MicroRNA Expression Profile in Acute Ischemic Stroke

MicroRNA Expression Profile in Acute Ischemic Stroke | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MicroRNA Expression Profile in Acute Ischemic Stroke Shraddha Mainali, Gaurav Nepal, Amy Webb, Paolo Fadda, Darya Mirebrahimi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3754883/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Introduction: Acute ischemic stroke with large vessel occlusion (LVO) continues to present a considerable challenge to global health, marked by substantial morbidity and mortality rates. Although definitive diagnostic markers exist in the form of neuroimaging, their expense, limited availability, and potential for diagnostic delay can often result in missed opportunities for life-saving interventions. Despite several past attempts, research efforts to date have been fraught with challenges likely due to multiple factors such as inclusion of diverse stroke types, variable onset intervals, differing pathobiologies, and a range of infarct sizes, all contributing to inconsistent circulating biomarker levels. In this context, microRNAs (miRNAs) have emerged as a promising biomarker, demonstrating potential as biomarkers across various diseases, including cancer, cardiovascular conditions, and neurological disorders. These circulating miRNAs embody a wide spectrum of pathophysiological processes, encompassing cell death, inflammation, angiogenesis, neuroprotection, brain plasticity, and blood-brain barrier integrity. This pilot study explores the utility of circulating exosome-enriched extracellular vesicle (EV) miRNAs as potential biomarkers for anterior circulation LVO (acLVO) stroke. Methods: In our longitudinal prospective cohort study, we collected data from acute large vessel occlusion (acLVO) stroke patients at four critical time intervals post-symptom onset: 0–6 hours, 6–12 hours, 12–24 hours, and 5–7 days. For comparative analysis, healthy individuals were included as control subjects. In this study, extracellular vesicles (EVs) were isolated from the plasma of participants, and the miRNAs within these EVs were profiled utilizing the NanoString nCounter system. Complementing this, a scoping review was conducted to examine the roles of specific miRNAs such as miR-140-5p, miR-210-3p, and miR-7-5p in acute ischemic stroke (AIS). This review involved a targeted PubMed search to assess their influence on crucial pathophysiological pathways in AIS, and their potential applications in diagnosis, treatment, and prognosis. The review also included an assessment of additional miRNAs linked to stroke. Results: Within the first 6 hours of symptom onset, three specific miRNAs (miR-7-5p, miR-140-5p, and miR-210-3p) exhibited significant differential expression compared to other time points and healthy controls. These miRNAs have previously been associated with neuroprotection, cellular stress responses, and tissue damage, suggesting their potential as early markers of acute ischemic stroke. Conclusion: This study highlights the potential of circulating miRNAs as blood-based biomarkers for hyperacute acLVO ischemic stroke. However, further validation in a larger, risk-matched cohort is required. Additionally, investigations are needed to assess the prognostic relevance of these miRNAs by linking their expression profiles with radiological and functional outcomes. acute ischemic stroke miRNA biomarker micro-RNA miR large vessel occlusion LVO stroke biomarker Figures Figure 1 Figure 2 Introduction Acute ischemic stroke (AIS) is a medical emergency characterized by the sudden blockage of blood flow to the brain, resulting in high morbidity and mortality rates worldwide(1). Emergent treatment decisions are time-critical, necessitating precise determination of stroke onset time or its practical surrogate, the 'last known well' (LKW) time, to expedite the initiation of appropriate interventions(2). Over 30% of AIS cases involve large vessel occlusion (LVO), particularly in major arteries such as the internal carotid artery (ICA) and the anterior (ACA), middle (MCA), and posterior cerebral arteries, significantly contributing to the burden of stroke due to the large area of ischemic tissue and infarction(3). According to current clinical guidelines, patients presenting with AIS within 4.5 hours from symptom onset are candidates for intravenous (IV) thrombolysis. Initiating IV thrombolysis within this timeframe increases the likelihood of improved functional outcomes across all age groups, with the magnitude of benefit being highly time-dependent (4,5). For patients with anterior circulation large vessel occlusion (acLVO), endovascular thrombectomy (ET) is typically indicated within 6 hours of onset without the need for advanced perfusion imaging. Beyond this window, up to 24 hours, ET may be considered based on a thorough risk/benefit assessment (4). Contemporary stent retriever devices can achieve successful recanalization in over 87% of patients, significantly enhancing outcomes with a number needed to treat (NNT) of 8 for an excellent clinical outcome and an NNT of 3 for a favorable functional outcome, without markedly increasing mortality or hemorrhagic complications(6). It is estimated that increasing the rate of near-complete to complete reperfusion by just 10% could result in an additional 3656 quality-adjusted life years (QALYs) and save $ 21.0 million and $ 36.8 million for the US healthcare system and society, respectively (7). Without timely intervention, the progression of stroke leads to rapid loss of neural tissue. In LVO patients, an estimated 120 million neurons, 830 billion synapses, and 714 km (447 miles) of myelinated fibers are lost every hour(8). As the stroke advances, the risk of intracranial hemorrhage (ICH) begins to outweigh the benefits of recanalization therapy, typically beyond 24 hours (9,10). Therefore, determination of stroke onset time is paramount in delivering safe and effective treatment for stroke patients. Nevertheless, a substantial proportion of AIS patients, approximately one in four, present with unclear stroke onset time or LKW, making them ineligible for potentially life-saving acute stroke intervention(11). The lack of reliable methods to estimate the time of stroke onset and accurately gauge the extent of tissue injury poses a significant challenge in managing AIS effectively, especially in cases where the precise timing of symptom onset remains uncertain. Recent literature has highlighted the significance of molecular intercellular messaging and signaling in determining the state of tissue injury in various diseases, including stroke(12). MicroRNAs (miRNAs) have emerged as a class of non-coding RNA molecules that play a pivotal role in intercellular communication by regulating the expression of target mRNAs(13). In the context of AIS, miRNAs have shown promise as potential biomarkers for diagnostic and prognostic applications(14–17). Studies have reported altered miRNA expression profiles in blood and brain tissues of AIS patients, suggesting their potential as biomarkers for stroke detection, subtyping, and prognosis (18,19). However, to date, no study has comprehensively evaluated the temporal miRNA expression profiles in hyperacute AIS patients with acLVO stroke over 7 days following symptom onset. Understanding the dynamic changes in miRNA expression during the hyperacute phase of acLVO would be highly beneficial for unraveling the early molecular signals underpinning this devastating condition. This knowledge opens avenues for potential blood-based biomarkers that could transform early diagnosis and monitor treatment efficacy. Moreover, it sheds light on the molecular underpinnings of stroke progression and tissue damage, offering opportunities for improved clinical decision-making, prognostication, and the discovery of new therapeutic targets (20). This pilot study provides critical insights into the dynamic shifts in miRNA expression patterns related to hyperacute acLVO stroke, observed longitudinally over a week. Methods Study Design This longitudinal, prospective cohort study, conducted at the Joint Commission-certified Comprehensive Stroke Center of Ohio State University—a tertiary referral medical center—explores the viability of circulating EV-encapsulated miRNAs as blood-based biomarkers for acLVO ischemic stroke. The study protocol received approval from the Ohio State University Institutional Review Board, and informed consent was secured from all participants or their legally authorized representatives. Our scoping review was designed to elucidate the roles of certain miRNAs, specifically miR-140-5p, miR-210-3p, and miR-7-5p, within the acute ischemic stroke (AIS) framework. To achieve this, we conducted a comprehensive PubMed search using terms like 'acute ischemic stroke', 'stroke', 'miR', 'miRNA', 'micro RNA', and the specific miRNAs of interest (miR-140-5p, miR-210-3p, and miR-7-5p). We employed Boolean operators "AND" and "OR" to refine the search. Our primary objective was to explore the current research on how these miRNAs influence key pathways in ischemic stroke pathophysiology, including apoptosis, inflammation, oxidative stress, and neuronal damage, and their potential roles in diagnosis, treatment, and prognosis. The results section of this manuscript presents an in-depth review of the three principal miRNAs, based on our lab research. Furthermore, we provide a summary of important findings from other stroke related miRNA in Supplementary File 1. Sampling and Enrollment: The study enrolled all patients who arrived at the adult Emergency Department within 6 hours of witnessed stroke symptom onset. Inclusion required a confirmed diagnosis of acLVO by CT Angiogram. Healthy individuals formed the control group. Exclusion criteria included individuals with significant atherothrombotic disorders—such as pronounced coronary or peripheral vascular disease, deep vein thrombosis, or pulmonary embolism—patients with concurrent neurological conditions, a stroke in the preceding three months, posterior circulation LVO, uncertain time since last seen well, and pregnancy. Patients with recent thrombosis or severe atherosclerosis were excluded to avoid interference from clot associated miRNAs, like platelet-derived miRNAs. Individuals with recent brain injuries were excluded to prevent confounding results from miRNA profiles linked to these recent injuries. Pregnant women were excluded due to potential variations in miRNA profiles in expectant mothers with growing fetus. Sample collection and processing: Blood samples were collected from acLVO patients at four time points: 0–6 hours, 6–12 hours, 12–24 hours, and 5–7 days after symptom onset. Controls were healthy volunteers without any acute disease process or chronic stroke risk factors and had blood samples collected at a single time point. After initial sample collection and centrifugation, plasma was stored at -80°C until further processing. Subsequently, extracellular vesicles (EV) enriched in exosomes were isolated from the cell-free plasma using the Total Exosome Isolation Kit (Invitrogen) as previously described(21). The isolated EVs were characterized for quantity and size using the NanoSight NS300 (22). Total RNA were isolated using the Maxwell RSC miRNA tissue kit (Promega)(23). MiRNA profiling was performed using the multiplexed NanoString nCounter miRNA system as previously described (22). Nanostring counts exported from nSolver were filtered and normalized with in-house scripts where miRNA and samples were filtered based on negative background probes (NegCutoffS1 = meanNegS1 + 1.5*stdevNegS1) and normalized based on the geometric mean of expression and log2 transformed. Statistical Analysis: Statistics was performed in R. Heatmaps with hierarchical clustering, and principal component analysis (PCA) was performed with pheatmap and prcomp to visually group samples into clusters to give us an idea of the differences and similarities between samples and sample categories. Modest changes (< 2 fold) in miRNA expression are known to be associated with changes in target gene expression(24–26). Change of miRNAs across time points in LVO patients was assessed using repeated measures ANOVA, and we tested time point differences between any two-time points with a mixed model with a sample included as a random effect. The significance for any statistical test was defined as FDR < 0.05. Results Analysis was performed on a total of 24 samples from six patients with confirmed acLVO stroke, with 12 samples from patients presenting with right ICA/MCA involvement and the remaining 12 samples with left ICA/MCA involvement. Individual patient characteristics are presented in Table 1. All patients received IV thrombolytic therapy (tPA) within the appropriate therapeutic window. Furthermore, some patients underwent endovascular thrombectomy as an additional intervention to restore blood flow, resulting in the collection of plasma samples during (1 patient) and after the thrombectomy procedure (2 patients). Control included 5 healthy volunteers (3 males, 2 females) between the ages of 18-60 years. The ANOVA analysis of the raw data revealed statistically significant differential expression of 11 microRNAs (miR 210-3p, miR 7-5p, miR 122-5p, miR 140-5p, miR 378i, miR-320e, miR 448, miR 1258, miR 26a-5p, miR 