The DOI matches its Crossref record; 287 of the 287 references it cites were found in a registry or an index; 14 of the 277 sources its claims cite were checked for support.
Inorganic nitrite therapy: historical perspective and future directions
Open accessAbstract
Over the past several years, investigators studying nitric oxide (NO) biology and metabolism have come to learn that the one electron oxidation product of NO, nitrite anion, serves as a unique player in modulating tissue NO bioavailability. Numerous studies have examined how this oxidized metabolite of NO can act as a salvage pathway for maintaining NO equivalents through multiple reduction mechanisms in permissive tissue environments. Moreover, it is now clear that nitrite anion production and distribution throughout the body can act in an endocrine manner to augment NO bioavailability that is important for physiological and pathological processes. These discoveries have led to renewed hope and efforts for an effective NO based therapeutic agent through the unique action of sodium nitrite as an NO pro-drug. More recent studies also indicate that sodium nitrate may also increase plasma nitrite levels via the enterosalivary circulatory system resulting in nitrate reduction to nitrite by microorganisms found within the oral cavity. In this review, we discuss the importance of nitrite anion in several disease models along with an appraisal of sodium nitrite therapy in the clinic, potential caveats of such clinical uses, and future possibilities of nitrite based therapies.
Overview
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Written from the paper’s full text.
TL;DR
This review argues that inorganic nitrite is not an inert NO byproduct but a recyclable NO reservoir/salvage pathway, with sodium nitrite showing therapeutic potential across ischemic, inflammatory, cardiovascular, and infectious conditions. It surveys historical, biochemical, preclinical, and clinical evidence while cautioning that dose, route, tissue conditions, and trial design critically determine benefit.
Key findings
- Nitrite is reduced back to NO under hypoxia/ischemia via deoxyhemoglobin/myoglobin, xanthine oxidase, acidic disproportionation, mitochondrial cytochrome c oxidase, and other mechanisms; plasma nitrite is usually 200–600 nM, up to 70–90% derives from eNOS, and exogenous nitrite half-life is 20–30 minutes.
- Sodium nitrite is protective in preclinical ischemia-reperfusion (heart, liver, brain, kidney), chronic hindlimb ischemia/angiogenesis, sickle cell disease, hypertension/pulmonary hypertension, cerebral vasospasm, colitis, cystic fibrosis biofilm infections, and shock; effective doses range from high nanomolar/low micromolar for ischemia to high micromolar/low millimolar for colitis and cystic fibrosis.
- Oral sodium nitrite has >98% bioavailability, peak plasma levels at 15–30 minutes, and a circulating half-life of 25–35 minutes; nitrate peaks at ~1.5 hours with an 8–13 hour half-life, and methemoglobinemia of 1–3% may occur at doses >2–3 mg/kg. For cyanide poisoning, sodium nitrite 30 mg/ml over 5–20 minutes (~300 mg total) raises metHb to ~20%.
- The NTP 2-year study found no carcinogenicity in male or female F344/N rats or male B6C3F1 mice given 35–150 mg/kg sodium nitrite, with equivocal female B6C3F1 forestomach epithelial hyperplasia at 150 mg/kg; nitrite may also transiently increase tumor pO2 and improve radiotherapy efficacy.
Methods
- Narrative review, not a systematic review or meta-analysis; it synthesizes historical accounts, NO/nitrite biochemistry, endogenous and exogenous nitrite sources, reduction pathways, disease models, and clinical trial information.
- Draws on cited preclinical and human studies, including pharmacokinetic data from Hunault et al. and references to Clinicaltrials.gov tables (Tables 1–2 are referenced but not included in the supplied text).
- No primary experiments, systematic search strategy, or formal quantitative synthesis are described.
Limitations
- The paper states that many mechanisms remain incompletely understood, including nitrite-heme export/adduct formation, compartment-specific contributions to nitrite reduction, immune modulation, and effects on cancer; it calls for additional study and well-controlled trials.
- It notes that the number of clinical trials involving sodium nitrite is relatively small and that trial designs vary widely, warning that poorly designed or executed trials could impede progress.
- Evident from the text: as a narrative review, it lacks systematic search/inclusion criteria and formal risk-of-bias assessment; the referenced Tables 1–2 are not present in the provided text.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
174 Not checked yet · 23 Own interpretation · 19 No basis given · 6 Partly supported · 2 Supported · 2 Sources not found · 1 Own result · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Importantly, during inflammatory reactions or infection involving increased iNOS expression large amounts of NO are produced resulting in significant increases in plasma nitrate and nitrite [42–44].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
What the sources say
- Partly supportedcites [42] Dykhuizen RS Masson J McKnight G Mowat AN Smith CC Smith LM Benjamin N Plasma nitrate concentration in infective gastroenteritis and inflammatory bowel disease Gut 39 393 395 1996 8949643 PMC1383345 sourceExperimental — accuracy not yet measured
The Abstract and Results report significantly increased plasma nitrate in infective gastroenteritis, consistent with increased NO production. But the Results say most patients with inflammatory bowel disease did not have increased plasma nitrate, and the paper does not establish increased plasma nitrite or iNOS expression as the cause of the measured rise. Page numbers were not supplied for these passages. (LLM, conf=0.89)
- Partly supportedcites [43] Hibbs JB Jr Westenfelder C Taintor R Vavrin Z Kablitz C Baranowski RL Ward JH Menlove RL McMurry MP Kushner JP Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy The Journal of clinical investigation 89 867 877 1992 1541678 PMC442932 sourceExperimental — accuracy not yet measured
The Introduction describes a cytokine-inducible pathway that produces high levels of NO, and the Results report a significant rise in serum nitrate during IL-2 therapy. The paper does not establish that both plasma nitrate and plasma nitrite rise during inflammatory reactions or infection; its measured human setting was IL-2 treatment. (LLM, conf=0.85)
- Not checked yetcites [44] Shi Y Li HQ Shen CK Wang JH Qin SW Liu R Pan J Plasma nitric oxide levels in newborn infants with sepsis J Pediatr 123 435 438 1993 8355123 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It was also shown that the addition of NO to blood generates significant concentrations of plasma nitrite that involved copper oxidation, which was found to be ceruloplasmin dependent NO oxidation [78, 79].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite- Heme interactions
What the sources say
- Not checked yetcites [78] Shiva S WX Ringwood LA Xu X Yuditskaya S Annavajjhala V Miyajima H Hogg N Harris ZL Gladwin MT Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis Nat Chem Biol 2 486 493 2006 16906150 source
- Partly supportedcites [79] Wang X Tanus-Santos JE Reiter CD Dejam A Shiva S Smith RD Hogg N Gladwin MT Biological activity of nitric oxide in the plasmatic compartment Proceedings of the National Academy of Sciences of the United States of America 101 11477 11482 2004 15258287 PMC509225 sourceExperimental — accuracy not yet measured
The Results report that about 30% of added NO below 2 μM formed nitrite in plasma, supporting the nitrite-formation part of the claim. They describe the possible NO oxidase pathway as “likely metal-based,” but do not identify copper or establish ceruloplasmin dependence. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, now it is clear that nitrite anion is recycled back to NO in multiple ways.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO
What the sources say
- Supportedcites [73] Lundberg JO Weitzberg E NO generation from nitrite and its role in vascular control Arteriosclerosis, thrombosis, and vascular biology 25 915 922 2005 15746440 source
The Abstract says nitrite can be recycled back to bioactive NO in blood and tissues and that its reduction occurs through several routes. The “Nitrite Reduction to NO In Vivo” section also describes several alternative pathways for generating NO from nitrite. (LLM, conf=0.94)
- Supportedcites [82] Bryan NS Grisham MB Methods to detect nitric oxide and its metabolites in biological samples Free radical biology & medicine 43 645 657 2007 17664129 PMC2041919 source
The Introduction states that nitrite can be recycled to produce NO in various ways and lists several mechanisms, including mitochondrial electron transport, protonation, deoxyhemoglobin, and xanthine oxidase. This directly supports the paraphrase. (LLM, conf=0.94)
- Supportedcites [83] Calvert JW Lefer DJ Clinical translation of nitrite therapy for cardiovascular diseases Nitric Oxide 22 91 97 2010 19909823 PMC3263353 source
The Introduction says nitrite, once considered an inert NO metabolite, can be reduced back to NO. The Clinical Translation section identifies ischemia, hypoxia, and low pH as conditions under which nitrite releases NO, supporting the broad claim that this occurs in multiple ways. (LLM, conf=0.86)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Shiva et al elegantly demonstrated that nitrite therapy significantly blunted mitochondrial uncoupling during in vivo ischemia reperfusion through nitrite mediated, NO dependent, inhibition of mitochondrial complex I activity [40].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Partly supportedcites [40] Shiva S Sack MN Greer JJ Duranski M Ringwood LA Burwell L Wang X MacArthur PH Shoja A Raghavachari N Calvert JW Brookes PS Lefer DJ Gladwin MT Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J Exp Med 204 2089 2102 2007 17682069 PMC2118713 sourceExperimental — accuracy not yet measured
The Results sections “Nitrite inhibits complex I after I/R” and “Nitrite-dependent protection occurs at the mitochondrial level” support NO-dependent complex I inhibition and improved post-anoxia ATP recovery after nitrite treatment. They do not establish that nitrite significantly blunted mitochondrial uncoupling during in vivo I/R; the paper says ATP formation was measured to exclude uncoupling as a major explanation for the differing respiratory rates. Page numbers are unavailable in our copy. (LLM, conf=0.87)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
In the paper
“nitrite mediated changes in blood flow and endothelial cell growth were blocked by the NO scavenger cPTIO”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“delayed sodium nitrite therapy 5 days after ischemic induction still augments ischemic tissue reperfusion and arteriogenesis development (Pattillo in press).”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites Pattillo in press
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“nitrite therapy significantly increased ischemic tissue nitrite/nitrosothiol levels”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“sodium nitrate therapy was unable to mediate similar responses to nitrite therapy over the duration of study”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“administration of a single dose of sodium nitrite after induction of ischemia did not augment hind limb reperfusion (unpublished observations)”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Our group has reported that continuous sodium nitrite administration increases ischemic hind limb blood flow after permanent femoral artery ligation.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 72
- Probably not a substantial claim. 13
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, nitrite anion has emerged as a reversible metabolite of NO that facilitates endogenous signaling responses differentially affecting gene expression [3, 4], serves as a diagnostic marker of cardiovascular health, and acts as a potential therapeutic agent for several disease states.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Historical account of Nitrite
What the sources say
