Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase

Classified as probably not a substantial claim.

Nox1 deletion increases survival in a mouse model of amyotrophic lateral sclerosis.

“Nox1 deletion was reported to increase survival in a mouse model of amyotrophic lateral sclerosis (ALS)”

• cites Marden et al., 2007 sourceSupported

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

Nox1 is predominantly expressed in colon epithelium but also detected in other peripheral tissues, including dorsal root ganglia and vascular cells.

“Nox1 is predominantly expressed in colon epithelium, but was also detected in other peripheral tissues, including dorsal root ganglia and in vascular cells (Suh et al., 1999;Bedard and Krause, 2007;Ibi et al., 2008).”

• cites Suh et al., 1999 sourceNot checked — no full text of the source
• cites Bedard and Krause, 2007 sourceNot checked — no full text of the source
• cites Ibi et al., 2008 sourceSupported

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

The cellular sources of Nox1 and the mechanisms by which Nox1 may promote neural tissue damage remained undetermined.

“but the cellular sources of Nox1 and the mechanisms by which Nox1 may promote neural tissue damages remained undetermined (Marden et al., 2007).”

• cites Marden et al., 2007 sourcePartly supported

  The Introduction reports that Nox1 deletion delayed motor-neuron disease in ALS mice, and the Conclusions (indexed under Figure 2; page unavailable) describe possible ways oxidase-derived ROS could contribute to neurodegeneration. Our copy does not identify Nox1’s cellular sources or explicitly state that its specific damage mechanisms remained undetermined; the proposed mechanisms concern ROS generally. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Microglia express the phagocyte NADPH oxidase.

“Like other phagocytes, microglia express the phagocyte NADPH oxidase (Sankarapandi et al., 1998;Bianca et al., 1999)”

• cites Sankarapandi et al., 1998 sourceSupported
• cites Bianca et al., 1999 sourceSupported

May combine two claims.

Activation of microglia with LPS and injection of LPS in the brain induce IL-1β and NO production via Nox1.

“activation of microglia with lipopolysaccharide (LPS), a component of Gram-negative bacteria commonly used to model proinflammatory and neurotoxic activation of microglia (Lehnardt et al., 2003;Qin et al., 2004), and injection of LPS in the brain induce IL-1␤ and NO⅐ production via Nox1”

• cites Lehnardt et al., 2003 sourceSupported
• cites Qin et al., 2004 sourceSupported

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

Like Nox2, Nox1 is a transmembrane protein that forms a heterodimer with p22phox and generates O2−.

“Like Nox2, Nox1 is a transmembrane protein which forms a heterodimer with p22 phox and generates O 2 ⅐Ϫ (Ambasta et al., 2004;Kawahara et al., 2005).”

• cites Ambasta et al., 2004 sourcePartly supported

  The opening summary (p. 1) says Nox1 mediates superoxide formation and directly interacts with p22phox; the Discussion (p. 5) reports their co-precipitation. The Discussion (p. 6) describes membrane localization, but our copy does not establish the more specific claim that Nox1 is transmembrane. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Kawahara et al., 2005 sourceSupported

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

Microglia express the full set of specific proteins that compose the phagocyte oxidase (Nox2, p22phox, p47phox, p40phox, p67phox, and Rac).

“Previous studies have shown that microglia express the full set of specific proteins that compose the phagocyte oxidase (Nox2, p22 phox , p47 phox , p40 phox , p67 phox , and Rac) (Bianca et al., 1999)”

• cites Bianca et al., 1999 sourcePartly supported

  The Results section (page unavailable) lists gp91phox (Nox2), p22phox, p47phox, p40phox, p67phox, and Rac as components of the classical NADPH oxidase, which the paper reports is activated in microglia. It does not demonstrate expression of every listed protein in microglia: the Results state that testing oxidase-component translocation in rat microglia was not feasible because suitable antibodies were unavailable. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

O2− and NO combine at diffusion-limited rates to form highly reactive ONOO− that has been implicated in the death of cultured neurons or oligodendrocyte progenitors exposed to LPS-activated microglia.

“O 2 ⅐Ϫ and NO⅐ combine at diffusion-limited rates to form highly reactive ONOO Ϫ that has been implicated in the death of cultured neurons or oligodendrocyte progenitors exposed to LPS-activated microglia (Xie et al., 2002;Li et al., 2005).”