28-5p, miR 510-3p ) across various time points and healthy volunteer comparisons. Recognizing the clinical importance of the hyperacute period within 6 hours from stroke onset, our study concentrated on identifying specific microRNAs that exhibit unique expression profiles during this initial phase, in contrast to subsequent time points and healthy volunteers. Notably, three microRNAs (figure 1) exhibited significant differential expressions within the first 6 hours compared to both the healthy volunteers and other time points. Particularly intriguing was the observation that microRNA 140-5p displayed noticeable elevation within 6 hours, gradually normalizing between 12-24 hours and ultimately approaching the volunteer level after 7 days (figure 2). Similarly, microRNA 7-5p exhibited clear overexpression within the first 6 hours, followed by a gradual downtrend towards the volunteer level by 24 hours, maintaining stable expression within a similar range at 7 days. In contrast, microRNA 210-3p demonstrated under-expression at 6 hours, gradually increasing towards the volunteer level over the next 12-24 hours and maintaining that level through 7 days. Review of Current Knowledge on miR-140-5p, miR-210-3p, and miR-7-5p in Acute Ischemic Stroke A concise review of the existing literature regarding the role of these three miRNAs in AIS is presented in Table 2. In animal models simulating ischemic stroke, a significant decrease in miR-140-5p expression was observed within the ischemic core (27–29). Conversely, when examining human serum samples, all studies consistently reported an elevation in serum miR-140-5p levels after cerebral ischemia (30–32). This alignment with our findings suggests the potential utility of miR-140-5p as a diagnostic marker, a notion supported by these consistent outcomes. The observed elevation of miR-140-5p in circulation and its concurrent reduction within the ischemic brain tissue during the initial 6-hour window may reflect a response to ischemic insult. Ischemia/reperfusion injury might trigger the translocation of miR-140-5p from the affected neurons to the circulatory system. This process could be related to the mobilization of inflammatory mediators and growth factors, crucial for the brain's intrinsic response to ischemic damage. Moreover, studies have also explored the therapeutic potential of miR-140-5p. Wang et al. demonstrated that administration of encapsulated miR-140-5p could alleviate neuronal damage in subarachnoid hemorrhage(27). Liang et al.'s work showcased that overexpressing miR-140-5p using adeno-associated viruses reduced inflammatory and vascular growth factors in the ischemic mouse hippocampus, inhibiting neurogenesis and capillary density(30). Similarly, Sun et al. revealed that miR-140-5p hinders angiogenesis after cerebral ischemia, potentially contributing to the mitigation of hemorrhagic transformation and edema(28). Additionally, Song et al. provided evidence that miR-140-5p overexpression inhibited neuron apoptosis and decelerated stroke progression(29). While these animal model and in vitro studies show promise for the therapeutic role of miR-140-5p, it is important to note that the limited number of studies and inconsistencies in miR-140-5p delivery methods preclude any definitive conclusions. As illustrated in Table 2, our literature search found two human-based studies regarding the role of miR-7-5P as a biomarker in stroke. In contrast to our study, Ni et al. observed a reduction in miR-7-5p levels following stroke. However, in contrast to our study, they did not detail the precise timing of sample collection, referring instead to a broader 48-hour window(33). Meanwhile, Chen et al. demonstrated that in humans with intracerebral hemorrhage (ICH), the serum levels of miR-7-5p were significantly higher on day one compared to day 7, demonstrating time dependent evolution in ICH (34). Most studies in animal models of cerebral ischemia and intracerebral hemorrhage have indicated a decrease in miR-7-5P levels in brain tissue samples (33–36). Similarly, in a model of carotid artery injury, miR-7-5p was found to be downregulated when examining carotid endarterectomy samples(37). Similar to 140-5p, the decreases in tissue miR-7-5p levels might be attributed to the release of miR-7-5P from injured tissue into the serum. However, Zhao et al. observed a contrasting trend, with miR-7-5P significantly upregulated in ischemic brain tissue in a time-dependent manner (38). Dharap et al. noted no initial change in miR-7-5P levels, followed by a decline after 12 hours in a rat model of focal ischemia (39). Given these conflicting results in varied models with varied tissue types and sampling time points, the utility of circulating miR-7-5P as a diagnostic biomarker remains uncertain and needs further evaluation. Several investigations have focused on the therapeutic implications of miR-7-5p. Chen et al. found that miR-7-5p levels were raised by Butylphthalide via intracerebroventricular administration, which contributed to the alleviation of brain edema(34). Xu et al. reported that curcumin regulates miR-7-5p, conferring neuroprotection and ameliorating cognitive deficits in ischemic reperfusion injury. (35). Kim et al. observed that preischemic administration of miR-7 mimics enhanced motor function and diminished lesion volume in young male rats, while post ischemic treatment was effective in reducing brain damage across all rats, improving cognitive outcomes and expediting motor recovery (36).Additionally, Ni et al. demonstrated that elevating let-7c-5p levels via intra-cerebrovascular injection reduced infarct size and lessened neurological impairments (33). Conversely, Zhao et al., studying a rat model of ischemia reperfusion, identified that an increase in miR-7-5p was associated with heightened inflammation, apoptosis, and the exacerbation of ischemic damage(38). Overall, the current body of research on miR 7-5p also reveals variations in miRNA expression profile possibly linked to varied type of biological specimen, disease severity, sampling timepoint, and miRNA profiling techniques. MiR-210 has also received considerable attention in stroke research, as detailed in Table 2, with investigations encompassing in vitro analyses, animal models, and clinical studies to evaluate its diagnostic, prognostic, and therapeutic potential. Across these studies, a recurrent finding is the elevation of miR-210 expression within brain tissue following cerebral ischemia, including ischemic stroke and hypoxic-ischemic encephalopathy (40–46). In contrast, circulating levels of miR-210 in ischemic stroke patients appear to be suppressed when compared to those of healthy controls (41,42,47,48). This same trend is observed in patients with symptomatic carotid stenosis, where miR-210 is downregulated in carotid fibrous cap tissue (48). This finding underscores the potential of miR-210 as a reliable biomarker for cerebral ischemia. Supporting its diagnostic role, Rahmati et al. established a threshold for miR-210 with a fold change of 0.26, correlating with a modest diagnostic performance characterized by an area under the receiver operating characteristic curve (AUC) of 0.61 and exhibiting 59.62% sensitivity and 65.38% specificity (49). Zeng et al. identified a higher sensitivity at a diagnostic cutoff point of 0.505 for miR-210, achieving 88.3% sensitivity(42). Complementing these studies, Tian et al. confirmed the high diagnostic accuracy of miR-210 for acute cerebral infarction, presenting an AUC of 0.836 (47). These findings collectively point towards the potential of miR-210 as an informative biomarker for the identification of acute ischemic events. The role of miR-210 in prognostication for ischemic stroke patients has been substantiated by multiple studies. For instance, Rahmati et al. found a positive correlation between elevated miR-210 levels at three months post-stroke and enhanced survival rates.(49). Zeng et al. reported that patients with favorable recovery showed higher miR-210 expression than those with adverse outcomes (42). On the contrary, Tian et al. reported that patients with lower miR-210 expression levels had increased one-year mortality, with miR-210 levels emerging as a robust predictor of mortality (AUC = 0.786) (47). While the current body of research presents variability, likely attributable to insufficient control of confounding variables across different studies, the aggregated evidence nonetheless points to miR-210 as a potentially valuable marker for predicting neurological outcomes in acute ischemic stroke scenarios. In terms of therapeutic implications, miR-210 has shown potential in both in vitro and animal models as summarized in Table 2. Research by Eken et al. demonstrated the prophylactic effect of miR-210 mimics on carotid plaque stability, suggesting a preventative role against ischemic stroke (48). Pfeiffer et al.'s subgroup analysis revealed that pretreatment with a miR-210-3p mimic substantially mitigated hemispheric swelling and infarct size(40). Similarly, Huang et al. validated the protective effects of miR-210, noting that both pre- and post-treatment with a miR-210 locked nucleic acid (LNA) conjugate led to reduced cerebral infarct and edema, alongside behavioral improvements in mice models of middle cerebral artery occlusion (MCAO)(46). Additionally, Zeng et al. illustrated the efficacy of miR-210 gene transfer in enhancing recovery in transient MCAO models (41). Additionally, research by Li et al. and Zhang et al. has highlighted miR-210's role in attenuating inflammation and reducing ischemic damage in both in vitro settings and cerebral ischemia models(44,45). Ma et al. demonstrated the neuroprotective effects of exogenous miR-210 mimics in a model of neonatal hypoxic-ischemic brain injury.(43), while Lu et al. documented enhanced function of endothelial progenitor cells under hypoxic conditions when treated with miR-210(50). Yerrapragada et al. further corroborated the neuroprotective role of miR-210 in a hypoxia and reoxygenation model, indicating its therapeutic potential in mitigating hypoxic-ischemic neuronal damage(51). Extending beyond cerebral models, Ujigo et al. found that intracranial administration of miR-210 contributed to functional recovery in cases of traumatic spinal cord injury(52). These studies, underscore the promising therapeutic avenues miR-210 may offer for ischemic stroke intervention. Discussion Our study revealed that, upon comparing each time point against the remaining three time points in acLVO patients and a single time point in healthy volunteers, a total of 11 microRNAs exhibited significantly altered expression across these comparative analyses. Notably, within the first 6 hours of acLVO stroke onset, three microRNAs (140-5p, 7-5p, and 210-3p) exhibited significant differential expression compared to healthy volunteers and other time points. MiRNA 140-5p showed relative increase within the first 6 hours, gradually normalizing between 12–24 hours and reaching volunteer levels within seven days. Similarly, miRNA 7-5p displayed significant overexpression within the first 6 hours, followed by a gradual decline towards volunteer levels by 24 hours, maintaining stable expression within a similar range around seven days. In contrast, miRNA 210-3p demonstrated relative under-expression at 6 hours, gradually increasing towards the volunteer level over the next 12–24 hours and maintaining that level through 7 days. Our study and existing literature have highlighted the significant roles played by microRNAs (140-5p, 7-5p, and 210-3p) in stroke pathophysiology and therapy. Of note, these microRNAs employ diverse mechanisms to exert their effects. We have provided an overview of the various pathways they operate within stroke and related disorders in Table 2 . Many of these pathways are closely linked to inflammation, oxidative stress, cell death, and angiogenesis. Utilizing molecular drug discovery to target these pathways or the microRNAs themselves holds promise as an effective strategy for stroke prevention and treatment. In our study, we have also identified other microRNAs, such as miR 210-3p, miR 122-5p, miR 378i, miR-320e, miR 448, miR 1258, miR 26a-5p, miR 28-5p, and miR 510-3p in association with ischemic stroke. The functions and potential pathways of these miRNAs and other relevant miRNAs are summarized in supplementary file 1. These microRNAs are subjects of ongoing research, aiming to elucidate their roles and mechanisms further. Our study has several strengths. In this pilot project, we endeavored to meticulously assemble a homogenous cohort of patients, each presenting with anterior circulation acLVO, to maintain uniformity in the stroke phenotype for our analyses. Recognizing the potential for variability introduced by timing, we strictly limited the collection of blood samples to within a 6-hour window following the onset of symptoms, which we hoped would reduce confounding factors related to timing ambiguities. We adopted a longitudinal design for the study, which permitted us to cautiously interpret the evolution of miRNA profiles over time, treating each time point as an intrinsic control against the baseline hyperacute samples. This careful approach, while preliminary, was expected to offer valuable insights into the dynamic changes of miRNAs in this