- Partly supportedcites [3] Pattillo CB Fang K Pardue S Kevil CG Genome expression profiling and network analysis of nitrite therapy during chronic ischemia: possible mechanisms and interesting molecules Nitric Oxide 22 168 179 2010 19963074 PMC4599788 sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says nitrite can be reduced to NO during ischemia, but does not establish that nitrite is a reversible metabolite of NO. The Results and Discussion (pages unavailable) show that nitrite therapy differentially changes gene expression in chronically ischemic tissue. They do not establish the broader claim about endogenous signaling responses. (LLM, conf=0.86)
- Supportedcites [4] Raat NJ Noguchi AC Liu VB Raghavachari N Liu D Xu X Shiva S Munson PJ Gladwin MT Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response Free radical biology & medicine 47 510 517 2009 19464364 PMC2744499 source
The Introduction (page not provided) says NO can be oxidized to nitrite and nitrite can be reduced back to NO, supporting its description as a reversible NO metabolite. The Results and Discussion (pages not provided) report that nitrite modulates cellular responses and differential gene expression, particularly after ischemia-reperfusion. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is well known that endothelium-derived nitric oxide (NO) plays an important role in vascular homeostasis and cardiac function based on seminal studies leading to the Nobel Prize in Physiology or Medicine in 1998 [9, 10].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > NO Generation and metabolism
What the sources say
- Partly supportedcites [9] Bian K Doursout MF Murad F Vascular system: role of nitric oxide in cardiovascular diseases J Clin Hypertens (Greenwich) 10 304 310 2008 18401228 PMC8109995 sourceExperimental — accuracy not yet measured
The opening section describes endothelium-derived NO as important to vascular health, and the Endothelium-Centered Healthy Environment for Vasculature section (p. 306) links it to regulation of arterial tone. The opening section also identifies the 1998 Nobel Prize for discoveries about NO signaling in the cardiovascular system. Our copy does not specifically establish a role for endothelium-derived NO in cardiac function. (LLM, conf=0.83)
- Supportedcites [10] Mizuno A Baretti R Buckberg GD Young HH Vinten-Johansen J Ma XL Ignarro LJ Endothelial stunning and myocyte recovery after reperfusion of jeopardized muscle: a role of L-arginine blood cardioplegia J Thorac Cardiovasc Surg 113 379 389 1997 9040633 source
The Discussion (page not specified) links reduced endothelial NO generation to increased vasoconstriction and reports that inhibiting NO production worsened postischemic contractile dysfunction. It concludes that basal NO participates in protection of the myocardium during ischemia and reperfusion, supporting the claim about vascular and cardiac function. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, given the appreciation of the reciprocal relationship between nitrite and NO plus the fact that NO bioavailability is well known to contribute to numerous disease states [136, 137], therapeutic use of inorganic nitrite may be of widespread benefit.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite
What the sources say
- Supportedcites [136] Arnal JF Dinh-Xuan AT Pueyo M Darblade B Rami J Endothelium-derived nitric oxide and vascular physiology and pathology Cell Mol Life Sci 55 1078 1087 1999 10442089 PMC11146781 source
The citation is attached to the statement about NO bioavailability and disease, not the citing authors’ proposed use of inorganic nitrite. In “NO and vascular pathology,” the source says that decreased NO production or bioactivity contributes to several major cardiovascular diseases. (LLM, conf=0.88)
- Partly supportedcites [137] Li H Forstermann U Nitric oxide in the pathogenesis of vascular disease The Journal of pathology 190 244 254 2000 10685059 sourceExperimental — accuracy not yet measured
The ‘NO and vascular pathology’ section says that decreased NO production or bioactivity contributes to several major cardiovascular diseases. Our copy does not establish a reciprocal relationship between inorganic nitrite and NO. The proposed widespread benefit of nitrite therapy is the citing authors’ inference, not a finding reported by this source. (LLM, conf=0.84)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Lastly, Crawford et al further demonstrated that deoxygenated red cells were able to reduce nitrite to NO which mediated vessel ring dilation, solidifying the biological importance of deoxyhemoglobin reduction of nitrite [109].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by heme containing proteins
What the sources say
- Supportedcites [109] Crawford JH Isbell TS Huang Z Shiva S Chacko BK Schechter AN Darley-Usmar VM Kerby JD Lang JD Jr Kraus D Ho C Gladwin MT Patel RP Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation Blood 107 566 574 2006 16195332 PMC1895612 source
The Discussion states that deoxygenating red blood cells and nitrite produce NO and stimulate NO-dependent vasodilation. The aortic-ring experiments report that red blood cells increased nitrite-dependent dilation at low oxygen tensions, and the NO-dependent vasodilation section reports that an NO scavenger inhibited the relaxation. Page numbers are not provided in the supplied copy. (LLM, conf=0.93)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
In the paper
“These beneficial effects were PKA and eNOS dependent as the effects of dipyridamole were absent in eNOS knockout mice.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [170] Venkatesh PK Pattillo CB Branch B Hood J Thoma S Illum S Pardue S Teng X Patel RP Kevil CG Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway Cardiovascular research 85 661 670 2010 20061326 PMC2819839 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“low dose sodium nitrite therapy quickly restored ischemic hind-limb blood flow within several days and did not affect flow in the contralateral non-ischemic limb”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Chronic tissue ischemia
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Many of these treatment studies involve multiple institutional sponsors and it is clear that the trials exhibit a wide range of designs with respect to randomization, blindedness, and controls.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“All three of these isoforms progressively oxidize and reduce L-arginine to L-citrulline resulting in NO production [13].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > NO Generation and metabolism
What the sources say
- Not checked yetcites [13] Moncada S Higgs A The L-arginine-nitric oxide pathway N Engl J Med 329 2002 2012 1993 7504210 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Recent studies show the potential role of nitrite reduction back to NO under appropriate pathophysiological conditions to generate many nitroso species or that nitrite itself may mediate intracellular nitrosation reactions (e.g. RSNO formation) [22, 23].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > NO Generation and metabolism
What the sources say
- Not checked yetcites [22] Bryan NS Fernandez BO Bauer SM Garcia-Saura MF Milsom AB Rassaf T Maloney RE Bharti A Rodriguez J Feelisch M Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues Nat Chem Biol 1 290 297 2005 16408059 source
- Not checked yetcites [23] Ng ES Jourd’heuil D McCord JM Hernandez D Yasui M Knight D Kubes P Enhanced S-nitroso-albumin formation from inhaled NO during ischemia/reperfusion Circulation research 94 559 565 2004 14739156 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, conditions during tissue ischemia-reperfusion or chronic ischemia are optimal for the reduction of nitrite to NO, where multiple reduction mechanisms may be invoked (e.g. deoxyhemoglobin/myoglobin, xanthine oxidoreductase, acidosis, and others).”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Relation between Nitrite and NO
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Unlike prokaryotes, humans lack defined enzymatic machinery to efficiently reduce nitrate to nitrite although it has been reported that mammalian tissues can reduce nitrate on a less efficient scale [48].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
What the sources say
- Not checked yetcites [48] Jansson EA Huang L Malkey R Govoni M Nihlen C Olsson A Stensdotter M Petersson J Holm L Weitzberg E Holm L Lundberg JO A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis Nat Chem Biol 4 417 417 2008 18516050 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“NO is a well-characterized regulator of mitochondrial function that inhibits cytochrome c oxidase, decreases mitochondrial ROS formation, and limits apoptotic cytochrome c release [32–36].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Relation between Nitrite and NO
What the sources say
- Not checked yetcites [32] Poderoso JJ Carreras MC Lisdero C Riobo N Schopfer F Boveris A Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles Arch Biochem Biophys 328 85 92 1996 8638942 source
- Not checked yetcites [33] Brookes PD-UV Hypothesis: the mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase Free radical biology & medicine 32 370 374 2002 11841927 source
- Not checked yetcites [34] Brookes PS Salinas EP Darley-Usmar K Eiserich JP Freeman BA Darley-Usmar VM Anderson PG Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release The Journal of biological chemistry 275 20474 20479 2000 10791954 source
- Not checked yetcites [35] Burwell LS Nadtochiy SM Brookes PS Cardioprotection by metabolic shut-down and gradual wake-up J Mol Cell Cardiol 46 804 810 2009 19285082 PMC2683198 source
- Not checked yetcites [36] Kim YM Kim TH Seol DW Talanian RV Billiar TR Nitric oxide suppression of apoptosis occurs in association with an inhibition of Bcl-2 cleavage and cytochrome c release The Journal of biological chemistry 273 31437 31441 1998 9813055 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“NO is readily oxidized to nitrite and subsequently nitrate in an oxygen dependent manner; thus, the physiological concentrations of nitrite vary between tissues reflecting the degree of NOS activity as well as oxidation pathways of NO [20, 45].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
What the sources say
- Not checked yetcites [20] Bryan NS Rassaf T Maloney RE Rodriguez CM Saijo F Rodriguez JR Feelisch M Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo Proceedings of the National Academy of Sciences of the United States of America 101 4308 4313 2004 15014175 PMC384737 source
- Not checked yetcites [45] Rodriguez J Maloney RE Rassaf T Bryan NS Feelisch M Chemical nature of nitric oxide storage forms in rat vascular tissue Proceedings of the National Academy of Sciences of the United States of America 100 336 341 2003 12502793 PMC140970 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Usual concentrations of plasma nitrite range from 200–600 nM in many mammals including humans [17].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
What the sources say
- Not checked yetcites [17] Kleinbongard P Dejam A Lauer T Rassaf T Schindler A Picker O Scheeren T Godecke A Schrader J Schulz R Heusch G Schaub GA Bryan NS Feelisch M Kelm M Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals Free radical biology & medicine 35 790 796 2003 14583343 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“However, Cosby et al has shown that the presence of deoxygenated hemoglobin reduced nitrite to NO, which may activate soluble guanylate cyclase to mediate vasodilation [19].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite- Heme interactions
What the sources say
- Not checked yetcites [19] Cosby K Partovi KS Crawford JH Patel RP Reiter CD Martyr S Yang BK Waclawiw MA Zalos G Xu X Huang KT Shields H Kim-Shapiro DB Schechter AN Cannon RO 3rd Gladwin MT Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation Nature medicine 9 1498 1505 2003 14595407 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Nitrite concentrations in plasma and in tissues correlate closely following administration, as transport of nitrite is aided by anion transporters across membranes due to the high concentration gradient from plasma to cells [71].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite chemical reactions and homeostasis
What the sources say
