunteers, indicating that there was soluble guanylate cyclase-cGMP-mediated vasodilation following a conversion of the nitrite to bioactive NO [85].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Kapil, 2010, Inorganic nitrate supplementation lowers blood pressure in humans: Role for nitrite-derived NO, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Daily dietary nitrate supplementation (250 mL beetroot juice daily) for four weeks reduces blood pressure and improves endothelial function and arterial stiffness in patients with hypertension.

    “They later presented the effects of dietary nitrate on hypertension, and showed the first evidence that daily dietary nitrate supplementation (250 mL of beetroot juice daily) for four weeks reduced the blood pressure, with improvements in the endothelial function and arterial stiffness in patients with hypertension [90].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Kapil, 2015, Dietary nitrate provides sustained blood pressure lowering in hypertensive patients, Hypertension source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bryan et al. showed that dietary nitrite (50 mg/L) or nitrate (1 g/L) supplementation in drinking water for seven days maintained higher steady-state levels of nitrite, nitroso compounds, and nitrosyl-heme in mouse cardiac muscle, and these mice exhibited a smaller cardiac infarct size after ischemia/reperfusion injury compared with control mice fed a diet deficient in nitrate/nitrite for seven七天.

    “Indeed, Bryan et al., showed that dietary nitrite (50 mg/L) or nitrate (1 g/L) supplementation in drinking water for seven days maintained higher steady-state levels of nitrite and nitroso compounds, as well as nitrosyl-heme, in mouse cardiac muscle, and these mice exhibited a smaller cardiac infarct size after ischemia/reperfusion injury compared with control mice fed a diet deficient in nitrate/”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Bryan, 2007, Dietary nitrite supplementation protects against ischemia-reperfusion injury, Proc. Natl. Acad. Sci. USA source

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  • May combine two claims.

    Premisecitation

    The nitrite level in cardiac tissue is a couple of times higher than in plasma due to an unknown form of active transport from blood to tissues or due to oxidation of endogenously generated NO to nitrite by ceruloplasmin, and serves as a significant extravascular pool for NO during tissue hypoxia.

    “The nitrite level in cardiac tissue is a couple of times higher than that in plasma due to an unknown form of active transport from blood to tissues or due to the oxidation of endogenously generated-NO to nitrite by ceruloplasmin [96], and serves as a significant extravascular pool for NO during tissue hypoxia [97].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] Shiva, 2006, Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis, Nat. Chem. Biol. source

      Not checked in the free run.

    • cites [97] Bryan, 2004, Cellular targets and mechanisms of nitros(yl)ation: An insight into their nature and kinetics in vivo, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Vascular NO availability is expected to be impaired due to reduced NOS activity in ischemia and subsequent consumption by superoxide during reperfusion, resulting in severe ischemia/reperfusion injury.

    “The availability of vascular NO would thus be expected to be impaired due to the reduced NOS activity in ischemia and subsequent consumption by superoxide during reperfusion [95], resulting in severe ischemia/reperfusion injury [30].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] Murata, 2012, Nitrite reduces ischemia/reperfusion-induced muscle damage and improves survival rates in rat crush injury model, J. Trauma Acute Care Surg. source

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    • cites [30] Raat, 2009, Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response, Free Radic. Biol. Med. source

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  • May combine two claims.

    Interpretationcitation

    Tissue levels of S-nitrosothiols are enhanced through nitrite reduction due to NOS inhibition, hypoxia, and acidosis, suggesting that tissue nitrite stores can be regarded as a backup and on-demand NO donor.

    “Indeed, the tissue levels of S-nitrosothiols (NO-mediated signaling molecules) are enhanced through the nitrite reduction due to NOS inhibition, hypoxia, and acidosis [97], suggesting that the tissue nitrite stores can be regarded as a backup and on-demand NO donor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Bryan, 2004, Cellular targets and mechanisms of nitros(yl)ation: An insight into their nature and kinetics in vivo, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another possible cytoprotective effect of nitrite may be mediated by S-nitrosylation effects on intracellular Ca2+ handling, which decreases Ca2+ entry by inhibiting L-type Ca2+ channels and increases sarcoendoplasmic reticulum Ca2+ uptake by activating SERCA2a.

