The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index; 7 of the 28 sources its claims cite were checked for support.
MicroRNA‐21 protects neurons from ischemic death
Open accessAbstract
MicroRNAs are small RNAs that attenuate protein expression by complementary binding to the 3′‐UTR of a target mRNA. Currently, very little is known about microRNAs after cerebral ischemia. In particular, microRNA‐21 (miR‐21) is a strong antiapoptotic factor in some biological systems. We investigated the role of miR‐21 after stroke in the rat. We employed in situ hybridization and laser capture microdissection in combination with real‐time RT‐PCR to investigate the expression of miR‐21 after stroke. In situ hybridization revealed that miR‐21 expression was upregulated in neurons of the ischemic boundary zone, and quantitative real‐time RT‐PCR analysis revealed that stroke increased mature miR‐21 levels by approximately threefold in neurons isolated from the ischemic boundary zone by laser capture microdissection as compared with homologous contralateral neurons 2 days (n = 4; P < 0.05) and 7 days (n = 3; P < 0.05) after stroke. In vitro, overexpression of miR‐21 in cultured cortical neurons substantially suppressed oxygen and glucose deprivation‐induced apoptotic cell death, whereas attenuation of endogenous miR‐21 by antisense inhibition exacerbated cell death after oxygen and glucose deprivation. Moreover, overexpression of miR‐21 in neurons significantly reduced FASLG levels, and introduction of an miR‐21 mimic into 293‐HEK cells substantially reduced luciferase activity in a reporter system containing the 3′‐UTR of Faslg. Our data indicate that overexpression of miR‐21 protects against ischemic neuronal death, and that downregulation of FASLG, a tumor necrosis factor‐α family member and an important cell death‐inducing ligand whose gene is targeted by miR‐21, probably mediates the neuroprotective effect. These novel findings suggest that miR‐21 may be an attractive therapeutic molecule for treatment of stroke.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In rat stroke and cultured cortical neurons, miR-21 is upregulated in ischemic boundary zone neurons and protects against oxygen-glucose deprivation-induced apoptosis, at least partly by targeting the Faslg 3′UTR and reducing FASLG protein.
Key findings
- Stroke increased mature miR-21 in laser-captured IBZ neurons by 3.5 ± 1.8 fold at 2 days (n=4; P<0.05) and 3.2 ± 0.5 fold at 7 days (n=3; P<0.05) versus contralateral neurons; miR-9 and miR-335 showed no significant changes (n=3; P>0.2).
- In cultured cortical neurons after OGD, miR-21 overexpression reduced dead cells to 24.6 ± 4.7% versus 31.7 ± 4.9% for miR-67 control, while antisense inhibition increased death to 42.2 ± 6.8% (n=5; P<0.05, ANOVA). TUNEL positivity was 9.9 ± 7.7% with miR-21 overexpression versus 37.8 ± 15.8% with miR-21 inhibition (n=10; P<0.05, ANOVA).
- OGD induced FASLG protein 1.37 ± 0.23 fold (n=3; P<0.05); miR-21 overexpression knocked down FASLG protein by 32 ± 11% (n=4; P<0.05) without significantly changing Faslg mRNA (1.17 ± 0.34; n=3; P>0.4).
- A Faslg 3′UTR luciferase reporter was attenuated by 43 ± 13% with miR-21 mimic versus miR-67 (n=4; P<0.02); mutation of the putative 9-mer binding site abolished the effect.
Methods
- Male Wistar rats (350–450 g) underwent embolic middle cerebral artery occlusion; brains were analyzed by in situ hybridization, immunofluorescence, laser capture microdissection of NeuN-positive IBZ and contralateral neurons, and real-time RT-PCR.
- Primary rat embryonic day 17 cortical neurons were subjected to 3 h oxygen-glucose deprivation followed by 24 h recovery; neurons were transfected with miR-21 mimic, miR-21 inhibitor, or miR-67 control and assessed by live/dead assay, TUNEL, and Western blot.
- Target prediction used PicTar, TargetScan 5.1, and miRanda; luciferase reporter assays were performed in 293-HEK cells. Statistics used one-way ANOVA and two-sample t-tests with P<0.05 considered significant.
Limitations
- The paper states the data are preliminary and that further investigation of miR-21 modulation on neuronal cell death in vivo is warranted.
- Evident from the text: in vitro OGD did not significantly change miR-21 expression (0.63 ± 0.24 at 2 days, n=3, P>0.1; 0.78 ± 0.47 at 7 days, n=3, P>0.5), possibly because the cultured neurons were immature or lacked glial factors; functional protection was shown in vitro, not in an in vivo stroke outcome model.
- Evident from the text: several experiments used small sample sizes (n=3–5 in some assays), and the live/dead assay difference was described as statistically insignificant, attributed to background necrosis.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
13 No full text of the sources · 12 Own result · 6 Own interpretation · 3 Partly supported · 2 Supported · 2 Supported so far · accuracy not yet measured
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In particular, miRNA-21 (miR-21) has been shown to be a strong antiapoptotic factor [5, 9–11].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Not checked — no full text of the sourcecites [5] Chan JA Krichevsky AM Kosik KS 2005 MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells Cancer Res 65 6029 6033 65/14/6029 [pii] 10.1158/0008-5472.CAN-05-0137 16024602 source
- Not checked — no full text of the sourcecites [9] Chen Y Liu W Chao T Zhang Y Yan X Gong Y Qiang B Yuan J Sun M Peng X 2008 MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G Cancer Lett 272 197 205 S0304-3835(08)00526-0 [pii] 10.1016/j.canlet.2008.06.034 19013014 source
- Not checked — no full text of the sourcecites [10] Frankel LB Christoffersen NR Jacobsen A Lindow M Krogh A Lund AH 2008 Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells J Biol Chem 283 1026 1033 M707224200 [pii] 10.1074/jbc.M707224200 17991735 source
- Supportedcites [11] Papagiannakopoulos T Shapiro A Kosik KS 2008 MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells Cancer Res 68 8164 8172 68/19/8164 [pii] 10.1158/0008-5472.CAN-08-1305 18829576 source
The MiR-21 target validation section reports that reducing miR-21 increased apoptosis in two glioblastoma cell lines, while miR-21 overexpression inhibited drug-induced apoptosis. The paper concludes that miR-21 suppresses cell death in glioblastoma cells. Page numbers are not provided in our copy. (LLM, conf=0.92)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“miR-21 functions–at least in part–by targeting a host of pro-apoptotic genes [13, 14].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Not checked — no full text of the sourcecites [13] Kim YJ Hwang SJ Bae YC Jung JS 2009 MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue Stem Cells 27 3093 3102 10.1002/stem.235 19816956 source
- Partly supportedcites [14] Meng F Henson R Wehbe-Janek H Ghoshal K Jacob ST Patel T 2007 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer Gastroenterology 133 647 658 S0016-5085(07)01002-5 [pii] 10.1053/j.gastro.2007.05.022 17681183 PMC4285346 sourceExperimental — accuracy not yet measured
The Results identify PTEN as a direct target of miR-21, and the Discussion reports anti-apoptotic effects of miR-21 in other cancers. But this paper does not show that miR-21 targets a host of pro-apoptotic genes; it identifies one direct target and only speculates about others. Page numbers were not provided in our copy. (LLM, conf=0.84)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“when miR-21 and a miR-21 antisense inhibitor were simultaneously cotransfected with Faslg-luc plasmid, the attenuation completely recovered, showing only a 2 ± 4% difference from the control (n=4; P<0.8; Fig. 3C).”