- Not checked yetcites [71] Vitturi DA Teng X Toledo JC Matalon S Lancaster JR Jr Patel RP Regulation of nitrite transport in red blood cells by hemoglobin oxygen fractional saturation American journal of physiology 296 H1398 1407 2009 19286940 PMC2685350
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Endogenous nitrite generation primarily involves two pathways; 1) one electron oxidation of endogenously produced NO to nitrite, and 2) reduction of salivary nitrate to nitrite by commensal bacteria and reabsorption back into the organism.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“NOS3 dependent NO production plays an important role in regulating steady state plasma nitrite levels, while also influencing nitrate, nitroso, and nitrosyl products in tissues [72, 73].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite chemical reactions and homeostasis
What the sources say
- Not checked yetcites [72] Carlstrom M Larsen FJ Nystrom T Hezel M Borniquel S Weitzberg E Lundberg JO Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice Proceedings of the National Academy of Sciences of the United States of America 107 17716 17720 2010 20876122 PMC2955084 source
- Not checked yetcites [73] Lundberg JO Weitzberg E NO generation from nitrite and its role in vascular control Arteriosclerosis, thrombosis, and vascular biology 25 915 922 2005 15746440 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This report clearly demonstrated that the dominant oxidation product of NO in aqueous solution is nitrite and that nitrate formation requires additional oxidation by heme proteins.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite- Heme interactions
What the sources say
- Not checked yetcites [76] Ignarro LJ Fukuto JM Griscavage JM Rogers NE Byrns RE Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine Proceedings of the National Academy of Sciences of the United States of America 90 8103 8107 1993 7690141 PMC47296 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Ingestion of foods rich in nitrates results in elevated plasma levels of both nitrate and nitrite and may help explain the health benefits of certain diets (e.g. Mediterranean) [58].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Exogenous sources of nitrite
What the sources say
- Not checked yetcites [58] Lundberg JO Feelisch M Bjorne H Jansson EA Weitzberg E Cardioprotective effects of vegetables: is nitrate the answer? Nitric Oxide 15 359 362 2006 16563818 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Nitrate intake from sources other than food was estimated to be around 35–44 mg/person/day [64].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Exogenous sources of nitrite
What the sources say
- Not checked yetcites [64] EFSA Nitrate in vegetables: scientific opinion of the panel on contaminants in the food chain The EFSA Journal 689 1 79 2008 PMC10193653 37213838
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“NO readily reacts with molecular oxygen through a single electron oxidation to HNO. Further oxidation of this species results in the formation of nitrite (NO2−) with the major pathway for NO metabolism being oxidation to nitrite and nitrate under normal physiological conditions [67].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite chemical reactions and homeostasis
What the sources say
- Not checked yetcites [67] Yoshida K Kasama K Kitabatake M Imai M Biotransformation of nitric oxide, nitrite and nitrate Int Arch Occup Environ Health 52 103 115 1983 6629503 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Apart from food sources, nitrite (NO2−) is also found in environmental toxicants such as cigarette smoke and car exhaust [63].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Exogenous sources of nitrite
What the sources say
- Not checked yetcites [63] Norman V KC Nitrogen oxides in tobacco smoke Nature 205 915 916 1965 source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Intake of nitrite from environmental sources also occurs through contaminated ground water, commonly due to fertilizers, livestock and human excreta, which pose a potential hazard to health [59, 65].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Exogenous sources of nitrite
What the sources say
- Not checked yetcites [59] Hord NG Tang Y Bryan NS Food sources of nitrates and nitrites: the physiologic context for potential health benefits Am J Clin Nutr 90 1 10 2009 19439460 source
- Not checked yetcites [65] Johnson CJ Kross BC Continuing importance of nitrate contamination of groundwater and wells in rural areas Am J Ind Med 18 449 456 1990 2248249 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Moreover, nitrite administration can precondition liver and heart tissue against subsequent ischemic injury by protecting against mitochondrial dysfunction, enhancing tissue reperfusion respiration and energetics, and limiting ROS-mediated cellular dysfunction [40].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Relation between Nitrite and NO
What the sources say
- Not checked yetcites [40] Shiva S Sack MN Greer JJ Duranski M Ringwood LA Burwell L Wang X MacArthur PH Shoja A Raghavachari N Calvert JW Brookes PS Lefer DJ Gladwin MT Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J Exp Med 204 2089 2102 2007 17682069 PMC2118713 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The main source of endogenous nitrite in mammals is produced through the L-arginine-NO pathway, which is constitutively active in multiple cell types throughout the body [41].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Endogenous sources of nitrite
What the sources say
- Not checked yetcites [41] Leaf CD WJ Tannenbaum SR L-arginine is a precursor for nitrate biosynthesis in humans Biochem Biophys Res Commun 163 1032 1037 1989 2783109 source
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Under acidic conditions (pH 3.2–3.4), nitrite converts to HNO2, which is unstable and forms N2O3 that can subsequently generate free NO (reactions (1), (2) and (3)).”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Acidic reduction of nitrite to NO
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Work from the Zweier lab demonstrated that nitrite reduction to NO in ischemic rat hearts occurred in a NOS independent manner but was associated with tissue pH of 5.5 or below [84].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Acidic reduction of nitrite to NO
What the sources say
- Not checked yetcites [84] Zweier JL Wang P Kuppusamy P Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy The Journal of biological chemistry 270 304 307 1995 7814391 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been reported that peroxynitrite markedly inhibits XO activity in a dose-dependent manner, thus it is possible that subsequent nitrosation of XO due to nitrite reduction to NO in the presence of superoxide may also influence XO activity [104].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Xanthine oxidase
What the sources say
- Not checked yetcites [104] Lee CI Liu X Zweier JL Regulation of xanthine oxidase by nitric oxide and peroxynitrite The Journal of biological chemistry 275 9369 9376 2000 10734080 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, oral ingestion of nitrite into the acidic environment of the stomach produces NO that augments mucus secretion, antibacterial effects of gastric fluids, and ulcer healing [93–97].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Acidic reduction of nitrite to NO
What the sources say
- Not checked yetcites [93] Bjorne HH Petersson J Phillipson M Weitzberg E Holm L Lundberg JO Nitrite in saliva increases gastric mucosal blood flow and mucus thickness The Journal of clinical investigation 113 106 114 2004 14702114 PMC300767 source
- Not checked yetcites [94] Larauche M Anton PM Garcia-Villar R Theodorou V Frexinos J Bueno L Fioramonti J Protective effect of dietary nitrate on experimental gastritis in rats Br J Nutr 89 777 786 2003 12828794 source
- Not checked yetcites [95] Miyoshi M Kasahara E Park AM Hiramoto K Minamiyama Y Takemura S Sato EF Inoue M Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat Free Radic Res 37 85 90 2003 12653221 source
- Not checked yetcites [96] Duncan C Dougall H Johnston P Green S Brogan R Leifert C Smith L Golden M Benjamin N Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate Nat Med 1 564 551 1995 7585121 source
- Not checked yetcites [97] Lundberg JO Weitzberg E Lundberg JM Alving K Intragastric nitric oxide production in humans: measurements in expelled air Gut 35 1543 1546 1994 7828969 PMC1375608 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Xanthine oxidase is structurally related to bacterial nitrate and nitrite reductases and can reduce both nitrate and nitrite [102].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Xanthine oxidase
What the sources say
- Not checked yetcites [102] Alikulov ZA L’Vov NP Kretovich VL Nitrate and nitrite reductase activity of milk xanthine oxidase Biokhimiia 45 1714 1718 1980 6894704
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This concept is confirmed in mice deficient for ceruloplasmin that showed lower basal concentrations of plasma nitrite and less plasma nitrite elevation upon NO administration [78].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite- Heme interactions
What the sources say
- Not checked yetcites [78] Shiva S WX Ringwood LA Xu X Yuditskaya S Annavajjhala V Miyajima H Hogg N Harris ZL Gladwin MT Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis Nat Chem Biol 2 486 493 2006 16906150 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Vessel relaxation was blocked by the soluble guanylyl cyclase inhibitor, ODQ, supporting the conclusion that NO was responsible for these effects.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Acidic reduction of nitrite to NO
What the sources say
- Not checked yetcites [92] Modin A Bjorne H Herulf M Alving K Weitzberg E Lundberg JO Nitrite-derived nitric oxide: a possible mediator of ‘acidic-metabolic’ vasodilation Acta Physiol Scand 171 9 16 2001 11350258
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Thus, nitrite present in blood can react either with oxyhemoglobin (oxyHb) to form nitrate (NO3−) and methemoglobin (metHb) or with deoxyhemoglobin (deoxyHb) to form NO, nitrosylhemoglobin (NO-Hb), and NO adducts.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sources of Nitrite > Nitrite- Heme interactions
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A later study by Modin et al demonstrated that vascular nitrite reduction could occur under moderately acidic pH changes indicating that this pathway may indeed be important for augmenting tissue NO levels [92].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Acidic reduction of nitrite to NO
What the sources say
- Not checked yetcites [92] Modin A Bjorne H Herulf M Alving K Weitzberg E Lundberg JO Nitrite-derived nitric oxide: a possible mediator of ‘acidic-metabolic’ vasodilation Acta Physiol Scand 171 9 16 2001 11350258
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“However, experiments by Cosby et al showed that intra-arterial infusion of nitrite at near-physiological levels causes vasodilation in an arterio-venous gradient manner that is influenced by R-T state conversion and oxygen tension implicating red cell reduction of nitrite to NO [19, 106, 107].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by heme containing proteins
What the sources say
- Not checked yetcites [19] Cosby K Partovi KS Crawford JH Patel RP Reiter CD Martyr S Yang BK Waclawiw MA Zalos G Xu X Huang KT Shields H Kim-Shapiro DB Schechter AN Cannon RO 3rd Gladwin MT Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation Nature medicine 9 1498 1505 2003 14595407 source
- Not checked yetcites [106] Huang KT Keszler A Patel N Patel RP Gladwin MT Kim-Shapiro DB Hogg N The reaction between nitrite and deoxyhemoglobin. Reassessment of reaction kinetics and stoichiometry The Journal of biological chemistry 280 31126 31131 2005 15837788 source
- Not checked yetcites [107] Huang Z Shiva S Kim-Shapiro DB Patel RP Ringwood LA Irby CE Huang KT Ho C Hogg N Schechter AN Gladwin MT Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control The Journal of clinical investigation 115 2099 2107 2005 16041407 PMC1177999 source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Likewise, work from the Jones laboratory also found that dietary nitrate administration through beetroot juice consumption decreased oxygen cost during exercise that was also associated with increased plasma nitrite levels and extended time to exhaustion [125–127].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Mitochondrial Enzymes