• cites Xie et al., 2002 sourceSupported
• cites Li et al., 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Both iNOS and IL-1β signaling have been implicated in the loss of synaptic proteins in mouse models of Alzheimer's disease.

“whereas both iNOS and IL-1␤ signaling have been implicated in the loss of synaptic proteins in mouse models of Alzheimer's disease (Craft et al., 2005;Medeiros et al., 2007).”

• cites Craft et al., 2005 sourcePartly supported

  The Results (‘Increased synaptic degeneration in Aβ-infused IL1raKO mice’) report greater loss of PSD-95 in mice with enhanced IL-1 signaling. The Discussion says IL-1β can stimulate glial iNOS production and potentially cause neuronal damage, but does not link iNOS specifically to the loss of synaptic proteins. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Medeiros et al., 2007 sourcePartly supported

  The Results section, “Prevention of synaptic dysfunction by TNF-α and iNOS inhibition” (page not provided), reports that iNOS inhibition or deletion protected against amyloid-β-induced loss of the synaptic protein synaptophysin in mice. The Discussion says further studies are needed to determine whether IL-1β participates; this paper does not establish the IL-1β part of the claim. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Microglial Nox1 and Nox2 target different redox-sensitive signaling compounds, possibly because of differences in the subcellular distributions of catalytically active Nox and LPS-signaling components.

“differential effects of Nox proteins in microglial expression of IL-1␤ and iNOS genes suggest that microglial Nox1 and Nox2 target different redoxsensitive signaling compounds, possibly because of differences in the subcellular distributions of catalytically active Nox and LPSsignaling components (Hunter, 2000).”

• cites Hunter, 2000 sourcePartly supported

  The section “Spatiotemporal Aspects of Signaling” (page unavailable) says that the location of signaling components can determine signaling specificity, supporting the proposed spatial mechanism in general. It does not address microglial Nox1 or Nox2, their redox-sensitive targets, or LPS-signaling components, so it does not support the specific application to them. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

LPS signals through TLR4, which promotes LPS-triggered microglial neurotoxicity.

“LPS signals through the toll-like receptor 4 (TLR4), which promotes LPS-triggered microglial neurotoxicity (Lehnardt et al., 2003)”

• cites Lehnardt et al., 2003 sourceSupported

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

Microglia release O2− or O2−-derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases.

“release O 2 ⅐Ϫ or O 2 ⅐Ϫ -derived hydrogen peroxide when exposed to LPS, opsonized zymosan, or aggregated proteins that accumulate in the brain during neurodegenerative diseases (Sankarapandi et al., 1998;Zhang et al., 2005;B. Qin et al., 2006;Wilkinson et al., 2006).”

• cites Sankarapandi et al., 1998 sourcePartly supported

  The Abstract and Discussion report that microglia generate superoxide when stimulated with opsonified zymosan. The paper does not establish the same response to LPS or to aggregated proteins associated with neurodegenerative disease, and it does not directly establish hydrogen peroxide release under those conditions. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Zhang et al., 2005 sourceNot checked — no full text of the source
• cites B. Qin et al., 2006 sourcePartly supported

  The Discussion (page unavailable) reports superoxide production by amyloid-β-stimulated microglia and refers to free-radical-producing microglia activated by amyloid-β or LPS. Our copy does not establish release of hydrogen peroxide or address opsonized zymosan, so it supports only part of the sentence. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Cultured rat microglia express Nox4, unlike the mouse microglia investigated here.

“However, a recent study suggests that cultured rat microglia express Nox4 (Harrigan et al., 2008), unlike the mouse microglia investigated here.”

• cites Harrigan et al., 2008 sourceSupported

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

These same compounds have also been implicated in the neural tissue damage induced by injection of LPS in rodent brain.

“These same compounds have also been implicated in the neural tissue damage induced by injection of LPS in rodent brain (Iravani et al., 2002;Cai et al., 2003;Arai et al., 2004;Qin et al., 2004).”

• cites Iravani et al., 2002 sourceNot checked — no full text of the source
• cites Cai et al., 2003 sourceNot checked — no full text of the source
• cites Arai et al., 2004 sourceSupported

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

Loss of synaptic proteins associated with microglial activation has been observed in neuroinflammatory states such as multiple sclerosis and Alzheimer's disease.