§ miR-21 protects neurons from ischemic death > Results > miR-21 attenuates expression of FASLG protein by binding to Faslg transcript
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The miR-21 binding site in the Faslg 3′UTR characterized in 293T-HEK cells is functional in neurons.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“quantitative real-time RT-PCR analysis revealed that stroke increased mature miR-21 levels by ~3 fold in neurons isolated from the IBZ by LCM compared to homologous contralateral neurons 2 (n=4; P<0.05) and 7(n=3; P<0.05) days after stroke.”
- Also stated in: § miR-21 is expressed in neurons in the IBZ · plain
“At 2 days post-MCAo, we found that there is a notable upregulation of miR-21 in ipsilateral neurons compared to those in the homologous region of the contralateral hemisphere, with an average induction of 3.5 ± 1.8 fold (n=4; P<0.05), when normalized to U6 snRNA. At 7d after stroke miR-21 expression remained robust, with an average induction of 3.2 ± 0.5 times contralateral expression (n=3; P<0.05”
§ miR-21 protects neurons from ischemic death > Abstract
plaindirectn = 4 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § miR-21 is expressed in neurons in the IBZ · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After transfection with Mut-luc, there was no statistically significant difference in any experimental group (Fig. 3C), indicating that the 9-mer portion of Faslg that is complementary to miR-21 is necessary for translational inhibition.”
§ miR-21 protects neurons from ischemic death > Results > miR-21 attenuates expression of FASLG protein by binding to Faslg transcript
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The miR-21 binding site in the Faslg 3′UTR characterized in 293T-HEK cells is functional in neurons.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“attenuation of endogenous miR-21 by antisense inhibition exacerbated cell death after OGD.”
- Also stated in: § miR-21 protects cultured cortical neurons in vitro · plain
“antisense inhibition of endogenous miR-21 had a significantly higher average proportion of dead cells, 42.2 ± 6.8% (n=5)”
§ miR-21 protects neurons from ischemic death > Abstract
plaindirectn = 5- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Antisense inhibition reduces endogenous miR-21 levels in cultured neurons.
- Also stated in: § miR-21 protects cultured cortical neurons in vitro · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“overexpression of miR-21 in cultured cortical neurons substantially suppressed oxygen and glucose deprivation (OGD)-induced apoptotic cell death”
- Also stated in: § miR-21 protects cultured cortical neurons in vitro · plain
“overexpression of miR-21 in neurons suppressed OGD induced TUNEL reactivity (9.9 ± 7.7%; n=10; Fig. 2B, D; P<0.05, ANOVA).”
- Also stated in: § miR-21 protects cultured cortical neurons in vitro · plain
“fewer cells died upon overexpression of miR-21 (24.6 ± 4.7%; n=5; P<0.05, ANOVA).”
§ miR-21 protects neurons from ischemic death > Abstract
plaindirectn = 10 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: miR-67 is inert and not expressed in mammals.
- Rests on an assumption: Transfection with miR-21 mimic increases functional miR-21 levels in cultured neurons.
- Also stated in: § miR-21 protects cultured cortical neurons in vitro · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we did not observe a significant change in miR-21 expression at either 2 d (0.63 ± 0.24 compared to naïve neurons; n=3; P>0.1), or 7 d (0.78 ± 0.47; n=3; P>0.5; data not shown) after OGD.”
§ miR-21 protects neurons from ischemic death > Results > miR-21 protects cultured cortical neurons in vitro
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overexpression of miR-21 had no significant effect on Faslg mRNA after OGD compared to miR-67 negative control (1.17 ± 0.34; n=3; P>0.4; Fig. 3B).”
§ miR-21 protects neurons from ischemic death > Results > miR-21 attenuates expression of FASLG protein by binding to Faslg transcript
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: miR-67 is inert and not expressed in mammals.
- Rests on an assumption: Transfection with miR-21 mimic increases functional miR-21 levels in cultured neurons.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“after OGD, FASLG was induced by 1.37 ± 0.23 fold compared to naïve neurons (n=3, P<0.05; Fig. 3A).”
§ miR-21 protects neurons from ischemic death > Results > miR-21 attenuates expression of FASLG protein by binding to Faslg transcript
plaindirectn = 3 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 12
- It may state two separate claims as one. 9
Every source the paper cites for this claim was checked and supports it.
