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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Dynamic release of neuronal extracellular vesicles containing miR‐21a‐5p is induced by hypoxia
Korvenlaita, N., Gómez‐Budia, M., Scoyni, F., Pistono, C., Giudice, L., Eamen, S., Loppi, S. H., de Sande, A. H., Huremagic, B., Bouvy‐Liivrand, M., et al. (2023) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12297 · Cited by 39
“The role of miR-21a-5p has been studied in multiple cell types but data regarding its enrichment in different central nervous system (CNS) cell types remains inconclusive (Buller et al., 2010; Jovicic et al., 2013).”
BackgroundInfluentialFan, H., Sun, X., Niu, W., Zhao, L., Zhang, Q., Li, W., Zhong, A., Zhang, L.-Y., & Lu, J. Z. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0503-z · Cited by 40
Self-citationGiuliani, A., Gaetani, S., Sorgentoni, G., Agarbati, S., Laggetta, M., Matacchione, G., Gobbi, M., Rossi, T., Galeazzi, R., Piccinini, G., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.647015 · Cited by 41
“Moreover, miR-21 has been proposed as a component of a neuronal stress response in many models of neurodegeneration and neuroinflammation (Buller et al., 2010; Shi et al., 2012; Zhang et al., 2012; Ge et al., 2014), including AD (Hwang et al.”
BackgroundInfluentialPrabowo, A. S., van Scheppingen, J., Iyer, A. M., Anink, J. J., Spliet, W. G. M., van Rijen, P. C., Meeteren, A. Y. N. S., & Aronica, E. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0315-7 · Cited by 38
“Recent studies indicate expression of this miRNA in both neuronal and glial cells [26, 51 – 53].”
Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury
Kaur, P., Liu, F., Tan, J., Lim, K. J., Sepramaniam, S., Karolina, D. S., Armugam, A., & Jeyaseelan, K. (2013) · Brain Sciences · doi:10.3390/brainsci3010360 · Cited by 38
“In addition, miR-21 has been further demonstrated to protect neurons from microglial mediated neuronal cell death by targeting FASLG in microglial following ischemia [230]. miR-181 targets GRP78 (heat shock 70kDa protein 5; glucose-regulated protein, 78kDa) during cerebral ischemia and the down-regulation of miR-181 w…”
BackgroundInfluentialPonnusamy, V., Kapellou, O., Yip, E., Evanson, J., Wong, L., Michael-Titus, A. T., Yip, P. K., & Shah, D. K. (2015) · Pediatric Research · doi:10.1038/pr.2015.276 · Cited by 38
“Let7b and miR-21 have both been shown to be important in adult brain pathology following trauma in animal studies (11-12), ischemia/stroke (13-14), and Alzheimer’s disease (15-16).”
BackgroundInfluentialImplications of Epigenetic Mechanisms and their Targets in Cerebral Ischemia Models
Jhelum, P., Karisetty, B. C., Kumar, A., & Chakravarty, S. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666161213143907 · Cited by 38
“Further to add complexity, spatial expression of miRNAs was observed, such as a regional expression of miR-121 in the ischemic penumbra [101] and an upregulation of miR181a in hippocampus following 30 min of reperfusion.”
BackgroundLuteolin protects PC-12 cells from H2O2-induced injury by up-regulation of microRNA-21
Zhang, Z., Xu, P., Yu, H., & Shi, L. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2019.108698 · Cited by 38
Self-citationPerdoncin, M., Konrad, A., Wyner, J. R., Lohana, S., Pillai, S. S., Pereira, D. G., Lakhani, H. V., & Sodhi, K. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.756499 · Cited by 39
The dysregulation of miRNAs in epilepsy and their regulatory role in inflammation and apoptosis
Xie, G., Chen, H., He, C., Hu, S., Xiao, X., & Luo, Q. (2023) · Functional & Integrative Genomics · doi:10.1007/s10142-023-01220-y · Cited by 35
“This altered miR-21-5p expression is thought to counteract edema and mediate anti-apoptotic effects (Buller et al. 2010).”
BackgroundZhang, Y., Chopp, M., Liu, X., Kassis, H., Wang, X., Li, C., An, G., & Zhang, Z. G. (2015) · Developmental Neurobiology · doi:10.1002/dneu.22292 · Cited by 35
“TUNEL staining was performed with ApopTag kit (Chemicon) according to the manufacturer’s instructions (Buller et al., 2010).”