    “Another possible cytoprotective effects of nitrite may be mediated by the effects of S-nitrosylation on the intracellular Ca2+ handling, which decreases Ca2+ entry by inhibiting L-type Ca2+ channels and increasing the sarcoendoplasmic reticulum (SR) Ca2+ uptake by activating SR Ca2+ transport ATPase (SERCA2a) [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Calvert, 2009, Myocardial protection by nitrite, Cardiovasc. Res. source

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  • May combine two claims.

    Premisecitation

    Recent large-scale epidemiological studies reported preventive effects of antioxidant supplementations including vitamins E, C, and beta carotene rich in fruits and vegetables on cardiovascular disease, whereas other studies showed no beneficial effects, and in some cases a decrease in cardiovascular protection was observed.

    “Intriguingly, recent large-scale epidemiological studies reported the preventive effects of antioxidant supplementations including vitamins E, C, and beta carotene rich in fruits and vegetables on cardiovascular disease, whereas no beneficial effects were shown in other studies, and in some cases a decrease in cardiovascular protection with these supplementations was observed [103,104,105].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Vivekananthan, 2003, Use of antioxidant vitamins for the prevention of cardiovascular disease: Meta-analysis of randomized trials, Lancet source

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    • cites [104] Bjelakovic, 2007, Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systemic review and meta-analysis, JAMA source

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    • cites [105] Sesso, 2008, Vitamins E and C in the prevention of cardiovascular disease in men, JAMA source

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  • May combine two claims.

    Premisecitation

    ROS-mediated dysfunction of the sarcoplasmic reticulum induces massive intracellular calcium overload, leading to opening of the mitochondrial permeability transition pore and causing cell apoptosis or necrosis depending on intracellular ATP levels.

    “ROS-mediated dysfunction of the sarcoplasmic reticulum also induces massive intracellular calcium overload, leading to the opening of the mitochondrial permeability transition pore and causing cell apoptosis or necrosis, depending on the intracellular ATP levels [93,94].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [93] Leist, 1997, Intracellular adenosine triphosphate (ATP) concentration: A switch in the decision between apoptosis and necrosis, J. Exp. Med. source

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    • cites [94] Eguchi, 1997, Intracellular ATP levels determine cell death fate by apoptosis or necrosis, Cancer Res.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These effects lead to attenuation of the increase in cytosolic Ca2+ during ischemia and Ca2+ overload during reperfusion.

    “These effects will lead to an attenuation of the increase in cytosolic Ca2+ during ischemia and Ca2+ overload during reperfusion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Carlström et al. showed that dietary nitrate increased tissue levels of nitrite and S-nitrosothiols in the heart, attenuated oxidative stress, and prevented cardiac injury in Sprague-Dawley rats subjected to unilateral nephrectomy and a high-salt diet.

    “Carlström et al., showed that dietary nitrate increased the tissue levels of nitrite and S-nitrosothiols in the heart, and attenuated oxidative stress and prevented cardiac injury in Sprague-Dawley rats subjected to unilateral nephrectomy and a high-salt diet [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Persson, 2011, Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension, Cardiovasc. Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Cured meats generally comprise only 4.8% of daily nitrite intake, and 93% of total nitrite ingestion is derived from saliva, suggesting that cured meats provide minimal contributions to human nitrite intake even if frequently consumed.

    “In fact, cured meats have been reported to generally comprise only 4.8% of the daily nitrite intake, and surprisingly, 93% of the total ingestion of nitrite is derived from saliva [114], suggesting that cured meats provide minimal contributions to the human intake of nitrite, even if they are frequently consumed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Archer, 2002, Evidence that ingested nitrate and nitrite are beneficial to health, J. Food Prot. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Because cured meats such as bacon, sausage, and ham contain high doses of nitrite for preservation, antimicrobial, and color fixation, epidemiological studies have demonstrated that consumption of cured meats is positively linked to the risk of newly diagnosed COPD.

    “Because cured meats such as bacon, sausage and ham contain high doses of nitrite for preservation, antimicrobial and color fixation, epidemiological studies have demonstrated that the consumption of cured meats is positively linked to the risk of newly diagnosed COPD [109,110,111].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [109] Jiang, 2007, Cured meat consumption, lung function, and chronic obstructive pulmonary disease among United States adult, Am. J. Respir. Crit. Care Med. source

      Not checked in the free run.