In the paper
“miRNAs inhibit translation of mRNAs by guiding an inhibitory protein complex, the RNA induced silencing complex (RISC) to the mRNA via complementarity to its 3′ untranslated region (3′UTR), thereby limiting a gene’s functionality, even though transcription of the gene may not be stopped [4].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Supportedcites [4] Pillai RS 2005 MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11 1753 1761 11/12/1753 [pii] 10.1261/rna.2248605 16314451 PMC1370863 source
The Biogenesis of miRNAs section says that a miRNA guides its effector complex to a target mRNA by base-pairing and that most investigated animal miRNAs bind sites in the 3′UTR. The Inhibition of protein synthesis section reports that this binding can inhibit protein production without a major change in mRNA levels, supporting the distinction from stopping transcription. The paper also notes that miRNAs can sometimes reduce mRNA levels. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“It is upregulated in most solid tumors, including breast, colo-rectal and glioma [5, 10, 12].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Not checked — no full text of the sourcecites [5] Chan JA Krichevsky AM Kosik KS 2005 MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells Cancer Res 65 6029 6033 65/14/6029 [pii] 10.1158/0008-5472.CAN-05-0137 16024602 source
- Not checked — no full text of the sourcecites [10] Frankel LB Christoffersen NR Jacobsen A Lindow M Krogh A Lund AH 2008 Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells J Biol Chem 283 1026 1033 M707224200 [pii] 10.1074/jbc.M707224200 17991735 source
- Partly supportedcites [12] Zhang Z Li Z Gao C Chen P Chen J Liu W Xiao S Lu H 2008 miR-21 plays a pivotal role in gastric cancer pathogenesis and progression Lab Invest 88 1358 1366 labinvest200894 [pii] 10.1038/labinvest.2008.94 18794849 sourceExperimental — accuracy not yet measured
The Abstract reports miR-21 overexpression in diverse solid tumors and specifically describes elevated expression in breast tumors and glioblastoma. It does not establish upregulation in most solid tumors, and its mention of colon cancer concerns aberrant miRNA expression generally, not miR-21 specifically. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“cardiac fibroblasts have been shown to increase miR-21 expression specifically in the injured region after myocardial infarction, and that this increase serves a protective role [30].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Partly supportedcites [30] Dong S Cheng Y Yang J Li J Liu X Wang X Wang D Krall TJ Delphin ES Zhang C 2009 MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction J Biol Chem 284 29514 29525 M109.027896 [pii] 10.1074/jbc.M109.027896 19706597 PMC2785585 sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports increased miR-21 in the border area after infarction and decreased expression in the infarcted area. The Abstract and Discussion report protective effects of miR-21, but the experiments identify cardiac myocytes, not fibroblasts; they do not show that fibroblasts specifically increase miR-21 in the injured region. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“RNAi has been employed preclinically and clinically in treatment of several types of disease including viruses and cancer [26, 27], but has not been employed in stroke therapy.”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Supportedcites [26] Huang DD 2008 The potential of RNA interference-based therapies for viral infections Curr HIV/AIDS Rep 5 33 39 18417033 PMC7088822 source
The paper's summary (p. 33) describes in vitro and in vivo RNAi studies against viral infections and reports two initiated clinical trials, for respiratory syncytial virus and HIV. Those passages support this source's contribution to the jointly cited claim. The stroke-therapy statement follows the citations and is not attributed to this paper; the paper does not establish the broader cancer claim. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [27] Pirollo KF Chang EH 2008 Targeted delivery of small interfering RNA: approaching effective cancer therapies Cancer Res 68 1247 1250 68/5/1247 [pii] 10.1158/0008-5472.CAN-07-5810 18316585 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Cheng et al. have shown that miR-21 is upregulated in response to H2O2 injury in cardiac myocytes, and that it functions to attenuate apoptosis in that cell population [29].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Supportedcites [29] Cheng Y Liu X Zhang S Lin Y Yang J Zhang C 2009 MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4 J Mol Cell Cardiol 47 5 14 S0022-2828(09)00017-0 [pii] 10.1016/j.yjmcc.2009.01.008 19336275 PMC3593965 source
Results §3.1 reports that H2O2 exposure increased miR-21 expression in cultured cardiac myocytes. Results §3.4 reports that increasing miR-21 reduced H2O2-induced apoptosis, while inhibiting miR-21 increased it. The Discussion specifies that the apoptosis experiments used neonatal rat cardiac myocytes. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“overexpression of miR-21 knocked down FASLG protein by 32 ± 11% (n=4; P<0.05; Fig. 3B), which completely recoved it to levels we observed in naïve neurons.”
§ miR-21 protects neurons from ischemic death > Results > miR-21 attenuates expression of FASLG protein by binding to Faslg transcript
plaindirectn = 4 ·- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Transfection with miR-21 mimic increases functional miR-21 levels in cultured neurons.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Neither miR-9 nor miR-335 showed significant changes at either timepoint, and neither were consistently up or downregulated after MCAo at either timepoint (n=3; P>0.2 for all genes/timepoints).”
§ miR-21 protects neurons from ischemic death > Results > miR-21 is expressed in neurons in the IBZ
plainn = 3- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“ischemia induced enhancement of FASLG expression recruits imflammatory cells to the infarcted area [22].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [22] Rosenbaum DM Gupta G D’Amore J Singh M Weidenheim K Zhang H Kessler JA 2000 Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia J Neurosci Res 61 686 692 10.1002/1097-4547(20000915) 61:6<686::AID-JNR12>3.0.CO;2-7 [pii] 10972965 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“FASLG has therefore been proposed as a therapeutic target for acute treatment of stroke [25].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [25] French LE Tschopp J 2003 Protein-based therapeutic approaches targeting death receptors Cell Death Differ 10 117 123 10.1038/sj.cdd.4401185 4401185 [pii] 12655300 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Neurons in the IBZ may be salvageable, and the viability of these cells has been correlated to positive functional outcomes [3].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Not checked — no full text of the sourcecites [3] Lim SH Lee JS Lee JI Im S Ko YJ Kim HW 2008 The quantitative assessment of functional impairment and its correlation to infarct volume in rats with transient middle cerebral artery occlusion Brain Res 1230 303 309 S0006-8993(08)01655-7 [pii] 10.1016/j.brainres.2008.07.002 18675259 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“TNFα signaling is well known to contribute to ischemic injury of neurons [23].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [23] Barone FC Arvin B White RF Miller A Webb CL Willette RN Lysko PG Feuerstein GZ 1997 Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury Stroke 28 1233 1244 9183357 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Cultured neurons derived from mice with mutant FASLG that cannot interact with FAS, have been shown to be more resistant to cell death from OGD [24].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [24] Martin-Villalba A Hahne M Kleber S Vogel J Falk W Schenkel J Krammer PH 2001 Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke Cell Death Differ 8 679 686 10.1038/sj.cdd.4400882 11464212 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“FASLG induces cell death by binding to its receptor, FAS, leading to caspase-dependant apoptosis [16, 17].”