MethodSelf-citationHuang, J., Cao, Y. B., Zeng, L., Wang, G., Cao, M., Lü, H., & Hu, J. (2016) · Brain Research · doi:10.1016/j.brainres.2016.07.023 · Cited by 36
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“Immunoreactive cells and nerve fibres were imaged using laser scanning confocal microscopy (LSCM) and were quantified according to our published protocols (Buller et al., 2010; Wang et al., 2014).”
MethodSelf-citationIL-1β-induces NF-κB and upregulates microRNA-372 to inhibit spinal cord injury recovery
Zhou, W., Yuan, T., Gao, Y., Yin, P., Liu, W., Pan, C., Liu, Y., & Yu, X. (2017) · Journal of Neurophysiology · doi:10.1152/jn.00936.2016 · Cited by 33
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Neurotrophin-3 mRNA a putative target of miR21 following status epilepticus
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“Decreased NT-3 mRNA following traumatic brain injury has been implicated in neuronal cell loss (Cheng and Mattson, 1994; Hicks, et al., 1997; Yang, et al., 2005).”
BackgroundPinchi, E., Frati, A., Cipolloni, L., Aromatario, M., Gatto, V., Russa, R. L., Pesce, A., Santurro, A., Fraschetti, F., Frati, P., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20699-1 · Cited by 30
Identification and Functional Analysis of MicroRNAs in Mice following Focal Cerebral Ischemia Injury
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“Currently, many miRNAs have been considered as innovative targets for cerebral ischemia and stroke [13,14].”
BackgroundPotential of different cells-derived exosomal microRNA cargos for treating spinal cord injury
Pan, D., Liu, W., Zhu, S., Fan, B., Yu, N., Ning, G., & Feng, S. (2021) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2021.09.008 · Cited by 30
“Oligodendrocytes includes multivesicular bodies (MVBs) at the axon perimeter, express exosomes involving proteolipid proteins (PLP), myelin proteins, and anti-oxidative stress-related proteins [113,114].”
BackgroundMiR-21-5p protects against ischemic stroke by targeting IL-6R
Zhan, L., Mu, Z., Jiang, H., Zhang, S., Pang, Y., Jin, H., Chen, J., Jia, C., & Guo, H.-Y. (2023) · Annals of Translational Medicine · doi:10.21037/atm-22-6451 · Cited by 30
Expression Profiling of RNA Transcripts during Neuronal Maturation and Ischemic Injury
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MicroRNA-21 in the Pathogenesis of Traumatic Brain Injury
Ji, W., Jiao, J., Cheng, C., & Shao, J. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2602-z · Cited by 28
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“Moreover, during tissue damage, an increase in miRNA-21 expression has been highlighted, with a reduction in neuronal apoptosis via the phosphatase and tensin homolog (PTEN)-protein kinase B (Akt) signalling pathway, as well as the modulation of the expression levels of protein-related apoptosis, including Bcl-2, Bax,…”
BackgroundIdentifying the role of microRNAs in spinal cord injury
Dong, J., Lü, M., He, X., Xu, J., Qin, J., Cheng, Z., Liang, B., Wang, D., & Li, H. (2014) · Neurological Sciences · doi:10.1007/s10072-014-1940-0 · Cited by 29
Overexpression of microRNA-21 protects spinal cords against transient ischemia
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Expression profiles of microRNAs after focal cerebral ischemia/reperfusion injury in rats.
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“Figure 2 Real-time PCR analysis confirmed the expression level of the five differentially expressed microRNAs (miRNAs) 24 hours after middle cerebral artery occlusion (MCAO), as observed by microarray analysis.”
InfluentialMicroRNA Changes in Preconditioning-Induced Neuroprotection
Bell, J. D., Cho, J.-E., & Giffard, R. G. (2017) · Translational Stroke Research · doi:10.1007/s12975-017-0547-1 · Cited by 27
MicroRNAs: emerging driver of cancer perineural invasion
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“It can also participate in nerve remodeling through orchestrating growth signaling, accelerating axon growth [35] and inhibiting neuron death [36].”