context. While the study presents intriguing outcomes, it is important to recognize its limitations. A key limitation is the modest cohort size, comprising a total of 29 samples, which may limit the generalizability of the findings. The LVO group included a total of 4 female samples only, which hindered the assessment of potential sex-related differences in miRNA profiles. Although stroke typically occurs in older individuals, the majority of our study's participants were middle-aged, with one patient being a minor. This distribution may not accurately reflect the age-related risk of stroke in the general population. Additionally, the use of healthy controls who were not matched for stroke risk factors could introduce confounders into the miRNA expression profiles. As Toor et al. indicated, miR-140-5p levels were found to be elevated in stroke patients with diabetes relative to non-diabetic patients (32), suggesting that miRNA expression may differ with underlying risk factors. Moreover, our research was confined to the study of EV encapsulated miRNA and the potential role of non-vesicular, free circulating miRNAs was not investigated, which constitutes an area for further research. Our literature review disclosed considerable heterogeneity within the corpus of research investigating the role of miRNAs in ischemic stroke. This variation is likely due to a lack of standardization across several critical aspects of study design and methodology. These aspects include the criteria for control group selection, the source of the miRNAs (serum, plasma, CSF or brain tissue), the protocols used for miRNA isolation, the timing of sample collection (ranging from hyperacute to delayed phases), the selection of reference standards (internal and external controls), the choice of detection and quantification techniques (such as Nanostring, Next-Generation Sequencing, or RT-qPCR), and the breadth of the infarct sizes. Additionally, the biological origin of the miRNAs—whether cellular, vesicular, or cell-free—also contributes to the variability of the results, further complicating the interpretation and comparison of findings across studies. To enhance the reliability of biomarker studies, future investigations should aim for rigorously matched control groups that align with stroke patients' symptoms and risk factors, utilizing consistent and validated methodologies within a well-defined stroke cohort. Adopting a multi-center design would improve the robustness and applicability of miRNA biomarkers for diagnostic purposes. Additionally, it is crucial to assess the prognostic value of these miRNAs by examining their associations with both radiological findings and clinical outcomes. Implementing miRNA profiles in the elucidation of disease pathways could inform treatment strategies and support timely consultations with patients and their families. Moreover, in-depth mechanistic research is needed to decipher the roles of specific miRNAs in the pathogenesis of acute large vessel occlusion (acLVO) strokes, potentially uncovering novel therapeutic avenues. These efforts will deepen our understanding of miRNA-mediated regulation in stroke and could lead to significant advances in patient care Conclusion In conclusion, our investigation has shed light on the intricate role of miRNAs in stroke pathophysiology, highlighting their potential as biomarkers for acute cerebrovascular events. By identifying 11 microRNAs, particularly miR-140-5p, miR-7-5p, and miR-210-3p, with significant differential expression within 6 hours of stroke onset, our study suggests these miRNAs could potentially serve as valuable indicators for diagnosis and possible targets for therapy, given their involvement in critical pathways like inflammation, oxidative stress, and angiogenesis. Despite promising indications for early detection and stroke management, the limitations of our study call for extensive validation through larger, risk-matched cohorts in multi-center trials. Such rigorous research is essential for confirming miRNAs' utility as reliable clinical biomarkers and for potentially uncovering new therapeutic strategies that could significantly improve patient outcomes. It is anticipated that the present findings will encourage further detailed exploration of miRNA functions post-ischemic stroke, fostering advancements in clinical approaches and patient care. Declarations Funding Declaration : This project was supported by the Ohio State University Neuroscience Research Institute (NRI) award and the Center for Clinical and Translational Science at Ohio State University, UL1TR002733 Conflict of Interest: 1) Shraddha Mainali: Has received funding support from Ohio State University Neuroscience Research Institute for this pilot study. Has received funding from Center for Clinical and Translational Science at The Ohio State University sponsored by the National Center for Advancing Translational Sciences (UL1TR002733). Has received research consultation fees from Marinus Pharmaceuticals. 2) Nicholas E. Johnson: Has received grant funding from NINDS (R01NS104010, U01NS124974), NCATS (R21TR003184), CDC (U01DD001242) and the FDA (2R01FD006071). He receives royalties from the CCMDHI and the CMTHI. He receives research funds from Avidity, Takeda, Sanofi Genzyme, Dyne, Novartis, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio, and Sarepta. He has provided consultation for Arthex, Novartis, AMO Pharma, Takeda, Design, Dyne, Avidity, Rgenta, and Vertex Pharmaceuticals. Remaining authors: GN, AW, PF, DM, MH, PS, BW and DW report no relevant disclosures. Author Contribution SM: designed, conducted and led the study, drafted and finalized the manuscript; GN: substantial contribution to the scoping review of the manuscript and provided initial draft of the review and tables; AW: substantial contribution in bioinformatics analysis for the pilot study, provided critical input in the manuscript; PF: substantial contribution to sample analysis for the pilot study, provided critical inputs and edits to the manuscript; DM: substantial contribution in review of literature for the scoping review, provided critical input to the manuscript, MH: substantial contribution in collection of samples and conduct of the study, review and critical input to the manuscript; PN-S: Substantial contribution in design of the manuscript, critical input and edits to the manuscript; BW: substantial contribution in the design of the manuscript, critical input and edits to the manuscript; DW: substantial contribution in the design of the manuscript, critical input and edits to the manuscript; NJ: substantial contribution in the design of the manuscript, critical input, edits and finalization of the manuscript. 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Tables Table 1: Demographics and clinical characteristics of acLVO patients Variables/ Patient ID PT1 PT2 PT3 PT4 PT5 PT6 Age 85 57 45 56 43 14 Gender Male Female Male Male Male Male Race White White White White White White IPA (Yes/No) Yes Yes Yes Yes Yes Yes Biosampling time (pre, intra & post ET) pre (TICI3) pre (NT) post (TICI2b) pre (TICI2b) pre (NT) intra (TICI2b) Etiology Cryptogenic Cryptogenic Cryptogenic Cardioembolic LAA LAA HTN Yes Yes No Yes No No HLD Yes Yes No Yes No No DM No No No No No No Atrial fib/Flutter No No No Yes No No IV Drug use No No No No No No Smoking No Yes No No No No Hx of CAD No No No No No No Anticoagulants No No Yes No No No Antiplatelets Yes Yes No Yes Yes Yes Statin Use Yes Yes No Yes Yes Yes Site of Occlusion R-ICA R-MCA L-MCA R-MCA L-ICA L-MCA NIHSS at presentation 17 3 17 10 4 1 NIHSS at discharge 8 10 10 10 8 3 MRS at discharge 4 3 4 2 1 2 HT Yes No No No No No Hypertension (HTN), Hyperlipidemia (HLD), Diabetes Mellitus (DM), Atrial fibrillation/Atrial flutter (Atrial fib/flutter), NIH stroke scale (NIHSS), Modified Rankin Scale (MRS), Hemorrhagic Transformation (HT); Patient (PT) Table 2: Essential methodological aspects and insights from stroke literature investigating the function of three principal miRNAs identified in our study miR Author Country Study subjects Disease /Model studied Sample tissue Sample Collection time Major findings Function/Pathway Evaluated for miR 140-5P Wang 2022 China Rats/invitro Endovascular perforation models of SAH Brain tissue 93 3 rd day Exoencapsulated miR-140-5p can relieve neuronal injury following SAH Modulation of the IGFBP5-mediated PI3K/AKT signaling pathway Therapy Liang 2019 China Human Post-stroke depression Plasma 252 within 24 h MiR‐140-5p (P = 0.0016, log2 (fold change) = 3.5) had significantly higher expression in the late-onset PSD group than in controls, The miR-140- 5p expression on admission was significantly positively correlated with Hamilton Depression Rating Scale assessed at 3 months after stroke. The predictive value of miR-140-5p for late-onset PSD is 83.3% sensitivity and 72.6% specificity (AUC = 0.8127). Regulate IL1rap, IL1rapl1, VEGF, and MEGF10 Prognostication Sørensen 2014 Denmark Human Acute Ischemic Stroke CSF and blood 10 cases and control each NA Blood: miR-140-5p (P=0.02) was up-regulated in stroke patients compared to controls. CSF: Not detected NA Diagnosis Song 2021 China Rats/Invitro Acute Ischemic Stroke Brain tissue 60 case And 15 control NA miR-140-5p exhibited decreased expression, while TLR4 displayed increased expression. MiR-140-5p directly targeted and reduced TLR4 expression. MiR-140-5p over-expression inhibited neuron apoptosis and slowed stroke progression. TLR4 over-expression promoted neuron apoptosis and stroke progression. MiR-140-5p reduced NF-κB protein levels, while TLR4 overexpression increased them. Regulation of the TLR4/NF-κB axis Therapeutic Toor 2022 Qatar Humans/invitro Acute Ischemic Stroke Serum 190 Within 24 hours miR-140-5p was observed to be up-regulated in stroke patients with diabetes Regulate genes involved in inflammation and oxidative stress. Diagnostic and therapeutic Sun 2016 China Rats/invitro Acute Ischemic Stroke Brain tissue 24 cases and 8 control 12, 24, 48 hours The expression of miR-140-5p exhibited a significant reduction at 12, 24, and 48 hours post-MCAO compared to the control. Conversely, the protein expression levels of VEGFA showed a significant increase at 12, 24, and 48 hours following MCAO compared to the control. Suppresses angiogenesis by targeting VEGFA. Diagnostic and therapeutic miR 210-3P Pfeiffer 2021 Ireland Rats/invitro Acute ischemic stroke Brain tissue 75 24 h after ischemia In response to transient focal ischemia with reperfusion, miR-210-3p is up-regulated in the cortex. When a miR-210-3p mimic is administered in vivo, it changes the expression of key signaling molecules like PTEN, PDK1, p70S6K, and RPS6. This manipulation also results in a decrease in p70S6K activity following an ischemic stroke. miR-210-3p influences p70S6K activity in response to NMDA-mediated excitotoxicity, and this effect can be reversed by inhibiting miR-210-3p. Pre-treatment with 5 pmol miR-210-3p mimic resulted in a significant decrease in hemispheric swelling and infarct volume. AMPK regulates miR-210-3p to control p70S6K activity Prognosis Rahmati 2021 Iran Humans Acute ischemic stroke Serum 52 cases Admission, 24 and 48 hours after admission, upon discharge, and 3 months later Serum miR-210 levels in cases were initially lower upon admission compared to normal controls but increased progressively over three months. A diagnostic cutoff point was set at a fold change of 0.26 with an AUC of 0.61, 59.62% sensitivity, and 65.38% specificity. Higher miR-210 expression at the three-month follow-up was linked to improved survival in IS patients. NA Diagnosis and prognosis Eken 2016 Denmark Humans and rat model/invitro Carotid atherosclerosis CEA tissue and blood samples Symptomatic humans: 7 in each cohort. Asymptomatic humans: 5 in the discovery and 7 in the validation cohort. Rats: 48 At the time of surgery MiR-210 is downregulated in symptomatic carotid stenosis patients' plasma and fibrous cap tissue. It is repressed in experimental artery remodeling and influences plaque stability in atherosclerosis. MiR-210 mimics prevent plaque rupture in vivo and protect smooth muscle cell apoptosis by targeting APC in vitro. Inhibits APC Ujigo 2014 Japan Rats/invitro Spinal cord injury Spinal cord tissue 30 2, 3, 5, 7, and 14 days after SCI Hsa-miR-210 up-regulated miR-210 expression, leading to enhanced neovascularization, astrogliosis, axon growth, and myelination in the injured spinal cord. In the miR-210 group, there were significantly fewer apoptotic cells at the lesion site, and caspase-3 and cleaved caspase-3 levels were markedly reduced compared to the control group. miR-210 administration promoted functional recovery after spinal cord injury Inhibits Ptpib and Efna3 Therapy Zeng 2016 China Human/ Rats/invitro AIS Serum for humans Brain tissue for rats Humans: 5 cases, 5 controls. Rats: 124 total, divided into sham, transient MCAO, tMCAO+LV-GFP, and tMCAO+LV-miR-210 groups. Humans: Within 48 hours and the 10th day of AIS Rats: 7, 14, and 28 days after tMCAO MiR-210 downregulated in stroke patients vs. healthy controls. MiR-210 gene transfer improved outcomes in tMCAO mice. BDNF regulation Therapeutic Zeng 2011 China Humans/Rats AIS Human: Serum Rats: Brain tissue and serum Stroke patients (n=112) and healthy controls (n= 60) 9 rats Human blood: 3, 7, and 