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7 publications mentioning mml-mir-21

Open access articles that are associated with the species Macaca mulatta and mention the gene name mir-21. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 155
For the first time, we report that miR-21 is upregulated in EVs in the diseased brain and can activate TLR signaling in neurons during SIV infection. [score:6]
The results revealed that miR-21 was significantly upregulated in EVs derived from the SIVE brain samples when compared to uninfected animals, as well as to SIV infected animals that did not have CNS disease (Fig 1B and S1 Table). [score:5]
Analysis revealed significantly increased expression of miR-21-5p, miR-100-5p and miR-146-5p, and decreased expression miR-126-5p, in SIVE. [score:5]
The change in expression of miR-21 was then validated by quantitative real time polymerase chain reaction (qRT-PCR) on the EV samples for miR-21, revealing significantly elevated expression of miR-21 in SIVE samples (Fig 1C). [score:5]
MiR-21 expression is significantly upregulated in extracellular vesicles isolated from the SIVE macaque brains. [score:5]
In the diseased brain, microglial/macrophages express miR-21; and in vitro, macrophage produces EVs containing miR-21. [score:5]
Several lines of evidence suggest that miR-21 is upregulated during inflammation in the brain [24, 31, 32]. [score:4]
Our initial studies found that in SIVE miR-21 is upregulated in neurons [11]. [score:4]
We have previously identified that miR-21 is significantly upregulated during SIV/HIV infection in the brain [11]. [score:4]
Previously, we determined that miR-21 is upregulated in SIVE and HIVE [11]. [score:4]
Previously, we showed that miR-21 causes alterations in neuronal physiology by acting through its target gene MEF2C [11]. [score:3]
In uninfected controls, miR-21 expression was below the detection limit, although U6 could still be detected (Fig 2, Uninfected panels). [score:3]
miR-21 neurotoxicity is rescued by Nec-1, a necroptosis inhibitor. [score:3]
In order to examine whether such non-neuronal cells in the brain express miR-21 during infection, we performed fluorescence in situ hybridization (FISH) coupled with immunofluorescent (IF) labeling on brain tissue sections of SIVE and uninfected macaques. [score:3]
We found that miR-21 when associated with EVs exhibit neurotoxicity, and this neurotoxicity is dependent upon neuronal expression of TLR7. [score:3]
Through the repression of its targets, miR-21 was shown previously to act as both pro-apoptotic [35] and anti-apoptotic miRNA [36]. [score:3]
MAPK activation is linked to apoptosis accompanied by caspase activation, in parallel with not finding activation of MAPK members treatment with a pan caspase inhibitor, z-VAD-fmk, did not rescue the neurons from undergoing death indicating that EV-miR-21 caused neurotoxicity by activating a different cell death pathway. [score:3]
1005032.g006 Fig 6 (A) HEK-Blue Null (HEK-control) or TLR7 overexpressing (HEK-TLR7) cells were incubated with 1 μg of synthetic miRNAs; miR21-WT, miR21-Mut, and CL264, a TLR7 ligand. [score:3]
The relative amount of miR-21 was determined by comparison to a standard dilution curve, made from a cDNA preparation from a miR-21 overexpressing cell line. [score:3]
Necrostatin-1, a necroptosis inhibitor, prevents neuronal cell death caused by miR-21. [score:3]
The results indicate a significant increase when TLR7 expressing cells were treated with miR21-WT, Let-7b and CL264; whereas, no difference was seen in DOTAP control and miR21-Mut. [score:3]
Increased expression of miR-21 is seen in macrophage/microglial cells in SIVE brain tissues. [score:3]
It is interesting that a significant change in miR-21 levels was not seen in animals without CNS disease, which is in support with studies referring to miR-21 as a critical player in inflammation. [score:3]
Intriguingly, temporal differences in expression patterns have been detected in neurons and astrocytes after ischemic injury, where the miR-21 increase in neurons was much later when compared to astrocytes, which occurred 12 hr post injury [41]. [score:2]
