Circulating miR-9* and miR-384-5p as Potential Indicators for Trimethyltin-induced Neurotoxicity

Ogata, Keiko; Sumida, Kayo; Miyata, Kaori; Kushida, Masahiko; Kuwamura, Mitsuru; Yamate, Jyoji

doi:10.1177/0192623314530533

Cited by 36 publications

(28 citation statements)

References 62 publications

(86 reference statements)

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“…Another study demonstrated that miR-384 is a promising candidate as a biomarker of spinal cord injury, because of a significant increase in miR-384 in the serum, which correlates with injury severity (Hachisuka et al, 2014). In addition, miR-384 is elevated in the hippocampus during neural cell death and is, therefore, considered to have potentially novel roles in neurotoxicity (Ogata et al, 2015) and the development of Parkinson’s disease (Jiang et al, 2016) and Alzheimer’s disease (Liu et al, 2014). In this study, we discovered another novel function of miR-384, namely a critical involvement in the development of the Th17/Treg imbalance and demyelination in the CNS during the pathogenesis of EAE through targeting of SOCS3 .…”

Section: Discussionmentioning

confidence: 99%

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

Han

Zhang

et al. 2017

Front. Cell. Neurosci.

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Specific miRNAs are involved in the pathogenesis of multiple sclerosis (MS), during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the central nervous system (CNS). In this study, we identified levels of miR-384 as significantly increased in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Over-expression of miR-384 in vivo led to severe EAE, characterized by exacerbated demyelination, and increased inflammatory cell infiltration of the spinal cord; inhibition of miR-384 reversed these changes. Both the percentage of Th17, and ratio of Th17/regulatory T (Treg), cells were elevated in miR-384-transfected EAE mice, which was consistent with the observed upregulation of expression of IL-17 and the Th17 lineage-specific transcription factor, RORγt. Importantly, transfer of miR-384 overexpressing naïve T cells from wild-type (WT) to Rag1−/− mice, which are deficient in functional autologous T and B cells, led to aggravated EAE pathogenesis, while an miR-384 inhibited group was protected from EAE. Moreover, miR-384 promoted differentiation of naïve T cells into Th17 cells in vitro. Furthermore, target prediction and dual luciferase reporter assays demonstrated that suppressor of cytokine signaling 3 (SOCS3), a gene encoding protein with an established role in Th17 differentiation, was a direct target of miR-384. Our results demonstrate an important role for miR-384 in regulation of the Th17/Treg ratio during the pathogenesis of EAE, indicating that this molecule may have potential as a biomarker and/or therapeutic target in MS.

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Section: Discussionmentioning

confidence: 99%

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

Han

Zhang

et al. 2017

Front. Cell. Neurosci.

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“…It has been reported that the serum level of miR-384-5p was significantly increased in mice with acute spinal cord injury and that miR-384-5p might be used as a promising biomarker for predicting the severity of acute spinal cord injury (13). In rats treated with trimethyltin, miR-384-5p was significantly upregulated with the evolution of neural cell death that was regarded as potential indicators of neurotoxicity (32). The decreased expression of miR-384-5p is required for spine enlargement associated with long-term potentiation (12).…”

Section: Discussionmentioning

confidence: 99%

“…Spinal cord injury significantly increases the expression of miR-384-5p in the serum (13). Importantly, miR-384-5p has been shown to be an indicator for trimethyltin-induced neurotoxicity (32) and is found to be differentially expressed in dopaminergic neurons following cocaine addiction (42). However, whether miR-384-5p is associated with neurotoxicity in PD remains unknown.…”

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confidence: 99%

Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

Jiang

Yun

Feng

et al. 2016

American Journal of Physiology-Cell Physiology

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lation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress. Am J Physiol Cell Physiol 310: C755-C763, 2016. First published February 10, 2016 doi:10.1152/ajpcell.00226.2015.-Endoplasmic reticulum (ER) stress has been linked to the pathogenesis of Parkinson's disease (PD). However, the role of microRNAs (miRNAs) in this process involved in PD remains poorly understood. Recent studies indicate that miR-384-5p plays an important role for cell survival in response to different insults, but the role of miR-384-5p in PD-associated neurotoxicity remains unknown. In this study, we investigated the role of miR-384-5p in an in vitro model of PD using dopaminergic SH-SY5Y cells treated with rotenone. We found that miR-384-5p was persistently induced by rotenone in neurons. Also, the inhibition of miR-384-5p significantly suppressed rotenone-induced neurotoxicity, while overexpression of miR-384-5p aggravated rotenone-induced neurotoxicity. Through bioinformatics and dual-luciferase reporter assay, miR-384-5p was found to directly target the 3=-untranslated region of glucose-regulated protein 78 (GRP78), the master regulator of ER stress sensors. Quantitative polymerase chain reaction and Western blotting analysis showed that miR-384-5p negatively regulated the expression of GRP78. Inhibition of miR-384-5p remarkably suppressed rotenone-evoked ER stress, which was evident by a reduction in the phosphorylation of activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1␣). The downstream target genes of ER stress including CCAAT/enhancer-binding protein-homologous protein (CHOP) and X box-binding protein-1 (XBP-1) were also decreased by the miR-384-5p inhibitor. In contrast, overexpression of miR-384-5p enhanced ER stress signaling. In addition, knockdown of GRP78 significantly abrogated the inhibitory effect of miR-384-5p inhibitors on cell apoptosis and ER stress signaling. Moreover, we observed a significant increase of miR-384-5p expression in primary neurons induced by rotenone. Taken together, our results suggest that miR-384-5p mediated ER stress by negatively regulating GRP78 and that miR-384-5p inhibition might be a novel and promising approach for the treatment of PD. endoplasmic reticulum stress; Parkinson's disease; miR-384-

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“…By targeting the PTEN gene, mir-222 has been shown to promote neurite outgrowth (34). Additionally, mir-384 has been shown to be an indicator of neurotoxicity (35) and was found to be differentially expressed in dopaminergic neurons following cocaine addiction (36). …”

Section: Discussionmentioning

confidence: 99%

Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

2014

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Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression.

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Circulating miR-9* and miR-384-5p as Potential Indicators for Trimethyltin-induced Neurotoxicity

Cited by 36 publications

References 62 publications

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis

Downregulation of miR-384-5p attenuates rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through inhibiting endoplasmic reticulum stress

Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

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