14 days post-stroke. Rat blood and brain tissue: 1, 7, and 14 days post-MCAO. In stroke patients, blood miRNA-210 levels were significantly lower, particularly at 7 and 14 days post-stroke onset, compared to healthy controls. MiR-210 rose one day after MCAO in rats, declining gradually at 7 and 14 days, and a significant positive correlation existed between blood and brain miR-210 levels. A diagnostic cutoff point of 0.505 for miR-210 yielded an 88.3% sensitivity. Stroke patients with favorable outcomes exhibited higher miR-210 levels than those with poor outcomes. NA Diagnosis and prognosis Ma 2021 China Rats/invitro Neonatal hypoxic-ischemic brain injury Brain tissue NA 48 hours after HI In neonatal mouse pups, hypoxic-ischemic (HI) conditions increased miR-210, which suppressed TET2 expression and led to enhanced p65 acetylation and binding at the IL-1β promoter in the brain. TET2's interacted with HDAC3 regulated NF-κB p65's DNA binding at the IL-1β gene promoter. TET2 knockdown elevated p65 acetylation, increased pro-inflammatory cytokine and chemokine expression after HI, and worsened neonatal HI brain injury. It also counteracted the anti-inflammatory effect of miR-210 inhibition in neonatal HI brain injury and BV2 microglia cell line experiments in vitro. TET2 downregulation Therapeutic Li 2023 USA Rats/invitro AIS/MCAO model Brain tissue 204 NA miR210 injection reduced TET2 in the brain, but miR210 inhibition or KO preserved TET2, irrespective of brain injury. TET2 reduction reversed miR210 inhibition's protective effects on stroke-induced brain damage and neurobehavioral deficits. Lowering TET2 weakened miR210's anti-inflammatory impact on microglial activation and IL-6 release after stroke. Boosting TET2 in microglia counteracted miR210-induced cytokine increase. TET2 downregulation Therapeutic Yerrapragada 2022 USA Invitro Hypoxia and reoxygenation (H/R) models were applied to neurons to mimic AIS. Invitro NA NA Endothelial progenitor cell (EPC)-borne miR-210 can be time-dependently transferred to neurons, exerting a protective impact against H/R-induced neuron apoptosis, oxidative stress, and reduced viability. BDNF/TrkB and Nox2/Nox4 pathways regulation Therapeutic Zhang 2019 China Rats/invitro AIS/MCAO model Brain tissue NA 24 h after MCAO RGD-exo:miR-210 targets the ischemic brain lesion upon intravenous delivery, elevating miR-210 levels at the site. Administered every other day for 14 days, it notably boosts the expression of integrin β3, vascular endothelial growth factor (VEGF), and CD34, leading to an improved animal survival rate. RGD‑exo:miR‑210 promotes VEGF expression and angiogenesis Therapeutic Huang 2018 USA Rats/invitro AIS/MCAO model Brain tissue 96 - miR-210-LNA treatment (n = 44) - negative control (n = 41) -other experiments (n=11) 24 h after MCAO MiR-210-LNA pre-treatment reduced brain infarct volume edema and improved post-stroke behavior in MCAO mice. It also suppressed pro-inflammatory cytokines, chemokines, immune cell infiltration, and microglial activation induced by MCAO. Posttreatment with MiR-210-LNA was also protective in MCAO mice. MiR-210-LNA mitigates inflammatory response after cerebral ischemia Therapeutic Tian 2021 China Humans AIS Serum 76 cases 64 controls At admission miR-210 levels were significantly lower in the mortality group compared to the survival group. MiR-210 had high diagnostic accuracy for acute cerebral infarction (AUC = 0.836) and was associated with lower 1-year survival in the low-expression group. It also showed good predictive capability for mortality (AUC = 0.786). NA Diagnosis and prognosis Lu 2019 China Invitro Endothelial progenitor cells (EPCs) under hypoxic condition Invitro NA NA In OGD-treated EPCs, miR-210-3p expression was higher than in normal EPCs. Increased miR-210-3p enhanced proliferation, migration, and tube formation under OGD conditions, while decreased miR-210-3p hindered these capabilities in OGD-treated EPCs. Elevated miR-210-3p suppressed Repulsive guidance molecule A (RGMA) protein expression in OGD-treated EPCs, while reduced miR-210-3p led to increased RGMA expression. Inhibits RGMA, a negative regulator of angiogenesis. Therapeutic miR 7-5P Chen 2020 China Humans and rats/invitro Intracerebral hemorrhage (ICH) Serum in humans Brain tissue in rats invitro 60 rats 1, 7, and 14 days after ICH Humans: The miR-7-5p level decreased significantly on day 7 after ICH compared to day 1 but showed partial recovery by day 14. MiR-7-5p expression significantly decreased on days 1, 3, and 7 after ICH, with the most pronounced decrease on day 3. Partial recovery occurred after butylphthalide intervention. The brain water content decreased in the butylphthalide group. PI3K/AKT pathway regulation Therapy Xu 2019 China Rats Ischemic stroke Brain tissue/Invitro NA Curcumin prevented the decrease of miR-7-5p expression and the increase of RelA p65 expression caused by cerebral ischemia-reperfusion injury (CIR) in vivo and oxygen-glucose deprivation/reoxygenation (ODG/R) in vitro. MiR-7-5p was found to target RelA p65. MiR-7-5p antagonists reversed curcumin's impact on RelA p65 expression in ischemic brain tissue and cells. Curcumin regulates miR-7/RELA p65 axis Therapeutic Kim 2018 USA Rats Ischemic stroke Brain tissue/invitro NA Day 7 and 31 Ischemia reperfusion-induced 2.1- to 3-fold decrease in miR-7 expression in the ipsilateral cortex of both young and aged rats of both sexes compared with the sham-operated controls. Preischemic intracerebral administration of miR-7 mimics improved motor function recovery and decreased lesion volume in young male rats. Postischemic intracerebral administration of miR-7 mimics decreased ischemic brain damage irrespective of sex and age in rats. Postischemic intravenous administration of miR-7 mimic decreased the stroke-induced cognitive deficit and accelerated motor recovery but failed to do so in alpha syn knockout mice α-Synuclein regulation Prevention, prognostication, and therapy Dharap 2009 USA Rats Ischemic stroke Brain tissue 30 cases and 6 controls 3, 6, 12, 24, and 72 hr Transient focal ischemia in a rat model induced no change in miR 7-5P in the first 12 hours, followed by a sustained decrease. NA Pathobiology Zhao 2020 China Rats Ischemic stroke Brain tissue/invitro 36 24 hours after reperfusion MiR-7-5p Exhibited High Expression in a Rat Model With Cerebral I/R Injury and OGD/RInduced SH-SY5Y Cells increasing progressively with time. Silence of miR-7-5p Impaired ischemia-reperfusion injury Caused Cerebral Injury. Attenuation of miR-7-5p Hindered I/R Caused Cerebral Inflammation. Depletion of miR-7-5p Impeded Neuronal Cell Apoptosis miR-7-5p Regulated Neuronal Cell Apoptosis by Targeting sirt1 MiR-7-5p Knockdown Blocked the NF-kB Pathway sirt1 regulation Prognosis and therapy Ni 2015 China Human Ischemic stroke Plasma and brain tissue/invitro 8 human cases and controls Brain tissue: 24 h and 96 h after occlusion Plasma: within 48 h of stroke miR-7c-5p was significantly decreased in the plasma of ischemic stroke patients and experimental animals. There was a significant decrease of let-7c-5p in the ipsilateral cortex and striatum in mice subjected to middle cerebral artery occlusion (MCAO) at 24 h reperfusion. Overexpression of let-7c-5p via ICV injection decreased the infarction volume and attenuated the neurological deficits. miR-7c-5p directly targeted the 30-untranslated region of the caspase 3 mRNA to reduce caspase 3 levels, which may underline the miRNA–modulated microglial activity. Inhibition of microglia activation Prognosis and therapy Yuan 2023 China Rats Carotid injury Carotid artery sample/invitro NA After 12 weeks of treatment MiR-7-5p was downregulated, and NF-κB p65 was up-regulated in injured carotid arteries in the rat model. MiR-7-5p relieves intimal hyperplasia in carotid artery injury rat model. MiR-7-5p attenuates the proliferation and migration of VSMCs MiR-7-5p represses NF-κB p65 in VSMCs and inhibits the proliferation and migration of VSMCs. NF-kB signaling. Prognosis and therapy Additional Declarations No competing interests reported. Supplementary Files microRNApaperSupplementarytable.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 19 Mar, 2024 Reviewers agreed at journal 06 Feb, 2024 Reviews received at journal 22 Jan, 2024 Reviewers agreed at journal 03 Jan, 2024 Reviewers invited by journal 02 Jan, 2024 Editor assigned by journal 28 Dec, 2023 Submission checks completed at journal 28 Dec, 2023 First submitted to journal 14 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Woo","suffix":""},{"id":264094836,"identity":"81272f4a-be7d-4efe-b528-c1b53f1d3367","order_by":8,"name":"Nicholas Johnson","email":"","orcid":"","institution":"Virginia Commonwealth University","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Johnson","suffix":""},{"id":264094838,"identity":"3903460c-a640-43fb-999d-8033611e8d96","order_by":9,"name":"Mohammad Hamed","email":"","orcid":"","institution":"The Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Hamed","suffix":""}],"badges":[],"createdAt":"2023-12-14 17:59:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3754883/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3754883/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49125426,"identity":"ffaad1f3-038d-4406-bbd9-cf57e8249216","added_by":"auto","created_at":"2024-01-03 14:49:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":359809,"visible":true,"origin":"","legend":"\u003cp\u003eHeat map shows over-expression of miRs 140-5p and 7-5p (red) and under-expression of miR 210-3p (blue) within 6h of onset (PT#_06h): Note: 6h expression is marked by black outline.\u003c/p\u003e","description":"","filename":"11.png","url":"https://assets-eu.researchsquare.com/files/rs-3754883/v1/0e62c5d2c49b20568dc7cd7a.png"},{"id":49125425,"identity":"4bbfc3ca-66b6-45f9-be37-dd93be535dca","added_by":"auto","created_at":"2024-01-03 14:49:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":123060,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBox plots of miRs 140-5p, 7-5p, and 210-3p showing differential expression at 6h (2nd box plot) compared to healthy controls (1st box) and remaining time points (3rd, 4th and 5th box plots)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"22.png","url":"https://assets-eu.researchsquare.com/files/rs-3754883/v1/fe0b26932a476e74fb6a58c1.png"},{"id":49126690,"identity":"45850a0e-d9ba-45f1-8c26-7c7acb114e19","added_by":"auto","created_at":"2024-01-03 14:57:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":898723,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3754883/v1/9a543a35-d56a-4204-8b4d-687156bd7282.pdf"},{"id":49125427,"identity":"05d969f1-5dca-4948-8960-9dbd6a4f6ae0","added_by":"auto","created_at":"2024-01-03 14:49:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1152681,"visible":true,"origin":"","legend":"","description":"","filename":"microRNApaperSupplementarytable.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3754883/v1/a8f6cc95350429fdeda716c8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MicroRNA Expression Profile in Acute Ischemic Stroke","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute ischemic stroke (AIS) is a medical emergency characterized by the sudden blockage of blood flow to the brain, resulting in high morbidity and mortality rates worldwide(1). Emergent treatment decisions are time-critical, necessitating precise determination of stroke onset time or its practical surrogate, the 'last known well' (LKW) time, to expedite the initiation of appropriate interventions(2). Over 30% of AIS cases involve large vessel occlusion (LVO), particularly in major arteries such as the internal carotid artery (ICA) and the anterior (ACA), middle (MCA), and posterior cerebral arteries, significantly contributing to the burden of stroke due to the large area of ischemic tissue and infarction(3).\u003c/p\u003e \u003cp\u003e According to current clinical guidelines, patients presenting with AIS within 4.5 hours from symptom onset are candidates for intravenous (IV) thrombolysis. Initiating IV thrombolysis within this timeframe increases the likelihood of improved functional outcomes across all age groups, with the magnitude of benefit being highly time-dependent (4,5). For patients with anterior circulation large vessel occlusion (acLVO), endovascular thrombectomy (ET) is typically indicated within 6 hours of onset without the need for advanced perfusion imaging. Beyond this window, up to 24 hours, ET may be considered based on a thorough risk/benefit assessment (4). Contemporary stent retriever devices can achieve successful recanalization in over 87% of patients, significantly enhancing outcomes with a number needed to treat (NNT) of 8 for an excellent clinical outcome and an NNT of 3 for a favorable functional outcome, without markedly increasing mortality or hemorrhagic complications(6). It is estimated that increasing the rate of near-complete to complete reperfusion by just 10% could result in an additional 3656 quality-adjusted life years (QALYs) and save \u003cspan\u003e$\u003c/span\u003e21.0\u0026nbsp;million and \u003cspan\u003e$\u003c/span\u003e36.8\u0026nbsp;million for the US healthcare system and society, respectively (7). Without timely intervention, the progression of stroke leads to rapid loss of neural tissue. In LVO patients, an estimated 120\u0026nbsp;million neurons, 830\u0026nbsp;billion synapses, and 714 km (447 miles) of myelinated fibers are lost every hour(8). As the stroke advances, the risk of intracranial hemorrhage (ICH) begins to outweigh the benefits of recanalization therapy, typically beyond 24 hours (9,10). Therefore, determination of stroke onset time is paramount in delivering safe and effective treatment for stroke patients.