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Cited by 150Nitric Oxide and Endothelin EffectsRedox biology and oxidative stressNeutrophil, Myeloperoxidase and Oxidative Mechanisms

Signaling and stress: The redox landscape in NOS2 biology

Open access
Thomas, Douglas D., Heinecke, Julie L., Ridnour, Lisa A., Cheng, Robert Y., Kesarwala, Aparna H., Switzer, Christopher H., McVicar, Daniel W., Roberts, David D. +4 more·2015·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2015.06.002PMC PMC4852151
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Abstract

Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including the chemistry of RNS and their molecular targets.

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Crossref · 10.1016/j.freeradbiomed.2015.06.002

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 336 cited sources checked · 0 supported · 0 flagged

  • Premisereasoning

    NO donors that release NO in a controlled manner are useful mimics of NOS.

    “In particular, NO donors that release NO in a controlled manner have proven to be useful mimics of NOS.”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Redox signaling during inflammation has significant potential to positively affect disease etiology.

    “Furthermore, it is now apparent that redox signaling, particularly during inflammation, has significant potential to positively impact disease etiology.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Constitutive eNOS/NOS3 and nNOS/NOS1 produce low cellular NO, generally for cGMP regulation and subsequent events.

    “The constitutive isoforms, endothelial and neuronal NOS (eNOS/NOS3 and nNOS/NOS1), produce low cellular levels of NO, generally for regulation of cGMP and subsequent events (for example, [15]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Murad, 2006, Nitric oxide and cyclic GMP in cell signaling and drug development, N. Engl. J. Med. source

      Not checked in the free run.

  • Premisecitation

    Immune activators such as LPS and IL-2 drive increases in plasma nitrate/nitrite in mice and humans.

    “Early studies demonstrated that immune activators such as LPS and IL-2 clearly drive increases in plasma nitrate/nitrite in mice and in humans [34-42].”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [34] Ochoa, 1991, Nitrogen oxide levels in patients after trauma and during sepsis, Ann. Surg. source

      Not checked in the free run.

    • cites [35] Guarner, 1993, Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia, Hepatology source

      Not checked in the free run.

    • cites [36] Jacob, 1993, Nitric oxide production is inhibited in trauma patients, J. Trauma source

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    • cites [37] Miles, 1994, Association between biosynthesis of nitric oxide and changes in immunological and vascular parameters in patients treated with interleukin-2, Eur. J. Clin. Invest. source

      Not checked in the free run.

    • cites [38] Citterio, 1996, Plasma nitrate plus nitrite changes during continuous intravenous infusion interleukin 2, Br. J. Cancer source

      Not checked in the free run.

    • cites [39] Billiar, 1990, Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-l-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage, J. Leukoc. Biol. source

      Not checked in the free run.

    • cites [40] Tracey, 1995, Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors, J. Pharmacol. Exp. Ther. source

      Not checked in the free run.

    • cites [41] Rees, 1998, Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse, Br. J. Pharmacol. source

      Not checked in the free run.

    • cites [42] Stuehr, 1985, Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • Interpretationreasoning

    Under acute and chronic inflammation, increased levels and duration of redox signaling agents reduce kinetic specificity, increasing the contribution of slower signaling processes.

    “Under acute and chronic inflammation, both the levels and duration of redox signaling agent production can reduce the kinetic specificity that exists under normal physiological conditions, such that there is an increased contribution from slower signaling processes.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 71
  • May combine two claims. 102
  • The quote only partly states this claim. 1

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

    Premisecitation

    NO levels were historically thought to be bimodal: low nanomolar to activate sGC or low micromolar in immune response.

    “In correlation with the sGC/macrophage debate, NO levels have been historically thought to be bimodal: in the low nanomolar range to activate sCG or approaching low micromolar levels in localized regions as a function of immune response [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wink, 1998, Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Premisecitation

    Under hypoxia, nitrite reduction provides an oxygen-independent source of low NO.

    “Under hypoxia, reduction of nitrite (NO2−) can provide an alternative, oxygen-independent source of low levels of NO (for example, [16]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Modin, 2001, Nitrite-derived nitric oxide: A possible mediator of ‘acidic-metabolic’ vasodilation, Acta Physiol. Scand.

      Not checked in the free run.

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

    Premisecitation

    NOX1, 3, 4, 5, and 6 produce lower superoxide fluxes and are considered more regulatory.

    “In contrast, NOX1, 3, 4, 5 and 6 all produce lower fluxes of O2− and are considered to serve more regulatory roles [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Leto, 2006, Role of Nox family NADPH oxidases in host defense, Antioxid. Redox Signal. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Physiological NO signaling primarily occurs through interaction with the heme protein soluble guanylyl cyclase.

    “Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    iNOS/NOS2 is constitutively expressed for kidney and lung function, but upon induction produces sustained micromolar NO fluxes for days.

    “Inducible NOS (iNOS/NOS2) is also constitutively expressed for kidney and lung function, but upon induction can produce sustained NO fluxes in the micromolar range for days [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ridnour, 2008, Molecular mechanisms for discrete nitric oxide levels in cancer, Nitric Oxide source

      Not checked in the free run.

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

    Premisecitation

    cGMP amplification after sGC activation stimulates a biological cascade leading to vasodilation.

    “The resulting amplification of cGMP production then stimulates a biological cascade leading to vasodilation (for example, [12]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Ignarro, 1999, Nitric oxide: a unique endogenous signaling molecule in vascular biology, Biosci. Rep. source

      Not checked in the free run.

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

    Premisecitation

    COX2 is induced under inflammatory conditions to produce PGE2 and prostacyclin, while COX1 leads to signaling primarily through thromboxane A2.

    “Isoforms can also produce different signaling agents as exemplified by the COX enzymes; COX2 is induced under inflammatory conditions to produce PGE2 and prostacyclin (PGI2) while COX1 leads to a signaling cascade primarily through thromboxane A2 (TXA2) [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Caughey, 2001, Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2, J. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rate constant for NO association with heme centers is typically very high relative to other targets, so low nanomolar NO is sufficient to activate sGC.

    “The rate constant for association of NO to heme centers is typically very high relative to other potential targets [11], such that low nanomolar levels of NO are sufficient to activate sGC.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Ford, 2002, Mechanistic aspects of the reactions of nitric oxide with transition-metal complexes, Chem. Rev. source

      Not checked in the free run.

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

    Premisecitation

    NOS2 can be upregulated by cytokine exposure, hypoxia, or serum withdrawal.

    “In such systems, NOS2 can be upregulated by a variety of conditions including cytokine exposure, hypoxia or serum withdrawal [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Heinecke, 2014, Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

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

    Premisecitation

    NOX2 is generally associated with high superoxide production for pathogen control and is critical for inflammatory signaling in myeloid cells.

    “For instance, the NOX2 isoform is generally associated with production of high levels of superoxide (O2−) for pathogen control, but is also critical for signaling in the inflammatory cascade in myeloid cells [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Reddy, 2011, NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases, Leukemia source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Reduced bioavailability of tetrahydrobiopterin is critical in limiting NOS2 activity.

    “This study suggested that reduced bioavailability of tetrahydrobiopterin was critical in limiting NOS2 activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Weinberg, 1995, Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOS2 is involved in sterilization, immunosuppression, and wound healing responses, and is critical to initiation and resolution of inflammation.

    “NOS2 is involved in sterilization, immunosuppression and in a variety of wound healing responses and thus is critical to initiation and resolution of inflammation [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ridnour, 2008, Molecular mechanisms for discrete nitric oxide levels in cancer, Nitric Oxide source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thiols can be converted into numerous oxidized products of varying stability, and thiol oxidation or nitrosation may facilitate S-glutathionylation.