BackgroundLi, J., Lv, H., & Che, Y. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.01.014 · Cited by 26
Emerging role of MicroRNAs in peripheral nerve system
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Can MiR-503 be used as a marker in diabetic patients with ischemic stroke?
Sheikhbahaei, S., Danesh, M., Saadatnia, M., Hasan, T. M., Saman, N., Rafiee, L., Motieian, M., Amoushahi, S., & Shaghayegh, H. J. (2019) · BMC Endocrine Disorders · doi:10.1186/s12902-019-0371-6 · Cited by 25
Habashi, S. A., Jickling, G. C., & Winship, I. R. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.746486 · Cited by 25
“demonstrated that elevated miR-21 level after focal ischemia attenuated the expression of Fas ligand (FasL) via complementary base-pairing with FasL transcript and blocking its translation into FasL protein ligands (208).”
MicroRNA-21 promotes neurite outgrowth by regulating PDCD4 in a rat model of spinal cord injury
Jiang, Y., Zhao, S., Ding, Y., Nong, L., Li, H., Gao, G., Zhou, D., & Xu, N. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6862 · Cited by 28
Upadhya, R., Madhu, L. N., Rao, S., & Shetty, A. K. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.845542 · Cited by 24
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miR-21-5p protects hippocampal neurons of epileptic rats via inhibiting STAT3 expression
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Kaidonis, G., Rao, A. N., Ouyang, Y., & Stary, C. M. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.08.001 · Cited by 22
“MiR-21, miR-25, miR-181c are involved in the extrinsic apoptotic pathway through regulation of TNF signaling (Buller et al., 2010; Zhang et al., 2012, 2016).”
Non-coding RNAs in Ischemic Stroke: Roles in the Neuroinflammation and Cell Death
Lü, M., Xingang, D., Zhang, Z., Li, W., & Khoshnam, S. E. (2020) · Neurotoxicity Research · doi:10.1007/s12640-020-00236-7 · Cited by 24
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“Moreover, miR-21 has been repeatedly proved to be a powerful anti-apoptotic factor, and plays a neuro-protective role in cerebral ischemic and refusion injury [2,37,38].”
BackgroundJoerger-Messerli, M. S., Thomi, G. F., Haesler, V., Keller, I., Renz, P., Surbek, D., & Schoeberlein, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.622539 · Cited by 21
Li, Z., Wang, S., Li, W., & Yuan, H. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00183 · Cited by 20
“The locomotor function of rats was determined based on the BBB scale as described (Buller et al., 2010).”
MethodChiang, C.-S., Fu, S.-J., Hsu, C., Jeng, C., Tang, C., Huang, Y., & Tang, S. (2021) · NeuroMolecular Medicine · doi:10.1007/s12017-020-08641-z · Cited by 20
microRNA-367-3p regulation of GPRC5A is suppressed in ischemic stroke
Tabet, F., Lee, S., Zhu, W., Levin, M. G., Toth, C. L., Torres, L., Vinh, A., Kim, H. A., Chu, H. X., Evans, M. A., et al. (2019) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x19858637 · Cited by 19
“Gene expression in the brain is greatly affected by ischemic stroke,(28) and miRNAs are likely contribute to those changes.(15,25,26,29,30) To determine if the changes in brain miRNAs coincided with changes to mRNA target genes, and thus identify new miRNA-mediated gene regulatory modules associated with ischemia and…”
BackgroundRao, S., Madhu, L. N., Babu, R. S., Shankar, G., Kotian, S., Nagarajan, A., Upadhya, R., Narvekar, E., Cai, J. J., & Shetty, A. K. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04324-3 · Cited by 22
“Additionally, the antiapoptotic effects of hiPSC-NSC-EVs are likely due to miRNA-103a-3p and miRNA-21-5p, as well as PTX3 protein carried by them, as they can promote neuroprotection through antiapoptotic mechanisms [39–42].”
Yue, Y., Zhao, H., Yue, Y., Zhang, Y., & Wei, W. (2020) · NeuroMolecular Medicine · doi:10.1007/s12017-020-08600-8 · Cited by 18
Minhas, G., Mathur, D., Balakrishnan, R., Sharma, N. K., Paanu, V., & Anand, A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00386 · Cited by 20
“The findings of Buller et al. (2010) showed that expression of miR-21 is enhanced by three-folds following stroke in vivo. miR-21 overexpression inhibits apoptosis and mediates neuroprotection in vitro.”