    • cites [110] Mendez, 2012, Cured meat consumption increases risk of readmission in COPD patients, Eur. Respir. J. source

      Not checked in the free run.

    • cites [111] Varraso, 2007, Prospective study of cured meats consumption and risk of chronic obstructive pulmonary disease in men, Am. J. Epidemiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The dose of nitrite used in that animal study was 250-350 mg/kg/day, which was too high to compare with those achieved in standard human diets.

    “However, the dose of nitrite used in that study was 250–350 mg/kg/day, which was too high to compare with those achieved in standard human diets [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Hsu, 2009, Nitrate and nitrite quantification from cured meat and vegetables and their estimated dietary intake in Australians, Food Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite generates reactive nitrogen species, which may cause nitrosative damage to the lungs, eventually leading to structural changes like emphysema.

    “Nitrite generates reactive nitrogen species, which may cause nitrosative damage to the lungs, eventually leading to structural changes like emphysema [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Varraso, 2007, Prospective study of cured meats consumption and risk of chronic obstructive pulmonary disease in men, Am. J. Epidemiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High dietary nitrate intake does not cause the expected elevation of gastric nitrite concentrations or appreciable changes in serum nitrite concentrations.

    “It has been shown that high dietary nitrate intake does not cause the expected elevation of the gastric nitrite concentrations or appreciable changes in the serum nitrite concentrations [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Pannala, 2003, The effect of dietary nitrate on salivery, plasma, and urinary nitrate metabolism in humans, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The entero-salivary route of dietary nitrate/nitrite might enhance NO availability through formation of S-nitrosothiols and transnitrosylation to other thiol residues of proteins, suggesting that separate metabolic pathways might exist for NO availability depending on tissues and organs.

    “As mentioned above, different from the effects of the direct elevation of nitrite concentration in the plasma, the entero-salivary route of dietary nitrate/nitrite might enhance the availability of NO through the formation of S-nitrosothiols and its transnitrosylation to the other thiol residues of proteins, suggesting that, depending on the tissues and organs, separate metabolic pathways might ex”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because COPD is a state of protein-energy malnutrition due to increased resting metabolic rate and VO2, the effects of dietary nitrate on reduction of RMR and VO2 might be advantageous for patients with COPD.

    “Because COPD is a state of protein-energy malnutrition due to an increased resting metabolic rate and VO2, the effects of dietary nitrate on the reduction of the RMR and VO2 might be advantageous for patients with COPD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: COPD is a state of protein-energy malnutrition due to an increased resting metabolic rate and VO2.

  • May combine two claims.

    Interpretationcitation

    Dietary nitrate significantly reduced VO2 and RMR by improving mitochondrial respiratory chain function and enhancing efficient O2 consumption, suggesting that biologically active nitrogen oxide, including S-nitrosothiols produced in the stomach, might be an important molecule for transfer of biological NO activity for cardiopulmonary function.

    “Instead, dietary nitrate significantly reduced the VO2 and RMR by improving the mitochondrial respiratory chain function and enhancing efficient O2 consumption, suggesting that rather than direct nitrite infusion to enhance the plasma nitrite levels, biologically active nitrogen oxide (including the S-nitrosothiols produced in the stomach) might be an important molecule for the transfer of bi”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Larsen, 2014, Dietary nitrate reduces resting metabolic rate: A randomized, crossover study in humans, Am. J. Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Larsen et al. demonstrated that acute intravenous infusion of nitrite enhanced plasma nitrite levels but did not affect oxygen consumption (VO2) or resting metabolic rate (RMR) in humans.

    “Larsen et al., recently demonstrated that acute intravenous infusion of nitrite enhanced the plasma levels of nitrite, whereas it did not affect the oxygen consumption (VO2) or the resting metabolic rate (RMR) in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Larsen, 2014, Dietary nitrate reduces resting metabolic rate: A randomized, crossover study in humans, Am. J. Clin. Nutr. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Large-scale epidemiological evidence of the impact of nitrate is still lacking.