“Loss of synaptic proteins associated with microglial activation has been observed in neuroinflammatory states such as multiple sclerosis and Alzheimer's disease (Lue et al., 1996;Vercellino et al., 2007).”

• cites Lue et al., 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Vercellino et al., 2007 sourceSupported

May combine two claims.

Hydroethidine oxidation was >60% lower in shNox1-transduced cells than in nontransduced cells, whereas shCtrl transduction had no significant effect.

“Hydroethidine oxidation was Ͼ60% lower in shNox1-transduced cell than in nontransduced cells, whereas shCtrltransduction had no significant effect on the level of hydroethidine oxidation (Fig. 4C).”

May combine two claims.

[Nox1-p22phox] dimers localize in intracellular compartments and are recruited to phagosome membranes during microglial phagocytosis of zymosan.

“[Nox1-p22 phox ] dimers localized in intracellular compartments are recruited to phagosome membranes during microglial phagocytosis of zymosan”

May combine two claims.

Activation of microglia with LPS and injection of LPS in the brain favors loss of synapse proteins.

“and favors peroxynitrite-mediated tyrosine nitration as well as loss of synapse proteins.”

The quote only partly states this claim.

In Nox2-KO cells, there was only a fivefold increase in hydroethidine oxidation after zymosan.

“In Nox2-KO cells, there was only a fivefold increase in hydroethidine oxidation.”

May combine two claims.

Both Nox2 and Nox1 transcripts were clearly expressed by microglia from newborn mice, whereas Nox3, Nox4, Duox1, or Duox2 transcripts were not detectable.

“Both Nox2 and Nox1 transcripts were clearly expressed by microglia from newborn mice, whereas Nox3, Nox4, Duox1, or Duox2 transcripts were not detectable (Fig. 1).”

May combine two claims.

DPI prevented phagosome staining in Nox2-KO engulfing cells, although it did not block microglial phagocytosis of zymosan.

“Cell treatment with DPI (1 M) prevented phagosome staining in Nox2-KO engulfing cells, although it did not block microglial phagocytosis of zymosan (Fig. 3A).”

May combine two claims.

In Nox2-KO microglia, the plasma membrane was not stained, although p22phox was detected in vesicles, including LAMP1-positive lysosomes, at lower levels than in WT cells.

“In Nox2-KO microglia, the plasma membrane was not stained, although p22 phox was clearly detected in vesicles, including LAMP1-positive lysosomes (Fig. 2 A, white arrowheads), albeit at lower levels than in WT cells.”

May combine two claims.

DPI fully prevented LPS-induction of O2− in Nox2-KO microglia, indicating that Nox1 is also implicated in LPS-stimulated O2− production.

“DPI also fully prevented LPSinduction of O 2 ⅐Ϫ in Nox2-KO microglia, indicating that Nox1 is also implicated in LPS-stimulated O 2 ⅐Ϫ production (Fig. 4 A, B).”

May combine two claims.

In WT microglia, anti-p22phox immunoreactivity was observed at the plasma membrane and on intracellular vesicles, some of which expressed LAMP1.

“In WT microglia, anti-p22 phox immunoreactivity was observed at the plasma membrane and on intracellular vesicles, some of which expressed the lysosome marker LAMP1 (Fig. 2 A).”

May combine two claims.

Nox1 produces O2−, which may react with NO formed in microglia.

“(2) Nox1 produces O 2 ⅐Ϫ , which may react with NO⅐ formed in microglia.”

May combine two claims.

Nox1, but not Nox2, is implicated in microglial LPS-stimulated IL-1β production.

“Interestingly, Nox1, but not Nox2, was implicated in microglial LPS-stimulated IL-1␤ production”

May combine two claims.

Nox1 activity generates O2− and promotes NO production in purified microglia.

“The preceding experiments show that Nox1 activity generates O 2 ⅐Ϫ and promotes NO⅐ production in purified microglia.”

May combine two claims.

NOS inhibitor NMMA prevented NO production but did not reduce LPS-triggered IL-1β secretion.

“Treatment of microglia with the NO synthase inhibitor N-monomethyl-L-arginine (500 M) prevented NO⅐ production but did not reduce LPS-triggered IL-1␤ secretion (data not shown)”

May combine two claims.