Using a nonhuman primate mo del of HAND, simian immunodeficiency virus encephalitis (SIVE), we find that exosomes isolated from SIVE brains contain,microRNAs, including miR-21, that can serve as ligands to the key immune regulatory receptors, toll-like receptors, and can elicit neurotoxicity. [score:2]
To determine if necroptosis was involved in the neurotoxicity induced by miR-21, we treated the cultures with necrostatin-1, which specifically inhibits RIPK-1. Indeed the LDH assay results indicate that Nec-1 was able to prevent EV-miR-21 induced neurotoxicity in hippocampal neurons (Fig 6D). [score:2]
Expanding upon its pathogenic actions, in this study we found that miR-21 is released via EVs and that it can directly activate neurotoxic signaling pathways by activating TLR7 receptors in the neuron. [score:2]
We found increased miR-21 expression in EVs derived from SIVE brains when compared to controls. [score:2]
1005032.g003 Fig 3 (A) Wildtype (WT) mouse hippocampal neurons were incubated with 1 μg of synthetic miRNAs; miR-21 (miR21-WT), miR-21 containing a mutation in TLR7 binding site (miR21-Mut) and a known TLR7 activator, Let-7b, and DOTAP artificial EVs. [score:2]
To do so, we used miRNA oligonucleotides (oligos) of wildtype miR-21 (miR-21-WT), a mutant miR-21 (miR-21-Mut) containing a point mutation in one of the uridine residues in a small G/U sequence in the TLR binding motif (U to G, since uridines are more crucial ligands to TLRs [29]). [score:2]
In SIVE brains, there is a marked inflammatory cytokine response to the presence of the virus; and therefore, up regulation in miR-21 levels could be expected. [score:2]
After pre-treatment, neurons were treated simultaneously with 1 μg of synthetic miRNAs; miR-21 (miR21-WT), miR-21 containing a mutation in TLR7 binding site (miR21-Mut) and DOTAP artificial EVs. [score:2]
We also report for the first time that EV-miR-21 causes neurotoxicity by activating necroptosis, a novel cell death pathway. [score:1]
Therefore, it is possible that during infection macrophages could secrete EVs containing miR-21 that could then affect neurons. [score:1]
Next, we asked if the TLR7 pathway is activated by EV-miR-21. [score:1]
Interestingly, miR-21 is one such miRNA. [score:1]
Treating the TLR7 [-/-] neurons with WT-EVs and miR-21 [-/-] EVs demonstrated that toxicity depended not only on the presence of miR-21 in the EVs but also upon the presence of TLR7 in the neurons (Fig 4D). [score:1]
Thus, we hypothesized that miR-21 may be present within EVs during SIV/HIV associated neuroinflammation and therefore, can be damaging to neurons. [score:1]
A number of studies have revealed that several miRNAs, such as miR-21, miR-29a and let-7b, can even serve as physiological ligands of the ssRNA-sensing [25– 27]. [score:1]
No miR-21-EV induced toxicity was found when hippocampal neurons from TLR7 [-/-] mice were used. [score:1]
Indeed, there is a significant increase in neuronal cell death when cultures were treated with EVs derived from WT than from miR-21 [-/-] macrophage cultures (Fig 4B). [score:1]
It is also unclear as to why miR-21 is localized to specific cell types in the brain, either through its production or its uptake from EVs. [score:1]
Hence, we questioned whether miR-21 in association with EVs in SIVE neuropathology and whether this EV miR-21 (EV-miR-21) causes neuronal damage. [score:1]
Furthermore, we also discovered that neurotoxicity by EV-miR-21 is not caused by an apoptotic mechanism but through the activation of a programmed necrotic pathway termed necroptosis. [score:1]
In the context of HIV infection, they are mediators of many neurotoxic factors, miR-21, being one of them. [score:1]
In this present study, we showed that EV-miR-21 could activate the TLR7 signaling pathway thus leading to neurotoxicity in SIV neuropathogenesis. [score:1]
Combined FISH and IF for miR-21, CD163 and GFAP. [score:1]