    “However, large-scale epidemiological evidence of the impact of nitrate is still lacking.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the 1950s, Magree et al. first reported that N-nitrosodimethylamine caused malignant primary hepatic tumors in rats.

    “In the 1950s, Magree et al., first reported that N-nitrosodimethylamine caused malignant primary hepatic tumors in rats [133].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Magee, 1956, The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine, Br. J. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    According to average nitrate/nitrite intake of adults in the US, most daily nitrate intake comes from vegetables, nitrite intake is primarily derived from recycled nitrate in saliva, and very little comes from cured meats and other dietary sources, suggesting that the entero-salivary route may be a more important source of nitrosamine exposure than exogenous intake including cured meats.

    “This is because, according to the average nitrate/nitrite intake of adults in the US, most of the daily nitrate intake (around 90%) comes from vegetables, and the nitrite intake is primarily derived from recycled nitrate in the saliva (5.2–8.6 mg/day nitrite), with very little coming from cured meats (0.05–0.6 mg/day nitrite in 50g/day cured meats) and other dietary sources (0–0.7 mg/day nitrite)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Bryan, 2012, Ingested nitrate and nitrite and stomach cancer risk: An updated review, Food Chem. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Deleterious effects of NO on development of COPD might be derived from iNOS-mediated pro-inflammatory signaling, which is consequently reflected by the huge amount of NO in exhaled air of patients with COPD.

    “However, the deleterious effects of NO on the development of COPD might be derived from iNOS-mediated pro-inflammatory signaling [128], which is consequently (not causally) reflected by the huge amount of NO in the exhaled air of patients with COPD [129].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] Hansel, 2003, A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics, FASEB J. source

      Not checked in the free run.

    • cites [129] Brindicci, 2005, Exhaled nitric oxide from lung periphery is increased in COPD, Eur. Respir. J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent human studies demonstrated that dietary nitrate (beetroot juice containing approximately 200-400 mg of nitrate) improved exercise performance and reduced blood pressure in COPD patients.

    “Recent human studies have demonstrated that dietary nitrate (beetroot juice containing approximately 200–400 mg of nitrate) improved the exercise performance and reduced blood pressure in COPD patients [130,131].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [130] Berry, M.J., Justus, N.W., Hauser, J.I., Case, A.H., Helms, C.C., Basu, S., Rogers, Z., Lewis, M.T., and Miller, G.D. (2014). Dietary nitrate supplementation improves exercise performance and decreases blood pressure in COPD patients. Nitric Oxide. source

      Not checked in the free run.

    • cites [131] Kerley, 2015, Dietary nitrate supplementation in COPD: An acute, double-blind, randomized, placebo-controlled, crossover trial, Nitric Oxide source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    After that report, a number of studies followed in relation to the carcinogenic effects of N-nitroso compounds in animal models.

    “After this report, a number of studies followed in relation to the carcinogenic effects of N-nitroso compounds in animal models [134,135].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Mirvish, 1977, N-nitroso compounds: Their chemical and in vivo formation and possible importance as environmental carcinogenesis, J. Toxicol. Environ. Health source

      Not checked in the free run.

    • cites [135] Mirvish, 1995, Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC, Cancer Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Meta-analyses of primary and secondary cancer prevention trials of dietary antioxidant supplements such as beta carotene, vitamins A, C, and E showed a lack of efficacy and, on the contrary, an increased risk of mortality.

    “Meta-analyses of primary and secondary cancer prevention trials of dietary antioxidant supplements, such as beta carotene, vitamins A, C, and E, showed a lack of efficacy, and on the contrary, an increased risk of mortality [104].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Bjelakovic, 2007, Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systemic review and meta-analysis, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic inflammation, including inflammatory bowel disease and Helicobacter pylori-induced gastritis, induces iNOS and generates large quantities of NO, forming nitrosating and oxidant species such as N2O3 and peroxynitrite, which might cause mutagenesis through deamination, nitration of DNA, or inhibition of the DNA repair system.

    “However, chronic inflammation, including inflammatory bowel disease and Helicobacter pylori-induced gastritis induce inducible NOS (iNOS) and generate large quantities of NO [22,146,147], forming nitrosating and oxidant species such as N2O3 and peroxynitrite, which might cause mutagenesis through deamination, nitration of DNA, or inhibition of the DNA repair system [148,149].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [22] Lundberg, 1994, Greatly increased luminal nitric oxide in ulcerative colitis, Lancet source

      Not checked in the free run.