What the sources say
- Not checked yetcites [125] Bailey SJ Winyard P Vanhatalo A Blackwell JR Dimenna FJ Wilkerson DP Tarr J Benjamin N Jones AM Dietary nitrate supplementation reduces the O2 cost of low-intesity exercise and enhances tolerance to high-intensity exercise in humans J Appl Physiol 107 1144 1155 2009 19661447 source
- Not checked yetcites [126] Bailey SJ Fulford J Vanhatalo A Winyard PG Blackwell JR DiMenna FJ Wilkerson DP Benjamin N Jones AM Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor excercise in humans J Appl Physiol 109 135 148 2010 20466802 source
- Not checked yetcites [127] Lansley KE Winyard PG Fulford J Vanhatalo A Bailey SJ Blackwell JR DiMenna FJ Gilchrist M Benjamin N Jones AM Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study J Appl Physiol 110 591 600 2011 21071588 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In two studies by Larsen et al, it is clear that dietary nitrate consumption increased plasma nitrite levels and decreased muscle oxygen cost during both sub-maximal and maximal exercise [123, 124].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Mitochondrial Enzymes
What the sources say
- Not checked yetcites [123] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Effects of dietary nitrate on oxygen cost during exercise Acta Physiol (Oxf) 191 59 66 2007 17635415 source
- Not checked yetcites [124] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise Free Radic Biol Med 48 342 347 2010 19913611 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, sodium nitrite mediated metHb formation is slower than other cyanide antidotes (e.g. 4-dimethylaminophenol) and has lead to the notion that the cardiovascular effects of nitrite may also be protective against cyanide mediated increases in central venous pressure [135].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite
What the sources say
- Not checked yetcites [135] Beasley DM Glass WI Cyanide poisoning: pathophysiology and treatment recommendations Occup Med (Lond) 48 427 431 1998 10024740 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Therapeutic administration of sodium nitrite 30 mg/ml over 5–20 minutes (~300 mg total) significantly increases metHb (i.e. ferric heme) levels (~20%) that can bind with cyanide to form cyanmethemoglobin thus competing with cytochrome oxidase a3 [134].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite
What the sources say
- Not checked yetcites [134] Baskin SI Horowitz AM Nealley EW The antidotal action of sodium nitrite and sodium thiosulfate against cyanide poisoning J Clin Pharmacol 32 368 375 1992 1569239 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These studies further demonstrated that the effect of dietary nitrate did not alter heart rate, lactate accumulation, or ventilation, and correlated with an increased time to exhaustion.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Mitochondrial Enzymes
What the sources say
- Not checked yetcites [123] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Effects of dietary nitrate on oxygen cost during exercise Acta Physiol (Oxf) 191 59 66 2007 17635415 source
- Not checked yetcites [124] Larsen FJ Weitzberg E Lundberg JO Ekbolm B Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise Free Radic Biol Med 48 342 347 2010 19913611 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The beneficial effect of sodium nitrite stems from the fact that cyanide has a high binding affinity for ferric iron, which is the basis of cyanide inhibition of cytochrome oxidase a3 thus decreasing mitochondrial respiration [133].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite
What the sources say
- Not checked yetcites [133] Gracia R Shepard G Cyanide poisoning and its treatment Pharmacother 24 1358 1365 2004 15628833 source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these studies demonstrate that nitrite/nitrate positively affects mitochondrial function to alter muscle metabolism, which could similarly affect mitochondrial function of other tissues.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Mitochondrial Enzymes
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“It is well accepted that decreased NO levels contribute to endothelial cell dysfunction, atherosclerotic plaque development, arteriosclerosis, vessel restenosis, peripheral vascular disease, and ischemia-reperfusion injury [14, 15, 138–140].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite
What the sources say
- Not checked yetcites [14] Garcia-Cardena G Martasek P Masters BS Skidd PM Couet J Li S Lisanti MP Sessa WC Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo The Journal of biological chemistry 272 25437 25440 1997 9325253 source
- Not checked yetcites [15] Kolluru GK Siamwala JH Chatterjee S eNOS phosphorylation in health and disease Biochimie 92 1186 1198 2010 20363286 source
- Not checked yetcites [138] Maxwell AJ Cooke JP The role of nitric oxide in atherosclerosis Coronary artery disease 10 277 286 1999 10421966 source
- Not checked yetcites [139] Naseem KM The role of nitric oxide in cardiovascular diseases Molecular aspects of medicine 26 33 65 2005 15722114 source
- Not checked yetcites [140] Grisham MB Granger DN Lefer DJ Modulation of leukocyte-endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemic heart diseases Free Radic Biol Med 25 404 433 1998 9741579 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Castello and coworkers have also shown nitrite-derived NO production by rat liver mitochondria was inhibited by cyanide and enhanced cytochrome c oxidase in a pH dependent manner [84, 117].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > From Nitrite to NO > Reduction by Mitochondrial Enzymes
What the sources say
- Not checked yetcites [84] Zweier JL Wang P Kuppusamy P Direct measurement of nitric oxide generation in the ischemic heart using electron paramagnetic resonance spectroscopy The Journal of biological chemistry 270 304 307 1995 7814391 source
- Not checked yetcites [117] Meyer DJ Enzymatic/non-enzymatic formation of nitric oxide Nature medicine 1 1103 1104 1995 7584968 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Upon oral consumption, inorganic nitrite absorption occurs quickly and primarily in the upper small intestinal region (duodenum and jejunem) typically reaching a peak plasma level between 15–30 minutes that may be influenced by the amount administered and the presence of food in the stomach.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Nitrite pharmacokinetics
What the sources say
- Not checked yetcites [69] Hunault CC van Velzen AG Sips AJ Schothorst RC Meulenbelt J Bioavailability of sodium nitrite from an aqueous solution in healthy adults Toxicology letters 190 48 53 2009 19576277 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“work from Bryan et al demonstrated that nitrite anion itself could stimulate cGC activity and other signaling mediators as treatment with the NO scavenger carboxy-PTIO was unable to prevent these effects by nitrite administration [20].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [20] Bryan NS Rassaf T Maloney RE Rodriguez CM Saijo F Rodriguez JR Feelisch M Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo Proceedings of the National Academy of Sciences of the United States of America 101 4308 4313 2004 15014175 PMC384737 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“cPTIO treatment was shown by numerous groups to attenuate nitrite mediated protection against ischemia-reperfusion injury in vivo indicating that protective mechanisms likely involve NO dependent signaling pathways and molecular responses [47, 89, 156, 162].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [47] Kumar D Branch BG Pattillo CB Hood J Thoma S Simpson S Illum S Arora N Chidlow JH Jr Langston W Teng X Lefer DJ Patel RP Kevil CG Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis Proceedings of the National Academy of Sciences of the United States of America 105 7540 7545 2008 18508974 PMC2396555 source
- Not checked yetcites [89] Webb A Bond R McLean P Uppal R Benjamin N Ahluwalia A Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage Proceedings of the National Academy of Sciences of the United States of America 101 13683 13688 2004 15347817 PMC518813 source
- Not checked yetcites [156] Duranski MR Greer JJ Dejam A Jaganmohan S Hogg N Langston W Patel RP Yet SF Wang X Kevil CG Gladwin MT Lefer DJ Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver The Journal of clinical investigation 115 1232 1240 2005 15841216 PMC1077170 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Specifically, nitrite contributes to intravascular endocrine nitric oxide (NO) transport, hypoxic vasodilation, signaling responses, and tissue cytoprotection after ischemia-reperfusion.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Nitrite relationship with hypoxia
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, peak plasma nitrate levels from sodium nitrite consumption are observed on average by 1.5 hours with a circulating half-life of 8–13 hours depending on dose and route of administration.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Nitrite pharmacokinetics
What the sources say
- Not checked yetcites [69] Hunault CC van Velzen AG Sips AJ Schothorst RC Meulenbelt J Bioavailability of sodium nitrite from an aqueous solution in healthy adults Toxicology letters 190 48 53 2009 19576277 source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Experiments also showed that pharmacological scavengers PTIO and NEM inhibited the protective effects in CS-eNOS-Tg mice, indicating a role for nitrite reduction to NO and S-nitrosylation for cytoprotection [164].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [164] Elrod JW Calvert JW Gundewar S Bryan NS Lefer DJ Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide Proceedings of the National Academy of Sciences of the United States of America 105 11430 11435 2008 18685092 PMC2516252 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Subsequent work by the same group revealed that nitrite therapy potently decreases mitochondrial respiration during ischemia thereby preventing uncoupling of electron transport that increases reactive oxygen species formation leading to cytochrome c release and apoptosis activation [4, 39, 40].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [4] Raat NJ Noguchi AC Liu VB Raghavachari N Liu D Xu X Shiva S Munson PJ Gladwin MT Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response Free radical biology & medicine 47 510 517 2009 19464364 PMC2744499 source
- Not checked yetcites [39] Shiva S HZ Grubina R Sun J Ringwood LA MacArthur PH Xu X Murphy E Darley-Usmar VM Gladwin MT Deoxymyoglobin is a nitrite reducatse that generates nitric oxide and regulates mitochondrial respiration Circulation research 100 654 661 2007 17293481 source
- Not checked yetcites [40] Shiva S Sack MN Greer JJ Duranski M Ringwood LA Burwell L Wang X MacArthur PH Shoja A Raghavachari N Calvert JW Brookes PS Lefer DJ Gladwin MT Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J Exp Med 204 2089 2102 2007 17682069 PMC2118713 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the route of administration did not significantly alter the protective outcome of nitrite therapy as oral administration of sodium nitrite was able to attenuate myocardial ischemia-reperfusion injury [163].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [163] Bryan NS Calvert JW Elrod JW Gundewar S Ji SY Lefer DJ Dietary nitrite supplementation protects against myocardial ischemia-reperfusion injury Proceedings of the National Academy of Sciences of the United States of America 104 19144 19149 2007 18025468 PMC2141922 source
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data are encouraging and strongly suggest that sodium nitrite could ameliorate endothelial cell dysfunction and ischemic injury in this patient population.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sickle cell disease
boostedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.