BackgroundNampoothiri, S. S., Fayaz, S. M., & Rajanikant, G. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0963-6 · Cited by 17
Chen, R., Tai, Y., Zhang, Y., Wang, L., Yang, Y., Yang, N., Ma, S., Xue, F., & Wang, J. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.09.060 · Cited by 17
Gusar, V. A., Timofeeva, A. V., Сергеевич, Ж. И., Shram, S. I., & Pinelis, V. G. (2017) · Molecular Biology · doi:10.7868/s0026898417040103 · Cited by 16
Placenta-Derived Cells for Acute Brain Injury
Pischiutta, F., Sammali, E., Parolini, O., Carswell, H. V. O., & Zanier, E. R. (2018) · Cell Transplantation · doi:10.1177/0963689717732992 · Cited by 17
Gusar, V. A., Timofeeva, A. V., Сергеевич, Ж. И., Shram, S. I., & Pinelis, V. G. (2017) · Molecular Biology · doi:10.1134/s0026893317040100 · Cited by 16
“Another miRNA, miR-21, is viewed as a strong antiapoptotic factor [2, 37].”
MicroRNA: Not Far from Clinical Application in Ischemic Stroke
Li, Y., Liu, Y., Wang, Z., Hou, H., Lin, Y., & Jiang, Y. (2013) · ISRN Stroke · doi:10.1155/2013/858945 · Cited by 16
“[37] B.”
BackgroundXu, X., Jiao, X., Song, N., Luo, W., Liang, M., Ding, X., & Teng, J. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.6870 · Cited by 16
“Certain studies have suggested that miR-21 expression may be increased in cells tolerant to hypoxia and may be protective against hypoxia (13,26,27).”
BackgroundIdentification and functional analysis of microRNAs in rats following focal cerebral ischemia injury
Duan, X., Gan, J., Peng, D., Bao, Q., Xiao, L., Wei, L., & Wu, J. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10073 · Cited by 16
Ghibaudi, M., Boido, M., Green, D., Signorino, E., Berto, G. E., Pourshayesteh, S., Singh, A., Cunto, F. D., Dalmay, T., & Vercelli, A. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.618869 · Cited by 16
“Then, 5 nmol of miR-7b-3p mimic (Invitrogen) per 1 × 106 cells or negative control (Invitrogen) were added to the suspension (Buller et al., 2010).”
MethodLiving Proof of Activity of Extracellular Vesicles in the Central Nervous System
Mahjoum, S., Rufino‐Ramos, D., de Almeida, L. P., Broekman, M. L. D., Breakefield, X. O., & van Solinge, T. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147294 · Cited by 14
“miR-21 has a wide range of functions and has been implicated in various neuroprotective processes, protecting neurons from ischemic death in stroke [72] and reducing glial scarring in spinal trauma [73].”
BackgroundАйтбаев, К. А., Murkamilov, I. T., Fomin, V. V., Абдилалимовна, М. Ж., & Yusupov, F. A. (2018) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20181183248-56 · Cited by 15
Therapeutic potential of amniotic fluid-derived cells for treating the injured nervous system
Rennie, K., Haukenfrers, J., Ribecco‐Lutkiewicz, M., Ly, D., Jezierski, A., Smith, B., Zurakowski, B., Martina, M., Gruslin, A., & Bani‐Yaghoub, M. (2013) · Biochemistry and Cell Biology · doi:10.1139/bcb-2013-0019 · Cited by 15
“2012a), and miR-21 (Buller et al. 2010; Zhang et al. 2012b), have been shown to confer neuroprotection in in vitro or in vivo models of neural injury, and thus the delivery of specific miRs to the injured nervous systemmay represent a valid therapeutic strategy.”