    • cites [146] Lim, 2001, NF-κB, inducible nitric oxide synthase and apoptosis by Helicobacter pylori infection, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [147] Wilson, 1996, Helicobacter pylori stimulates inducible nitric oxide synthase expression and activity in a murine macrophage cell line, Gastroenterology source

      Not checked in the free run.

    • cites [148] Jaiswal, 2001, Nitric oxide in gastrointestinal epithelial cell cartinogenesis: Linking inflammation to oncogenesis, Am. J. Physiol. Gastrointest. Liver physiol. source

      Not checked in the free run.

    • cites [149] Zhao, 2001, DNA damage by nitrite and peroxynitrite: Protection by dietary phenols, Methods Enzymol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Lifestyle habits such as smoking, alcohol intake, little or no exercise, and inadequate calcium intake all influence calcium-vitamin D metabolism and bone mineral density, in some cases leading to osteoporosis, particularly in postmenopausal women.

    “Lifestyle habits, such as smoking, alcohol intake, little or no exercise, and an inadequate amount of calcium intake all influence the calcium-vitamin D metabolism [152,153,154,155] and bone mineral density, in some cases leading to osteoporosis, particularly in postmenopausal women [156].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [152] Brot, 1999, The influence of smoking on vitamin D status and calcium metabolism, Eur. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [153] Maurel, 2012, Alcohol and bone: Review of dose effects and mechanisms, Osteoporos. Int. source

      Not checked in the free run.

    • cites [154] Holbrook, 1988, Dietary calcium and risk of hip fracture: 14-year prospective population study, Lancet source

      Not checked in the free run.

    • cites [155] Feskanich, 2003, Calcium, vitamin D, milk consumption, and hip fractures: A prospective study among postmenopausal women, Am. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [156] Muraki, 2007, Diet and lifestyle associated with increased bone mineral density: Cross-sectional study of Japanese elderly women at an osteoporosis outpatient clinic, J. Orthop. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There was an inverse association between fruit intake and risk of upper gastrointestinal tract and lung cancer, as well as an inverse association between fiber intake and liver cancer.

    “They showed that there was an inverse association between fruit intake and the risk of upper gastrointestinal tract and lung cancer, as well as an inverse association between fiber intake and liver cancer.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Bradbury, 2014, Fruit, vegetable, and fiber intake in relation to cancer risk: Findings from the European Prospective Investigation into Cancer and Nutrition (EPIC), Am. J. Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Dietary intake of vegetables, fruits, and fiber was inversely associated with risk of colorectal cancer, suggesting little evidence that vegetable intake is associated with risk of any of the individual cancer sites reviewed.

    “The dietary intake of vegetables, as well as fruits and fiber, was inversely associated with the risk of colorectal cancer, suggesting that there is little evidence that vegetable intake is associated with the risk of any of the individual cancer sites reviewed [145].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Bradbury, 2014, Fruit, vegetable, and fiber intake in relation to cancer risk: Findings from the European Prospective Investigation into Cancer and Nutrition (EPIC), Am. J. Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent experimental and epidemiological studies could not demonstrate a positive relationship between nitrate consumption and cancer risk, and the Joint FAO/WHO Expert Committee on Food Additives concluded in 2008 that there was no evidence that nitrate was carcinogenic in humans.

    “However, recent experimental and epidemiological studies could not demonstrate a positive relationship between nitrate consumption and the risk of cancer [121,134], and the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives concluded in 2008 that there was no evidence that nitrate was carcinogenic in humans.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [121] Smit, 1999, Dietary influences on chronic obstructive lung disease and asthma: A review of the epidemiological evidence, Proc. Nutr. Soc. source

      Not checked in the free run.

    • cites [134] Mirvish, 1977, N-nitroso compounds: Their chemical and in vivo formation and possible importance as environmental carcinogenesis, J. Toxicol. Environ. Health source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Few studies have evaluated the detailed mechanism by which inorganic nitrate/nitrite prevents osteoporosis at the molecular level, and further basic research is needed for this purpose.