\u003c/p\u003e \u003cp\u003eNevertheless, a substantial proportion of AIS patients, approximately one in four, present with unclear stroke onset time or LKW, making them ineligible for potentially life-saving acute stroke intervention(11). The lack of reliable methods to estimate the time of stroke onset and accurately gauge the extent of tissue injury poses a significant challenge in managing AIS effectively, especially in cases where the precise timing of symptom onset remains uncertain.\u003c/p\u003e \u003cp\u003eRecent literature has highlighted the significance of molecular intercellular messaging and signaling in determining the state of tissue injury in various diseases, including stroke(12). MicroRNAs (miRNAs) have emerged as a class of non-coding RNA molecules that play a pivotal role in intercellular communication by regulating the expression of target mRNAs(13). In the context of AIS, miRNAs have shown promise as potential biomarkers for diagnostic and prognostic applications(14\u0026ndash;17). Studies have reported altered miRNA expression profiles in blood and brain tissues of AIS patients, suggesting their potential as biomarkers for stroke detection, subtyping, and prognosis (18,19). However, to date, no study has comprehensively evaluated the temporal miRNA expression profiles in hyperacute AIS patients with acLVO stroke over 7 days following symptom onset. Understanding the dynamic changes in miRNA expression during the hyperacute phase of acLVO would be highly beneficial for unraveling the early molecular signals underpinning this devastating condition. This knowledge opens avenues for potential blood-based biomarkers that could transform early diagnosis and monitor treatment efficacy. Moreover, it sheds light on the molecular underpinnings of stroke progression and tissue damage, offering opportunities for improved clinical decision-making, prognostication, and the discovery of new therapeutic targets (20). This pilot study provides critical insights into the dynamic shifts in miRNA expression patterns related to hyperacute acLVO stroke, observed longitudinally over a week.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cstrong\u003eStudy Design\u003c/strong\u003e \u003cp\u003eThis longitudinal, prospective cohort study, conducted at the Joint Commission-certified Comprehensive Stroke Center of Ohio State University\u0026mdash;a tertiary referral medical center\u0026mdash;explores the viability of circulating EV-encapsulated miRNAs as blood-based biomarkers for acLVO ischemic stroke. The study protocol received approval from the Ohio State University Institutional Review Board, and informed consent was secured from all participants or their legally authorized representatives.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e Our scoping review was designed to elucidate the roles of certain miRNAs, specifically miR-140-5p, miR-210-3p, and miR-7-5p, within the acute ischemic stroke (AIS) framework. To achieve this, we conducted a comprehensive PubMed search using terms like 'acute ischemic stroke', 'stroke', 'miR', 'miRNA', 'micro RNA', and the specific miRNAs of interest (miR-140-5p, miR-210-3p, and miR-7-5p). We employed Boolean operators \"AND\" and \"OR\" to refine the search. Our primary objective was to explore the current research on how these miRNAs influence key pathways in ischemic stroke pathophysiology, including apoptosis, inflammation, oxidative stress, and neuronal damage, and their potential roles in diagnosis, treatment, and prognosis. The results section of this manuscript presents an in-depth review of the three principal miRNAs, based on our lab research. Furthermore, we provide a summary of important findings from other stroke related miRNA in Supplementary File 1.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSampling and Enrollment:\u003c/h2\u003e \u003cp\u003eThe study enrolled all patients who arrived at the adult Emergency Department within 6 hours of witnessed stroke symptom onset. Inclusion required a confirmed diagnosis of acLVO by CT Angiogram. Healthy individuals formed the control group. Exclusion criteria included individuals with significant atherothrombotic disorders\u0026mdash;such as pronounced coronary or peripheral vascular disease, deep vein thrombosis, or pulmonary embolism\u0026mdash;patients with concurrent neurological conditions, a stroke in the preceding three months, posterior circulation LVO, uncertain time since last seen well, and pregnancy. Patients with recent thrombosis or severe atherosclerosis were excluded to avoid interference from clot associated miRNAs, like platelet-derived miRNAs. Individuals with recent brain injuries were excluded to prevent confounding results from miRNA profiles linked to these recent injuries. Pregnant women were excluded due to potential variations in miRNA profiles in expectant mothers with growing fetus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSample collection and processing:\u003c/h2\u003e \u003cp\u003eBlood samples were collected from acLVO patients at four time points: 0\u0026ndash;6 hours, 6\u0026ndash;12 hours, 12\u0026ndash;24 hours, and 5\u0026ndash;7 days after symptom onset. Controls were healthy volunteers without any acute disease process or chronic stroke risk factors and had blood samples collected at a single time point. After initial sample collection and centrifugation, plasma was stored at -80\u0026deg;C until further processing. Subsequently, extracellular vesicles (EV) enriched in exosomes were isolated from the cell-free plasma using the Total Exosome Isolation Kit (Invitrogen) as previously described(21). The isolated EVs were characterized for quantity and size using the NanoSight NS300 (22). Total RNA were isolated using the Maxwell RSC miRNA tissue kit (Promega)(23). MiRNA profiling was performed using the multiplexed NanoString nCounter miRNA system as previously described (22). Nanostring counts exported from nSolver were filtered and normalized with in-house scripts where miRNA and samples were filtered based on negative background probes (NegCutoffS1\u0026thinsp;=\u0026thinsp;meanNegS1\u0026thinsp;+\u0026thinsp;1.5*stdevNegS1) and normalized based on the geometric mean of expression and log2 transformed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003eStatistics was performed in R. Heatmaps with hierarchical clustering, and principal component analysis (PCA) was performed with pheatmap and prcomp to visually group samples into clusters to give us an idea of the differences and similarities between samples and sample categories. Modest changes (\u0026lt;\u0026thinsp;2 fold) in miRNA expression are known to be associated with changes in target gene expression(24\u0026ndash;26). Change of miRNAs across time points in LVO patients was assessed using repeated measures ANOVA, and we tested time point differences between any two-time points with a mixed model with a sample included as a random effect. The significance for any statistical test was defined as FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAnalysis was performed on a total of 24 samples from six patients with confirmed acLVO stroke, with 12 samples from patients presenting with \u0026nbsp;right ICA/MCA involvement and the remaining 12 samples with left ICA/MCA involvement. Individual patient characteristics are presented in Table 1. All patients received IV thrombolytic therapy (tPA) within the appropriate therapeutic window. Furthermore, some patients underwent endovascular thrombectomy as an additional intervention to restore blood flow, resulting in the collection of plasma samples during (1 patient) and after the thrombectomy procedure (2 patients). Control included 5 healthy volunteers (3 males, 2 females) between the ages of 18-60 years.\u003c/p\u003e\n\u003cp\u003eThe ANOVA analysis of the raw data revealed statistically significant differential expression of 11 microRNAs (miR 210-3p, miR 7-5p, miR 122-5p, miR 140-5p, miR 378i, miR-320e, miR 448, miR 1258, miR 26a-5p, miR 28-5p, miR 510-3p ) across various time points and healthy volunteer comparisons. Recognizing the clinical importance of the hyperacute period within 6 hours from stroke onset, our study concentrated on identifying specific microRNAs that exhibit unique expression profiles during this initial phase, in contrast to subsequent time points and healthy volunteers. Notably, three microRNAs (figure 1) exhibited significant differential expressions within the first 6 hours compared to both the healthy volunteers and other time points.\u003c/p\u003e\n\u003cp\u003eParticularly intriguing was the observation that microRNA 140-5p displayed noticeable elevation within 6 hours, gradually normalizing between 12-24 hours and ultimately approaching the volunteer level after 7 days (figure 2). Similarly, microRNA 7-5p exhibited clear overexpression within the first 6 hours, followed by a gradual downtrend towards the volunteer level by 24 hours, maintaining stable expression within a similar range at 7 days. In contrast, microRNA 210-3p demonstrated under-expression at 6 hours, gradually increasing towards the volunteer level over the next 12-24 hours and maintaining that level through 7 days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReview of Current Knowledge on miR-140-5p, miR-210-3p, and miR-7-5p in Acute Ischemic Stroke\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA concise review of the existing literature regarding the role of these three miRNAs in AIS is presented in Table 2. In animal models simulating ischemic stroke, a significant decrease in miR-140-5p expression was observed within the ischemic core\u0026nbsp;(27\u0026ndash;29). Conversely, when examining human serum samples, all studies consistently reported an elevation in serum miR-140-5p levels after cerebral ischemia\u0026nbsp;(30\u0026ndash;32). This alignment with our findings suggests the potential utility of miR-140-5p as a diagnostic marker, a notion supported by these consistent outcomes.\u0026nbsp;The observed elevation of miR-140-5p in circulation and its concurrent reduction within the ischemic brain tissue during the initial 6-hour window may reflect a response to ischemic insult. Ischemia/reperfusion injury might trigger the translocation of miR-140-5p from the affected neurons to the circulatory system. This process could be related to the mobilization of inflammatory mediators and growth factors, crucial for the brain\u0026apos;s intrinsic response to ischemic damage.\u003c/p\u003e\n\u003cp\u003eMoreover, studies have also explored the therapeutic potential of miR-140-5p. Wang et al. demonstrated that administration of encapsulated miR-140-5p could alleviate neuronal damage in subarachnoid hemorrhage(27). Liang et al.\u0026apos;s work showcased that overexpressing miR-140-5p using adeno-associated viruses reduced inflammatory and vascular growth factors in the ischemic mouse hippocampus, inhibiting neurogenesis and capillary density(30). Similarly, Sun et al. revealed that miR-140-5p hinders angiogenesis after cerebral ischemia, potentially contributing to the mitigation of hemorrhagic transformation and edema(28). Additionally, Song et al. provided evidence that miR-140-5p overexpression inhibited neuron apoptosis and decelerated stroke progression(29). While these animal model and in vitro studies show promise for the therapeutic role of miR-140-5p, it is important to note that the limited number of studies and inconsistencies in miR-140-5p delivery methods preclude any definitive conclusions.\u003c/p\u003e\n\u003cp\u003eAs illustrated in Table 2, our literature search found two human-based studies regarding the role of miR-7-5P as a biomarker in stroke. In contrast to our study, Ni et al. observed a reduction in miR-7-5p levels following stroke. However, in contrast to our study, they did not detail the precise timing of sample collection, referring instead to a broader 48-hour window(33). Meanwhile, Chen et al. demonstrated that in humans with intracerebral hemorrhage (ICH), the serum levels of miR-7-5p were significantly higher on day one compared to day 7, demonstrating time dependent evolution in ICH\u0026nbsp;(34). Most studies in animal models of cerebral ischemia and intracerebral hemorrhage have indicated a decrease in miR-7-5P levels in brain tissue samples\u0026nbsp;(33\u0026ndash;36). Similarly, in a model of carotid artery injury, miR-7-5p was found to be downregulated when examining carotid endarterectomy samples(37). Similar to 140-5p, the decreases in tissue miR-7-5p levels might be attributed to the release of miR-7-5P from injured tissue into the serum. However, Zhao et al. observed a contrasting trend, with miR-7-5P significantly upregulated in ischemic brain tissue in a time-dependent manner\u0026nbsp;(38).\u0026nbsp;Dharap et al. noted no initial change in miR-7-5P levels, followed by a decline after 12 hours in a rat model of focal ischemia\u0026nbsp;(39).