RNA in Stroke Pathology, Diagnostics, and Therapeutics

At a glance

Introduction of RNA in Stroke

These past several years have seen thousands of differentially expressed RNAs be determined in the blood of patients suffering from ischemic stroke or in ischemic injured animals, by the advent of technologies like RNA sequencing, deep sequencing, and microarrays. These have been able to separate ischemic stroke from hemorrhagic stroke, and from cardiogenic, large-vessel atherosclerotic, and small-vessel luminal stroke. Such gene expression variations are now used as a precise biomarker for stroke diagnosis and stroke causes. The RNAs being examined so far are messenger RNA (mRNA), microRNA (miRNA), long-non-coding RNA (lncRNA), and circular RNA (circRNA). Continuing to define how and what these RNAs work in biological systems both normal and pathologically could lead to biomarkers and new targets for stroke therapies.

Ace Therapeutics provides reliable services to analyze the function and mechanism of RNA in ischemic stroke and help clients identify novel therapeutic targets for stroke. We utilize high-throughput sequencing, advanced bioinformatics tools, and experimental validation studies to ensure the highest quality analysis for our clients.

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mRNAs in Stroke

Messenger RNAs are transcription products containing the genetic information of the DNA to be translated. The expression of multiple mRNAs is different after stroke in whole blood and peripheral blood mononuclear cells (PBMCs). These changes can provide insight into the underlying mechanisms of stroke and help identify potential biomarkers for diagnosis and prognosis.

ARG1 LY96 MMP9 CCR7 INPP5D
ITA4 NAV1 CREM PELI1 ZAK
CD46 CCL2 IL8 LAG3 HLA-DQA1

CircRNAs in Stroke

CircRNA is a newly discovered class of endogenous non-coding RNA formed through cyclization, driven by intron pairing and regulated by specific factors. One of its key functions is to act as a molecular sponge, significantly affecting microRNA levels in a short time. Research has indicated a strong association between circRNA and stroke.

Differential expression of circRNA in ischemic stroke

Many experiments that have shown circRNA expression in brain and plasma is modulated after cerebral infarction. In an in vitro ischemic stroke model of oxygen-glucose deprivation/re-oxygenation (OGD/R), scientists have found different expressions of circRNA. There are also differences in circRNA expression in patients of different stroke types and inon-ischemic areas of the brain affected by ischemic stroke.

CircHECTD1 CircTLK1 CircDLGAP4 Circ-0072309 Circ_016719
CircCCDC9 CircMH 1 Si-CircHIPK2-NSCs Circ-HECTD1 CircSHOC2
hsa-Circ 0078299 CircR-284 CircFUNDC1 cGLIS3 Circ-camk4

Potential role of circRNAs in the treatment of ischemic stroke

CircRNAs are tightly related to stroke severity and inflammatory response, and are essential for stroke diagnosis, prognosis, and therapy. Across the organisms and tissues, more and more circRNAs have been discovered using new sequencing technology and bioinformatics tools. These findings have expanded the understanding of RNA classification and function. The relationship and specific mechanisms of circRNAs with stroke occurrence, development, and prognosis will be gradually clarified.

MiRNAs in Stroke

MiRNAs regulate gene expression by binding to messenger RNAs and degrading or sequestering them. miRNAs are characterized as single-stranded non-coding (nc) RNAs consisting of 20-24 nucleotides. miRNAs are extensively involved in the pathophysiology of post-stroke pathology, including apoptosis, neuroinflammation, oxidative stress, blood-brain barrier (BBB) disruption, and brain edema. Information about the stroke-miRNA system may contribute to therapeutic and diagnostic approaches to stroke treatment.

Fig.1. The involvement of microRNAs in the pathology and recovery processes of stroke is significant. Fig.1. Role of microRNAs in stroke pathology and recovery. (Kumar, et al., 2022)

Differential expression of miRNAs in ischemic stroke

In stroke, miRNAs have been studied in both plasma (extracellular RNA) and blood cells (intracellular RNA). The following are miRNAs in the blood and cerebrospinal fluid (CSF) of stroke patients.