    “However, few studies have been conducted to evaluate the detailed mechanism by which inorganic nitrate/nitrite prevents osteoporosis at the molecular level, and thus further basic research will be needed for this purpose.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Organic nitrate NO donors such as glycerol trinitrate, isosorbide dinitrate, and mononitrate all have beneficial effects on experimental and clinical osteoporosis, and a number of epidemiological studies indicated that high fruit and vegetable intake appears protective against osteoporosis in men and pre- and postmenopausal women.

    “In this context, it has been shown that organic nitrate NO donors, such as glycerol trinitrate, isosorbide dinitrate and mononitrate all have beneficial effects on experimental and clinical osteoporosis [161,162,163], and a number of epidemiological studies also indicated that a high fruit and vegetable intake appears to have a protective effect against osteoporosis in men and pre- and post”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [161] Wimalawansa, 1996, Nitric oxide donor alleviates ovariectomy-induced bone loss, Bone source

      Not checked in the free run.

    • cites [162] Hao, 2005, Different doses of nitric oxide donor prevent osteoporosis in ovariectomized rats, Clin. Orthop. Relat. Res. source

      Not checked in the free run.

    • cites [163] Jamal, 2013, The effects of organic nitrates on osteoporosis: A systematic review, Osteoporos. Int. source

      Not checked in the free run.

    • cites [164] Prynne, 2006, Fruit and vegetable intakes and bone mineral status: A cross sectional study in 5 age and sex cohorts, Am. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [165] Tucker, 1999, Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women, Am. J. Clin. Nutr. source

      Not checked in the free run.

    • cites [166] Macdonald, 2004, Nutritional associations with bone loss during the menopausal transition: Evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids, Am. J. Clin. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Although the role of diet-derived NO activity in lifestyle-related diseases is complex and remains to be fully elucidated, intake of nitrate as a nutrient in vegetables might be beneficial to human health as a result of synergistic effects with other nutrients present in vegetables, and would be recommended as a nutritional approach to prevention and treatment of lifestyle-related diseases.

    “Although the role of diet-derived NO activity in lifestyle-related diseases is complex and remains to be fully elucidated, the intake of nitrate as a nutrient in vegetables might be beneficial to human health as a result of synergistic effects with other nutrients present in vegetables, and would be recommended as a nutritional approach to the prevention and treatment of the lifestyle related”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    eNOS plays an important role in regulating osteoblast activity and bone formation, because eNOS knockout mice exhibit osteoporosis due to defective bone formation, and eNOS gene polymorphisms were reported to be causally linked to osteoporosis in postmenopausal women.

    “On the other hand, eNOS, a constitutive NO synthase, plays an important role in regulating osteoblast activity and bone formation, because eNOS knockout mice exhibit osteoporosis due to defective bone formation, and eNOS gene polymorphisms were reported to be causally linked to osteoporosis in postmenopausal women [159].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Liu, 2009, Relationships between endothelial nitric oxide synthase gene polymorphisms and osteoporosis in postmenopausal women, J. Zhejiang. Univ. Sci. B source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The implications of NOS-mediated NO in the regulation of bone cell function have been well described in a number of publications.

    “The implications of NOS-mediated NO in the regulation of bone cell function have been well described in a number of publications [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Ralston, 2001, Nitric oxide and bone, Immunology source

      Not checked in the free run.

60 of 60

  • The paper relies on this without support.

    The mechanisms and effects of dietary nitrate/nitrite observed in animal and in vitro studies are applicable to humans.

    “These results suggest that dietary nitrate intake is important in the maintenance of steady-state tissue levels of nitrate/nitrite for NO-mediated cytoprotection.”

  • The paper relies on this without support.

    During heart ischemia, ATP is progressively depleted in cardiac muscle cells, which impairs ion pumps, leads to accumulation of calcium ion, and consequently damages cell membrane stability.

    “During heart ischemia, ATP is progressively depleted in cardiac muscle cells, which impairs ion pumps, leads to the accumulation of calcium ion, and consequently damages the cell membrane stability.”

  • The paper relies on this without support.