To further examine whether EV-miR-21 activates the TLR7 pathway, we isolated EVs from bone marrow derived macrophage cultures prepared from wildtype (WT) and miR-21 [-/-] mice and used these, differing in the presence of miR-21, to examine potential neurotoxicity (Fig 4A). [score:1]
First, we asked if the presence of extracellular miR-21 could render neurotoxicity. [score:1]
We find that miR-21 is increased in EVs during SIVE pathogenesis and that it is deleterious to neurons by activating TLR7 dependent downstream cell death pathways. [score:1]
Given the prime role of macrophages in neuropathogenesis of HIV/SIV and the presence of miR-21 in macrophages in the infected brain, we used macrophages as the cellular mo del for EV release in our experiments. [score:1]
Raw CT values confirm the absence of miR-21 in the EVs isolated from miR-21 [-/-] BMDMs. [score:1]
Presence of miR-21 in synthetic EVs renders neurotoxicity. [score:1]
Recent studies reported that certain miRNAs such as miR-21, if present extracellulary or in extracellular vesicles (EVs) could trigger TLR signaling pathways by acting as a ligand leading to cell injury [25– 27]. [score:1]
To study pathways potentially activated upon treatment with EV-miR-21 leading to neurotoxicity, we first looked at changes in the phosphorylation of signaling proteins such as ERK, JNK and p-38 in the MAPK pathway. [score:1]
Hence for the first time we report that a miRNA (miR-21) in EVs could cause cell death through a necroptotic cell death pathway. [score:1]
In order to determine if the miR-21 induced TLR7 signaling, HEK-TLR7 cells were treated with EV-like vesicles. [score:1]
We next examined if the cell death observed in the EV-miR-21 treated neuronal cultures occurs via apoptosis. [score:1]
indicate that miR-21 induced signaling but not the vehicle control or the miR-21 mutant (miR-21-Mut) (Fig 6A). [score:1]
In clear distinction to what we saw with free miR-21, the delivery of miR-21 in EV-like vesicles is essential to elicit neurotoxicity. [score:1]
It was shown previously that miR-21 levels markedly increased during tissue injury and inflammation in the heart [52], spinal cord [53], neurons and astrocytes [41], and in traumatic brain injury [54– 58]. [score:1]
Previously, we showed that miR-21 is significantly increased in neurons. [score:1]
Here, we significantly expand this to reveal the presence of miR-21 in brain EVs from macaques with SIV neuropathogenesis. [score:1]
Using in vitro constructed EVs, EVs from mouse macrophages, and EVs isolated from primate brains, we provide multiple lines of evidence revealing EV-miR-21 signaling through TLR7, resulting in neuronal demise. [score:1]
Brain macrophages are the most likely source for EV-miR-21, although we cannot exclude the possibility that neurons to secrete miR-21 associated EVs as well. [score:1]
indicate a significantly higher cell death with miR-21-WT and Let-7b than with miR-21-Mut and DOTAP control. [score:1]
The sequences of the probes are; U6: CAC GAA TTT GCG TGT CAT CCT Y; miR-21: 5’- TCA ACA TCA GTC TGA TAA GCT A -3’; Scramble (Scr) 5’- GTG TAA CAC GTC TAT ACG CCC A -3’. [score:1]
Since miR-21 is increased in EVs from the brains of monkeys with SIVE, and EV associated miR-21 (EV-miR-21) is associated with neurotoxicity, we then assessed whether EVs isolated from the SIVE (SIVE-EV) and uninfected (control-EV) brains would show differences in neurotoxicity. [score:1]
Hence, we tested to see if Nec-1 will be able to rescue neuronal death triggered by EV-miR-21. [score:1]
1005032.g002 Fig 2 In SIVE brain sections containing macrophage/microglial nodules, miR-21 (magenta) partially colocalized with the macrophage/microglia marker CD163 (green). [score:1]
indicate that Nec-1 was able to protect neurons from undergoing cell death by miR-21 containing artificial EVs. [score:1]
miR-21 acts via TLR7 to exert neurotoxicity. [score:1]
1005032.g004 Fig 4 (A) Quantitative reat-time PCR (qRT-PCR) for miR-21 was performed on EVs isolated from WT and miR-21 [-/-] BMDMs. [score:1]
The changed base in miR21-mut (U to G at position 20) is underlined. [score:1]
