Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes

In the paper

“XIAP inhibits TNF-α-induced cell death and its expression is regulated by NF-κB (Chu et al., 1997; Rothe et al., 1995; Stehlik et al., 1998).”

What the sources say

• Disputed

  The Discussion identifies c-IAP2—not XIAP—as the protein whose expression responds to NF-κB and whose overexpression suppresses TNF-induced cell death. The cited paper does not establish either claim for XIAP. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Chu et al., 1997 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Rothe et al., 1995 source
• Supported

  The Results and Discussion report that inhibiting NF-κB suppresses inducible xiap expression in endothelial cells. They also report that ectopic xiap expression protects those cells from TNF-α-induced apoptosis. The claim accurately summarizes those findings in the cells studied. (LLM, conf=0.93)

  cites Stehlik et al., 1998 source

In the paper

“HMGA1 activation of STAT3, which results in an increase of miR-181 expression, could represent an important feedback loop to regulate expression of HMGA1 in adult tissues (Hillion et al., 2008).”

What the sources say

• Partly supported

  The Results (page not provided) show that HMGA1 directly activates STAT3 transcription in malignant hematopoietic cells. The paper does not report that STAT3 increases miR-181 expression or propose a miR-181 feedback loop regulating HMGA1 in adult tissues; searches for miR-181 and that feedback relationship found no supporting passage. (LLM, conf=0.88)

  cites Hillion et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“Pro-inflammatory stimuli such as lipopolysaccharide (LPS), an endotoxin component of gram-negative bacterial cell membranes, engage an innate immune response through TLR4 receptors, resulting in activation of astrocytes (Sofroniew et al., 2009b; Tang et al., 2007; Okun et al., 2012).”

What the sources say

• ?Not matched

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

  cites Sofroniew et al., 2009b
• Supported

  The Results identify LPS as a TLR4 ligand and report a robust NF-κB response to it in astrocytes. The Discussion likewise describes a robust astrocyte response to LPS and explains that TLR activation by bacterial LPS initiates innate-immune signaling. (LLM, conf=0.91)

  cites Tang et al., 2007 source
• ?Not matched

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

  cites Okun et al., 2012

In the paper

“Activation of Stat3, an important component of the NF-κB signaling pathway, has also been shown to increase miR-181 expression (Iliopoulos et al., 2010).”

What the sources say

• Partly supported

  The Results section reports that inhibiting STAT3 reduces miR-181b-1 expression and that activating STAT3 up-regulates it. The Discussion places STAT3 in an inflammatory feedback loop involving NF-κB, but the paper identifies miR-181b-1 specifically, not the miR-181 family generally. (LLM, conf=0.84)

  cites Iliopoulos et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“Particularly relevant to the role of miR-181 repression of HMGA1 in the inflammatory response, HMGA1 has been shown to promote an inflammatory transcriptional profile, at least in part by increasing Cox-2 and STAT-3 levels (Resar, 2010 for a review; Schuldenfrei et al., 2011).”

What the sources say

• Supported

  The HMGA1 Function in Cancer section describes HMGA1-regulated genes involved in inflammatory pathways. The COX-2 and STAT3 subsections report that HMGA1 increases expression of each, supporting the proposed mechanism. (LLM, conf=0.90)

  cites Resar, 2010 source
• Partly supported

  The Results and Discussion link HMGA1 to inflammatory transcriptional pathways during lymphoid tumorigenesis. The Discussion reports COX-2 up-regulation in only 50% of lymphoid cells early in tumorigenesis and none in established tumors; our copy does not report increased STAT-3 levels. Thus, the proposed mechanism is only partly supported. (LLM, conf=0.88)

  cites Schuldenfrei et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“Reactive gliosis is broadly characterized by an increase in expression of the cytoskeletal protein GFAP, activation of the transcription factor NF-κB, and the production of nitric oxide and inflammatory cytokines such as TNFα (Pekny et al., 2005; Kang et al., 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Pekny et al., 2005 source
• Partly supported

  The paper’s Abstract identifies increased GFAP as a marker of reactive astrocytes and says they are likely to increase cytokine expression. The “NF-κB and Inflammation” section discusses NF-κB activation in some brain pathologies, but cautions that activation in astrocytes is not established in every injury model. The passages do not identify nitric oxide or TNFα as general features of reactive gliosis. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites Kang et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“GDNF can protect dopaminergic neurons against oxidative and metabolic stress in experimental models of Parkinson’s disease (Ramaswamy et al., 2009).”