\u0026nbsp;Given these conflicting results in varied models with varied tissue types and sampling time points, the utility of circulating miR-7-5P as a diagnostic biomarker remains uncertain and needs further evaluation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral investigations have focused on the therapeutic implications of miR-7-5p. Chen et al. found that miR-7-5p levels were raised by Butylphthalide via intracerebroventricular administration, which contributed to the alleviation of brain edema(34). Xu et al. reported that curcumin regulates miR-7-5p, conferring neuroprotection and ameliorating cognitive deficits in ischemic reperfusion injury.\u0026nbsp;(35). Kim et al. observed that preischemic administration of miR-7 mimics enhanced motor function and diminished lesion volume in young male rats, while post ischemic treatment was effective in reducing brain damage across all rats, improving cognitive outcomes and expediting motor recovery\u0026nbsp;(36).Additionally, Ni et al. demonstrated that elevating let-7c-5p levels via intra-cerebrovascular injection reduced infarct size and lessened neurological impairments\u0026nbsp;(33).\u0026nbsp;Conversely, Zhao et al., studying a rat model of ischemia reperfusion, identified that an increase in miR-7-5p was associated with heightened inflammation, apoptosis, and the exacerbation of ischemic damage(38). Overall, the current body of research on miR 7-5p also reveals variations in miRNA expression profile possibly linked to varied type of biological specimen, disease severity, sampling timepoint, and miRNA profiling techniques.\u003c/p\u003e\n\u003cp\u003eMiR-210 has also received considerable attention in stroke research, as detailed in \u003cstrong\u003eTable 2,\u003c/strong\u003e with investigations encompassing in vitro analyses, animal models, and clinical studies to evaluate its diagnostic, prognostic, and therapeutic potential. Across these studies, a recurrent finding is the elevation of miR-210 expression within brain tissue following cerebral ischemia, including ischemic stroke and hypoxic-ischemic encephalopathy\u0026nbsp;(40\u0026ndash;46).\u0026nbsp;In contrast, circulating levels of miR-210 in ischemic stroke patients appear to be suppressed when compared to those of healthy controls\u0026nbsp;(41,42,47,48). This same trend is observed in patients with symptomatic carotid stenosis, where miR-210 is downregulated in carotid fibrous cap tissue\u0026nbsp;(48). This finding underscores the potential of miR-210 as a reliable biomarker for cerebral ischemia. Supporting its diagnostic role, Rahmati et al. established a threshold for miR-210 with a fold change of 0.26, correlating with a modest diagnostic performance characterized by an area under the receiver operating characteristic curve (AUC) of 0.61 and exhibiting 59.62% sensitivity and 65.38% specificity\u0026nbsp;(49).\u0026nbsp;Zeng et al. identified a higher sensitivity at a diagnostic cutoff point of 0.505 for miR-210, achieving 88.3% sensitivity(42).\u0026nbsp;Complementing these studies, Tian et al. confirmed the high diagnostic accuracy of miR-210 for acute cerebral infarction, presenting an AUC of 0.836\u0026nbsp;(47).\u0026nbsp;These findings collectively point towards the potential of miR-210 as an informative biomarker for the identification of acute ischemic events.\u003c/p\u003e\n\u003cp\u003eThe role of miR-210 in prognostication for ischemic stroke patients has been substantiated by multiple studies. For instance, Rahmati et al. found a positive correlation between elevated miR-210 levels at three months post-stroke and enhanced survival rates.(49).\u0026nbsp;Zeng et al. reported that patients with favorable recovery showed higher miR-210 expression than those with adverse outcomes\u0026nbsp;(42). On the contrary, Tian et al. reported that patients with lower miR-210 expression levels had increased one-year mortality, with miR-210 levels emerging as a robust predictor of mortality (AUC = 0.786)\u0026nbsp;(47). While the current body of research presents variability, likely attributable to insufficient control of confounding variables across different studies, the aggregated evidence nonetheless points to miR-210 as a potentially valuable marker for predicting neurological outcomes in acute ischemic stroke scenarios.\u003c/p\u003e\n\u003cp\u003eIn terms of therapeutic implications, miR-210 has shown potential in both in vitro and animal models as summarized in Table 2. Research by Eken et al. demonstrated the prophylactic effect of miR-210 mimics on carotid plaque stability, suggesting a preventative role against ischemic stroke (48). Pfeiffer et al.\u0026apos;s subgroup analysis revealed that pretreatment with a miR-210-3p mimic substantially mitigated hemispheric swelling and infarct size(40). Similarly, Huang et al. validated the protective effects of miR-210, noting that both pre- and post-treatment with a miR-210 locked nucleic acid (LNA) conjugate led to reduced cerebral infarct and edema, alongside behavioral improvements in mice models of middle cerebral artery occlusion (MCAO)(46). Additionally, Zeng et al. illustrated the efficacy of miR-210 gene transfer in enhancing recovery in transient MCAO models \u0026nbsp;(41). Additionally, research by Li et al. and Zhang et al. has highlighted miR-210\u0026apos;s role in attenuating inflammation and reducing ischemic damage in both in vitro settings and cerebral ischemia models(44,45). Ma et al. demonstrated the neuroprotective effects of exogenous miR-210 mimics in a model of neonatal hypoxic-ischemic brain injury.(43), while Lu et al. documented enhanced function of endothelial progenitor cells under hypoxic conditions when treated with miR-210(50). Yerrapragada et al. further corroborated the neuroprotective role of miR-210 in a hypoxia and reoxygenation model, indicating its therapeutic potential in mitigating hypoxic-ischemic neuronal damage(51). Extending beyond cerebral models, Ujigo et al. found that intracranial administration of miR-210 contributed to functional recovery in cases of traumatic spinal cord injury(52). These studies, underscore the promising therapeutic avenues miR-210 may offer for ischemic stroke intervention.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study revealed that, upon comparing each time point against the remaining three time points in acLVO patients and a single time point in healthy volunteers, a total of 11 microRNAs exhibited significantly altered expression across these comparative analyses. Notably, within the first 6 hours of acLVO stroke onset, three microRNAs (140-5p, 7-5p, and 210-3p) exhibited significant differential expression compared to healthy volunteers and other time points. MiRNA 140-5p showed relative increase within the first 6 hours, gradually normalizing between 12\u0026ndash;24 hours and reaching volunteer levels within seven days. Similarly, miRNA 7-5p displayed significant overexpression within the first 6 hours, followed by a gradual decline towards volunteer levels by 24 hours, maintaining stable expression within a similar range around seven days. In contrast, miRNA 210-3p demonstrated relative under-expression at 6 hours, gradually increasing towards the volunteer level over the next 12\u0026ndash;24 hours and maintaining that level through 7 days.\u003c/p\u003e \u003cp\u003eOur study and existing literature have highlighted the significant roles played by microRNAs (140-5p, 7-5p, and 210-3p) in stroke pathophysiology and therapy. Of note, these microRNAs employ diverse mechanisms to exert their effects. We have provided an overview of the various pathways they operate within stroke and related disorders in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Many of these pathways are closely linked to inflammation, oxidative stress, cell death, and angiogenesis. Utilizing molecular drug discovery to target these pathways or the microRNAs themselves holds promise as an effective strategy for stroke prevention and treatment. In our study, we have also identified other microRNAs, such as miR 210-3p, miR 122-5p, miR 378i, miR-320e, miR 448, miR 1258, miR 26a-5p, miR 28-5p, and miR 510-3p in association with ischemic stroke. The functions and potential pathways of these miRNAs and other relevant miRNAs are summarized in supplementary file 1. These microRNAs are subjects of ongoing research, aiming to elucidate their roles and mechanisms further.\u003c/p\u003e \u003cp\u003eOur study has several strengths. In this pilot project, we endeavored to meticulously assemble a homogenous cohort of patients, each presenting with anterior circulation acLVO, to maintain uniformity in the stroke phenotype for our analyses. Recognizing the potential for variability introduced by timing, we strictly limited the collection of blood samples to within a 6-hour window following the onset of symptoms, which we hoped would reduce confounding factors related to timing ambiguities. We adopted a longitudinal design for the study, which permitted us to cautiously interpret the evolution of miRNA profiles over time, treating each time point as an intrinsic control against the baseline hyperacute samples. This careful approach, while preliminary, was expected to offer valuable insights into the dynamic changes of miRNAs in this context.\u003c/p\u003e \u003cp\u003eWhile the study presents intriguing outcomes, it is important to recognize its limitations. A key limitation is the modest cohort size, comprising a total of 29 samples, which may limit the generalizability of the findings. The LVO group included a total of 4 female samples only, which hindered the assessment of potential sex-related differences in miRNA profiles. Although stroke typically occurs in older individuals, the majority of our study's participants were middle-aged, with one patient being a minor. This distribution may not accurately reflect the age-related risk of stroke in the general population. Additionally, the use of healthy controls who were not matched for stroke risk factors could introduce confounders into the miRNA expression profiles. As Toor et al. indicated, miR-140-5p levels were found to be elevated in stroke patients with diabetes relative to non-diabetic patients (32), suggesting that miRNA expression may differ with underlying risk factors. Moreover, our research was confined to the study of EV encapsulated miRNA and the potential role of non-vesicular, free circulating miRNAs was not investigated, which constitutes an area for further research.\u003c/p\u003e \u003cp\u003eOur literature review disclosed considerable heterogeneity within the corpus of research investigating the role of miRNAs in ischemic stroke. This variation is likely due to a lack of standardization across several critical aspects of study design and methodology. These aspects include the criteria for control group selection, the source of the miRNAs (serum, plasma, CSF or brain tissue), the protocols used for miRNA isolation, the timing of sample collection (ranging from hyperacute to delayed phases), the selection of reference standards (internal and external controls), the choice of detection and quantification techniques (such as Nanostring, Next-Generation Sequencing, or RT-qPCR), and the breadth of the infarct sizes. Additionally, the biological origin of the miRNAs\u0026mdash;whether cellular, vesicular, or cell-free\u0026mdash;also contributes to the variability of the results, further complicating the interpretation and comparison of findings across studies.\u003c/p\u003e \u003cp\u003eTo enhance the reliability of biomarker studies, future investigations should aim for rigorously matched control groups that align with stroke patients' symptoms and risk factors, utilizing consistent and validated methodologies within a well-defined stroke cohort. Adopting a multi-center design would improve the robustness and applicability of miRNA biomarkers for diagnostic purposes. Additionally, it is crucial to assess the prognostic value of these miRNAs by examining their associations with both radiological findings and clinical outcomes. Implementing miRNA profiles in the elucidation of disease pathways could inform treatment strategies and support timely consultations with patients and their families. Moreover, in-depth mechanistic research is needed to decipher the roles of specific miRNAs in the pathogenesis of acute large vessel occlusion (acLVO) strokes, potentially uncovering novel therapeutic avenues. These efforts will deepen our understanding of miRNA-mediated regulation in stroke and could lead to significant advances in patient care\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our investigation has shed light on the intricate role of miRNAs in stroke pathophysiology, highlighting their potential as biomarkers for acute cerebrovascular events. By identifying 11 microRNAs, particularly miR-140-5p, miR-7-5p, and miR-210-3p, with significant differential expression within 6 hours of stroke onset, our study suggests these miRNAs could potentially serve as valuable indicators for diagnosis and possible targets for therapy, given their involvement in critical pathways like inflammation, oxidative stress, and angiogenesis. Despite promising indications for early detection and stroke management, the limitations of our study call for extensive validation through larger, risk-matched cohorts in multi-center trials. Such rigorous research is essential for confirming miRNAs' utility as reliable clinical biomarkers and for potentially uncovering new therapeutic strategies that could significantly improve patient outcomes. It is anticipated that the present findings will encourage further detailed exploration of miRNA functions post-ischemic stroke, fostering advancements in clinical approaches and patient care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003cstrong\u003eDeclaration\u003c/strong\u003e: This project was supported by the Ohio State University Neuroscience Research Institute (NRI) award and the Center for Clinical and Translational Science at Ohio State University, UL1TR002733\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1) Shraddha Mainali: Has received funding support from Ohio State University Neuroscience Research Institute for this pilot study. Has received funding from Center for Clinical and Translational Science at The Ohio State University sponsored by the National Center for Advancing Translational Sciences (UL1TR002733). Has received research consultation fees from Marinus Pharmaceuticals. 