None of the sources cited for this claim have been checked yet.
In the paper
“Reports from several laboratories demonstrate that sodium nitrite can stimulate hypoxic vasodilation of the pulmonary vasculature indicating that nitrite therapy might be clinically useful for PAH [87, 195, 196].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium Nitrite for Hypertension and Pulmonary Hypertension
What the sources say
- Not checked yetcites [87] Hunter CJ Dejam A Blood AB Shields H Kim-Shapiro DB Machado RF Tarekegn S Mulla N Hopper AO Schechter AN Power GG Gladwin MT Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator Nature medicine 10 1122 1127 2004 15361865 source
- Not checked yetcites [195] Casey DB Badejo AM Jr Dhaliwal JS Murthy SN Hyman AL Nossaman BD Kadowitz PJ Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat American journal of physiology 296 H524 533 2009 19074675 PMC2643888 source
- Not checked yetcites [196] Ingram TE Pinder AG Bailey DM Fraser AG James PE Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite American journal of physiology 298 H331 339 2010 19940079 PMC2822592 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.
In the paper
“Work by Yoon et al demonstrated that acidified sodium nitrite mediated anaerobic killing of mucoid Pseudomonas aeruginosa in cultured biofilms and enhanced killing against this and antibiotic resistant strains in lungs in vivo [200].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Cystic fibrosis and biofilm infection
What the sources say
- Not checked yetcites [200] Yoon SS Coakley R Lau GW Lymar SV Gaston B Karabulut AC Hennigan RF Hwang SH Buettner G Schurr MJ Mortensen JE Burns JL Speert D Boucher RC Hassett DJ Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions The Journal of clinical investigation 116 436 446 2006 16440061 PMC1350997 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.
In the paper
“An initial study by Larsen et al reported that 3 day dietary nitrite supplementation of healthy volunteers with sodium nitrate (0.1 mmol/kg/day) significantly increased plasma nitrite/nitrate levels and decreased diastolic pressure by 3.7 mm Hg [190].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium Nitrite for Hypertension and Pulmonary Hypertension
What the sources say
- Not checked yetcites [190] Larsen FJ Ekblom B Sahlin K Lundberg JO Weitzberg E Effects of dietary nitrate on blood pressure in healthy volunteers N Engl J Med 355 2792 2793 2006 17192551 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It was shown that supplementation of nitrite reduced allograft inflammation, apoptosis, and macrophage recruitment and mitigated donor-specific alloimmune responses to prolong allograft survival.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium nitrite therapy for ischemic tissue disorders
What the sources say
- Not checked yetcites [165] Zhan J Nakao A Sugimoto R Dhupar R Wang Y Wang Z Billiar TR McCurry KR Orally administered nitrite attenuates cardiac allograft rejection in rats Surgery 146 155 165 2009 19628069 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It was also found that nitrite mediated therapy partially involved p21 cyclin-dependent kinase inhibitor as hypoxia pulmonary hypertension was still evident upon nitrite therapy in p21 deficient mice yet reduced pulmonary pressures and ventricular remodeling responses were still reduced.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium Nitrite for Hypertension and Pulmonary Hypertension
What the sources say
- Not checked yetcites [197] Zuckerbraun BS Shiva S Ifedigbo E Mathier MA Mollen KP Rao J Bauer PM Choi JJ Curtis E Choi AM Gladwin MT Nitrite potently inhibits hypoxic and inflammatory pulmonary artery hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation Circulation 121 98 109 2010 20026772
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Mack et al has shown that in human subjects with SCD, small doses of sodium nitrite were adequate to provide detectable changes in systemic plasma nitrite levels and augment forearm blood flow [187].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sickle cell disease
What the sources say
- Not checked yetcites [187] Mack AK McGowan VR II Tremonti CK Ackah D Barnett C Machado RF Gladwin MT Kato GJ Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study British journal of haematology 142 971 978 2008 18671702 PMC2766260 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, sodium nitrite therapy minimally increased plasma and lung nitrite levels but still ameliorated disease.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium Nitrite for Hypertension and Pulmonary Hypertension
What the sources say
- Not checked yetcites [197] Zuckerbraun BS Shiva S Ifedigbo E Mathier MA Mollen KP Rao J Bauer PM Choi JJ Curtis E Choi AM Gladwin MT Nitrite potently inhibits hypoxic and inflammatory pulmonary artery hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation Circulation 121 98 109 2010 20026772
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Webb et al investigated the possibility of increasing plasma nitrite levels through dietary nitrate by consumption of beetroot juice (~500 mls) that was also found to acutely lower arterial BP, augment endothelial function during ischemia, and inhibit platelet aggregation as a result of bioconversion to NO in healthy individuals [191].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Therapeutic implications of sodium nitrite > Sodium Nitrite for Hypertension and Pulmonary Hypertension
What the sources say
- Not checked yetcites [191] Webb AJ Patel N Loukogeorgakis S Okorie M Aboud Z Misra S Rashid R Miall P Deanfield J Benjamin N MacAllister R Hobbs AJ Ahluwalia A Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite Hypertension 51 784 790 2008 18250365 PMC2839282 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“It was also determined that nitrite mediated protection was independent of eNOS function but was lost in sGC knockout animals.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases
What the sources say
- Not checked yetcites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Oral nitrite therapy reversed the loss of colonic nitrite levels and decreased TNF-α expression, which was associated with clinical and histological improvements.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Experimental colitis
What the sources say
- Not checked yetcites [233] Ohtake K Koga M Uchida H Sonoda K Ito J Uchida M Natsume H Kobayashi J Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice Nitric Oxide 23 65 73 2010 20399279 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In 1956, Magee and Barnes reported that certain nitrosamines could cross react with nitrite and naturally occur as secondary amines in food, compounds that act as carcinogens in rodents [256].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy and Cancer
What the sources say
- Not checked yetcites [256] Magee PN Barnes JM The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine Br J Cancer 10 114 122 1956 13342328 PMC2074083 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Lastly, the protective effect of nitrite was not restricted to TNF-α but also protected against LPS induce sepsis.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases
What the sources say
- Not checked yetcites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, it is important to understand that organic inhalant nitrites are completely different than inorganic nitrite anion including separate metabolic pathways for NO formation and lack of tissue specificity.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy and Cancer
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“the effects of 5-aminosalicylic acid (5-ASA- an anti-inflammatory agent for the treatment of inflammatory bowel disease) attenuated depletion of colon tissue nitrite levels, increased systemic nitrite levels, and oxidative stress during DSS colitis.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Experimental colitis
What the sources say
- Not checked yetcites [234] Saijo F Milsom AB Bryan NS Bauer SM Vowinkel T Ivanovic M Andry C Granger DN Rodriguez J Feelisch M On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease Nitric Oxide 22 155 167 2010 20005300 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Nitrite was shown to protect mitochondria against oxidative stress thus shielding organs from shock-induced damage.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases
What the sources say
- Not checked yetcites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“This study found that the development of DSS colitis involves an early loss of colon tissue nitrite levels with a concomitant increase in systemic nitrite.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Experimental colitis
What the sources say
- Not checked yetcites [234] Saijo F Milsom AB Bryan NS Bauer SM Vowinkel T Ivanovic M Andry C Granger DN Rodriguez J Feelisch M On the dynamics of nitrite, nitrate and other biomarkers of nitric oxide production in inflammatory bowel disease Nitric Oxide 22 155 167 2010 20005300 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Bjorne et al demonstrated that salivary nitrite increases gastric mucosal blood flow and mucus production [93].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Gastric ulcer and wound healing
What the sources say
- Not checked yetcites [93] Bjorne HH Petersson J Phillipson M Weitzberg E Holm L Lundberg JO Nitrite in saliva increases gastric mucosal blood flow and mucus thickness The Journal of clinical investigation 113 106 114 2004 14702114 PMC300767 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“It was found that daily administration of 85 mg/L−1 in the drinking water for 8–10 weeks decreased body weight, plasma triglycerides, and visceral fat while improving glucose tolerance and fasting blood glucose levels in eNOS deficient mice.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Hypercholesterolemia
What the sources say
- Not checked yetcites [72] Carlstrom M Larsen FJ Nystrom T Hezel M Borniquel S Weitzberg E Lundberg JO Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice Proceedings of the National Academy of Sciences of the United States of America 107 17716 17720 2010 20876122 PMC2955084 source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“A recent study by Cauwels et al shows that exogenous sodium nitrite treatment, in sharp contrast to exacerbation by NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress, tissue ischemia, and mortality in a TNF-α induced murine shock model [214].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases
What the sources say
- Not checked yetcites [214] Buys ES Cauwels A Raher MJ Passeri JJ Hobai I Cawley SM Rauwerdink KM Thibault H Sips PY Thoonen R Scherrer-Crosbie M Ichinose F Brouckaert P Bloch KD sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models American journal of physiology 297 H654 663 2009 19502556 PMC2724210 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, the relationship between nitrite and nitrate exposure and human cancer remains equivocal.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy and Cancer
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“It was reported that during the development of colitis, tissue levels of nitrite dropped quickly along with a concomitant increase in colonic TNF-α expression by day three followed by increased myeloperoxidase activity, and iNOS and HO-1 expression at day 7.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Experimental colitis
What the sources say
- Not checked yetcites [233] Ohtake K Koga M Uchida H Sonoda K Ito J Uchida M Natsume H Kobayashi J Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice Nitric Oxide 23 65 73 2010 20399279 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, the duration and route of administration of inorganic nitrite clearly influences observed beneficial effects such that continuous dosing is required to alleviate chronic tissue ischemia versus single dose therapy for acute ischemia, and that topical/oral administration (skin, mucosal surfaces, or internal organs) of nitrite can differentially affect biological responses versus intravascular”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Innate and acquired immune responses
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Second, the required dose of nitrite necessary for beneficial effects differs significantly amongst disorders such that high nanomolar to low micromolar nitrite levels are protective during tissue ischemia, yet high micromolar to low millimolar doses appear to be required for attenuating colitis pathology and bacterial growth associated with cystic fibrosis.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy for Inflammatory Diseases > Innate and acquired immune responses
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: High doses of sodium nitrite are toxic in humans.