Nox1 promotes LPS-triggered expression of iNOS and NO production in microglia.

“(1) Nox1 promotes LPS-triggered expression of iNOS and NO⅐ production in microglia.”

May combine two claims.

Both Nox1 and Nox2 upregulate microglial O2− and NO production in response to LPS.

“whereas both oxidases upregulated microglial O 2 ⅐Ϫ and NO⅐ production in response to LPS.”

May combine two claims.

High levels of Ntyr were observed at the level of the microglial reaction, but less in Nox1-KO than in WT mice.

“High levels of Ntyr were observed at the level of the microglial reaction, but less in Nox1-KO than in WT mice.”

May combine two claims.

In addition to the Nox2-dependent phagocyte oxidase, microglia express a Nox1 oxidase that catalyzes intracellular and intraphagosomal production of O2−.

“this study shows that in addition to the Nox2-dependent phagocyte oxidase, microglia express a Nox1 oxidase that catalyzes intracellular and intraphagosomal production of O 2 ⅐Ϫ .”

Classified as probably not a substantial claim.

Lentiviral vectors shCtrl and shNox1 were applied to freshly purified microglial cells at equivalent numbers of transduction units.

“Lentiviral vectors shCtrl and shNox1 were applied to freshly purified microglial cells at equivalent numbers of transduction units (TU), as assessed by EGFP labeling.”

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

Mean percentage of transduced microglia exceeded 85% for each genotype.

“Mean percentage of transduced microglia exceeds 85% for each genotype (WT or Nox2-KO).”

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

Controls performed by substituting primary antibodies with rabbit nonimmune serum or unrelated monoclonal antibodies of matched isotypes were negative.

“Controls performed by substituting primary antibodies with rabbit nonimmune serum or unrelated monoclonal antibodies of matched isotypes were negative.”

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

All procedures were performed in accordance with guidelines for care and use of experimental animals of the European Economic Community and approved by the ethics committee for animal experimentation in Ile-de-France.

“All procedures were performed in accordance with the guidelines for care and use of experimental animals of the European Economic Community (ref 86/609/CEE) and approved by the ethics committee for animal experimentation in Ile-de-France.”

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

Nox1 activity requires rac proteins and is optimized in the presence of NOXO1 and NOXA1.

“Nox1 activity requires rac proteins and is optimized in the presence of NOXO1 and NOXA1, two functional homologues of p47 phox and p67 phox , respectively (Ba ´nfi et al., 2003).”

• cites Ba ´nfi et al., 2003Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Microglia may promote neurodegeneration by producing proinflammatory or potentially neurotoxic effectors, including IL-1β, NO, or ROS.

“but they may also promote neurodegeneration by producing proinflammatory or potentially neurotoxic effectors, including interleukin-1␤ (IL-1␤), nitric oxide (NO⅐), or reactive oxygen species (ROS) (Allan et al., 2005;Block et al., 2007;Hanisch and Kettenmann, 2007).”

• cites Allan et al., 2005 sourceNot checked — no full text of the source
• cites Block et al., 2007 sourceNot checked — no full text of the source
• cites Hanisch and Kettenmann, 2007 sourceNot checked — no full text of the source

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

Lentiviral transduction did not affect microglial cell morphologies.

“Lentiviral transduction did not affect microglial cell morphologies examined by phase contrast microscopy (data not shown).”

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

Nox2 promotes neural cell death in animal models of neurodegenerative diseases and stroke.

“but also promotes neural cell death in animal models of neurodegenerative diseases and stroke (Walder et al., 1997;Wu et al., 2003Wu et al., , 2006)).”

• cites Walder et al., 1997 sourceNot checked — no full text of the source
• cites Wu et al., 2003Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Wu et al., 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Nox2 generates superoxide ion, which ensures phagocytic neutralization of microorganisms.

“Nox2 generates superoxide ion (O 2 ⅐Ϫ ), which ensures the phagocytic neutralization of microorganisms (Nauseef, 2007)”

• cites Nauseef, 2007 sourceNot checked — no full text of the source

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

O2− is converted to hydrogen peroxide that contributes to intracellular cell signaling through redox modulation.