    “Furthermore, post-translational modification of thiols is by no means limited to S-nitrosation. Thiols can be converted into numerous oxidized products, of varying degrees of stability (see [60]). Thiol oxidation or nitrosation may also facilitate S-glutathionylation (see [61]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Poole, 2015, The basics of thiols and cysteines in redox biology and chemistry, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [61] Mieyal, 2008, Molecular mechanisms and clinical implications of reversible protein S-glutathionylation, Antioxid. Redox Signal. source

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  • May combine two claims.

    Premisecitation

    Human monocytes and peritoneal macrophages show virtually no nitrate/nitrite accumulation and exhibit 50-fold lower NOS2 activity than stimulated murine macrophages.

    “In contrast, human monocytes and peritoneal macrophages show virtually no accumulation of nitrate/nitrite and exhibit 50-fold lower NOS2 activity than stimulated murine macrophages [43].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Weinberg, 1995, Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages, Blood source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    When NO levels rise, more kinetically constrained reactions become consequential along with radical scavenging and heme protein interactions.

    “When NO levels rise, other, more kinetically constrained reactions begin to be consequential along with radical scavenging and interactions with heme proteins.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    NO signaling can be categorized into three tiers of steady-state NO concentration: low nanomolar (<100 nM), intermediate nanomolar (~100-500 nM), and above (approaching or exceeding 1 μM).

    “It is useful to categorize NO signaling into three distinct tiers of steady state NO concentrations: low nanomolar (<100 nM), intermediate nanomolar (~100-500 nM) and above (approaching or even exceeding 1 μM) (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Polymorphonuclear leukocytes show little NOS activity compared to endothelial cells, which upon LPS stimulation exhibit 400 times higher activity than resting cells.

    “Polymorphonuclear leukocytes showed little NOS activity compared to endothelial cells, which upon LPS-stimulation exhibit 400 times higher activity than resting cells [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Yan, 1994, Human polymorphonuclear leukocytes lack detectable nitric oxide synthase activity, J. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of prolyl hydroxylase by nitrosylation stabilizes HIF-1α, which increases endothelial cell proliferation and migration by stimulating VEGF release.

    “For example, inhibition of the nonheme iron protein prolyl hydroxylase by nitrosylation stabilizes hypoxia-inducible factor (HIF)-1α, a transcription factor that can in turn increase proliferation and migration of endothelial cells by stimulating release of vascular endothelial growth factor (VEGF) [20, 52].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Ridnour, 2006, The biphasic nature of nitric oxide responses in tumor biology, Antioxid. Redox Signal. source

      Not checked in the free run.

    • cites [52] Sandau, 2001, Accumulation of HIF-1alpha under the influence of nitric oxide, Blood source

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  • May combine two claims.

    Premisecitation

    LPS administration to mice leads to as much as 1 mM nitrate/nitrite, while human peak levels are only 50-115 μM.

    “While there are similar resting levels of nitrate (25 μM) and nitrite (1 μM) in both species, administration of LPS to mice led to as much as 1 mM nitrate/nitrite while in humans peak levels were only 50-115 μM [34, 39-42]).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [34] Ochoa, 1991, Nitrogen oxide levels in patients after trauma and during sepsis, Ann. Surg. source

      Not checked in the free run.

    • cites [39] Billiar, 1990, Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-l-arginine inhibits endotoxin-induced nitrate/nitrate biosynthesis while promoting hepatic damage, J. Leukoc. Biol. source

      Not checked in the free run.

    • cites [40] Tracey, 1995, Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors, J. Pharmacol. Exp. Ther. source

      Not checked in the free run.

    • cites [41] Rees, 1998, Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse, Br. J. Pharmacol. source

      Not checked in the free run.

    • cites [42] Stuehr, 1985, Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

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

    Premisenone given

    Conversion of NO into RNS can lead to indirect signaling through nitrosative, nitrative, and oxidative modifications.

    “In addition, conversion of NO into RNS can lead to indirect signaling through nitrosative, nitrative and oxidative modifications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At the lowest NO levels, NO reacts primarily with ferrous hemes to mediate cGMP-dependent signaling and with reactive radicals such as those from lipid peroxidation.

    “At the lowest levels, NO reacts primarily with ferrous hemes to mediate cGMP-dependent signaling as well as with reactive radicals [25, 48], such as those produced in lipid peroxidation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Wink, 1998, Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide, Free Radic. Biol. Med. source

      Not checked in the free run.

    • cites [48] Wink, 2001, Cytotoxicity related to oxidative and nitrosative stress by nitric oxide, Exp. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The intermediate level of NO provides immunosuppression with respect to Th1 responses, which is essential for tissue restoration.

    “Taken together, this level of NO provides immunosuppression with respect to Th1 type responses, which is essential for tissue restoration.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    NO can interact with cytosolic nonheme iron targets.

    “For instance, NO can interact with cytosolic, nonheme iron targets.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Different stimuli alter local nitric oxide concentrations, which in turn affect signaling and stress.

    “Thus, different stimuli impact local NO concentrations, which influence signaling and stress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    High levels of NO lead to phosphorylation and stabilization of p53, suggesting a role in cell cycle regulation, DNA repair, and apoptosis during inflammation.

    “For example, high levels of NO lead to phosphorylation and stabilization of p53 [31], suggesting a role for NO in cell cycle regulation, DNA repair and apoptosis, particularly during inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Hofseth, 2003, Nitric oxide-induced cellular stress and p53 activation in chronic inflammation, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Arginase can compete for substrate in activated cells and may regulate nitric oxide biosynthesis.

    “Arginase can function as a substrate competitor in activated cells, and thus may serve a regulatory role in NO biosynthesis [88-90].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [88] Kepka-Lenhart, 2008, Determination of mammalian arginase activity, Methods Enzymol. source

      Not checked in the free run.

    • cites [89] Christianson, 2005, Structure, mechanism, and physiological role in male and female sexual arousal, Acc. Chem. Res. source

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    • cites [90] Boucher, 1999, Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for l-arginine utilization, Cell Mol. Life Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Prolonged NO can induce apoptosis, and the highest NO levels lead to build up of RNS and damaged proteins, resulting in chemical stress.

    “Prolonged NO can induce apoptosis, and the highest levels of NO lead to a build up of RNS and damaged proteins, resulting in chemical stress.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    NOS-independent pathways to NO production exist, for instance by chemical reduction of dietary nitrite.

    “NOS-independent pathways to NO production also exist, for instance by chemical reduction of dietary nitrite.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    An active and functional endothelial-like nitric oxide synthase exists within erythrocytes, located in plasma membrane and cytoplasm, and controls NO-mediated pathways including platelet activation.

    “Interestingly, there are now reports characterizing an active and functional endothelial-like nitric oxide synthase within erythrocytes [80]. This enzyme is located in the plasma membrane and the cytoplasm of red blood cells and controls NO-mediated pathways including activation of platelets.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Kleinbongard, 2006, Red blood cells express a functional endothelial nitric oxide synthase, Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In murine leukemia models, NOS2 and NO have tumoricidal properties and induce p53 stabilization leading to apoptosis.

    “In murine models of leukemia, NOS2 and NO have tumoricidal properties and induce the stabilization of p53 leading to apoptosis [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Stuehr, 1989, Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells, J. Exp. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOS2 and p53 double knockout mice develop leukemia and tumors, indicating these proteins may serve as critical control switches for cancer development.

    “NOS2 and p53 double knockout mice develop leukemia and tumors, indicating that these proteins may serve as critical control switches for cancer development [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Hussain, 2008, Nitric oxide is a key component in inflammation-accelerated tumorigenesis, Cancer Res. source

      Not checked in the free run.

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

    Premisenone given

    Biosynthesis of NO by NOS is controlled by transcription, translation, post-transcriptional modification, and substrate/cofactor availability.

