Hyperglycemia‐related FAS gene and hsa‐let‐7b‐5p as markers of poor outcomes for ischaemic stroke

Abstract

Background and purpose Hyperglycemia in acute stroke leads to poor neurological outcomes. The role of microRNA (miRNA) in hyperglycemia‐associated genes can provide new avenues for stroke prognostic applications. We aimed to identify novel genes and their regulated miRNAs that are associated with hyperglycemia‐induced unfavorable stroke outcomes and further validated in the plasma exosome. Moreover, we intended to evaluate the prognostic ability of miRNA–messenger RNA (mRNA) biomarkers in addition to using traditional risk factors. Methods After the integration analysis of small RNA sequencing and mRNA polymerase chain reaction array, two mRNAs and six miRNAs were selected for validation in middle cerebral artery occlusion animal models and ischaemic stroke patients. Receiver operator characteristic analysis was used to determine the performance of mRNA and miRNA expression. Results The increased Fas expression was associated with hyperglycemia after acute stroke onset in animal and human studies. In addition, Fas gene level was significantly higher in patients with an unfavorable outcome when compared with patients with a favorable outcome. The expression of Fas and miRNA hsa‐let‐7b‐5p in addition to traditional risk factors could increase the discrimination and predictive ability for poor prognosis. The higher exosomal Fas was further observed among patients with an unfavorable outcome, suggesting Fas signal transporting through exosome in the circulation system. Conclusions Combined analyses of Fas and has‐let‐7b‐5p expression in addition to traditional risk factors are favorable prognostic biomarkers for predicting poor neurological outcomes at 3 months after stroke onset in ischaemic stroke patients. Additional studies are required to address the precise role of the apoptosis pathway in unfavorable hyperglycemia‐induced stroke outcomes.

Let‑7b‑5p promotes cell apoptosis in Parkinson's disease by targeting HMGA2

“…3B , let-7b-5p and miR-4458 were upregulated in response to MPP + treatment. Additionally, let-7b-5p has been widely reported to bind with HMGA2 ( 23 – 25 ), and can regulate the dysfunctions of neurons ( 11 – 13 ). Therefore, let-7b-5p was chosen for further exploration.…”

“…Let-7b-5p inhibited the mRNA expression of HMGA2, and further decreased its translation. Recently, let-7b-5p was confirmed to serve as a potential biomarker for ischemic stroke, Parkinsonian syndromes and Alzheimer's disease ( 11 – 13 ). Importantly, let-7b-5p can facilitate neuronal degeneration and cause neurotoxicity ( 36 ).…”

“…miRNAs are post-transcriptional modulators via sequence complementarity to the untranslated regions (UTRs) or the coding sequences of target mRNAs ( 10 ). Let-7b-5p was identified as a biomarker of various nervous system diseases including ischemic stroke, Parkinsonian syndromes and Alzheimer's disease ( 11 – 13 ). However, the potential mechanisms of let-7b-5p in PD have not been explored.…”

let-7 microRNAs: Their Role in Cerebral and Cardiovascular Diseases, Inflammation, Cancer, and Their Regulation

“…Furthermore, its expression remains elevated for weeks after multiple forms of ischemic injury, including large and small vessel stroke and cardiac embolism [18]. In fact, the elevated presence of let-7b is considered strongly predictive of poor outcome following ischemic stroke [19,20]. Such differences underscore the complexity of let-7's role in modulating vascular responses following inflammation and underly some of the difficulty in correcting let-7 expression following insult.…”

Recent Advances on Extracellular Vesicles in Central Nervous System Diseases

“…These two biomarkers may be candidate risk factors, pointing to poor neurological outcomes when combined with other traditional risk factors. 108 The therapy of stroke is unmet, since the time window for effective treatment (such as intravenous thrombolysis or mechanical thrombectomy) is narrow and few drugs are available or their efficacy is not widely recognized. Doeppner et al verified the curative effect of MSC-EVs is not inferior to MSCs transplantation in a mice IS model.…”