“However, O 2 ⅐Ϫ is also converted to hydrogen peroxide that primarily contributes to intracellular cell signaling processes through redox modulation of ion channels, enzymes, or transcription factors (Dro ¨ge, 2002;Veal et al., 2007).”

• cites Dro ¨ge, 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Veal et al., 2007 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Highly pure (>99%) microglia were isolated from 2-week-old glial primary cultures.

“Highly pure (Ͼ 99%) microglia were isolated from 2-week-old glial primary cultures”

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

Nox1-KO mice used were derived from at least 10 backcrosses with WT C57BL/6J mice.

“Nox1-KO mice (Gavazzi et al., 2006) used in our experiments were derived from at least 10 backcrosses with WT C57BL/6J mice.”

• cites Gavazzi et al., 2006 sourceNot checked — no full text of the source

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

O2− may be neurotoxic by fueling formation of hydroxyl free radical or peroxynitrite.

“O 2 ⅐Ϫ may be neurotoxic by fueling the formation of highly pro-oxidant hydroxyl free radical or peroxynitrite (Halliwell, 2006;Szabo ´et al., 2007).”

• cites Halliwell, 2006 sourceNot checked — no full text of the source
• cites Szabo ´et al., 2007 sourceNot checked — no full text of the source

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

O2− produced in phagolysosomes gives rise to halide derivatives, which eventually destroy ingested bacteria or fungi.

“and gives rise to halide derivatives (Nauseef, 2007), which eventually destroy ingested bacteria or fungi.”

• cites Nauseef, 2007 sourceNot checked — no full text of the source

May combine two claims.

Not only Nox2 but also Nox1 promoted microglial production of NO.

“Although quite low (20 -30% reduction in nitrite levels according to the experiments), this inhibitory effect suggested that not only Nox2 but also Nox1 promoted microglial production of NO⅐.”

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

TLR4 is not required for LPS activation of microglial Nox2.

“although this receptor is not required for LPS activation of microglial Nox2 (Qin et al., 2005).”

• cites Qin et al., 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Microglial Nox1 may contribute to an immune defense against microorganisms that threaten the CNS.

“It is therefore possible that microglial Nox1 contributes to an immune defense against microorganisms that threaten the CNS (Rock et al., 2004).”

• cites Rock et al., 2004 sourceNot checked — no full text of the source

May combine two claims.

LPS treatments and zymosan phagocytosis both activate Nox1 and Nox2 in microglia.

“LPS treatments and zymosan phagocytosis therefore both activate Nox1 and Nox2 in microglia.”

May combine two claims.

The functions of Nox1 and Nox2 were not redundant, because microglial production of NO was reduced by inactivating either the Nox2 or Nox1 gene.

“Despite this common effect on NO⅐ production, the functions of Nox1 and Nox2 were not redundant, because microglial production of NO⅐ was reduced by inactivating either the Nox2 or Nox1 gene.”

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

In Alzheimer's disease, loss of synaptic proteins has been correlated with neurological decline.

“In Alzheimer's disease, loss of synaptic proteins has been correlated with neurological decline (Terry et al., 1991)”

• cites Terry et al., 1991 sourceNot checked — no full text of the source

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

O2− produced in phagolysosomes indirectly activates proteases.

“The O 2 ⅐Ϫ produced in phagolysosomes indirectly activates proteases (Reeves et al., 2002)”

• cites Reeves et al., 2002 sourceNot checked — no full text of the source

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

TLR4 activates multiple intracellular signaling pathways leading to transcription of genes, such as iNOS and IL-1β.

“TLR4 activates multi-ple intracellular signaling pathways leading to transcription of genes, such as iNOS and IL-1␤ (O'Neill and Bowie, 2007).”

• cites O'Neill and Bowie, 2007 sourceNot checked — no full text of the source

May combine two claims.

Activated microglia may cause oxidative damage to neighboring neurons through the diffusion of ONOO−, which is known to induce structural and functional alterations of synapse components.

“the extensive formation of Ntyr in microglia suggests that activated microglia may cause oxidative damage to neighboring neurons through the diffusion of ONOO Ϫ , which is known to induce structural and functional alterations of synapse components (Zaidi and Michaelis, 1999).”

• cites Zaidi and Michaelis, 1999 sourceNot checked — no full text of the source

May combine two claims.