None of the sources cited for this claim have been checked yet.
In the paper
“As discussed above, sodium nitrite therapy may actually be an effective anti-tumor therapy through NO mediated radiosenitization or tumoricidal properties [278, 279].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite > Potential Downsides?
What the sources say
- Not checked yetcites [278] Brantley EC Guo L Zhang C Lin Q Yokoi K Langley RR Kruzel E Maya M Kim SW Kim SJ Fan D Fidler IJ Nitric oxide-mediated tumoricidal activity of murine microglial cells Translational oncology 3 380 388 2010 21151477 PMC3000463 source
- Not checked yetcites [279] Maksimovic-Ivanic D Mijatovic S Harhaji L Miljkovic D Dabideen D Fan Cheng K Mangano K Malaponte G Al-Abed Y Libra M Garotta G Nicoletti F Stosic-Grujicic S Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo Molecular cancer therapeutics 7 510 520 2008 18347138 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In short, these studies established biochemical and physiological parameters as well as addressing some safety concerns that provide useful baseline information for the field moving forward.”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“It is very important to emphasize that clinical trial design parameters strongly influence data outcome, interpretation, and conclusions [267, 268].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite
What the sources say
- Not checked yetcites [267] Pocock SJ Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation Controlled clinical trials 18 530 545 discussion 546-539 1997 9408716 source
- Not checked yetcites [268] Wade DT Outcome measures for clinical rehabilitation trials: impairment, function, quality of life, or value? American journal of physical medicine & rehabilitation/Association of Academic Physiatrists 82 S26 31 2003 14502036 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Conversely, it has been reported that sodium nitrite administration to tumor bearing mice does not significantly affect growth rates and that nitrite can inhibit cell division of certain tumor cell lines [263, 277].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite > Potential Downsides?
What the sources say
- Not checked yetcites [263] Morcos E Carlsson S Weitzberg E Wiklund NP Lundberg JO Inhibition of cancer cell replication by inorganic nitrite Nutrition and cancer 62 501 504 2010 20432171 source
- Not checked yetcites [277] Kitamura Y Yamagihi M Okazaki K Furukawa F Imazawa T Nishikawa A Hirose M Lack of enhancing effects of sodium nitrite on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) induced mammary carcinogenesis in female Sprague-Dawley rats Cancer Lett 235 69 74 2006 15951105 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Conversely, it has been reported that sodium nitrite administration to tumor bearing mice does not significantly affect growth rates and that nitrite can inhibit cell division of certain tumor cell lines [263, 277].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite > Potential Downsides?
What the sources say
- Not checked yetcites [263] Morcos E Carlsson S Weitzberg E Wiklund NP Lundberg JO Inhibition of cancer cell replication by inorganic nitrite Nutrition and cancer 62 501 504 2010 20432171 source
- Not checked yetcites [277] Kitamura Y Yamagihi M Okazaki K Furukawa F Imazawa T Nishikawa A Hirose M Lack of enhancing effects of sodium nitrite on 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) induced mammary carcinogenesis in female Sprague-Dawley rats Cancer Lett 235 69 74 2006 15951105 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies have addressed this concern with Veselik et al indicating that nitrite could potentially bind and activate ER-α+ breast cancer cells thereby influencing their growth [273–275].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Clinical Trials using Sodium Nitrite > Potential Downsides?
What the sources say
- Not checked yetcites [273] Furukawa F Nishikawa A Miyauchi M Nakamura H Son HY Yamagishi M Hirose M Concurrent administration of fish meal and sodium nitrite does not promote renal carcinogenesis in rats after initiation with N-ethyl-N-hydroxyethylnitrosamine Cancer Lett 154 45 51 2000 10799738 source
- Not checked yetcites [274] Masuda S Terashima Y Sano A Kuruto R Sugiyama Y Shimoi K Tanji K Yoshioka H Terao Y Kinae N Changes in the mutagenic and estrogenic activities of bisphenol A upon treatment with nitrite Mutation research 585 137 146 2005 15936980 source
- Not checked yetcites [275] Miyauchi M Nakamura H Furukawa F Son HY Nishikawa A Hirose M Promoting effects of combined antioxidant and sodium nitrite treatment on forestomach carcinogenesis in rats after initiation with N-methyl-N-nitro-N-nitrosoguanidine Cancer Lett 178 19 24 2002 11849737 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Findings from animal models of ischemia-reperfusion and other diseases are relevant to human patients.
“indicating that nitrite therapy might be clinically useful for PAH”
“suggesting that aerosolized sodium nitrite therapy might be beneficial for controlling CF associated bacterial infections.”
The paper relies on this without support.
High doses of sodium nitrite are toxic in humans.
“This is an important distinction given the fact that high doses of sodium nitrite can be toxic thus making nitrite therapy for certain diseases largely unrealistic.”
The paper relies on this without support.
Nitrite/nitrate levels measured in plasma or tissues reflect NO bioavailability and functional NO signaling.
“plasma nitrite levels may be an important indicator of vascular health and function in PAD patients”
The paper relies on this without support.
Nitrite anion is an important source of bioactive NO under low pH conditions.
“Nitrite anion is known to represent an important source of bioactive NO under low pH conditions.”
The paper relies on this without support.
NO drives local vasodilation and increases perfusion.
“The characteristic of NO, by driving local vasodilation and increasing perfusion, suggests that it may have therapeutic potential in tumors to allow transient increase in the delivery and efficacy of anti-cancer drugs.”
The paper relies on this without support.
Inflammatory activity influences nearly every aspect of human disease.
“In particular, recent developments regarding nitrite modulation of immune responses are very intriguing and merit further investigation as it is now known that inflammatory activity influences nearly every aspect of human disease.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The plethora of studies documenting protective effects of nitrite in cell culture or animal models, together with human use of nitrite in cyanide antidote kits, has laid the foundation for clinical evaluation of nitrite therapy for a variety of ischemia related disorders (summarized in [8, 11, 117]).”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [117]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Inorganic Nitrite Therapy: Historical perspective and future directions > References
“54. Duncan C Dougall H Johnston P Green S Brogan R Leifert C Smith L Golden M Benjamin N Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate Nature medicine 1 546 551 1995 7585121”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > References
“96. Duncan C Dougall H Johnston P Green S Brogan R Leifert C Smith L Golden M Benjamin N Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate Nat Med 1 564 551 1995 7585121”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Inorganic Nitrite Therapy: Historical perspective and future directions > Sodium Nitrite Therapy and Cancer
“Soderberg has previously reported that amyl nitrite inhalant exposure led to a significant increase in tumor growth rate in mice [259].”
§ Inorganic Nitrite Therapy: Historical perspective and future directions > References
“259. Soderberg LS Increased tumor growth in mice exposed to inhaled isobutyl nitrite Toxicology letters 104 35 41 1999 10048747”
Citations
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“Gaseous NO freely diffuses through the endothelial cell into the underlying smooth muscle cells to promote vasorelaxation [24], and can also affect cells passing through the blood stream, such as platelets and leukocytes to control inflammation [25–28].”
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“There are three isoforms which were initially named based on their location of expression and function which include: NOS1-neuronal nitric oxide synthase (nNOS), NOS2-inducible nitric oxide synthase (iNOS), and NOS3-endothelial nitric oxide synthase (eNOS) [11, 12].”
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“There are three isoforms which were initially named based on their location of expression and function which include: NOS1-neuronal nitric oxide synthase (nNOS), NOS2-inducible nitric oxide synthase (iNOS), and NOS3-endothelial nitric oxide synthase (eNOS) [11, 12].”
BackgroundThe nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
Lundberg, J. O., Weitzberg, E., & Gladwin, M. T. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2466 · Cited by 2,739
Evolving functions of endothelial cells in inflammation
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Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807 · cited 7×
“This paper proved that near physiological doses of sodium nitrite (high nanomolar) were highly cytoprotective in both myocardial and hepatic ischemia-reperfusion extending previous work from Cosby et al demonstrating that near physiological levels of nitrite anion mediated hypoxic vasodilation responses [19].”
BackgroundInfluential
Research works printed but not linked: 3
- Duncan, 1995, Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate, Nat. Med., 1, 564-551, 10.1038/nm0695-546 · DOI · Paper page
- Li, 2009, The protective effect of nitrite on liver cold ischemia reperfusion injury, Liver Transpl., 15, S236
- Pearse, 1891, The treatment of paroxysmal nerve disorders, Practitioner, 46, 29
Cited by
Sorted by citations
Lu, X., Naidis, G. V., Laroussi, M., Reuter, S., Graves, D. B., & Ostrikov, K. (2016) · Physics Reports · doi:10.1016/j.physrep.2016.03.003 · Cited by 1,247
Maia, L. B., & Moura, J. J. G. (2014) · Chemical Reviews · doi:10.1021/cr400518y · Cited by 401
Lidder, S., & Webb, A. J. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04420.x · Cited by 360
Reactive Species from Cold Atmospheric Plasma: Implications for Cancer Therapy
Graves, D. B. (2014) · Plasma Processes and Polymers · doi:10.1002/ppap.201400068 · Cited by 315
Bahadoran, Z., Mirmiran, P., Jeddi, S., Azizi, F., Ghasemi, A., & Hadaegh, F. (2016) · Journal of Food Composition and Analysis · doi:10.1016/j.jfca.2016.06.006 · Cited by 228
Azzariti, A., Iacobazzi, R. M., Fonte, R., Porcelli, L., Gristina, R., Favia, P., Fracassi, F., Trizio, I., Silvestris, N., Guida, G., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40637-z · Cited by 164
Mechanisms of nitrite bioactivation
Kim-Shapiro, D. B., & Gladwin, M. T. (2014) · Nitric Oxide · doi:10.1016/j.niox.2013.11.002 · Cited by 157
“Numerous other examples of nitrite bioactivation have been demonstrated after initial conversion from nitrate by oral bacteria [13, 14].”
