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Transient focal ischemia induces a sustained downregulation of miR-7 leading to derepression of its target α-synuclein (α-Syn), which promotes neuronal death. We previously showed that treatment with miR-7 mimic prevents α-Syn induction and protects brain after stroke in rodents irrespective of age and sex. To further decipher the role of miR-7, we currently studied infarction and motor function in miR-7 double knockout mice (lack both miR-7a and miR-7b) subjected to focal ischemia. Adult miR-7 -/- mice showed similar motor and cognitive functions to miR-7 +/+ mice. However, when subjected to even a mild focal ischemia, the miR-7 -/- mice showed exacerbated brain damage and worsened motor function compared with the miR-7 +/+ mice. Replenishing miR-7 in miR-7 -/- mice (IV injection of miR-7 mimic) restored miR-7 mediated neuroprotection and motor recovery, potentially by preventing α-Syn protein induction. Thus, we show that miR-7 is an essential miRNA in the brain that prevents α-Syn translation and the ensuing brain damage after stroke., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The mammalian brain expresses several classes of noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). These ncRNAs play vital roles in regulating cellular processes by RNA/protein scaffolding, sponging and epigenetic modifications during the pathophysiological conditions, thereby controlling transcription and translation. Some of these functions are the result of crosstalk between ncRNAs to form a competitive endogenous RNA network. These intricately organized networks comprise lncRNA/miRNA, circRNA/miRNA, or lncRNA/miRNA/circRNA, leading to crosstalk between coding and ncRNAs through miRNAs. The miRNA response elements predominantly mediate the ncRNA crosstalk to buffer the miRNAs and thereby fine-tune and counterbalance the genomic changes and regulate neuronal plasticity, synaptogenesis and neuronal differentiation. The perturbed levels and interactions of the ncRNAs could lead to pathologic events like apoptosis and inflammation. Although the regulatory landscape of the ncRNA crosstalk is still evolving, some well-known examples such as lncRNA Malat1 sponging miR-145, circRNA CDR1as sponging miR-7, and lncRNA Cyrano and the circRNA CDR1as regulating miR-7, has been shown to affect brain function. The ability to manipulate these networks is crucial in determining the functional outcome of central nervous system (CNS) pathologies. The focus of this review is to highlights the interactions and crosstalk of these networks in regulating pathophysiologic CNS function., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In mammals, many classes of noncoding RNAs (ncRNAs) are expressed at a much higher level in the brain than in other organs. Recent studies have identified a new class of ncRNAs called circular RNAs (circRNAs), which are produced by back-splicing and fusion of either exons, introns, or both exon-intron into covalently closed loops. The circRNAs are also highly enriched in the brain and increase continuously from the embryonic to the adult stage. Although the functional significance and mechanism of action of circRNAs are still being actively explored, they are thought to regulate the transcription of their host genes and sequestration of miRNAs and RNA binding proteins. Some circRNAs are also shown to have translation potential to form peptides. The expression and abundance of circRNAs seem to be spatiotemporally maintained in a normal brain. Altered expression of circRNAs is also thought to mediate several disorders, including brain-tumor growth, and acute and chronic neurodegenerative disorders by affecting mechanisms such as angiogenesis, neuronal plasticity, autophagy, apoptosis, and inflammation. This review discusses the involvement of various circRNAs in brain development and CNS diseases. A better understanding of the circRNA function will help to develop novel therapeutic strategies to treat CNS complications., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Purpose: Circular RNAs (circRNAs) are a novel class of noncoding RNAs formed from many protein-coding genes by backsplicing. Although their physiological functions are not yet completely defined, they are thought to control transcription, translation, and microRNA levels. We investigated whether stroke changes the circRNAs expression profile in the mouse brain., Methods: Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and circRNA expression profile was evaluated in the penumbral cortex at 6, 12, and 24 hours of reperfusion using circRNA microarrays and real-time PCR. Bioinformatics analysis was conducted to identify microRNA binding sites, transcription factor binding, and gene ontology of circRNAs altered after ischemia., Results: One thousand three-hundred twenty circRNAs were expressed at detectable levels mostly from exonic (1064) regions of the genes in the cerebral cortex of sham animals. Of those, 283 were altered (>2-fold) at least at one of the reperfusion time points, whereas 16 were altered at all 3 time points of reperfusion after transient middle cerebral artery occlusion compared with sham. Postischemic changes in circRNAs identified by microarray analysis were confirmed by real-time PCR. Bioinformatics showed that these 16 circRNAs contain binding sites for many microRNAs. Promoter analysis showed that the circRNAs altered after stroke might be controlled by a set of transcription factors. The major biological and molecular functions controlled by circRNAs altered after transient middle cerebral artery occlusion are biological regulation, metabolic process, cell communication, and binding to proteins, ions, and nucleic acids., Conclusions: This is a first study that shows that stroke alters the expression of circRNAs with possible functional implication to poststroke pathophysiology., (© 2017 American Heart Association, Inc.)

Chronic exposure to ultraviolet radiation (UVR) is linked to the development of cutaneous squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, is linked to UVR-induced development of SCC. To find clues about the mechanisms by which TNFα may promote UVR-induced development of SCC, we investigated changes in the expression profiling of microRNAs (miRNA), a novel class of short noncoding RNAs, which affects translation and stability of mRNAs. In this experiment, TNFα knockout (TNFα KO) mice and their wild type (WT) littermates were exposed to acute UVR (2.0 kJ/m2) and the expression profiling of epidermal miRNA was determined 4hr post UVR exposure. TNFα deletion in untreated WT mice resulted in differential expression (log fold change>1) of seventeen miRNA. UVR exposure in WT mice induced differential expression of 22 miRNA. However, UVR exposure in TNFα KO mice altered only two miRNAs. Four miRNA, were differentially expressed between WT+UVR and TNFα KO+UVR groups. Differentially expressed selected miRNAs were further validated using real time PCR. Few of the differentially expressed miRNAs (miR-31-5p, miR-196a-5p, miR-127-3p, miR-206-3p, miR-411-5p, miR-709, and miR-322-5p) were also observed in UVR-induced SCC. Finally, bio-informatics analysis using DIANA, MIRANDA, Target Scan, and miRDB algorithms revealed a link with major UVR-induced pathways (MAPK, PI3K-Akt, transcriptional mis-regulation, Wnt, and TGF-beta).

The mechanisms that promote brain dysfunction after acute liver failure (ALF) are not clearly understood. The small noncoding RNAs known as microRNAs (miRNAs) significantly control mRNA translation and thus normal and pathological functions in the mammalian body. To understand their significance in ALF, we currently profiled the expression of miRNAs in the cerebral cortex of mice sacrificed at coma stage following treatment with azoxymethane. Of the 470 miRNAs profiled using microarrays, 37 were significantly altered (20 up-and 17 down-regulated) in their expression in the ALF group compared to sham group. In silico analysis showed that the ALF-responsive miRNAs target on average 231 mRNAs/miRNA (range: 3 to 840 targets). Pathways analysis showed that many miRNAs altered after ALF target multiple mRNAs that are part of various biological and molecular pathways. Glutamatergic synapse, Wnt signaling, MAP-kinase signaling, axon guidance, PI3-kinase-AKT signaling, T-cell receptor signaling and ubiquitin-mediated proteolysis are the top pathways targeted by the ALF-sensitive miRNAs. At least 28 ALF-responsive miRNAs target each of the above pathways. We hypothesize that alterations in miRNAs and their down-stream mRNAs of signaling pathways might play a role in the induction and progression of neurological dysfunction observed during ALF.