BackgroundMarega, L. F., Teocchi, M. A., & Vilela, M. M. D. S. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12800 · Cited by 15
Wei, Y., Yang, J., He, Y.-L., et al. (2019) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.14499 · Cited by 15
The Role of miR-20 in Health and Disease of the Central Nervous System
Arzhanov, I., Sintakova, K., & Romanyuk, N. (2022) · Cells · doi:10.3390/cells11091525 · Cited by 16
“The overexpression of miR-21 protects neural cells from death by repressing the expression of pro-apoptotic molecules Fas ligand [54], tropomyosin alpha-1 chain (TPM1) and PTEN [55], and programmed cell death protein 4 (PDCD4) [56].”
BackgroundRole of Non-Coding RNA of Human Platelet in Cardiovascular Disease
Inzulza-Tapia, A., & Alarcón, M. A. (2021) · Current Medicinal Chemistry · doi:10.2174/0929867329666211230104955 · Cited by 13
Therapeutic potential of extracellular vesicles in neurodegenerative disorders
Roudi, S., Rädler, J., & Andaloussi, S. E. (2023) · Handbook of clinical neurology · doi:10.1016/b978-0-323-85555-6.00017-5 · Cited by 14
Involvement of microRNA-181a and Bim in a rat model of retinal ischemia-reperfusion injury
He, Y., Liu, J., Zhang, J.-J., & Fan, W. (2015) · International Journal of Ophthalmology · doi:10.18240/ijo.2016.01.06 · Cited by 14
Wiberg, R., Kingham, P. J., & Novikova, L. N. (2016) · Journal of Neurotrauma · doi:10.1089/neu.2015.4378 · Cited by 14
“38,39 Several studies have implicated microRNAs as important players in the functional outcome following different kinds of insults to the nervous system. miR-21 protects neurons from neuronal death by targeting FasL, 40 and knockdown of miR-21 by antagomir-21 leads to attenuated recovery in hindlimb motor function, i…”
Zhou, L., Yang, W., Yao, E., et al. (2021) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s255666 · Cited by 13
“For example, studies have reported that miRNA 21 and miR-99a decrease the ischemic infarction volume, reduce neuronal apoptosis, and improve the neurological scores in ischemic stroke rats.(12,13) Other studies presented that miR367 and miR-132 could relieve neuropathological alterations through reducing neuroinflamma…”
ResultMiRNAs: potential diagnostic and therapeutic targets for cerebral ischaemia
Zhu, R., Liu, X., Zhu, Y., & He, Z. (2016) · Neurological Research · doi:10.1080/01616412.2015.1136103 · Cited by 13
Self-citationChak, K., Roy‐Chaudhuri, B., Kim, H. K., Kobak, K. C., Porter, B. E., & Kay, M. A. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.10.003 · Cited by 13
“MicroRNA-21 (miR-21), an evolutionarily conserved miRNA, increases following a variety of brain insults including head trauma, stroke, and SE that are associated with increased risk of developing epilepsy (Buller et al., 2010; Gorter et al., 2014; Peng et al., 2013).”
InfluentialBizzarri, A. R., & Cannistraro, S. (2021) · Cancers · doi:10.3390/cancers13236108 · Cited by 12
“miR21-3p was shown to be a powerful factor that inhibits apoptosis and promotes survival in ischemia [85].”
BackgroundmiR‐378‐3p alleviates contusion spinal cord injury by negatively regulating ATG12
Zhang, H., Yu, H., Yang, H., et al. (2021) · International Journal of Experimental Pathology · doi:10.1111/iep.12400 · Cited by 12
Self-citationExosomes and MicroRNAs in Biomedical Science
Mirzaei, H., Rahimian, N., Mirzaei, H. R., Nahand, J. S., & Hamblin, M. R. (2022) · Synthesis lectures on biomedical engineering · doi:10.2200/s01171ed1v01y202202bme062 · Cited by 27
Systemic delivery of microRNA for treatment of brain ischemia
Liu, C., Wen, J., Li, D., Qi, H., Nih, L. R., Zhu, J., Xu, D., Ren, Y., Zhang, S., Han, D., et al. (2021) · Nano Research · doi:10.1007/s12274-021-3413-8 · Cited by 12
Epigenetics: an Expanding New Piece of the Stroke Puzzle
Pearce, W. J. (2011) · Translational Stroke Research · doi:10.1007/s12975-011-0094-0 · Cited by 10
“In addition, miRNAs have been suggested to regulate the effects of ischemia on aquaporin expression and function [70] and in some cases may be neuroprotective [71].”