§ miR-21 protects neurons from ischemic death > Introduction
What the sources say
- Not checked — no full text of the sourcecites [16] Becher B Barker PA Owens T Antel JP 1998 CD95-CD95L: can the brain learn from the immune system? Trends Neurosci 21 114 117 S0166-2236(97)01180-6 [pii] 9530918 source
- Not checked — no full text of the sourcecites [17] Nagata S Golstein P 1995 The Fas death factor Science 267 1449 1456 7533326 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Lei et al. have shown that miR-21 is globally upregulated in response to traumatic brain injury (TBI) [31].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [31] Lei P Li Y Chen X Yang S Zhang J 2009 Microarray based analysis of microRNA expression in rat cerebral cortex after traumatic brain injury Brain Res 1284 191 201 S0006-8993(09)01094-4 [pii] 10.1016/j.brainres.2009.05.074 19501075 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Currently, only one drug, tissue plasminogen activator (tPA) is available to stroke victims, and it has a limited window of about 4.5 hours from the onset of symptoms in which it can be used for treatment.”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [32] Fields JD Lindsay K Liu KC Nesbit GM Lutsep HL 2010 Mechanical thrombectomy for the treatment of acute ischemic stroke Expert Rev Cardiovasc Ther 8 581 592 10.1586/erc.10.8 20397831 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Hamar et al. targeted Faslg by synthetic siRNA in ischemic kidney and showed that knockdown of Faslg protects renal cells from apoptosis, and, in fact, whole animals from death [28].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [28] Hamar P Song E Kokeny G Chen A Ouyang N Lieberman J 2004 Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury Proc Natl Acad Sci U S A 101 14883 14888 0406421101 [pii] 10.1073/pnas.0406421101 15466709 PMC522049 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Furthermore, it is not safe for all patients, leading to only about 5% of stroke sufferers actually receiving tPA therapy [32].”
§ miR-21 protects neurons from ischemic death > Discussion
What the sources say
- Not checked — no full text of the sourcecites [32] Fields JD Lindsay K Liu KC Nesbit GM Lutsep HL 2010 Mechanical thrombectomy for the treatment of acute ischemic stroke Expert Rev Cardiovasc Ther 8 581 592 10.1586/erc.10.8 20397831 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
The role of miR-21 in stroke has not been reported.
“Specifically, its role in stroke has not been reported.”
The paper relies on this without support.
The underlying molecular mechanisms that determine which neurons live or die after stroke are not entirely understood.
“Currently, the underlying molecular mechanisms that determine which neurons live or die are not entirely understood.”
The paper relies on this without support.
OGD in cultured cortical neurons is a valid model of ischemic neuronal death in vivo.
“we employed a model of ischemia in which primary cortical neurons from rat embryos were subjected to oxygen and glucose deprivation (OGD).”
The paper relies on this without support.
miR-67 is inert and not expressed in mammals.
“cells transfected with miR-67, an inert, C. elegans-derived miRNA not expressed in mammal, were 31.7 ± 4.9% (average ± SD; n=5) dead.”
“negative control miRNA mimic (based on cel-miR-67 sequence, which lacks homology in mammal; Dharmacon, Lafayette, CO)”
The paper relies on this without support.
The miR-21 binding site in the Faslg 3′UTR characterized in 293T-HEK cells is functional in neurons.
“When Faslg-luc was cotransfected with miR-21 mimic into 293T-HEK cells, the luciferase activity was attenuated by 43 ± 13% compared to cells cotransfected with miR-67 mimic (n=4; P<0.02; Fig. 3C).”
The paper relies on this without support.
Antisense inhibition reduces endogenous miR-21 levels in cultured neurons.
“attenuation of endogenous miR-21 by antisense inhibition exacerbated cell death after OGD.”
The paper relies on this without support.
Transfection with miR-21 mimic increases functional miR-21 levels in cultured neurons.
“overexpression of miR-21 in cultured cortical neurons substantially suppressed oxygen and glucose deprivation (OGD)-induced apoptotic cell death”
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?
The cited source says what the claim attributes to it.
In the citing paper
“As for ischemia, miR-21 has been shown to be a strong anti-apoptosis and pro-survival factor, which could downregulate the expression of apoptosis related proteins32,33.”
From Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway (2017) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ miR-21 protects neurons from ischemic death > Results > miR-21 protects cultured cortical neurons in vitro
“The statistically insignificant data we gathered from our live/dead assay is likely due to a background level of necrosis”
§ miR-21 protects neurons from ischemic death > Results > miR-21 protects cultured cortical neurons in vitro
“antisense inhibition of endogenous miR-21 had a significantly higher average proportion of dead cells, 42.2 ± 6.8% (n=5), while fewer cells died upon overexpression of miR-21 (24.6 ± 4.7%; n=5; P<0.05, ANOVA).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ miR-21 protects neurons from ischemic death > Discussion
“Hamar et al. targeted Faslg by synthetic siRNA in ischemic kidney”
§ miR-21 protects neurons from ischemic death > References
“Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury”
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“Based on our literature review, Pdcd4, Pten and Faslg are target genes of miRNA-21-5p in endothelial cells, cardiomyocytes [35, 36] and neurons [37].”
BackgroundCardiovascular epigenetics: From DNA methylation to microRNAs
Udali, S., Guarini, P., Moruzzi, S., Choi, S., & Friso, S. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.08.001 · Cited by 176
Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21
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MicroRNA‐124 Protects Neurons Against Apoptosis in Cerebral Ischemic Stroke
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“miR-21 increases neuronal survival after stroke by targeting and blocking translation of the gene that encodes Fas ligand (a receptor that signals to induce apoptosis) [33].”
BackgroundSelf-citationThe MicroRNA-17–92 Cluster Enhances Axonal Outgrowth in Embryonic Cortical Neurons
Zhang, Y., Ueno, Y., Liu, X., Buller, B., Wang, X., Chopp, M., & Zhang, Z. G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.5180-12.2013 · Cited by 166
“TUNEL staining was performed, as previously described (Buller et al., 2010).”