BackgroundInorganic nitrite and nitrate: evidence to support consideration as dietary nutrients
Bryan, N. S., & Ivy, J. L. (2015) · Nutrition Research · doi:10.1016/j.nutres.2015.06.001 · Cited by 131
“As we advance the science of nitric oxide (NO), it is obvious from many basic science and clinical studies that nitrite and nitrate through the proper delivery at the right doses have an enormous impact on many diseases that we are faced with today [1,2].”
BackgroundInfluentialEmerging role of PKA/eNOS pathway in therapeutic angiogenesis for ischaemic tissue diseases
Bir, S. C., Xiong, Y., Kevil, C. G., & Luo, J. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs143 · Cited by 110
Self-citationOxy-nitroso shielding burst model of cold atmospheric plasma therapeutics
Graves, D. B. (2014) · Clinical Plasma Medicine · doi:10.1016/j.cpme.2014.11.001 · Cited by 103
NO donors as the wonder molecules with therapeutic potential: Recent trends and future perspectives
Navale, G. R., Singh, S., & Ghosh, K. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215052 · Cited by 101
Bahadoran, Z., Mirmiran, P., Ghasemi, A., Kabir, A., Azizi, F., & Hadaegh, F. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.04.002 · Cited by 95
Mechanisms of Plasma Medicine: Coupling Plasma Physics, Biochemistry, and Biology
Graves, D. B. (2017) · IEEE Transactions on Radiation and Plasma Medical Sciences · doi:10.1109/trpms.2017.2710880 · Cited by 96
“It is well documented that nitrite has a wide range of therapeutic applications [36].”
BackgroundAnti-obesity and anti-diabetic effects of nitrate and nitrite
Ghasemi, A., & Jeddi, S. (2017) · Nitric Oxide · doi:10.1016/j.niox.2017.08.003 · Cited by 92
Nitrite reduction by molybdoenzymes: a new class of nitric oxide-forming nitrite reductases
Maia, L. B., & Moura, J. J. G. (2015) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-014-1234-2 · Cited by 88
Plasma Free H 2 S Levels are Elevated in Patients With Cardiovascular Disease
Peter, E. A., Shen, X., Shah, S. H., Pardue, S., Glawe, J. D., Zhang, W., Reddy, P. C., Akkuş, N. İ., Varma, J., & Kevil, C. G. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000387 · Cited by 84
“isoenzymes with nonenzymatic reduction of nitrite/nitrate serving as alternative pathways.(1) Likewise, H2S is also produced by 3 principal enzymes including cystathionine c-lyase (CGL/CSE), cystathionine b-synthase (CBS), and 3-mercaptopyruvate transferase (3-MST),(2,3) with nonenzymatic generation via glutathione an…”
BackgroundSelf-citationGasotransmitter Heterocellular Signaling
Kolluru, G. K., Shen, X., Yuan, S. S., & Kevil, C. G. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6909 · Cited by 83
“Even though the medicinal effects of nitrate/nitrite have been known for centuries, these metabolites were considered inert by-products with no definitive biological role (117).”
BackgroundInfluentialSelf-citationCastiglione, N., Rinaldo, S., Giardina, G., Stelitano, V., & Cutruzzolà, F. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4196 · Cited by 81
Mechanisms of Human Erythrocytic Bioactivation of Nitrite
Liu, C., Wajih, N., Liu, X., Basu, S., Janes, J., Marvel, M., Keggi, C., Helms, C. C., Lee, A. N., Belanger, A. M., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.609222 · Cited by 76
Jädert, C., Phillipson, M., Holm, L., Lundberg, J. O., & Borniquel, S. (2014) · Redox Biology · doi:10.1016/j.redox.2013.12.012 · Cited by 73
“Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.redox.2013.12.012.”
BackgroundInfluentialLee, J., Hlaing, S. P., Cao, J., Hasan, N., Ahn, H., Song, K., & Yoo, J. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11100496 · Cited by 74
Nitrite and nitric oxide metabolism in peripheral artery disease
Allen, J. D., Giordano, T., & Kevil, C. G. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.003 · Cited by 71
Self-citationCystathionine γ-lyase regulates arteriogenesis through NO-dependent monocyte recruitment
Kolluru, G. K., Bir, S. C., Yuan, S. S., Shen, X., Pardue, S., Wang, R., & Kevil, C. G. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv198 · Cited by 65
Self-citationNitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling
Rajendran, S., Shen, X., Glawe, J. D., Kolluru, G. K., & Kevil, C. G. (2019) · Comprehensive physiology · doi:10.1002/cphy.c180026 · Cited by 69
Self-citationRegulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes
Gheibi, S., Samsonov, A. P., Gheibi, S., Vazquez, A. B., & Kashfi, K. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113819 · Cited by 63
“After oral loading, nitrate/nitrite is rapidly absorbed in the duodenum and jejunum [10, 67].”
BackgroundChen, X., Chen, L., Lin, G., Wang, Z., Kodali, M. C., Li, M., Chen, H., Lebovitz, S. G., Ortyl, T. C., Li, L., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01701-9 · Cited by 66
“Historical evidence suggests that using dietary supplements with natural products represents a safest strategy [71].”
Mechanisms impairing blood pressure responses to nitrite and nitrate
Oliveira‐Paula, G. H., Pinheiro, L. C., & Tanus-Santos, J. E. (2019) · Nitric Oxide · doi:10.1016/j.niox.2019.01.015 · Cited by 61
Vitturi, D. A., & Patel, R. P. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.05.037 · Cited by 59
“The plethora of studies documenting protective effects of nitrite in cell culture or animal models, together with human use of nitrite in cyanide antidote kits, has laid the foundation for the clinical evaluation of nitrite therapy for a variety of ischemia-related disorders (summarized in [8,11,117]).”
From nitrate to NO: potential effects of nitrate-reducing bacteria on systemic health and disease
Liu, H., Huang, Y., Huang, M., Wang, M., Ming, Y., Chen, W., Chen, Y., Tang, Z., & Jia, B. (2023) · European Journal of Medical Research · doi:10.1186/s40001-023-01413-y · Cited by 58
“3) [98, 103, 106].”
A NO way to BOLD?: Dietary nitrate alters the hemodynamic response to visual stimulation
Aamand, R., Dalsgaard, T., Ho, Y.-C. L., Møller, A., Roepstorff, A., & Lund, T. E. (2013) · NeuroImage · doi:10.1016/j.neuroimage.2013.06.069 · Cited by 55
“(Avery, 1999), but via its reduction to nitrite and NO, it is known to subserve several important physiological functions (Kevil et al., 2011).”
BackgroundMaia, L. B., & Moura, J. J. G. (2018) · Redox Biology · doi:10.1016/j.redox.2018.08.020 · Cited by 57
Montenegro, M. F., Pinheiro, L. C., Amaral, J. H., Marçal, D. M. O., Palei, A. C. T., Costa-Filho, A. J., & Tanus-Santos, J. E. (2012) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-011-0712-0 · Cited by 52
“Although many studies have addressed the physiological role of the nitrate–nitrite–NO pathway and explored the therapeutic potential of its activation (Kevil et al. 2011), the effects of nitrite therapy in hypertension remains poorly studied.”
BackgroundBir, S. C., Pattillo, C. B., Pardue, S., Kolluru, G. K., Shen, X., Giordano, T., & Kevil, C. G. (2013) · Diabetes · doi:10.2337/db13-0890 · Cited by 51
“Reports have suggested that nitrate anion (a oneelectron oxidation product of nitrite) could increase plasma nitrite levels through the enterosalivary pathway, thus serving as another modality to modulate plasma and tissue nitrite levels (17).”
BackgroundInfluentialSelf-citationNitric oxide formation versus scavenging: the red blood cell balancing act
Owusu, B. Y., Stapley, R., & Patel, R. P. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.234906 · Cited by 48
“…as a source for NO in ischaemia to limit ischaemia–reperfusion injury (higher endogenous or exogenously applied nitrite protects against numerous ischaemia–reperfusion injury insults; Kevil et al. 2011), RBCs may affect inflammatory disease by modulating the concentration of circulating nitrite.”
BackgroundDoes dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research
Siervo, M., Scialò, F., Shannon, O. M., Stephan, B. C. M., & Ashor, A. W. (2018) · Proceedings of The Nutrition Society · doi:10.1017/s0029665118000058 · Cited by 49
“In the circulation, NO2 may function as a source of NO that is activated in hypoxia and acidic conditions to increase blood flow and regulate BP((79,80)).”
BackgroundNitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections
Bath, P. M., Coleman, C. M., Gordon, A. L., Lim, W. S., & Webb, A. J. (2021) · F1000Research · doi:10.12688/f1000research.51270.2 · Cited by 46
Mohler, E. R., Hiatt, W. R., Gornik, H. L., Kevil, C. G., Quyyumi, A. A., Haynes, W. G., & Annex, B. H. (2013) · Vascular Medicine · doi:10.1177/1358863x13515043 · Cited by 43
Self-citationMcDonagh, S. T. J., Wylie, L. J., Webster, J., Vanhatalo, A., & JONES, A. M. (2017) · Nitric Oxide · doi:10.1016/j.niox.2017.12.001 · Cited by 48
Single-Dose Pharmacokinetics of Different Oral Sodium Nitrite Formulations in Diabetes Patients
Greenway, F. L., Predmore, B. L., Flanagan, D. R., Giordano, T., Qiu, Y., Brandon, A., Lefer, D. J., Patel, R. P., & Kevil, C. G. (2012) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2011.0291 · Cited by 43
“variety of mechanisms including, but not limited to, acidic disproportionation, deoxyhemoglobin and deoxymyoglobin, xanthine oxidoreductase, mitochondrial enzymes, and others.(24) As such, use of sodium nitrite as an NO prodrug for the treatment of various pathophysiological conditions involving decreased NO bioavaila…”
Self-citationH2S Regulation of Nitric Oxide Metabolism
Kolluru, G. K., Yuan, S. S., Shen, X., & Kevil, C. G. (2015) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2014.11.040 · Cited by 43
“In view of difficulties inherent to direct NO detection, measurement of accumulated nitrite and nitrate, stable metabolites of NO, is often used to monitor cumulative NO synthesis, cells in culture, tissue homogenates, perfused organs, and organisms (Kevil et al., 2011).”