BackgroundSič, A., Atanasković, M., Ahmed, A., Petrović, I., Simović, F., Burnjaković, B., Tonković, U., Manzar, A., Shadab, S., Gajić, S., et al. (2025) · Medical Sciences · doi:10.3390/medsci13030172 · Cited by 9
“This anti-apoptotic effect translated to smaller infarcts and improved cell survival in vivo, suggesting that miR-21 upregulation in neurons protects against ischemic cell death [30].”
Sarvestani, F. S., & Azarpira, N. (2020) · Immunological Investigations · doi:10.1080/08820139.2020.1808672 · Cited by 9
“…of miRNA-21 in neurons significantly reduced FasL levels, a tumor necrosis factor-α family member as an important cell death-inducing ligand (Buller et al. 2010). miRNA-22 Adenovirus-mediated miRNA-22 overexpression markedly can be reduced the neurological score and infarct size lessened…”
BackgroundSome miRNA expressions and their targets in ischemic stroke
Can, Ü., Özdemir, E. M., & Akdu, S. (2022) · Nucleosides Nucleotides & Nucleic Acids · doi:10.1080/15257770.2022.2098974 · Cited by 9
“The upregulation of miR-21 in the penumbra suppresses neuronal apoptosis by decreasing the protein expression of proapoptotic FasL and induces neuroprotection in vitro.[57] In IS, the increased expression of miR-21 is related to the extracellular signal-regulated kinase (ERK)-stimulated MMP-9 expression developing aft…”
BackgroundGu, J., Gui, S., Hu, L., Kong, L., Di, M., & Wang, Y. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.8249 · Cited by 9
Liu, Y., Zhang, X., Gao, C., Zhang, H., Zhang, H., & Qu, J. (2020) · Bioscience Reports · doi:10.1042/bsr20193531 · Cited by 9
Zhan, L., Pang, Y., Jiang, H., Zhang, S., Jin, H., Chen, J., Jia, C., Guo, H.-Y., & Mu, Z. (2022) · Journal of Healthcare Engineering · doi:10.1155/2022/4687349 · Cited by 9
“‘s in vivo and in vitro experimental studies, the level of miR-21 was significantly increased after ischemic stroke, inhibiting neuronal cell death by reducing Fas ligand (FasL) G (an important cell death-inducing ligand) [23].”
BackgroundRetractedISCHEMIRs: Finding a Way Through the Obstructed Cerebral Arteries
Nampoothiri, S. S., Menon, H. V., Das, D., & Krishnamurthy, R. G. (2016) · Current Drug Targets · doi:10.2174/1389450116666150518102404 · Cited by 9
Bibliometric Analysis of Non-coding RNAs and Ischemic Stroke: Trends, Frontiers, and Challenges
Zhang, H., Ma, G.-Q., Lv, H., & Peng, Y. (2023) · Molecular Biotechnology · doi:10.1007/s12033-023-00981-y · Cited by 8
“The seventh and ninth most cited articles published in 2010 highlighted the importance of miRNAs in cell death and proliferation after ischemic stroke [31, 32].”
Boxhammer, E., Dienhart, C., Rezar, R., Hoppe, U. C., & Lichtenauer, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25105568 · Cited by 8
“…the programmed cell death The upregulation of miRNA-21 in the context of hypoxia inhibits the programmed cell death 4 (PDCD4) gene and subsequently reduces the expression of the transcription factor Activator protein 1 (AP-1) and the helicase eukaryotic initiation factor-4A (elF4A) [76,77].”
BackgroundThe Emerging Impact of microRNAs in Neurotrauma Pathophysiology and Therapy
Bhalala, O. G. (2015) · Europe PMC (PubMed Central) · Cited by 8
The microRNA miR-21 conditions the brain to protect against ischemic and traumatic injuries.
Lopez, M. S., Dempsey, R. J., & Vemuganti, R. (2017) · PubMed · Cited by 8
MicroRNA profile of extracellular vesicles released by Müller glial cells
Lamb, W. D. B., Eastlake, K., Luis, J., et al. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1325114 · Cited by 7
“Interestingly, in vitro overexpression of miR-21 in cortical neurons was found to suppress oxygen and glucose deprivation-induced apoptosis, whereas inhibition of endogenous miR-21 expression enhanced cell death through post-transcriptional regulation of cell death-inducing ligand FASLG (Buller et al., 2010).”