Peroxynitrite triggers formation of nitrotyrosine residues, which provides a tissue marker for reactive nitrogen-related tissue damage.

“This compound triggers the formation of nitrotyrosine residues (Ntyr), which provides a tissue marker for reactive nitrogen-related tissue damage (Torreilles et al., 1999).”

• cites Torreilles et al., 1999 sourceNot checked — no full text of the source

May combine two claims.

Activation of microglial Nox1 may contribute to immune defenses, neuroregressive events during neurogenesis, and the neural tissue damage that occurs in neurodegenerative or inflammatory diseases.

“Activation of microglial Nox1 may therefore contribute to immune defenses, neuroregressive events during neurogenesis, and the neural tissue damage that occurs in neurodegenerative or inflammatory diseases.”

• AssumptionRests on an assumption: LPS injection into the mouse striatum produces a neuroinflammatory lesion that models the neural tissue damage occurring in human neurodegenerative or inflammatory diseases.

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

Nox1-dependent increase of IL-1β and iNOS transcripts might result from the oxidative modulation of a variety of redox-sensitive signaling proteins, such as MAP kinase family members, tyrosine protein phosphatases or transcription factors such as NFB or AP1.

“Nox1dependent increase of IL-1␤ and iNOS transcripts might result from the oxidative modulation of a variety of redox-sensitive signaling proteins, such as MAP kinase family members, Tyrosine protein phosphatases or transcription factors such as NFB or AP1 (Dro ¨ge, 2002;Veal et al., 2007).”

• cites Droge, 2002 sourceNot checked — no full text of the source
• cites Veal et al., 2007 sourceNot checked — no full text of the source

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

Nox was implicated in LPS-triggered rat microglial production of NO.

“It was previously shown with Nox inhibitors and ROS scavengers that Nox was implicated in LPS-triggered rat microglial production of NO⅐ (Pawate et al., 2004).”

• cites Pawate et al., 2004 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

LPS-activated microglia kill neurons or oligodendrocyte progenitors directly in cell culture via microglial production of IL-1β, NO, or Nox2-derived ROS.

“LPS-activated microglia kill neurons or oligodendrocyte progenitors directly in cell culture via microglial production of IL-1␤, NO⅐, or Nox2-derived ROS (Ma et al., 2002;Li et al., 2005).”

• cites Ma et al., 2002Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Li et al., 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

In a mouse model of human ALS, activated microglia accelerate disease progression.

“Recent studies in a mouse model of human ALS in which motoneurons progressively degenerate show that activated microglia accelerate disease progression (Boille ´e et al., 2006)”

• cites Boille´e et al., 2006Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Tyrosine nitration, a marker of ONOO− activity, has been correlated with tissue damages in human neuropathologies such as multiple sclerosis, ALS, and Parkinson's and Alzheimer's diseases, as well as in animal models of these diseases, including LPS-triggered neuroinflammation.

“Tyrosine nitration, a marker of ONOO Ϫ activity, has been correlated with tissue damages in human neuropathologies such as multiple sclerosis, ALS, and Parkinson's and Alzheimer's diseases, as well as in animal models of these diseases, including LPS-triggered neuroinflammation (Torreilles et al., 1999;Hill et al., 2004;Toma ´s-Camardiel et al., 2004).”

• cites Torreilles et al., 1999 sourceNot checked — no full text of the source
• cites Hill et al., 2004 sourceNot checked — no full text of the source
• cites Toma´s-Camardiel et al., 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Nox1 activity promotes LPS-induced IL-1β secretion at the transcriptional level or enhances stability of IL-1β transcript.

“Altogether, microglial treatment with NADPH oxidase inhibitors provides evidence that Nox1 activity promotes the LPS-induced IL-1␤ secretion at the transcriptional level or enhances the stability of IL-1␤ transcript.”

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

Intracellular ROS signaling is spatially restricted by the compartmentalization of peroxide-decomposing enzymes such as catalase, glutathione peroxidase, and thioredoxin peroxidase.

“increasing evidence indicates that intracellular ROS signaling is spatially restricted by the compartmentalization of peroxide-decomposing enzymes such as catalase, glutathione peroxidase, and thioredoxin peroxidase (Veal et al., 2007).”

• cites Veal et al., 2007 sourceNot checked — no full text of the source