    “Biosynthesis of NO by NOS is controlled by transcription, translation, post-transcriptional modification and substrate/cofactor availability.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Each specific regulatory, tissue restoration, or stress response pathway is mediated by interactions with unique molecular targets that are spatially and kinetically accessible.

    “Each specific regulatory, tissue restoration or stress response pathway is mediated by interactions with unique molecular targets that are both spatially and kinetically accessible.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    NFκB is downregulated by high NO, which may be important in leukocyte regulation.

    “Furthermore, nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) is down regulated, which may be important in leukocyte regulation.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    At the highest NO or stress alert level, p53 is induced and proteins such as MKP-1 antagonize pathways leading to NOS2 induction.

    “At the highest NO or stress alert level, p53 is induced and proteins such as MKP-1 antagonize pathways that lead to NOS2 induction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both NOS and arginase use arginine as a substrate and can be co-induced in macrophages by LPS.

    “Both NOS and arginase use arginine as a substrate and can be co-induced in macrophages by LPS [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Kepka-Lenhart, 2008, Determination of mammalian arginase activity, Methods Enzymol. source

      Not checked in the free run.

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

    Premisereasoning

    Both physical and chemical processes shape the NO profile, defined by concentration, duration, and spatial orientation.

    “Both physical and chemical processes are involved in shaping the NO profile, defined by concentration, duration and spatial orientation.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    NOS-independent NO production reactions are regulated particularly by oxygen tension.

    “Such reactions are also regulated, particularly by oxygen tension.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The lowest levels of NO induce normal physiological signaling, intermediate levels stimulate wound-healing responses, and high levels activate anti-pathogen and antitumor processes.

    “In summary, the lowest levels of NO induce normal physiological signaling while intermediate levels of NO stimulate wound-healing responses, and high levels anti-pathogen and antitumor processes are activated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nitrite is reduced to NO in the human vasculature with vasodilatory effects.

    “Over a decade ago, nitrite was shown to be reduced to NO in the human vasculature with vasodilatory effects [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Cosby, 2003, Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation, Nature Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of NO induce Nrf2 and increase proteins with antioxidant response element.

    “High levels of NO also induce the cellular growth transcription factor nuclear respiratory factor (NrF)-2A and an increase in proteins that have an antioxidant response element (ARE) [69, 70].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Um, 2011, Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells, Nitric Oxide source

      Not checked in the free run.

    • cites [70] Li, 2009, Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S-Nitrosation of cysteine 258 of MKP-1 increases its stability and activity, decreasing ERK signaling and causing cell cycle delay.

    “S-Nitrosation of cysteine 258 of the phosphatase MKP-1 also increases its stability and activity [68], which decreases ERK signaling, causing cell cycle delay.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Guan, 2012, S-Nitrosylation of mitogen activated protein kinase phosphatase-1 suppresses radiation-induced apoptosis, Cancer Lett. source

      Not checked in the free run.

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

    Interpretationnone given

    NO-dependent signaling is highly sensitive to the level of NO, primarily as a function of kinetic constraints.

    “As described in the previous section, NO-dependent signaling is highly sensitive to the level of NO, primarily as a function of kinetic constraints.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The intermediate level of NO produces a pro-growth, proliferative, immunosuppressed, pro-angiogenic, and enhanced mobility environment critical to wound healing and tissue restoration through specific post-translational modifications.

    “Together, such studies indicate that the intermediate level of NO produces a pro-growth, proliferative, immunosuppressed, pro-angiogenic and enhanced mobility environment that is critical to wound healing and tissue restoration through specific post-translational modifications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Over hours, nitric oxide autoxidation from chronic NOS2 upregulation can form enough RNS to induce long-term signaling, because the estimated amount is several orders of magnitude above that needed for EGFR activation.

    “Nonetheless, this approximation suggests that over the span of hours, NO autoxidation as derived from chronic upregulation of NOS2 can form sufficient RNS to induce long term signaling processes, since the estimated value is at least several orders of magnitude higher than required for activation of EGFR and other receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Peroxynitrite is itself an RNS, and its interaction with excess nitric oxide or superoxide can produce other RNS.

    “The product, peroxynitrite, is itself an RNS, and interaction with excess NO or O2− can produce still other RNS [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wink, 1998, Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Interpretationnone given

    Nitrosation can be reversed by several pathways.

    “Within the RNS signaling arena, nitrosation, which can be reversed by several pathways, has received significant attention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrite serves as both a NOS-dependent and an exogenous source of nitric oxide and RNS.

    “It is now clear, however, that nitrite serves as both a NOS-dependent and exogenous source of NO and RNS [122-124].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [122] Gladwin, 2005, Nitrite as an intrinsic signaling molecule, Nat. Chem. Biol. source

      Not checked in the free run.

    • cites [123] Williams, 1982, Inhibition of nitrosation of amines by thiols, alcohols and carbohydrates, Food Chem. Toxicol. source

      Not checked in the free run.

    • cites [124] Lundberg, 2009, Nitrate and nitrite in biology, nutrition and therapeutics, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Nitration is considered a permanent modification, which can impact versatility in signaling.

    “At present, nitration is considered to be a permanent modification, which can impact versatility in signaling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    High nitric oxide concentrations are consumed quickly, while low concentrations can persist for minutes or even hours.

    “High concentrations of NO will thus be quickly consumed, while low concentrations can persist for minutes or even hours [116, 118].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Ford, 1993, Autoxidation kinetics of aqueous nitric oxide, FEBS Lett. source

      Not checked in the free run.

    • cites [118] Wink, 1993, Reactions of the bioregulatory agent nitric oxide in oxygenated aqueous media-determination of the kinetics for oxidation and nitrosation by intermediates generated in the NO/O2 reaction, Chem. Res. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOS3 has a low oxygen KM, so it remains active under low oxygen, which may be needed to maintain blood flow.

    “NOS3 has a low KM for oxygen, indicating that it retains activity even under low oxygen, which may be necessary to maintain blood flow [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Abu-Soud, 2000, Electron transfer, oxygen binding, and nitric oxide feedback inhibition in endothelial nitric-oxide synthase, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The relative levels of nitric oxide and superoxide modulate signaling, with nitration yielding to nitrosation as nitric oxide fluxes increase.

    “Thus, the relative levels of NO and O2− may also modulate signaling mechanisms, with nitration yielding to nitrosation as NO fluxes increase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Spatial orientation affects nitric oxide flux, which can be tuned to influence cells differently and trigger specific phenotypic responses.

    “Spatial orientation also influences NO flux, which can be tuned to impact cells differently, thus setting in motion specific phenotypic responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Protein nitration is site specific but occurs at low levels.

    “Improvements in detection have led to demonstration that protein nitration is site specific but occurs at low levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrosation, nitration and oxidation can be initiated by several mechanisms, including NO autoxidation, protonation of nitrite, reaction of NO with superoxide, and metal-mediated processes, all of which play critical roles in different cellular compartments.

    “These include NO autoxidation, protonation of nitrite, reaction of NO with O2− and metal mediated processes (Figure 3), all of which play critical roles in different compartments in cells and tissue [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Thomas, 2008, The chemical biology of nitric oxide: implications in cellular signaling, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Nitric oxide autoxidation primarily occurs in hydrophobic environments, while protonation of nitrite and reaction of nitric oxide with superoxide principally take place in aqueous media.

    “Furthermore, while NO autoxidation is expected to primarily occur in hydrophobic environments, the latter two processes will principally take place in aqueous media.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In biological systems, oxygen is not in excess and varies by location, so the outcome of nitric oxide autoxidation depends on the redox landscape in terms of relative NO and O2 concentrations.