    Nitrite, nitrate, and NO-related compounds (e.g., S-nitrosothiols) are constitutively present in blood and tissues.

    “Nitrite, nitrate, and NO-related compounds (e.g., S-nitrosothiols) are constitutively present in blood and tissues.”

  • The paper relies on this without support.

    Arterial vascular remodeling is the major histological finding associated with aging, and these vascular structural changes represent vascular wall fibrosis with increased collagen deposits and reduced elastin fibers, which result in arterial stiffening and subsequent hypertension in elderly patients.

    “Because arterial vascular remodeling is the major histological finding associated with aging, these vascular structural changes represent vascular wall fibrosis with increased collagen deposits and reduced elastin fibers, which result in arterial stiffening and subsequent hypertension in elderly patients.”

  • The paper relies on this without support.

    COPD is a state of protein-energy malnutrition due to an increased resting metabolic rate and VO2.

    “Because COPD is a state of protein-energy malnutrition due to an increased resting metabolic rate and VO2, the effects of dietary nitrate on the reduction of the RMR and VO2 might be advantageous for patients with COPD.”

  • The paper relies on this without support.

    Dietary intake of red and cured meats is associated with an increased risk of certain types of cancer due to the relatively large amounts of nitrite added.

    “In particular, the dietary intake of red and cured meats was found to be associated with an increased risk of certain types of cancer due to the relatively large amounts of nitrite added.”

  • The paper relies on this without support.

    In the stomach, the nitrosonium ion (NO+) derived from nitrite can bind to thiol compounds (R-SH) and amines (especially secondary amines: R1-NH-R2), forming S-nitrosothiol and N-nitrosamine, respectively.

    “In the stomach, the nitrosonium ion (NO+) derived from nitrite can bind to thiol compounds (R-SH) and amines (especially secondary amines: R1-NH-R2), forming S-nitrosothiol and N-nitrosamine, respectively.”

  • The paper relies on this without support.

    N-nitrosamine formation occurs even at neutral or basic pH, while S-nitrosothiol formation tends to occur only under acidic conditions.

    “However, while N-nitrosamine formation occurs even at neutral or basic pH, S-nitrosothiol formation tends to occur only under acidic conditions.”

  • The paper relies on this without support.

    The reaction forming S-nitrosothiol kinetically occurs much more easily than N-nitrosamine formation, particularly in the presence of vitamins C and E and polyphenols, which also eliminate potent nitrosating agents such as N2O3 by decomposing them to NO.

    “In addition, this reaction kinetically occurs much more easily than N-nitrosamine formation, particularly in the presence of vitamins C and E and polyphenols, which are highly present in fruits and vegetables, which also eliminate potent nitrosating agents such as the N2O3 formed from nitrite by decomposing them to NO.”
9 of 9

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Mushroom nitrate mean exceeds its reported range

    Minor

    Table 1 reports a mean mushroom nitrate concentration of 59.0 mg/100 g, but its stated range ends at 8.5 mg/100 g. A mean cannot exceed the maximum of its own range.

1 of 1

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Authors
Kobayashi, J., Ohtake, K., & Uchida, H.
Affiliations
Josai University (JP)
Corresponding author
Kobayashi, Jun
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2015-06-17
Volume
7
Issue
6
Pages
4911-4937
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu7064911
PMC
PMC4488823
OpenAlex
W2149443096
Semantic Scholar
c7fdee6f6bde6eb8dee4ea1b7f03fd8eb1a576a8
Cited by
94
References
168
Citations by year
2026: 1 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 25 · 2021: 9 · 2020: 8 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 2
FWCI
1.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (publishedVersion, cc-by)
  • Josai University Repository of Academia (Josai University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords
nitric oxide, nitrate, nitrite, S-nitrosothiols, nitric oxide synthase, endothelial dysfunction, obesity, insulin resistance, lifestyle-related diseases, dietary nitrate intake, fruits and vegetables, hypertension, ischemic heart disease, osteoporosis, chronic obstructive pulmonary disease, cancer prevention
MeSH terms
Animals, Biological Availability, Chronic Disease, Diet, Disease Models, Animal, Fruit, Humans, Life Style, Nitrates, Nitric Oxide, Nitrites, Vegetables, S-Nitrosothiols

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