2) Nicholas E. Johnson: Has received grant funding from NINDS (R01NS104010, U01NS124974), NCATS (R21TR003184), CDC (U01DD001242) and the FDA (2R01FD006071). He receives royalties from the CCMDHI and the CMTHI. He receives research funds from Avidity, Takeda, Sanofi Genzyme, Dyne, Novartis, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio, and Sarepta. He has provided consultation for Arthex, Novartis, AMO Pharma, Takeda, Design, Dyne, Avidity, Rgenta, and Vertex Pharmaceuticals. Remaining authors: GN, AW, PF, DM, MH, PS, BW and DW report no relevant disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSM: designed, conducted and led the study, drafted and finalized the manuscript; GN: substantial contribution to the scoping review of the manuscript and provided initial draft of the review and tables; AW: substantial contribution in bioinformatics analysis for the pilot study, provided critical input in the manuscript; PF: substantial contribution to sample analysis for the pilot study, provided critical inputs and edits to the manuscript; DM: substantial contribution in review of literature for the scoping review, provided critical input to the manuscript, MH: substantial contribution in collection of samples and conduct of the study, review and critical input to the manuscript; PN-S: Substantial contribution in design of the manuscript, critical input and edits to the manuscript; BW: substantial contribution in the design of the manuscript, critical input and edits to the manuscript; DW: substantial contribution in the design of the manuscript, critical input and edits to the manuscript; NJ: substantial contribution in the design of the manuscript, critical input, edits and finalization of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHerpich F, Rincon F. 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Spine (Phila Pa 1976). 2014;39(14):1099\u0026ndash;107. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Demographics and clinical characteristics of acLVO patients\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"692\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables/ Patient ID\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eIPA (Yes/No)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eBiosampling time (pre, intra \u0026amp; post ET)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003epre (TICI3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003epre (NT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003epost (TICI2b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003epre (TICI2b)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003epre (NT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eintra (TICI2b)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eEtiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eCryptogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eCryptogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eCryptogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eCardioembolic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eLAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eLAA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eHTN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eHLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eDM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eAtrial fib/Flutter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eIV Drug use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eHx of CAD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eAnticoagulants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eAntiplatelets\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eStatin Use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eSite of Occlusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eR-ICA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eR-MCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eL-MCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eR-MCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eL-ICA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eL-MCA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eNIHSS at presentation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eNIHSS at discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eMRS at discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.562952243125906%\" valign=\"top\"\u003e\n \u003cp\u003eHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.748191027496382%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.603473227206946%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.76121562952243%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.918958031837915%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.985528219971057%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.419681620839363%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003eHypertension (HTN), Hyperlipidemia (HLD), Diabetes Mellitus (DM), Atrial fibrillation/Atrial flutter (Atrial fib/flutter), NIH stroke scale (NIHSS), Modified Rankin Scale (MRS), Hemorrhagic Transformation (HT); Patient (PT)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Essential methodological aspects and insights from stroke literature investigating the function of three principal miRNAs identified in our study\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"width: 1.2e+3pt;margin-left:-49.75pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:49.5pt;border:solid windowtext 1.0pt;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003emiR\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eAuthor\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eStudy subjects\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eDisease /Model studied\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eSample tissue\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eSample\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eCollection time\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eMajor findings\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eFunction/Pathway\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border:solid windowtext 1.0pt;border-left: none;background:#FF99FF;padding:0in 5.4pt 0in 5.4pt;height:.65in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style=\"color:black;\"\u003eEvaluated for\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width:49.5pt;border:solid windowtext 1.0pt;border-top:none;background:#A8D08D;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003emiR 140-5P\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eWang 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eEndovascular perforation models of SAH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e3\u003csup\u003erd\u003c/sup\u003e day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eExoencapsulated miR-140-5p can relieve neuronal injury following SAH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eModulation of the IGFBP5-mediated PI3K/AKT signaling pathway\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eLiang 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePost-stroke depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePlasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e252\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ewithin 24 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR‐140-5p (P = 0.0016, log2 (fold change) = 3.5) had significantly higher expression in the late-onset PSD group than in controls,\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eThe miR-140- 5p expression on admission was significantly positively correlated with Hamilton Depression Rating Scale assessed at 3 months after stroke. The predictive value of miR-140-5p for late-onset PSD is 83.3% sensitivity and 72.6% specificity (AUC = 0.8127).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRegulate IL1rap, IL1rapl1, VEGF, and MEGF10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrognostication\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eS\u0026oslash;rensen 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDenmark\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCSF and blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e10 cases and control each\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBlood: miR-140-5p (P=0.02) was up-regulated in stroke patients compared to controls.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCSF: Not detected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSong 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/Invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e60 case\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAnd 15 control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003emiR-140-5p exhibited decreased expression, while TLR4 displayed increased expression.\u003c/span\u003e\u003c/li\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-140-5p directly targeted and reduced TLR4 expression.\u003c/span\u003e\u003c/li\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-140-5p over-expression inhibited neuron apoptosis and slowed stroke progression.\u003c/span\u003e\u003c/li\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eTLR4 over-expression promoted neuron apoptosis and stroke progression.\u003c/span\u003e\u003c/li\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-140-5p reduced NF-\u0026kappa;B protein levels, while TLR4 overexpression increased them.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRegulation of the TLR4/NF-\u0026kappa;B axis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eToor 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eQatar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eWithin 24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003emiR-140-5p was observed to be up-regulated in stroke patients with diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRegulate genes involved in inflammation and oxidative stress.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnostic and therapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSun 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e24 cases and 8 control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e12, 24, 48 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eThe expression of miR-140-5p exhibited a significant reduction at 12, 24, and 48 hours post-MCAO compared to the control. Conversely, the protein expression levels of VEGFA showed a significant increase at 12, 24, and 48 hours following MCAO compared to the control.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSuppresses angiogenesis by targeting VEGFA.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnostic and therapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"13\" style=\"width:49.5pt;border:solid windowtext 1.0pt;border-top:none;background:#FFD966;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003emiR 210-3P\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePfeiffer 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIreland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute ischemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e24 h after ischemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIn response to transient focal ischemia with reperfusion, miR-210-3p is up-regulated in the cortex.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eWhen a miR-210-3p mimic is administered in vivo, it changes the expression of key signaling molecules like PTEN, PDK1, p70S6K, and RPS6.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eThis manipulation also results in a decrease in p70S6K activity following an ischemic stroke.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003emiR-210-3p influences p70S6K activity in response to NMDA-mediated excitotoxicity, and this effect can be reversed by inhibiting miR-210-3p.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePre-treatment with 5 pmol miR-210-3p mimic resulted in a significant decrease in hemispheric swelling and infarct volume.