MethodSelf-citationImpact of microRNAs on ischemic stroke: From pre- to post-disease
Li, G., Morris-Blanco, K. C., Lopez, M. S., Yang, T., Zhao, H., Vemuganti, R., & Luo, Y. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.002 · Cited by 159
“Furthermore, miR-203 was shown to suppress the production of pro-inflammatory cytokines IL-8 and TNF- and thereby attenuate post-ischemia inflammation and decrease neuronal death following OGD (Yang et al., 2015c).”
BackgroundInfluentialEmerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents
Khoshnam, S. E., Winlow, W., Farbood, Y., Moghaddam, H. F., & Farzaneh, M. (2017) · Journal of Stroke · doi:10.5853/jos.2016.01368 · Cited by 156
Anti-Apoptotic Effect of MicroRNA-21 after Contusion Spinal Cord Injury in Rats
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“FasL, a member of the TNF-a family of ligand, was one of validated targets of miR-21. miR-21 was shown to reduce the death of ischemic cortical neurons by downregulating FasL.15 Overexpression of miR-21 in transgenic mouse heart inhibited ischemia-induced upregulation of FasL expression, limited infarct size, attenuat…”
BackgroundInfluentialFunctions of Noncoding RNAs in Neural Development and Neurological Diseases
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Angiogenesis-regulating microRNAs and Ischemic Stroke
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“In the acute stage, miR-21 was significantly upregulated which is also shown in several brain injury models including epilepsy (Buller et al. 2010; Redell et al. 2011; Risbud et al. 2011).”
BackgroundMolecular Communication of a Dying Neuron in Stroke
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“Because miR21 has a neuroprotective role in an in vitro model of ischemia, it would be interesting to check if miR21 associated to EVs is also increased in animal models of stroke [136].”
MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics
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microRNAs: Innovative Targets for Cerebral Ischemia and Stroke
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“[77] demonstrated in a rat model of middle cerebral artery occlusion that miR-121 selectively downregulates Faslg, a TNFa family member, and that targeted inhibition of miR-121 was cytoprotective in vivo.”
BackgroundThomi, G. F., Joerger-Messerli, M. S., Haesler, V., Muri, L., Surbek, D., & Schoeberlein, A. (2019) · Cells · doi:10.3390/cells8080855 · Cited by 132
“Preliminary results indicate that several anti-apoptotic miRNAs are highly expressed in MSC-exosomes, including let-7, miR-21, and miR-22, verifying our previous findings [32,60,61].”
ResultmiR-21 in ischemia/reperfusion injury: a double-edged sword?
Xu, X., Kriegel, A. J., Jiao, X., Liu, H., Bai, X., Olson, J. M. G., Liang, M., & Ding, X. (2014) · Physiological Genomics · doi:10.1152/physiolgenomics.00020.2014 · Cited by 116
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“…between the dysregulation of miRNA and microglia-mediated neuronal apoptosis; therefore, we evaluated miR-21 in microglia, although it has been studied in cancer cells (Wang and Li, 2010), cardiac myocytes (Sayed et al., 2010), and neuronal cells (Buller et al., 2010; Ziu et al., 2011).”
BackgroundSelf-citationMicroRNAs Expression and Function in Cerebral Ischemia Reperfusion Injury
Yu, D., Yang, L., Feng, Y., Fan, C., Wang, S., & Mo, X. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0293-8 · Cited by 113
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“Furthermore, upregulation of miR-21 was also shown to prevent the translation of Fas ligand leading to decreased post-ischemic apoptosis [2].”
BackgroundProfile of Cerebrospinal microRNAs in Fibromyalgia
Bjersing, J. L., Lundborg, C., Bokarewa, M. I., & Mannerkorpi, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078762 · Cited by 98
“miR-21 is involved in glial[24,25] and neuronal[26,27] responses to injury in the central nervous system[28].”
BackgroundCentenarians, but not octogenarians, up-regulate the expression of microRNAs
Serna, E., Gambini, J., Borrás, C., Abdelaziz, K. M., Belenguer‐Varea, Á., Sanchis, P., Avellana, J. A., Rodríguez‐Mañas, L., & Viña, J. (2012) · Scientific Reports · doi:10.1038/srep00961 · Cited by 99
Huibregtse, M. E., Bazarian, J. J., Shultz, S. R., & Kawata, K. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.08.029 · Cited by 100
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Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms
Stanzione, R., Cotugno, M., Bianchi, F., Marchitti, S., Forte, M., Volpe, M., & Rubattu, S. D. (2020) · Genes · doi:10.3390/genes11010089 · Cited by 94
microRNAs Involved in Regulating Spontaneous Recovery in Embolic Stroke Model
Liu, F. J., Lim, K. Y., Kaur, P., Sepramaniam, S., Armugam, A., Wong, P. T.-H., & Jeyaseelan, K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066393 · Cited by 89
“We found miR-21 and miR-146a to be highly expressed in recovery phase compared to the acute phase of stroke and hence might be useful in predicting the recovery process (Figure 5, Table S1). miR-21 is known to prevent apoptosis by targeting Faslg [26]. miR-146a was reported to elicit neuroprotective effect by targetin…”
BackgroundInfluentialThe Roles of MicroRNAs in Stroke: Possible Therapeutic Targets
Xu, W., Gao, L., Zheng, J., Li, T., Shao, A., Reis, C., Chen, S., & Zhang, J. (2018) · Cell Transplantation · doi:10.1177/0963689718773361 · Cited by 85
The roles of microRNAs in spinal cord injury
Shi, Z., Zhou, H., Lu, L., Li, X., Fu, Z., Liu, J., Kang, Y., Wei, Z., Pan, B., Liu, L., et al. (2017) · International Journal of Neuroscience · doi:10.1080/00207454.2017.1323208 · Cited by 82
“has been found to be overexpressed after SCI in some studies [16,18,19,59].”