What the sources say

• Partly supported

  The “Injections in animal PD models” section reports that GDNF protected nigral neurons in rats with 6-OHDA lesions. Our copy does not characterize those lesions as oxidative stress or establish protection against metabolic stress, so it supports the experimental neuroprotection claim but not both specified stress types. Page numbers were unavailable. (LLM, conf=0.84)

  cites Ramaswamy et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“VEGF stimulates cerebral angiogenesis and neurogenesis (MacKenzie and Ruhrberg, 2012).”

What the sources say

• Supported

  The section “VEGF-A signalling during CNS angiogenesis” reports that removing VEGF-A expression impairs brain vascularisation. The section “VEGF-A and the angiogenic niche of neurogenesis” reports that delivering VEGF-A to the brain enhances neurogenesis in adult rats. Page numbers were not available in our copy. (LLM, conf=0.93)

  cites MacKenzie and Ruhrberg, 2012 source

In the paper

“Bcl-2, a previously validated miR-181 target (Ouyang et al., 2012a) and the predicted target NAMPT mRNA were also enriched in the pull-down (Figure 7A).”

In the paper

“The predicted MeCP2 binding site was validated as a miR-181 target, as the Psi-CHECK2 MeCP2 reporter showed a 72% reduction in light units (Figure 7C).”

• Also stated in: § Discussion · plain

  “In the present study we validated MeCP2 mRNA as a direct target of miR-181 by reporter assay.”

• Also stated in: § Discussion · plain

  “We have identified two novel targets of miR-181, MeCP2 and XIAP mRNAs, as well as a non-canonical potential target, HMGA1.”

In the paper

“The XIAP predicted binding site was also validated as a miR-181 target, with a roughly 63% decrease in relative light units for the Psi-CHECK2 XIAP reporter (Figure 7D).”

• Also stated in: § Discussion · plain

  “The mRNA encoding X-linked inhibitor of apoptosis (XIAP) is another miR-181 target that we validated by reporter assay.”

• Also stated in: § Discussion · boosted

  “We have identified two novel targets of miR-181, MeCP2 and XIAP mRNAs, as well as a non-canonical potential target, HMGA1.”

In the paper

“Taken together with our observation that miR-181b, c and d are present at high levels in the mature CNS, but not early in development prior to astrogenesis, these data support a possible role for miR-181 in developmental specification of cell fate in the CNS and warrant further investigation.”

In the paper

“It should be noted that miR-181 regulates other transcripts involved in cell survival and responses to stress including hsp-70, MCL-1 and Bim (Ouyang et al., 2011a, 2011b).”

What the sources say

• ?Not matched

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

  cites Ouyang et al., 2011a, 2011b

In the paper

“TNFα is produced by astrocytes exposed to LPS (Chung et al., 1990);”

What the sources say

• ?Not checked — no full text of the sourcecites Chung et al., 1990 source

In the paper

“Bcl-2, a previously validated miR-181 target (Ouyang et al., 2012a) and the predicted target NAMPT mRNA were also enriched in the pull-down (Figure 7A).”

What the sources say

• ?Not matched

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

  cites Ouyang et al., 2012a

In the paper

“HMGA1 has been observed to enhance NF-κB binding, as in the case of the IFN1-γ promoter (Thanos et al., 1992).”

What the sources say

• ?Not checked — no full text of the sourcecites Thanos et al., 1992 source

In the paper

“These results suggest that miR-181s negatively regulate the production of multiple cytokines and FGF2 in astrocytes, effectively suppressing their production in an inflammatory environment.”

In the paper

“miR-181 directly targets the mRNA encoding Bcl-2, a mitochondrial membrane-associated protein that inhibits apoptosis, and other mRNAs encoding proteins involved in responses to stress including heat-shock protein 70 (Chen et al., 2010; Ouyang et al., 2011a, b).”

What the sources say

• ?Not matched

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

  cites Chen et al., 2010
• ?Not matched

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

  cites Ouyang et al., 2011a, b

In the paper

“Our results therefore suggest that miR-181s are involved in a general cell stress response and cell survival-related changes in transcriptional profiles.”

In the paper

“By enabling the production of GDNF and VEGF, a reduction in miR-181s might therefore be expected to reduce neuronal vulnerability and enhance neurogenesis.”

In the paper

“Taken together with the other confirmed targets of the miR-181 family, our findings argue that miR-181s are fundamentally involved in major programs of posttranscriptional regulation of cell differentiation and stress responses in astrocytes, with increasing miR-181 expression resulting in increased differentiation and vulnerability to environmental stress.”

In the paper

“miR-181 repression of MeCP2 in astrocytes could therefore play a physiological role in reactive gliosis, the developmental differentiation of astrocytes, and possibly Rett Syndrome.”