    “First, O2 may no longer be an excess reagent, as is the case in open vessels, and the O2 concentration will vary depending on location. Thus, the biological outcome of NO autoxidation will depend on the redox landscape, in terms of the relative concentrations on NO and O2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Purified NOS2 has an oxygen KM of about 150 μM, but its activity varies greatly with factors such as NO scavenging, enzyme environment, nitrite presence and oxygen tension.

    “Purified NOS2 has a KM ~ 150 μM, but its activity is highly variable and depends on a number of factors including scavenging of NO, the environment of the enzyme (e.g., in cell lysate), the presence of nitrite and oxygen tension [95, 96].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [95] Dweik, 1998, Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism, J. Clin. Invest. source

      Not checked in the free run.

    • cites [96] Robinson, 2011, Oxygen-dependent regulation of nitric oxide production by inducible nitric oxide synthase, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOS1 has an oxygen KM greater than 400 μM, suggesting it may sense oxygen.

    “NOS1 has a KM > 400 μM, suggesting it may also have oxygen sensing capabilities [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Haque, 2013, Thermodynamic characterization of five key kinetic parameters that define neuronal nitric oxide synthase catalysis, FEBS Journal source

      Not checked in the free run.

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

    Premisecitation

    It is chemically incorrect to use the terms nitrosylation and nitrosation synonymously.

    “It is chemically incorrect to use the terms nitrosylation and nitrosation synonymously (for further details, see [166]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Heinrich, 2013, Biological nitric oxide signaling: chemistry and terminology, Br. J. Pharmacol. source

      Not checked in the free run.

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

    Interpretationnone given

    The reaction of nitric oxide with superoxide to form peroxynitrite is nearly diffusion-controlled and protects against oxidative damage by superoxide.

    “This nearly diffusion-controlled reaction provides protection against oxidative damage by O2−.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The reaction of nitric oxide with superoxide is often assumed to be the primary source of nitrogen dioxide and thus of nitrative modifications.

    “Although NO2 can be produced by multiple pathways (see [149, 157] and section IV), the reaction of NO with O2− is often assumed to be the primary source of NO2 and thus of nitrative modifications.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Thomas, 2002, Protein nitration is mediated by heme and free metals through Fenton-type chemistry: an alternative to the NO/O2- reaction, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [157] Radi, 2004, Nitric oxide, oxidants, and protein tyrosine nitration, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

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

    Premisecitation

    Nitric oxide autoxidation is 30-fold faster in membranes, and this compartment accounts for 90% of the total reaction.

    “Lancaster and colleagues have suggested that NO autoxidation is 30-fold faster in membranes and thus that this compartment accounts for 90% of the total reaction [119].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Liu, 1998, Accelerated reaction of nitric oxide with O2- within the hydrophobic interior of biological membranes, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Accumulation of N2O3 requires relatively high nitric oxide levels, and at least three different mechanisms lead to its formation in a site-specific manner.

    “As illustrated in Section IV, accumulation of N2O3 requires relatively high levels of NO, and at least three different mechanisms lead to its formation in a site-specific manner.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    RNS as a class are capable of nitrosative, nitrative and oxidative chemistry.

    “As a class, RNS are capable of nitrosative, nitrative and oxidative chemistry.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    N2O3 reacting with thiols can change the effects of NO and O2− and can generate a species capable of signaling.

    “In analogy to the reaction of NO and O2− (Eq. 6), association of N2O3 with thiols (Eq. 13) can modulate the effects of both reactants and can produce a species with its own signaling capacity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Kemp-Harper et al. suggested that HNO mediates dilation through activation of Kca and Kv channels in vascular smooth muscle.

    “Kemp-Harper et al. have suggested that HNO is a mediator of dilation through activation of Kca and Kv channels in vascular smooth muscle [196, 197].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [196] Irvine, 2008, Nitroxyl (HNO): the Cinderella of the nitric oxide story, Trends Pharmacol. Sci. source

      Not checked in the free run.

    • cites [197] Kemp-Harper, 2011, HNO): a novel redox signaling molecule, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    S-Nitrosothiols can be homolytically cleaved by light or trace metals, especially Cu+, and are therefore often used as NO donors.

    “Since S-nitrosothiols can be homolytically cleaved by light or traces metals, particularly Cu+ (Eq. 17), they are often used as NO donors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sulfinamides can hydrolyze to sulfinic acid or react with excess thiols to form thiosulfinates.

    “Sulfinamides may be hydrolyzed to the respective sulfinic acid (RSO2H) or react further with excess thiols to form thiosulfinates (RS(O)SR) [178].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Wong, 1998, Reaction between S-nitrosothiols and thiols: generation of nitroxyl (HNO) and subsequent chemistry, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia reduces the effect of HNO on calcium influx, potentially protecting against brain ischemia/reperfusion injury.

    “In contrast, hypoxia attenuates the effect of HNO on calcium influx, potentially offering a degree of protection toward ischemia/reperfusion injury in the brain.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Colton, 2001, Nitroxyl anion regulation of the NMDA receptor, J. Neurochem. source

      Not checked in the free run.

    • cites [189] Gbadegesin, 1999, Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death, Am. J. Physiol.-Cell Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Synthetic GS(O)NH2 is recovered in cell lysate and is observed after cells are exposed to an HNO donor.

    “Nonetheless, synthetic GS(O)NH2 has been detected with a reasonable recovery percentage in cell lysate and has been observed after exposure of cells to an HNO donor [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Johnson, 2014, Glutathione sulfinamide serves as a selective, endogenous biomarker for nitroxyl following exposure to therapeutic levels of donors, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Premisecitation

    S-Nitrosothiol activation has been known since Ignarro and coworkers described nitroglycerin metabolism.

    “S-Nitrosothiol activation has been well known since Ignarro and coworkers described metabolism of nitroglycerin [195].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Ignarro, 1980, Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrite: possible involvement of S-nitrosothiols, Biochim. Biophys. Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Both S-nitrosothiol formation via nitrosation chemistry and sulfinamide formation via HNO chemistry involve electrophilic reactions rather than radical intermediates.

    “Both modifications, S-nitrosothiol via nitrosation chemistry and sulfinamide via HNO chemistry, involve electrophilic reactions, rather than the intermediacy of radicals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both NO and HNO potentiate glutamate-mediated channel activation.

    “While both NO and HNO potentiate glutamate-mediated channel activation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Colton, 2001, Nitroxyl anion regulation of the NMDA receptor, J. Neurochem. source

      Not checked in the free run.

    • cites [189] Gbadegesin, 1999, Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death, Am. J. Physiol.-Cell Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia increases the NO-mediated response and enhances neuronal toxicity.

    “hypoxia augments the NO-mediated response, resulting in enhanced neuronal toxicity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Colton, 2001, Nitroxyl anion regulation of the NMDA receptor, J. Neurochem. source

      Not checked in the free run.

    • cites [189] Gbadegesin, 1999, Hypoxia modulates nitric oxide-induced regulation of NMDA receptor currents and neuronal cell death, Am. J. Physiol.-Cell Physiol source

      Not checked in the free run.

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

    Premisecitation

    Direct interconversion between NO and HNO is suggested to be limited.

    “Although direct interconversion is suggested to be limited [180]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Miranda, 2005, The chemistry of nitroxyl (HNO) and implications in biology, Coord. Chem. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As the thiol:HNO ratio increases, a second pathway forming disulfide and hydroxylamine becomes competitive, producing a mixture of sulfinamide and disulfide.

    “As the ratio of thiol to HNO increases, a second reaction pathway, in which the disulfide and hydroxylamine are formed (Eq. 20) [178], becomes progressively competitive such that a mixture of RS(O)NH2 and RSSR is produced.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [178] Wong, 1998, Reaction between S-nitrosothiols and thiols: generation of nitroxyl (HNO) and subsequent chemistry, Biochemistry source

      Not checked in the free run.