Ding, X., Li, Y., Liu, Z., Zhang, J., Cui, Y., Chen, X., & Chopp, M. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.50 · Cited by 80
Self-citationmicroRNAs in Cerebrovascular Disease
Volný, O., Kašičková, L., Coufalová, D., Cimflová, P., & Novák, J. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-22671-2_9 · Cited by 77
Yao, X., Wang, Y., & Zhang, D. (2018) · Journal of Molecular Neuroscience · doi:10.1007/s12031-018-1067-5 · Cited by 77
MicroRNA-21: a ubiquitously expressed pro-survival factor in cancer and other diseases
Li, S., Liang, Z., Liu, X., & Zou, F. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-011-1052-6 · Cited by 78
“Similarly, in a rat stroke model, overexpression of miR-21 can protect neurons from ischemic death by down-regulating Fas ligand translation [81].”
Self-citationTian, Y., Zhong, D., Liu, Q. Q., et al. (2018) · Journal of neurosurgery · doi:10.3171/2017.5.jns163165 · Cited by 74
Acute Spinal Cord Injury: A Systematic Review Investigating miRNA Families Involved
Pinchi, E., Frati, A., Cantatore, S., D’Errico, S., Russa, R. L., Maiese, A., Palmieri, M., Pesce, A., Viola, R. V., Frati, P., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081841 · Cited by 74
“All these findings suggest miR-21 to act as an antiapoptotic factor, which would protect neural cells from death through the silencing of proapoptotic molecules [123].”
BackgroundMiR-191 inhibit angiogenesis after acute ischemic stroke targeting VEZF1
Du, K., Zhao, C., Wang, L., Wang, Y., Zhang, K., Shen, X.-Y., Sun, H., Gao, W. Q., & Lü, X. (2019) · Aging · doi:10.18632/aging.101948 · Cited by 71
“Particularly, several angiogenesis-associated miRNAs, such as miR-210 [18, 19], miR-21 [20, 21], miR-126 [22, 23], miR-155 [24, 25], miR-31 [26], miR-223-3p [27], miR-191 [28] and miR-361 [29], are altered in patients with AIS and injured endothelial cells.”
Liu, X., Dong, Y., Chen, S., Zhang, G., Zhang, M., Gong, Y.-Z., & Li, X. (2015) · Cardiology · doi:10.1159/000437090 · Cited by 70
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The Interplay of MicroRNAs in the Inflammatory Mechanisms Following Ischemic Stroke
Khoshnam, S. E., Winlow, W., & Farzaneh, M. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlx036 · Cited by 69
Wang, C., Song, J., Lv, Q., Pan, H., Zhang, C.-N., Wu, J., Fan, C., Ma, L., Liu, T., & Wang, J. (2017) · Thrombosis and Haemostasis · doi:10.1160/th16-08-0606 · Cited by 68
Gubern, C., Camós, S., Ballesteros, I., Rodríguez-Romanos, R., Romera, V. G., Cañadas, R., Lizasoaín, I., Moro, M. Á., Serena, J. L., Mallolas, J., et al. (2013) · FEBS Journal · doi:10.1111/febs.12546 · Cited by 69
Borrás, C., Abdelaziz, K. M., Gambini, J., Serna, E., Inglés, M., la Fuente, M. D., García, I., Matheu, A., Sanchís, P., Belenguer‐Varea, Á., et al. (2016) · Aging · doi:10.18632/aging.101078 · Cited by 67
“…(scaRNA-17, mir-21, mir-130a, and mir-494) are known to be associated with a range of health-beneficial and life span-enhancing actions including telomerase over-expression in Cajal bodies, neuro-protection in ischemia, cardioprotection, and inhibition of mitochondrial damage and apoptosis [6-9].”
Molecular mechanisms of peripheral nerve regeneration: emerging roles of microRNAs
Wu, D., & Murashov, A. K. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00055 · Cited by 72
Bai, X., & Bian, Z. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.842288 · Cited by 66
All’s well that transcribes well: Non-coding RNAs and post-stroke brain damage
Vemuganti, R. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.07.014 · Cited by 71
“Furthermore, in one study, when cortical neuronal cultures were transfected with miR-21, they showed reduced expression of the pro-apoptotic FAS ligand and curtailed cell death when subjected to oxygen-glucose deprivation (Buller et al., 2010).”
BackgroundInfluentialHuman Brain Injury and miRNAs: An Experimental Study
Sessa, F., Maglietta, F., Bertozzi, G., Salerno, M., Mizio, G. D., Messina, G., Montana, A., Ricci, P., & Pomara, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071546 · Cited by 63
“, employing in situ hybridization, demonstrated that miR-21 expression was upregulated in neurons in the area adjacent to the ischemic area as an expression of protection from ischemic neuronal death [28].”
BackgroundTigchelaar, S., Gupta, R., Shannon, C. P., Streijger, F., Sinha, S., Flibotte, S., Rizzuto, M. A., Street, J., Paquette, S. J., Ailon, T. T., et al. (2019) · Journal of Neurotrauma · doi:10.1089/neu.2018.6256 · Cited by 62
“41 MiR-21 likely plays a role in astrogliosis 40 and targets Faslg, a tumor necrosis factor (TNF) a family member and an important cell death-inducing ligand, 41 underscoring its potential as both a biomarker and as a therapeutic target for SCI.”
Casas‐Agustench, P., Fernandes, F. S., do Carmo, M. G. T., Visioli, F., Herrera, E., & Dávalos, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117858 · Cited by 61
“Other validated target of miR-21 are the fas ligand (Faslg) [41], Pdcd4 [42], and Tiam1 [43] which are also related to diabetes [42,44].”
Temporal Profile of MicroRNA Expression in Contused Cortex after Traumatic Brain Injury in Mice
Meissner, L., Gallozzi, M., Balbi, M., Schwarzmaier, S., Tiedt, S., Terpolilli, N. A., & Plesnila, N. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4077 · Cited by 68
“37 It has also been shown to alleviate apoptosis in vitro by promoting the PTEN-Akt signaling pathway.”
miR-21 regulates ischemic neuronal injury via the p53/Bcl-2/Bax signaling pathway
Yan, H., Huang, W., Rao, J., & Yuan, J. (2021) · Aging · doi:10.18632/aging.203530 · Cited by 66
“com 22249 AGING ischemia, might be a potential diagnostic biomarker or therapeutic target for this type of stroke [4, 8, 9, 20].”