BackgroundSelf-citationFunctional Nitric Oxide Nutrition to Combat Cardiovascular Disease
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A “green” diet-based approach to cardiovascular health? Is inorganic nitrate the answer?
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Photoinitiated Reactivity of a Thiolate-Ligated, Spin-Crossover Nonheme {FeNO}7Complex with Dioxygen
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Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy
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Insulin secretion: The nitric oxide controversy
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“More recently this concept has been challenged, due to the accumulating experimental and clinical evidence, which shows that these molecules may play an important physiological role in mediating the biological effects of nitric oxide [1, 2].”
BackgroundBiomedical evaluation of a novel nitrogen oxides releasing wound dressing
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“attractive option for wound management [11].”
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Effects of Erythrocyte Aging on Nitric Oxide and Nitrite Metabolism
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“This paradigm has been supported by many recent studies, and nitrite/nitrate therapies are being tested as potential modalities to replete NO signaling in multiple disease settings (4, 6, 26, 55).”
BackgroundGlean, A. A., Ferguson, S. K., Holdsworth, C. T., Colburn, T. D., Wright, J. L., Fees, A. J., Hageman, K. S., Poole, D. C., & Musch, T. I. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00421.2015 · Cited by 25
“Given the attenuation of the NOS-mediated pathway of NO production in CHF, it has been proposed that an exogenous source of NO may serve as a novel therapy aimed at restoring peripheral vascular function (1, 32, 37, 47, 52).”
BackgroundZhao, X., Hu, J., Nie, J., Chen, D., Qin, G. W., & Zhang, E. (2023) · Journal of Material Science and Technology · doi:10.1016/j.jmst.2023.04.076 · Cited by 23
Nitrite therapy improves survival postexposure to chlorine gas
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“A functional role for the latter pathway has been demonstrated in both physiological and pathophysiological contexts, and perhaps the most evidence is in therapeutics where the goal is to improve or replete NO bioactivity in ischemic and inflammatory diseases (14, 19, 33).”
BackgroundNitrite attenuated peroxynitrite and hypochlorite generation in activated neutrophils
Ren, X., Ding, Y., & Lu, N. (2016) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2016.02.020 · Cited by 21
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“, 25–35 min) half-life of the currently available sodium nitrite formulations (24).”
BackgroundInorganic Nitrate Supplementation for Cardiovascular Health
Ivy, J. L. (2019) · Methodist DeBakey Cardiovascular Journal · doi:10.14797/mdcj-15-3-200 · Cited by 25
Oxygen tension, H2S, and NO bioavailability: is there an interaction?
Kolluru, G. K., Prasai, P. K., Kaskas, A. M., Letchuman, V., & Pattillo, C. B. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00365.2015 · Cited by 19
“In murine models of peripheral artery disease, nitrite therapy augmented angiogenesis in an NO-dependent manner (8, 37, 44, 66, 67).”
BackgroundSelf-citationPhysiological recycling of endogenous nitrate by oral bacteria regulates gastric mucus thickness
Petersson, J. H., Jädert, C., Phillipson, M., Borniquel, S., Lundberg, J. O., & Holm, L. P. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.07.003 · Cited by 21
Nitric Oxide Synthase and Nitric Oxide Involvement in Different Toxicities
Atakişi, E., & MERHAN, O. (2017) · InTech eBooks · doi:10.5772/intechopen.68494 · Cited by 15
“Recent data suggest that these anions are beneficial to gastrointestinal cancer [36] and cardiovascular diseases rather than having harmful effects.”
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The dual effects of nitrite on hemoglobin-dependent redox reactions
Lu, N., Chen, C., He, Y., Tian, R., Xiao, Q., & Peng, Y. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.04.010 · Cited by 13
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Bahadoran, Z., Mirmiran, P., Ghasemi, A., & Azizi, F. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.08.002 · Cited by 11
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“Among these, the decrease in NO bioavailability plays the most important role in CHF [6–8], which results in the decline of vascular relaxation and the increase in vascular contraction function [9, 10].”
BackgroundPharmacological therapies, lifestyle choices and nitric oxide deficiency: A perfect storm
Bryan, N. S. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.09.009 · Cited by 10
Bahadoran, Z., Carlström, M., Ghasemi, A., Mirmiran, P., Azizi, F., & Hadaegh, F. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0254-2 · Cited by 10
“Although accumulating evidence supports biological cardioprotective effects of inorganic NO3 /NO2 − following a short-time supplementation, in both experimental and clinical studies, [3, 35, 36], cardiovascular responses to habitual dietary intake of NO3 /NO2 − in a long-term period still remains unknown and seems to…”
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Kolliyedath, G., Shaju, C., Benny, A. P., & Kundu, S. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c13869 · Cited by 9
Natural Product Chemistry for Nitric Oxide Based Therapeutics
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Nitrite and Nitrate: From Bench to Bedside
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“Careful comparison and evaluation across multiple areas of investigation further revealed that nitrite/nitrate adverse effects and toxicity to be significantly above therapeutic amounts that have been used by numerous investigators [8; 9].”
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“on many disease states in animal models and human (12).”
BackgroundNew Thoughts in an Old Player: Role of Nitrite in the Treatment of Ischemic Revascularization
Jia, G., & Sowers, J. R. (2013) · Diabetes · doi:10.2337/db13-1530 · Cited by 8
“Diabetes is a major risk factor for the development of atherosclerotic peripheral arterial disease (PAD), which is typically caused by progressive narrowing of the arteries in the lower extremities (1).”
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“Evidence that inorganic nitrite anion therapy may have therapeutic effects for numerous pathological conditions, especially for treating cardiovascular disease, has been reviewed (Kevil et al., 2011; Omar et al., 2016; Blood, 2017), along with substantial experimental evidence for a protective effect from ischemia-rep…”
BackgroundSignificance of Inorganic Nitrate Supplement in Cardiovascular Health
Dudhe, R., Dudhe, A. R., & Raut, S. D. (2021) · Cardiovascular & Hematological Agents in Medicinal Chemistry · doi:10.2174/1871525719666210427130511 · Cited by 5
Nitrite attenuated hypochlorous acid-mediated heme degradation in hemoglobin
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Nitric Oxide and Hemoglobin: Physiological Implications
Shen, X., Kaye, A. D., Cornett, E. M., & Kevil, C. G. (2022) · Springer eBooks · doi:10.1007/978-3-030-95975-3_9 · Cited by 3
Self-citationSun, J., Zhang, X., Wang, X., Peng, J., Song, G., Di, Y., Feng, F., & Wang, S. (2022) · Angewandte Chemie · doi:10.1002/ange.202213765 · Cited by 3
CURING | Physiology of Nitric Oxide
Parthasarathy, D. K., & Bryan, N. S. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-384731-7.00115-x · Cited by 3
Quel avenir en thérapeutique cardiovasculaire pour le monoxyde d’azote et ses dérivés ?
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Miskolczi, G., Gönczi, M., Kovács, M., & Végh, Á. (2017) · Acta Biologica Hungarica · doi:10.1556/018.68.2017.1.4 · Cited by 2
“Acta Biologica Hungarica 68, 2017 evidence that inorganic nitrate and nitrite, the natural oxidative metabolites of NO, may serve as stores of NO [9, 10, 15, 17], since they are able to rapidly reduce back to NO, especially under hypoxic or anoxic conditions, when a drop in pH and oxygen tension promotes reductive pro…”
BackgroundLiu, Y., Qin, Q., Bo, A., Zhang, H., Zhang, Q. H., Hao, W., Hu, Y., & Sun, J. (2015) · Pharmacology & Pharmacy · doi:10.4236/pp.2015.611052 · Cited by 2
“However, nitrites are also used in the medicinal field [6] and sodium nitrite may have therapeutic potential as a nitric oxide (NO) prodrug in the treatment of tumors, allowing a transient increase in the delivery and efficacy of anti-cancer drugs [1].”
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Beets, Bacteria, and Blood Flow
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INORGANIC AND ORGANIC NITRATES AS SOURCES OF NITRIC OXIDE
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Nitrate/L-arginine Therapy and Nitric Oxide Levels in the Stomach and Liver of Rats
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“2015;17(9):e1056 4 correlation between plasma and tissue nitrite after nitrite administration has been previously reported [24].”
Background
Metadata
- Authors
- Kevil, C. G., Kolluru, G. K., Pattillo, C. B., & Giordano, T.
- Affiliations
- Louisiana State University (US)
- Louisiana State University Health Sciences Center Shreveport (US)
- Corresponding author
- Kevil, Christopher G.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 51
- Issue
- 3
- Pages
- 576-593
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC4414241
- OpenAlex
- W2075903936
- Semantic Scholar
- 50af9f1071748c47ba52cfe0f274e85cae813cfb
- Cited by
- 113
- References
- 285
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 3 · 2019: 10 · 2018: 8 · 2017: 8 · 2016: 6 · 2015: 17 · 2014: 11 · 2013: 10 · 2012: 14
- FWCI
- 1.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (HL80482, HL094021, DK043785)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- nitrite, nitric oxide, sodium nitrite, sodium nitrate, nitric oxide prodrug, nitric oxide bioavailability
- MeSH terms
- Animals, Autoimmune Diseases, Bacteria, Humans, Inflammation, Inorganic Chemicals, Ischemia, Mouth, Neoplasms, Nitric Oxide, Oxidation-Reduction, Sodium Nitrite
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