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

    Interpretationreasoning

    Hypoxia could instead lead to HNO production and HNO-mediated signaling.

    “Hypoxia could instead lead to HNO production and HNO-mediated signaling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    RSSR·− radical anions are strong reductants and can be further oxidized by O2 to produce O2− and RSSR'.

    “These species are very good reductants and can in turn be further oxidized by oxidants such as O2 (e.g., producing O2− and RSSR') [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Forman, 2010, Signaling functions of reactive oxygen species, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Changes in the NAD+/NADH ratio could affect sirtuin deacetylases, and reduced sirtuin activity could shift histone acetylation and gene transcription.

    “A change in the NAD+/NADH ratio could be important in the case of sirtuins, which are deacetylases. Since their enzymatic activity depends on NAD+, reduced sirtuin activity, by alterations in the NAD+/NADH ratio, could also shift the degree of histone acetylation, which directly influences chromatin structure and gene transcription [221].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [221] Hitchler, 2009, Metabolic defects provide a spark for the epigenetic switch in cancer, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Premisecitation

    H2S has been suggested to be a marker for a larger persulfide pool.

    “Very recently, the presence of H2S has been suggested to be a marker for a larger persulfide (RSS−) pool.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    LSD histone demethylases require FAD, while KDM demethylases require α-ketoglutarate.

    “LSD histone demethylases require FAD while KDM demethylases require α-ketoglutarate (α-KG) [222].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [222] Lu, 2012, Metabolic regulation of epigenetics, Cell Metab. source

      Not checked in the free run.

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

    Premisenone given

    Histone acetyltransferases require acetyl-CoA as the source of acetyl equivalents.

    “Histone acetyltransferases require acetyl-CoA as the source of acetyl equivalents to acetylate histones.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Sulfinamides are susceptible to hydrolysis to the corresponding sulfinic acid.

    “As mentioned above, sulfinamides are susceptible to hydrolysis to the corresponding sulfinic acid [178, 205].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [178] Wong, 1998, Reaction between S-nitrosothiols and thiols: generation of nitroxyl (HNO) and subsequent chemistry, Biochemistry source

      Not checked in the free run.

    • cites [205] Keceli, 2013, NMR detection and study of hydrolysis of HNO-derived sulfinamides, Biochemistry source

      Not checked in the free run.

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

    Premisecitation

    Histone and DNA methylation/demethylation are carried out by enzymes that use various cofactors.

    “Methylation and demethylation of histones and DNA is also accomplished by enzymes that utilize a variety of cofactors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Most acetyltransferase Km values fall in a range affected by intracellular acetyl-CoA changes, suggesting NO could indirectly affect histone acetylation by altering acetyl-CoA levels.

    “The Km values of most acetyltransferases are within the range that can be effected by changes in the intracellular acetyl-CoA pool, suggesting that NO could indirectly affect histone acetylation by altering acetyl-CoA levels [220].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220] Takahashi, 2006, Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription, Mol. Cell. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NO can influence gene expression and cell phenotype through direct mitochondrial interactions and indirectly through changes in metabolic intermediates and cofactors.

    “These examples highlight the numerous mechanisms whereby NO can influence gene expression and cell phenotype through direct mitochondrial interactions as well as indirectly by dynamic changes in metabolic intermediates and cofactors.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    TET enzymes oxidatively demethylate cytosine DNA bases.

    “TET enzymes oxidatively demethylate cytosine DNA bases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    The CBS/CSE system links methionine conversion to cysteine and is a critical source of GSH.

    “The CBS/CSE system is linked to conversion of methionine to cysteine, and as such, is a critical source of GSH (a cysteine-containing tripeptide).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    H2S is biosynthesized from CBS, CSE and MST.

    “The observation of biosynthesis of H2S from CBS and cystathionine gamma-lyase (CSE) as well as mercaptopyruvate sulfur transferase (MST) has led to a new field of study [223, 224].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [223] Kabil, 2014, H2S and its role in redox signaling, Biochim. Biophys. Acta source

      Not checked in the free run.

    • cites [224] Kabil, 2014, Enzymology of H2S biogenesis, decay and signaling, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    DETA/NO effects are reversible, likely because NO coordinates at the Complex IV heme rather than perturbing GAPDH.

    “These effects were reversible, likely due to coordination of NO at the Complex IV heme rather than perturbation of the glycolytic protein GAPDH.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Diers, 2011, Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells, Am. J. Physiol.-Heart Circul. Physiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The activities of α-KG-dependent TET enzymes depend on cofactor availability.

    “The activities of these α-KG-dependent enzymes also hinge on cofactor availability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NO stabilization of HIF-1α increases glycolytic pathways and activates AMPK.

    “Other studies indicate that stabilization of HIF-1α by NO leads to an increase in glycolytic pathways [217] as well as activation of AMPK [218].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [217] Garedew, 2008, Mitochondrial dysfunction and HIF1alpha stabilization in inflammation, J. Cell Sci. source

      Not checked in the free run.

    • cites [218] Erusalimsky, 2007, Nitric oxide and mitochondrial signaling: from physiology to pathophysiology, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

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

    Premisenone given

    During glycolysis, there is a shift from NAD+ to NADH.

    “During glycolysis, there is a shift from NAD+ to NADH.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    This could affect cell phenotype because histone methylation can positively or negatively impact gene expression depending on degree and location.

    “This could affect cell phenotype as histone methylation can either positively or negatively impact gene expression depending on the degree of methylation as well as the location.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DETA/NO (0.5 mM) reduces mitochondrial reserve capacity and increases glycolysis without affecting basal respiration.

    “DETA/NO (0.5 mM) reduced mitochondrial reserve capacity and increased glycolysis but did not impact basal respiration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Diers, 2011, Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells, Am. J. Physiol.-Heart Circul. Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CysNO inhibits basal respiration, ATP-dependent oxygen consumption rate and reserve capacity.

    “In contrast, treatment with CysNO led to inhibition of basal respiration, ATP-dependent oxygen consumption rate and reserve capacity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [215] Diers, 2011, Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells, Am. J. Physiol.-Heart Circul. Physiol source

      Not checked in the free run.

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

    Premisereasoning

    DNA methylation at promoter regions is associated with gene silencing, so TET-mediated demethylation can activate genes.

    “DNA methylation, especially at promoter regions, is associated with gene silencing and therefore demethylation of cytosines by TET enzymes can result in gene activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In specific proteins, oxidized products can be reduced by sulfiredoxin, revealing potential enzymatic cycling.

    “In specific proteins, such oxidized products can be reduced by sulfiredoxin (SRX) [206] revealing the potential of enzymatic cycling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Abbas, 2013, Peroxiredoxins and sulfiredoxin at the crossroads of the NO and H2O2 signaling pathways, Methods Enzymol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Off rates differ, and the impact on stability can be simplified by considering KNO.

    “The off rates also differ, and the impact on stability can be simplified by considering KNO [240].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Flores-Santana, 2009, Comparing the chemical biology of NO and HNO, Arch. Pharm. Res. source

      Not checked in the free run.

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

    Premisenone given

    Aconitase is a prototypical iron-sulfur cluster protein.

    “A prototypical example of an iron-sulfur cluster protein is the TCA cycle enzyme aconitase.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The hypothesis that NO acts as an epigenetic regulator by modulating TET pathways is compelling and could account for a significant proportion of phenotypic responses to NO.

    “The hypothesis that NO acts as an epigenetic regulator by modulating TET pathways is compelling and could account for a significant proportion of the phenotypic responses to NO.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ONS− is a stable species that activates sGC.