BackgroundMethodResultEmerging roles of microRNAs in chronic pain
Sakai, A., & Suzuki, H. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.05.010 · Cited by 64
“In the nervous system, miR-21 expression was reported to be upregulated in response to various types of damage, including ischemia (Buller et al., 2010), ionizing radiation (Shi et al., 2012) and traumatic brain injury (Redell et al., 2011).”
van Scheppingen, J., Iyer, A. M., Prabowo, A. S., Mühlebner, A., Anink, J. J., Scholl, T., Feucht, M., Jansen, F. E., Spliet, W. G., Krsek, P., et al. (2016) · Glia · doi:10.1002/glia.22983 · Cited by 60
“ISH showed expression in dysmorphic neurons, giant cells, and reactive astrocytes within the tuber, which is in agreement with previous studies (Bhalala et al., 2012; Buller et al., 2010; Gorter et al., 2014; Prabowo et al., 2015; Zhang et al., 2012).”
ResultMicroRNA Expression in the Glaucomatous Retina
Jayaram, H., Cepurna, W. O., Johnson, E. C., & Morrison, J. C. (2015) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.15-18088 · Cited by 60
Bulygin, K. V., Beeraka, N. M., Saitgareeva, A. R., Nikolenko, V. N., Фанилевич, Г. И., Beylerli, O., Ахмадеева, Л. Р., Михалева, Л. М., Solis, L. F. T., Herrera, A. S., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186728 · Cited by 60
“Overexpression of miR-21 downregulates “Fas-ligand expression” and prevents OGD-induced neuronal death in cultured cortical neurons [122,142].”
BackgroundThe protective effect of microRNA-21 in neurons after spinal cord injury
Zhang, T., Ni, S., Luo, Z., Lang, Y., Hu, J., & Lu, H. (2019) · Spinal Cord · doi:10.1038/s41393-018-0180-1 · Cited by 59
Neuroprotection of microRNA in neurological disorders (Review)
Wang, C., Ji, B., Cheng, B., Chen, J., & Bai, B. (2014) · Biomedical Reports · doi:10.3892/br.2014.297 · Cited by 59
“Buller et al (37) reported that stroke increases miR-21 expression by ~3-fold in the ischemic boundary zone in vivo .”
Identification of a MicroRNA Signature for the Diagnosis of Fibromyalgia
Cerdá‐Olmedo, G., Mena-Durán, A. V., Monsalve, V., & Oltra, E. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121903 · Cited by 58
“In addition to viral infections, hsa-miR-21 and hsa-miR-223 have been linked to inflammation and injury of the central nervous system [45–48], hsa-miR-143-3p/hsa-miR-145-5p to muscle functioning [49,50] and hsa-miR338/hsa-miR-451 downregulation to diabetes and inflammation [51,52].”
BackgroundZhang, H.-S., Liu, M., Ji, X., Jiang, C., Li, Z., & Ouyang, B. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116935 · Cited by 59
Non-Coding RNAs in Stroke and Neuroprotection
Saugstad, J. A. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00050 · Cited by 71
“miR-21 In situ hybridization showed increased expression of miR-21 in rat neurons in the ischemic boundary zone at 2 and 7 days after embolic MCAO, and RT-qPCR studies verified a quantitative increase in mature miR-21 in neurons isolated from the ischemic boundary zone (66).”
BackgroundExosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection
Nasirishargh, A., Kumar, P., Ramasubramanian, L., Clark, K. C., Hao, D., Lazar, S. V., & Wang, A. (2021) · World Journal of Stem Cells · doi:10.4252/wjsc.v13.i7.776 · Cited by 61
Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis
Joilin, G., Gray, E., Thompson, A. G., Bobeva, Y., Talbot, K., Weishaupt, J. H., Ludolph, A. C., Malaspina, A., Leigh, P. N., Newbury, S. F., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa053 · Cited by 59
Montalban, E., Mattugini, N., Ciarapica, R., Provenzano, C., Savino, M., Scagnoli, F., Prosperini, G., Carissimi, C., Fulci, V., Matrone, C., et al. (2014) · NeuroMolecular Medicine · doi:10.1007/s12017-014-8292-z · Cited by 56
“Such a neuroprotective role of miR-21 is coherent with recent evidence: miR-21 protects neurons from ischemic death (Buller et al. 2010), it is induced by axotomy and promotes axon growth (Strickland et al.”
Guo, D., Ma, J., Li, T., & Yan, L. (2018) · Experimental Cell Research · doi:10.1016/j.yexcr.2018.04.027 · Cited by 54
The Involvement of miRNA in Carotid-Related Stroke
Maitrias, P., Meuth, V. M., Nader, J., Reix, T., Caus, T., & Metzinger, L. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309233 · Cited by 56
Effect of Sex and Age Interactions on Functional Outcome after Stroke
Kim, T., & Vemuganti, R. (2014) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12346 · Cited by 56
The Emerging Role of Epigenetics in Cerebral Ischemia
Hu, Z., Zhong, B., Tan, J., Chen, C., Qiang, L., & Zeng, L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9788-3 · Cited by 53
Ji, W., Jiang, W.-T., Li, M., Li, J., & Li, Z. (2019) · Biochimie · doi:10.1016/j.biochi.2019.10.002 · Cited by 53
miRNA Expression Change in Dorsal Root Ganglia After Peripheral Nerve Injury
Chang, H.-L., Wang, H., Chunag, Y.-T., Chou, C.-W., Lin, I., Lai, C., Chang, L., & Cheng, K. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-016-0876-7 · Cited by 52
Shi, H., Sun, B.-L., Zhang, J., et al. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311312030011 · Cited by 51
MicroRNAs dysregulation in epilepsy
Li, M., Li, X., Zheng, X., Yu, J., & Tan, L. (2013) · Brain Research · doi:10.1016/j.brainres.2013.09.049 · Cited by 51
“MiR-21 has been shown to be increased in several brain injury models, stroke, trauma and SE (Buller et al., 2010; Hu et al., 2011; Redell et al., 2011; Risbud et al., 2011).”