Upregulation Downregulation
CSF miR-135a-5p, miR-219a-5p, miR-34b-5p, miR-92a-1-5p, miR-138-1-3p, miR-34b-3p, miR-33a-5p, miR-99a-3p, miR-338-5p, miR-519a-3p, miR-490-3p, miR-518e-3p, miR-138-2-3p, hsa-miR-217, hsa-miR-9-5p, hsa-miR-338-3p, hsa-miR-204-5p, hsa-miR-34c-5p miR-208b-3p, miR-493-3p, miR-301b, miR-219a-1-3p, miR-200a-5p, miR-126-5p, hsa-miR-19a-5p
Whole blood miR-1184, -1246, -1261, -1275, -1285, -1290, -181a, -25*, -513a-5p, -550, -602, -665, -891a, -933, -939, -923, hsa-let-7e miR-126, -1259, -142-3p, -15b, -186, -519e, -768-5p, hsa-let-7f
Plasma miR-30a, miR-126, hsa-miR-106b-5P, hsa-miR-4306,  hsa-let-7i-3p, hsa-miR-296-5p hsa-miR-320e, hsa-miR-320d, let-7b, other 78 miRNAs were downregulated

MicroRNA as a therapeutic for ischemic stroke

miRNAs have the potential to treat ischemic stroke. As a therapeutic approach, miRNA levels can be enhanced or inhibited to affect mRNA translation and modulate specific pathways in stroke, including thrombosis, blood-brain barrier disruption, inflammation, and angiogenesis. As most miRNAs target a broad range, we need to figure out what they do to act as intermediaries in stroke. The rapid, simple, and local drug delivery systems will have to be developed in the future.

LncRNAs in Stroke

LncRNAs, a set of molecules that often have 200 or more nucleotides each, are often cell- and tissue-specific RNAs that once occurred between the gene-coding sequences of DNA. As transcriptomics research is shifting from studying protein-coding genes to a search for the whole transcriptome, lncRNAs involved in the etiology and repair of ischemic stroke (oxidative stress, neuroinflammation, autophagy, BBB breakdown, neuronal death, and neurogenesis and angiogenesis) are now more prominent. Research into lncRNAs could be a means of learning about the biological processes occurring after stroke and potential targets for therapy.

Fig.2. Long non-coding RNAs (lncRNAs) play a crucial role in ischemic stroke.Fig.2. The role of lncRNAs in ischemic stroke. (Chen, et al., 2021)

Differential expression of lncRNAs in ischemic stroke

Using technologies such as microarrays or RNA sequencing, hundreds of aberrantly expressed lncRNAs have been identified in patients with ischemic stroke or in animal models of ischemic injury that affect apoptosis, inflammation, cell death, and angiogenesis during ischemic stroke.

ANRIL C2dat1 H19 MALAT1 N1LR
MEG3 FosDT SNHG14 TUG1 lncRNA-ENST00000568297
lncRNA-ENST00000568243 lncRNA- NR_046084 lncRNA-linc-OBP2B-1 lnc-OTTHUMT00000079682 LncRNA MACC1-AS1

LncRNAs as biomarkers for diagnosis and prognosis of ischemic stroke

As with roles in pathogenesis and the significant changes in expression of multiple lncRNAs, these RNA species have been studied as diagnostic and prognostic biomarkers, and as potential anti-ischemic stroke in interventions. Analyzing the correlation between changes in lncRNA expression before, during and after ischemic stroke could help us better understand the molecular mechanisms of ischemia-related brain injury, devise better diagnostic criteria, and propose new treatments for treatment.

References
  1. Kumari, N., et al. (2022). Role of MicroRNAs in Stroke Pathology and Recovery. In Regenerative Therapies in Ischemic Stroke Recovery (pp. 221-238). Singapore: Springer Nature Singapore.
  2. Chen, J., et al. (2021). The role of lncRNAs in ischemic stroke. Neurochemistry International, 147, 105019.
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