    “Interestingly, Feelisch and coworkers have shown that ONS− is a stable species that activates sGC [231].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Cortese-Krott, 2014, Nitrosopersulfide (SSNO-) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide, Redox Biol source

      Not checked in the free run.

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

    Premisecitation

    The recognition of H2S as an important physiological mediator led to the proposal that ONS− and related species may be significant signaling molecules.

    “The realization that H2S can be an important physiological mediator led to the proposal that, as mentioned above, ONS− and related/derived species may be significant signaling molecules [231].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Cortese-Krott, 2014, Nitrosopersulfide (SSNO-) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide, Redox Biol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    TET enzymes belong to the same Fe(II)-dependent mononuclear nonheme dioxygenase class as demethylases.

    “These TET enzymes belong to the same class of Fe(II)-dependent mononuclear nonheme dioxygenases as the demethylases.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    In biological systems, iron is typically bound by sulfur, oxygen and nitrogen ligands.

    “In biological systems, iron is typically bound by a variety of sulfur, oxygen and nitrogen containing ligands.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The ubiquitous presence of persulfides changes the perspective on RNS-thiol interactions and may add complexity to redox signaling.

    “The ubiquitous presence of persulfides changes the current perspective with respect to the interaction of RNS and thiols and may add a unique layer of complexity to the redox signaling landscape (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NO binding to JmjC histone demethylases remodels global histone methylation through direct inhibition, DNIC-mediated reduction in iron cofactor availability, and regulation of methyl-modifying enzyme gene expression.

    “Binding of NO to JmjC domain-containing histone demethylases orchestrates remodeling of global histone methylation patterns through three distinct mechanisms: direct inhibition, dinitrosyliron complex-mediated reduction in iron cofactor availability, and regulation of gene expression of methyl-modifying enzymes [249].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [249] Hickok, 2013, Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases, J. Biol. Chem. source

      Not checked in the free run.

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

    Premisenone given

    DNA cytosine methylation is a critical epigenetic event with profound effects on gene expression.

    “Another critical epigenetic event that has profound effects on gene expression is methylation of DNA cytosine bases.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Lysine methylation status is maintained by KMTs and KDMs.

    “Lysine methylation status is maintained by lysine methyltransferases (KMT) and KDMs, respectively.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Thionitrite (ONS−) has been proposed as an intermediate in NO and H2S chemistry.

    “Thionitrite (ONS−) has been proposed as an intermediate in NO and H2S chemistry, presumably through a nitrosative mechanism [230].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Filipovic, 2012, Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols, J. Am. Chem. Soc. source

      Not checked in the free run.

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

    Premisecitation

    JmjC class KDMs are mononuclear iron dioxygenases that use α-KG and O2 to demethylate specific lysine residues.

    “For example, the JmjC class of lysine specific demethylases (KDMs) are mononuclear iron dioxygenases that use α-KG and O2 as co-substrates to oxidatively demethylate specific lysine residues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    sGC has a KNO of 10^8, suggesting that a 10 nM NO flux is required for half occupancy.

    “For example, sGC has a KNO of 108 suggesting that a 10 nM NO flux is required to lead to occupation of half of the binding sites.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Because histone lysine methylation can influence transcription, the KMT/KDM balance can have acute and long-term impacts on chromatin structure and mRNA expression.

    “Since the methylation status of histone lysine residues can positively or negatively influence gene transcription, the KMT/KDM-driven balance can have both acute and long-term impacts on chromatin structure and mRNA expression.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The iron-binding site in prolyl hydroxylases consists of two histidines and an aspartate in a facial triad.

    “The iron-binding site in these proteins consists of two histidines and an aspartate residue in a facial triad.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Methylation status is a dynamic balance of KMT and KDM activities.

    “Methylation status is therefore a dynamic process that represents a balance of KMT and KDM activities.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    Detection of polysulfides suggests that species such as RSSNO or RSSOH can lead to RSSSR.

    “Ida and colleagues [225] detected polysulfides (RSSnR, n ≥ 2), which suggests the possibility that species like RSSNO or RSSOH can lead to RSSSR for example.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] Ida, 2014, Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

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

    Premisenone given

    Cytosine to 5-mC conversion is accomplished by DNA methyltransferases, while sequential oxidation of 5mC to 5fC and 5caC is catalyzed by TET proteins.

    “Conversion of cytosine to 5-mC is accomplished by DNA methyltransferases while the sequential oxidation of 5mC to 5fC and 5caC is catalyzed by the ten-eleven-translocation (TET) family of proteins.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    At physiological NO levels (<100 nM), heme proteins, especially sGC, are the primary targets of NO.

    “At physiological levels of NO (<100 nM), heme proteins, in particular sGC, are the primary targets of NO.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nonheme iron systems typically have lower KNO (~10^6), suggesting that a higher NO flux, around 300 nM, is required to significantly bind NO.

    “The KNO for nonheme iron systems is typically lower (~106) suggesting that a higher NO flux, in the 300 nM range, is required to significantly bind NO [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Thomas, 2008, The chemical biology of nitric oxide: implications in cellular signaling, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Interpretationreasoning

    These species may be part of a new signaling paradigm linking H2S/persulfides with NO and RNS.

    “As discussed below, these species may be part of a new signaling paradigm linking H2S/persulfides with NO and RNS.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Many studies of nonheme protein-mediated signaling focus on iron metabolism, iron binding and regulation of transferrin and ferritin.

    “Many studies of nonheme protein-mediated signaling have focused on iron metabolism, in particular iron binding and the regulation of transferrin and ferritin in iron homeostasis [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Bouton, 2003, Iron regulatory proteins as NO signal transducers, Sci STKE 2003

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TSP-1/CD47 pathway inhibits H2S signaling in T cells and inhibits activation-induced up-regulation of CBS and CSE expression.

    “The TSP-1/CD47 pathway also inhibits H2S signaling in T cells and inhibits activation-induced up-regulation of CBS and CSE expression [227].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] Miller, 2013, Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation, Matrix Biol. source

      Not checked in the free run.

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

    Premisenone given

    As NO levels rise, the kinetic accessibility of other targets, especially nonheme iron complexes, increases.

    “As NO levels rise, the kinetic accessibility of other targets, especially nonheme iron complexes, increases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    NO can act as a protective antioxidant by reacting with deleterious radicals or binding catalytic metals that generate oxidants.

    “Importantly, NO can serve a protective, antioxidant role in this regard since it can either react rapidly with deleterious radical intermediates associated with oxidative stress or bind catalytic metals responsible for oxidant generation.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    5-Methylcytosine is associated with transcriptional repression and is an important determinant of phenotypic outcome.

    “Specifically, 5-methylcytosine (5-mC) is associated with transcriptional repression and is an important determinant of the phenotypic outcome of numerous cellular events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    A similar coordinative mechanism regulates ferrochelatase, inhibiting heme synthesis and potentially providing negative feedback for NOS NO production.

    “Interestingly, a similar coordinative mechanism for the regulation of ferrochelatase leads to inhibition of heme synthesis [246], potentially serving as a negative feedback mechanism for NO production from NOS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [246] Kim, 1995, Loss and degradation of enzyme-bound heme induced by cellular nitric oxide synthesis, J. Biol. Chem. source

      Not checked in the free run.

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

    Premisenone given

    Iron-sulfur clusters are well-known nonheme complexes with roles ranging from electron transport to gene expression.

    “Perhaps the most well-known nonheme complexes are iron-sulfur clusters, which play diverse roles from electron transport to gene expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nitrosylation of nonheme iron sites in aconitase and prolyl hydroxylase inhibits these enzymes and can regulate metabolism and low-oxygen responses.