BackgroundTang, C., Gu, Y., Wang, H., Wu, H., Wang, Y., Meng, Y., Han, Z., Gu, Y., Ma, W., Jiang, Z., et al. (2018) · Epilepsy Research · doi:10.1016/j.eplepsyres.2018.05.001 · Cited by 50
Dissecting the role of miR-21 in different types of stroke
Panagal, M., Biruntha, M., Vidhyavathi, R., Paramasivam, S., Senthilkumar, S. R., & Sekar, D. (2018) · Gene · doi:10.1016/j.gene.2018.09.048 · Cited by 49
Kaur, P., Armugam, A., & Jeyaseelan, K. (2012) · Journal of Toxicology · doi:10.1155/2012/870150 · Cited by 48
“MiR-21 was demonstrated to target FASLG, a member of the tumour necrosis factor-α family and cell death inducing ligand [142].”
BackgroundThe brain-enriched microRNA miR-124 in plasma predicts neurological outcome after cardiac arrest
Gilje, P., Gidlöf, O., Rundgren, M., Cronberg, T., Al‐Mashat, M., Olde, B., Friberg, H., & Erlinge, D. (2014) · Critical Care · doi:10.1186/cc13753 · Cited by 46
“In animal models, cerebral ischemia and reperfusion alter the tissue expression of several miRNAs that are known to be associated with modulation of apoptosis [11,12], promotion of cell death [13] and cell-cycle regulation [14], thereby potentially influencing outcomes.”
BackgroundRegulatory roles of microRNA-21 in fibrosis through interaction with diverse pathways (Review)
Liu, R., Ning, B., MA, X.-E., Gong, W.-M., & Jia, T. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.4834 · Cited by 51
Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect
Harrison, E. B., Emanuel, K., Lamberty, B. G., Morsey, B. M., Li, M., Kelso, M. L., Yelamanchili, S. V., & Fox, H. S. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00228 · Cited by 48
“Increasing evidence points to important functions for inflammation-associated miRNAs in neurological disease (Buller et al., 2010; Yelamanchili et al., 2010; Harraz et al., 2012; Zhang L. et al., 2012; Ge et al., 2014).”
Vasudeva, K., & Munshi, A. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14695 · Cited by 49
“…miR-21 miR-21 overexpression protects the neurons from neural death by downregulating cell death inducing Fas Ligand (FALSG) a member of TNFα family Buller et al. (2010) 2 miR-96 It results in optimum regulation of VAMP8 in a manner to keep platelets at resting state and preventing platelet…”
BackgroundNew epigenetic players in stroke pathogenesis: From non-coding RNAs to exosomal non-coding RNAs
Mahjoubin‐Tehran, M., Rezaei, S., Jesmani, A., Birang, N., Morshedi, K., Khanbabaei, H., Khan, H. Z., Piranviseh, A., Nejati, M., Aschner, M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111753 · Cited by 48
Differential response of miRNA-21 and its targets after traumatic brain injury in aging mice
Sandhir, R., Gregory, E. J., & Berman, N. E. J. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.09.009 · Cited by 46
“These findings suggest that miR-21 is a neuroprotective molecule in TBI (Buller et al., 2010) and neuroprotective astrocyte response is diminished in aged brain.”
BackgroundWang, J., Zhu, Y., Jin, F., Tang, L. Y., He, Z., & He, Z. (2016) · Journal of International Medical Research · doi:10.1177/0300060516630852 · Cited by 45
“For example, miR-21 reduces apoptosis via Fas ligand regulation, which is associated with its protective effects on neurons as shown in a recent intracerebral ischaemia study.(23) In addition, miR-21 can repress the expression of the ‘phosphatase and tensin homolog deleted on chromosome 10’ (PTEN) gene, whose product…”
BackgroundMiguel-Hidalgo, J. J., Hall, K. O., Bonner, H., Roller, A., Syed, M., Park, C. J., Ball, J. P., Rothenberg, M. E., Stockmeier, C. A., & Romero, D. G. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.08.009 · Cited by 47
“By contrast, increased miR-21 expression may be neuroprotective in animal models of ischemia and traumatic brain injury (Buller et al., 2010; Ge et al., 2014).”
BackgroundInfluentialAltered microRNA expression following sciatic nerve resection in dorsal root ganglia of rats
Yu, B., Zhou, S., Qian, T., Wang, Y., Ding, F., & Gu, X. (2011) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmr083 · Cited by 43
Li, S., Chen, L., Pang, X., Su, S., Zhou, X., Chen, C.-Y., Huang, L., Li, J.-P., & Liu, J. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.01.011 · Cited by 44
“The identification of the miRNAs and target genes that are involved in AIS has shown that miRNAs play crucial roles in AIS initiation, progression, and tolerance (Buller et al., 2010).”
Background
Metadata
- Authors
- Buller, B., Liu, X., Wang, X., Zhang, R. L., Zhang, L., Hozeska‐Solgot, A., Chopp, M., & Zhang, Z. G.
- Affiliations
- Henry Ford Hospital (US)
- Oakland University (US)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2010-09-14
- Volume
- 277
- Issue
- 20
- Pages
- 4299-4307
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- PMC
- PMC2957309
- OpenAlex
- W1557444671
- Semantic Scholar
- dc4b4e4f4771a194e0af3821f06772f48410e241
- Cited by
- 242
- References
- 36
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 12 · 2021: 22 · 2020: 20 · 2019: 20 · 2018: 17 · 2017: 24 · 2016: 21 · 2015: 16 · 2014: 17 · 2013: 24 · 2012: 11
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- American Heart Association
- National Heart, Lung, and Blood Institute (R01 HL064766, R01HL64766)
- National Institute of Neurological Disorders and Stroke (P01NS42345, R01 NS062832, P01 NS042345)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Acute Ischemic Stroke Management
- Keywords
- miR-21, stroke, cerebral ischemia, neuronal apoptosis, neuroprotection, Fas ligand, oxygen-glucose deprivation, 3' UTR targeting, antisense inhibition
- MeSH terms
- Animals, Gene Expression Regulation, Ischemia, Neurons, Cell Death, Rats, Wistar, Protective Agents, Stroke, MicroRNAs, Rats, Fas Ligand Protein
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