BackgroundMicroRNAs in Non-Malignant Diseases
Mirzaei, H., Rahimian, N., Mirzaei, H. R., Nahand, J. S., & Hamblin, M. R. (2022) · Synthesis lectures on biomedical engineering · doi:10.1007/978-3-031-79177-2_3 · Cited by 6
Patnaik, S. K., Kannisto, E. D., & Yendamuri, S. (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-40 · Cited by 6
“Quantification of the ultrashort, non-coding microRNAs in microdissected cells is an effective approach to understand the physiological roles of microRNAs [2-5] as well as to characterize microRNA dysregulation in diseases [6-10].”
BackgroundWu, J. F., Wang, B., Zhou, J., & Ji, F.-J. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.7262 · Cited by 6
“For example, in rat brains after middle cerebral artery occlusion, miR-29b is upregulated by apoptosis regulator BCL2L2, while miR-21 selectively downregulates Faslg (53,54).”
BackgroundBreaking through barrier: The emerging role of nucleic acids-based drug delivery in stroke
Yin, G., Zheng, Y., Li, M., Wu, G., & Luo, Y. (2025) · Progress in Materials Science · doi:10.1016/j.pmatsci.2025.101436 · Cited by 5
Retinopathy of Prematurity and MicroRNAs
Albanese, G. M., Visioli, G., Alisi, L., Armentano, M., Giovannetti, F., Lucchino, L., Marenco, M., Pontecorvi, P., & Gharbiya, M. (2025) · Biomedicines · doi:10.3390/biomedicines13020400 · Cited by 6
“For instance, miR-9a-5p was activated, while miR-223-3p was suppressed, influencing VEGF signaling and inflammatory responses [55,65].”
Hao, Z., Guan, W., Wei, W., Li, M., Xiao, Z., Sun, Q., Pan, Y., & Xin, W. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03405-7 · Cited by 5
“MiR-21 also acts as an inflammation modulator in stroke and has been consistently shown to be a potent anti-apoptotic factor, playing a neuroprotective role in cerebral ischemic and reperfusion injury [209, 229, 230].”
The association of microRNAs in the development of retinopathy of prematurity
Ovalı, F., Hakbilen, M., Akalın, İ., et al. (2024) · Journal of Neonatal-Perinatal Medicine · doi:10.3233/npm-230029 · Cited by 4
“Although it cannot be concluded that it is specific for stage III ROP, it might still be used as a biomarker of severe ROP due to severe hypoxia and elevated levels may be a preventive mechanism acting to limit ischemic injury, as shown by Buller et al. in ischemic brain lesions [20].”
Post-stroke Depression: Genetics, Mechanisms, and Treatment
Popa‐Wagner, A., Udriștoiu, I., Greșiță, A., Lledós, M., & Fernández‐Cadenas, I. (2022) · Springer eBooks · doi:10.1007/978-3-030-62059-2_434 · Cited by 4
Unveiling the regulatory role of miRNAs in stroke pathophysiology and diagnosis
Abdel‐Reheim, M. A., Nomier, Y., Zaki, M. B., Abulsoud, A. I., Mohammed, O. A., Rashad, A. A., Oraby, M. A., Elballal, M. S., Tabaa, M. M. E., Elazazy, O. E., et al. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2023.155085 · Cited by 4
Expression profiles of miRNAs during ethanol-induced differentiation of neural stem cells
Park, J. H., Halder, D., Choi, M., Chai, J. C., Lee, Y. S., Jung, K. H., & Chai, Y. G. (2012) · BioChip Journal · doi:10.1007/s13206-012-6110-y · Cited by 4
Li, Y., Hu, J., Chen, J., Zhou, M., Liao, M., Yang, Y., Zhou, J., Han, Y., Wang, B., & Zhao, Y. (2026) · Journal of Extracellular Vesicles · doi:10.1002/jev2.70295 · Cited by 5
“Thus, we bio-engineered BMSC-derived sEVs with RVG and miR-21, which was previously reported as a PTEN regulator, and positively correlated with IS recovery (Buller et al. 2010 , Lopez et al. 2022 ).”
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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