    “Nitrosylation of the nonheme iron sites in aconitase [238] and prolyl hydroxylase [247] also lead to enzyme inhibition and thus can serve a regulatory role that impacts metabolism and response to low oxygen levels.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [238] Cooper, 1999, Nitric oxide and iron proteins, Biochim. Biophys. Acta-Bioenerg source

      Not checked in the free run.

    • cites [247] Metzen, 2003, Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases, Mol. Biol. Cell. source

      Not checked in the free run.

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

    Premisecitation

    Prolyl hydroxylases are classic nonheme iron complexes involved in collagen formation and HIF-1α stabilization.

    “Another classic example that highlights the diversity and importance of nonheme iron complexes in metabolism [235, 236] is the prolyl hydroxylases, which are involved in collagen formation and stabilization of HIF-1α [237-239].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [235] Halliwell, 1985

      Not checked in the free run.

    • cites [236] Minotti, 1992, The role of an endogenous nonheme iron in microsomal redox reactions, Arch. Biochem. Biophys. source

      Not checked in the free run.

    • cites [237] Butler, 2002, Non-heme iron nitrosyls in biology, Chem. Rev. source

      Not checked in the free run.

    • cites [238] Cooper, 1999, Nitric oxide and iron proteins, Biochim. Biophys. Acta-Bioenerg source

      Not checked in the free run.

    • cites [239] Fontecave, 1998, Ribonucleotide reductases and radical reactions, Cell Mol. Life Sci. source

      Not checked in the free run.

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

    Interpretationreasoning

    TET proteins are candidates for NO inhibition under normoxic conditions, which would alter 5-hmC patterns.

    “TET proteins should be candidates for inhibition by NO under normoxic conditions resulting in alterations in 5-hmC patterns.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    At least three other methylcytosine derivatives with gene regulatory functions exist: 5hmC, 5fC and 5caC.

    “Although 5-mC is the most studied epigenetic DNA modification, at least three other methylcytosine derivatives with gene regulatory functions exist: 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inhibition of NOS2 within cancer cells may be therapeutic, while delivery of exogenous NO may initiate tumor regression by simulating the immune system.

    “As such inhibition of NOS2 within cancer cells may be therapeutic [270] while delivery of exogenous NO may initiate tumor regression in simulation of the immune system.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [270] Singh, 2011, Nitric oxide: role in tumour biology and iNOS/NO-based anticancer therapies, Cancer Chemother. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    NO produced by cancer cells may modify unique targets or hijack an existing signaling modification.

    “It can be envisioned that production of NO by cancer cells may either modify unique targets or highjack an existing signaling modification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In chronic disease, increased ROS and oxidative stress can inhibit NO signaling in wound healing, leading to perpetual inflammation and tissue restoration.

    “In chronic disease, increases in ROS and oxidative stress can inhibit NO signaling in wound healing processes, leading to perpetual inflammation and tissue restoration.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oxidation of reduced species such as NH2OH has been extensively investigated with heme proteins.

    “The oxidation of reduced species such as NH2OH (Eq. 12) has been investigated extensively with heme proteins [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Donzelli, 2008, Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-l-arginine, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    NO-mediated suppression of tumor cell migration is mediated through NDRG1 expression, indicating a distinct functional consequence of NO reacting with chelatable iron.

    “These studies showed that NO-mediated suppression of tumor cell migration was mediated through NDRG1 expression, indicating a distinct functional consequence of the reaction of NO with chelatable iron.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252] Hickok, 2011, Nitric oxide suppresses tumor cell migration through N-Myc downstream-regulated gene-1 (NDRG1) expression: role of chelatable iron, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    DNICs have been detected under normal and pathological conditions, but their functional consequences remain obscure.

    “Although DNICs have been detected under both normal and pathological conditions, the functional consequences attributed to their formation have remained obscure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The antagonistic relationship between NO and ROS is an important aspect of NO signaling and a factor in tailoring the redox landscape.

    “The antagonistic relationship between NO and ROS is therefore an important aspect of NO signaling and is a factor in tailoring the redox landscape.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    PP2A is a threonine serine phosphatase that interacts with Akt, ERK and other downstream targets.

    “PP2A is a threonine serine phosphatase that interacts with Akt, ERK and other downstream targets.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Vanin proposed that DNICs could lead to reactions producing RSNO and possibly HNO.

    “However, Vanin originally proposed that DNICs could lead to a series of reactions that result in RSNO and possibly HNO formation [255, 256].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [255] Vanin, 1991, Endothelium-derived relaxing factor is a nitrosyl iron complex with thiol ligands, FEBS Lett. source

      Not checked in the free run.

    • cites [256] Ueno, 2002, In vivo nitric oxide transfer of a physiological NO carrier, dinitrosyl dithiolato iron complex, to target complex, Biochem. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO donors cause chemo- and radiosensitization and overcome drug resistance in tumor cells.

    “In fact, NO donors have been shown to lead to chemo- [271, 272] and radiosensitization [273-275] and to overcome drug resistance in tumor cells [276].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [271] Cook, 1997, Nitric oxide enhancement of melphalan-induced cytotoxicity, Br. J. Cancer source

      Not checked in the free run.

    • cites [272] Wink, 1997, Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin, Nitric Oxide source

      Not checked in the free run.

    • cites [273] Gray, 1958, Effect of nitric oxide on the radiosensitivity of tumour cells, Nature source

      Not checked in the free run.

    • cites [274] Mitchell, 1993, Hypoxic mammalian cell radiosensitization by nitric oxide, Cancer Res.

      Not checked in the free run.

    • cites [275] Mitchell, 1996, Radiation sensitisation by nitric oxide releasing agents, Br. J. Cancer

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure of NO to breast cancer cells increases HIF-1α and P-p53 levels and activates EGFR and Src via nitrosation.

    “Exposure of NO to breast cancer cells increased HIF-1α and P-p53 levels and activated EGFR and Src via nitrosation [27, 57, 282].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Thomas, 2004, Hypoxic inducible factor 1alpha, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [57] Switzer, 2012, S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer, Mol. Cancer Res. source

      Not checked in the free run.

    • cites [282] Switzer, 2012, S-Nitrosation mediates multiple pathways that lead to tumor progression in estrogen receptor-negative breast cancer, For. Immunopathol. Dis. Therap

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ApoE-3 displaces SET and increases PP2A activity, suggesting a potential role of ApoE at nitrosative NO levels.

    “Interestingly, apolipoprotein E (ApoE)-3 also displaces SET and increases PP2A activity, suggesting a potential role of ApoE at nitrosative levels of NO [281].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Christensen, 2011, and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A, J. Immunol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Premisecitation

    Previous reports indicated NDRG1 is strongly upregulated by iron chelators, so NDRG1 was hypothesized to be similarly regulated by iron sequestration through DNIC formation.

    “Previous reports indicated that NDRG1 is strongly upregulated by iron chelators [253], and therefore NDRG1 was hypothesized to be similarly regulated by iron sequestration through DNIC formation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [253] Sahni, 2014, The metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), inhibits stress-induced autophagy in cancer cells, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PP2A is inhibited by EGFR-mediated phosphorylation or by binding to SET and CIP2.

    “PP2A is inhibited by EGFR-mediated phosphorylation or binding to SET nuclear oncogene (SET) and cancerous inhibitor of protein phosphatase 2 (CIP2) [280].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [280] Switzer, 2011, Targeting SET/I(2)PP2 A oncoprotein functions as a multi-pathway strategy for cancer therapy, Oncogene source

      Not checked in the free run.

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

    Premisereasoning

    MMPs are involved in ECM breakdown and remodeling and are a critical component of metastasis.

    “As MMPs are involved in breakdown and remodeling of the extracellular matrix, they are a critical component of the metastatic process.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    NO and related species provide many reactions that shape the redox landscape.