Hence the necroptotic, rather than apoptotic, pathway is active in EV-miR-21 induced neurotoxicity. [score:1]
These results clearly indicate that both miR-21 and TLR7 are required for the activation of neurotoxic pathways. [score:1]
miR21-WT: 5'- UAG CUU AUC AGA CUG AUG UUG A -3'; miR21-Mut: 5'- UAG CUU AUC AGA CUG AUG U GG A -3'; and let-7b, 5’- UGA GGU AGU AGG UUG UGU GGU U -3′. [score:1]
In SIVE brain sections containing macrophage/microglial nodules, miR-21 (magenta) partially colocalized with the macrophage/microglia marker CD163 (green). [score:1]
miR-21 [−/−] and Tlr7 [−/−] mice were purchased from Jackson Laboratories (Bar Harbor, Maine) and bred in the UNMC animal facility. [score:1]
Through on EVs isolated from control and SIVE brains, we found differences in several miRNAs, the most striking being miR-21. [score:1]
Western blot analysis revealed that none of the signaling proteins such as p-ERK1/2, p-JNK and p-p38 changed by treatment with miR-21 WT EVs (Fig 6B). [score:1]
Interestingly, miR-21 signal was seen in CD163 positive macrophages/activated microglial cells and cells with the phenotypic appearance of neurons, whereas minimal signaling is seen in GFAP positive astrocytes (Fig 2, SIVE-Mag panel). [score:1]
Furthermore, it has been already shown that pro-inflammatory cytokine signaling, such as IL6 via the activation of STAT3 promoter, increases miR-21 [59]. [score:1]
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2
[+] score: 10
We also examined the expression of miR-21, which has recently been shown to be upregulated in the serum of individuals aged 66-95 [25], however, we did not find any significant differences in either miR-21-3p or miR-21-5p in our young and old cohorts. [score:6]
miR-21-3p expression was not different between our age groups and miR-21-5p levels decreased, albeit not significantly, in our older cohort. [score:3]
Given the recent data that serum miR-21 increases in abundance with age [25], we also examined miR-21 levels in young and old individuals. [score:1]
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3
[+] score: 8
Oncogene 36 Gong C Yao Y Wang Y Liu B Wu W 2011 Upregulation of MIR-21 mediates resistance to trastuzumab therapy for breast cancer. [score:4]
Additionally, miR-103, miR-21 and miR-378 possessed very high expression level (counts TPM>10000) in despite of origin from parthenogenesis or IVF. [score:3]
Consisting with Laurent and colleagues' reports [14], miR-183–182 cluster, miR-103, miR-21 and miR-378, which were reported to be related to many type carcinomas [33]– [36], were also enriched in both types of rhesus monkey ESCs. [score:1]
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4
[+] score: 5
While miR-21, miR-30a and miR-373 were expressed in all 7 tissues including testis, kidney, lung, spleen, heart, liver and skeletal muscle, miR-422, miR-28, miR-379, miR-431 and miR-648 demonstrated more restricted expression patterns (Figure 2). [score:5]
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5
[+] score: 3
A number of miRNAs were stably and highly expressed between species, such as the miR-17 family, miR-21 and miR-103, which suggested conserved functions in ESCs during evolution. [score:3]
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6
[+] score: 2
Therefore, ten miRNAs (miR-19b-3p, miR-21-5p, miR-25-3p, miR-30a-5p, miR-133b-3p, miR-140-5p, miR-150-5p, miR-199a-3p, miR-342-5p, miR-3473) were chosen as candidate reference genes. [score:1]
Three miRNAs (miR-21-5p, miR-30a-5p, miR-16-5p) showed significant differences between control group and HU group (p < 0.05). [score:1]
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7
[+] score: 2
In this work, the SVM method selected hsa-miR-146a-5p, hsa-miR-18b-5p, hsa-miR-21-3p, hsa-miR-22-3p, hsa-miR-29a-3p, hsa-miR-432-5p, hsa-miR-511-5p, and hsa-miR-596 as an EVD classifier. [score:1]
These trends were consistent among the macaque and human cohorts with the exception of miR-21-3p, -511-5p, and -596, which were not detected in human samples with low viral titers. [score:1]
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