    “Nonetheless, it is clear that NO and related species provide a multitude of reactions that shape the redox landscape.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CD63 is associated with autophagy induction and may trigger prosurvival autophagy.

    “CD63 is associated with induction of autophagy [290] and may be a trigger for prosurvival autophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Bampton, 2005, The dynamics of autophagy visualized in live cells: from autophagosome formation to fusion with endo/lysosomes, Autophagy source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationnone given

    NO-mediated reactions provide a chemical signaling approach independent of normal ligand activation but dependent on NO flux and NOS2 activity.

    “The reactions mediated by NO provide a chemical approach to signaling that is independent of normal ligand”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TIMP-1 from NO donor-treated cells shows enhanced nitration and co-immunoprecipitates with CD63 more than untreated controls.

    “Similarly, TIMP-1 from NO donor treated cells showed enhanced nitration and co-immunoprecipitated with CD63 to a higher degree than that of untreated controls [163].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Ridnour, 2012, Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation, PLOS ONE source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Elevated NO flux in high NOS2-expressing breast tumors may shift TIMP-1 function away from MMP inhibition toward TIMP1/CD63-mediated pro-survival signaling while maintaining MMP activity, promoting disease progression.

    “Collectively, these results suggest that elevated NO flux in high NOS2-expressing breast tumors may shift TIMP-1 function away from MMP-inhibition to favor TIMP1/CD63-mediated pro-survival signaling while maintaining MMP activity, which further promotes disease progression through the selection of invasive phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TIMP1 nitration is associated with enhanced CD63 binding, pro-survival PI3K/Akt/BAD signaling, increased drug resistance, proliferation and brain metastasis.

    “Nitration of TIMP1 is also associated with enhanced CD63 binding, which promotes pro-survival signaling through PI3K/Akt/BAD phosphorylation, as well as increased drug resistance, cellular proliferation and brain metastasis [33, 163].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Heinecke, 2014, Tumor microenvironment-based feed-forward regulation of NOS2 in breast cancer progression, Proc. Natl. Acad. Sci. U.S.A. source

      Not checked in the free run.

    • cites [163] Ridnour, 2012, Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation, PLOS ONE source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Internal tyrosines Y95 and Y143 of TIMP-1 are specifically nitrated, while more exposed residues are not modified.

    “Internal tyrosines were specifically nitrated (Y95 and Y143), while more exposed residues were not modified.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Ridnour, 2012, Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation, PLOS ONE source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO donor-mediated nitration occurs at 100-700 nM steady-state NO fluxes and correlates with Akt pathway activation and reduced survival in ER(−) breast cancer patients with high tumor NOS2.

    “NO donor-mediated nitration events occurred in the range of 100-700 nM steady state NO fluxes and correlated with NO-mediated Akt pathway activation and reduced survival in ER(−) breast cancer patients with high tumor NOS2 expression [163].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Ridnour, 2012, Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation, PLOS ONE source

      Not checked in the free run.

155 of 155

  • The paper relies on this without support.

    Nitrite is primarily found in aqueous media where antioxidants such as GSH, ascorbate and urate exist in high concentration.

    “Given that nitrite will primarily be found in aqueous media where these antioxidants also exist in high concentration, NO2 is expected to be primarily scavenged by the antioxidant defense system.”
1 of 1

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?

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.

  • The later summary substitutes TIMP1 for Src in its account of Section II

    Minor

    Section VII says Section II introduced S-nitrosation of H-Ras, EGFR, and TIMP1. The cited passage in Section II instead names H-Ras, EGFR, and Src; it does not name TIMP1 as the third membrane-protein target.

1 of 1

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References 301 · Cited by 150

Research works printed but not linked: 9

  1. Pogrebnaya, 1975, Oxidation of nitric-oxide by oxygen in liquid-phase, J. Appl. Chem. USSR (Engl. Transl.), 48, 1004
  2. Jourd’heuil, 2001, Reaction of superoxide and nitric oxide with peroxynitrite-implications for peroxynitrite-mediated oxidation reactions in vivo, J. Biol. Chem., 276, 28799, 10.1074/jbc.M102341200 · DOI
  3. Thomas, 2002, Protein nitration is mediated by heme and free metals through Fenton-type chemistry: an alternative to the NO/O2- reaction, Proc. Natl. Acad. Sci. U.S.A., 99, 12691, 10.1073/pnas.202312699 · DOI
  4. Hordijk, 2006, Regulation of NADPH oxidases: the role of Rac proteins, Circ. Res., 98, 453, 10.1161/01.RES.0000204727.46710.5e · DOI
  5. Radi, 1991, Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide, J. Biol. Chem., 266, 4244, 10.1016/S0021-9258(20)64313-7 · DOI
  6. Schopfer, 2005, Fatty acid transduction of nitric oxide signaling. Nitrolinoleic acid is a hydrophobically stabilized nitric oxide donor, J. Biol. Chem., 280, 19289, 10.1074/jbc.M414689200 · DOI
  7. Fukuto, 1992, Chemical oxidation of N-hydroxyguanidine compounds: release of nitric oxide, nitroxyl and possible relationship to the mechanism of biological nitric oxide generation, Biochem. Pharmacol., 43, 607, 10.1016/0006-2952(92)90584-6 · DOI · Paper page
  8. Dahm, 2006, Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite: implications for the interaction of nitric oxide with mitochondria, J. Biol. Chem., 281, 10056, 10.1074/jbc.M512203200 · DOI · Paper page
  9. Bouton, 1996, Modulation of iron regulatory protein functions. Further insights into the role of nitrogen- and oxygen-derived reactive species, J. Biol. Chem., 271, 2300, 10.1074/jbc.271.4.2300 · DOI

Authors
Thomas, D. D., Heinecke, J. L., Ridnour, L. A., Cheng, R. Y., Kesarwala, A. H., Switzer, C. H., McVicar, D. W., Roberts, D. D., Glynn, S., Fukuto, J. M., Wink, D. A., & Miranda, K. M.
Affiliations
  • University of Illinois Chicago (US)
  • National Institutes of Health (US)
  • National Cancer Institute (US)
  • Ollscoil na Gaillimhe – University of Galway (IE)
  • Sonoma State University (US)
  • University of Arizona (US)
Corresponding author
  • Wink, David A.
  • Miranda, Katrina M.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2015-10
Volume
87
Pages
204-225
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2015.06.002
PMC
PMC4852151
OpenAlex
W992309826
Semantic Scholar
d38357b6506abef8d5b7c79a5f3d45eae4a9722b
Cited by
150
References
301
Citations by year
2026: 13 · 2025: 9 · 2024: 15 · 2023: 15 · 2022: 13 · 2021: 15 · 2020: 12 · 2019: 13 · 2018: 14 · 2017: 12 · 2016: 17 · 2015: 2
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion)
  • ARAN (University of Galway Research Repository) (Ollscoil na Gaillimhe – University of Galway) (submittedVersion, cc-by-nc-nd)
  • University of Galway Research Repository (submittedVersion, cc-by-nc)
  • Research Repository UCD (University College Dublin) (cc-by-nc)
Funders
  • National Institutes of Health (GM076247, R01GM085232)
  • Intramural Research Program of the National Institutes of Health, the National Cancer Institute and the Center for Cancer Research (DAW, DDR) and the National Science Foundation (CHE-0645818 to KMM))
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
nitric oxide, NOS2, nitric oxide synthase, reactive nitrogen species, redox signaling, nitrosative stress, soluble guanylate cyclase, non-heme iron complexes, thiol modification, chemical stress, immune response
MeSH terms
Free Radicals, Humans, Neoplasms, Nitric Oxide, Oxidation-Reduction, Signal Transduction, Apoptosis, Oxidative Stress, Reactive Nitrogen Species, Nitric Oxide Synthase Type II

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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