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAMPK regulates miR-210-3p to control p70S6K activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRahmati 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIran\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAcute ischemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e52 cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAdmission, 24 and 48 hours after admission, upon discharge, and 3 months later\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum miR-210 levels in cases were initially lower upon admission compared to normal controls but increased progressively over three months.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eA diagnostic cutoff point was set at a fold change of 0.26 with an AUC of 0.61, 59.62% sensitivity, and 65.38% specificity.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHigher miR-210 expression at the three-month follow-up was linked to improved survival in IS patients.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnosis and prognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eEken 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDenmark\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans and rat model/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCarotid atherosclerosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCEA tissue and blood samples\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSymptomatic humans: 7 in each cohort.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAsymptomatic humans: 5 in the discovery and 7 in the validation cohort.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats: 48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAt the time of surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 is downregulated in symptomatic carotid stenosis patients\u0026apos; plasma and fibrous cap tissue.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIt is repressed in experimental artery remodeling and influences plaque stability in atherosclerosis.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 mimics prevent plaque rupture in vivo and protect smooth muscle cell apoptosis by targeting APC in vitro.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInhibits APC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUjigo 2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSpinal cord injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSpinal cord tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e2, 3, 5, 7, and 14 days after SCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHsa-miR-210 up-regulated miR-210 expression, leading to enhanced neovascularization, astrogliosis, axon growth, and myelination in the injured spinal cord.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIn the miR-210 group, there were significantly fewer apoptotic cells at the lesion site, and caspase-3 and cleaved caspase-3 levels were markedly reduced compared to the control group.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003emiR-210 administration promoted functional recovery after spinal cord injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInhibits Ptpib and Efna3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eZeng 2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman/ Rats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum for humans\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue for rats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans: 5 cases, 5 controls.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats: 124 total, divided into sham, transient MCAO, tMCAO+LV-GFP, and tMCAO+LV-miR-210 groups.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans: Within 48 hours and the 10th day of AIS\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats:\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e7, 14, and 28 days after tMCAO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 downregulated in stroke patients vs. healthy controls.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 gene transfer improved outcomes in tMCAO mice.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBDNF regulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eZeng 2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans/Rats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman: Serum\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats: Brain tissue and serum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eStroke patients (n=112) and healthy controls (n= 60)\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e9 rats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman blood: 3, 7, and 14 days post-stroke.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRat blood and brain tissue: 1, 7, and 14 days post-MCAO.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIn stroke patients, blood miRNA-210 levels were significantly lower, particularly at 7 and 14 days post-stroke onset, compared to healthy controls.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 rose one day after MCAO in rats, declining gradually at 7 and 14 days, and a significant positive correlation existed between blood and brain miR-210 levels.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eA diagnostic cutoff point of 0.505 for miR-210 yielded an 88.3% sensitivity.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eStroke patients with favorable outcomes exhibited higher miR-210 levels than those with poor outcomes.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnosis and prognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMa \u0026nbsp;2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNeonatal hypoxic-ischemic brain injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e48 hours after HI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIn neonatal mouse pups, hypoxic-ischemic (HI) conditions increased miR-210, which suppressed TET2 expression and led to enhanced p65 acetylation and binding at the IL-1\u0026beta; promoter in the brain. TET2\u0026apos;s interacted with HDAC3 regulated NF-\u0026kappa;B p65\u0026apos;s DNA binding at the IL-1\u0026beta; gene promoter.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTET2 knockdown elevated p65 acetylation, increased pro-inflammatory cytokine and chemokine expression after HI, and worsened neonatal HI brain injury. It also counteracted the anti-inflammatory effect of miR-210 inhibition in neonatal HI brain injury and BV2 microglia cell line experiments in vitro.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTET2 downregulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eLi 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS/MCAO model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e204\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003emiR210 injection reduced TET2 in the brain, but miR210 inhibition or KO preserved TET2, irrespective of brain injury.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTET2 reduction reversed miR210 inhibition\u0026apos;s protective effects on stroke-induced brain damage and neurobehavioral deficits.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eLowering TET2 weakened miR210\u0026apos;s anti-inflammatory impact on microglial activation and IL-6 release after stroke.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBoosting TET2 in microglia counteracted miR210-induced cytokine increase.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTET2 downregulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eYerrapragada 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInvitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHypoxia and reoxygenation (H/R) models were applied to neurons to mimic AIS.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInvitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eEndothelial progenitor cell (EPC)-borne miR-210 can be time-dependently transferred to neurons, exerting a protective impact against H/R-induced neuron apoptosis, oxidative stress, and reduced viability.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBDNF/TrkB and Nox2/Nox4 pathways regulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eZhang 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS/MCAO model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e24 h after MCAO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRGD-exo:miR-210 targets the ischemic brain lesion upon intravenous delivery, elevating miR-210 levels at the site. Administered every other day for 14 days, it notably boosts the expression of integrin \u0026beta;3, vascular endothelial growth factor (VEGF), and CD34, leading to an improved animal survival rate.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRGD‑exo:miR‑210 promotes VEGF expression and angiogenesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuang 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS/MCAO model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e96\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e- miR-210-LNA treatment (n = 44)\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e- negative control (n = 41)\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e-other experiments (n=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e24 h after MCAO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210-LNA pre-treatment reduced brain infarct volume edema and improved post-stroke behavior in MCAO mice. It also suppressed pro-inflammatory cytokines, chemokines, immune cell infiltration, and microglial activation induced by MCAO.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePosttreatment with MiR-210-LNA was also protective in MCAO mice.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210-LNA mitigates inflammatory response after cerebral ischemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTian 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAIS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e76 cases\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e64 controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eAt admission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003emiR-210 levels were significantly lower in the mortality group compared to the survival group.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-210 had high diagnostic accuracy for acute cerebral infarction (AUC = 0.836) and was associated with lower 1-year survival in the low-expression group. It also showed good predictive capability for mortality (AUC = 0.786).\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDiagnosis and prognosis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eLu 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInvitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eEndothelial progenitor cells (EPCs) under hypoxic condition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInvitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIn OGD-treated EPCs, miR-210-3p expression was higher than in normal EPCs. Increased miR-210-3p enhanced proliferation, migration, and tube formation under OGD conditions, while decreased miR-210-3p hindered these capabilities in OGD-treated EPCs.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eElevated miR-210-3p suppressed Repulsive guidance molecule A (RGMA) protein expression in OGD-treated EPCs, while reduced miR-210-3p led to increased RGMA expression.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInhibits RGMA, a negative regulator of angiogenesis.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"7\" style=\"width:49.5pt;border:solid windowtext 1.0pt;border-top:none;background:#8EAADB;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003emiR 7-5P\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChen 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans and rats/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIntracerebral hemorrhage (ICH)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eSerum in humans\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue in rats\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003einvitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e60 rats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e1, 7, and 14 days after ICH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHumans: The miR-7-5p level decreased significantly on day 7 after ICH compared to day 1 but showed partial recovery by day 14.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p expression significantly decreased on days 1, 3, and 7 after ICH, with the most pronounced decrease on day 3. Partial recovery occurred after butylphthalide intervention.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eThe brain water content decreased in the butylphthalide group.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePI3K/AKT pathway regulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eXu 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIschemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue/Invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCurcumin prevented the decrease of miR-7-5p expression and the increase of RelA p65 expression caused by cerebral ischemia-reperfusion injury (CIR) in vivo and oxygen-glucose deprivation/reoxygenation (ODG/R) in vitro.\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p was found to target RelA p65. MiR-7-5p antagonists reversed curcumin\u0026apos;s impact on RelA p65 expression in ischemic brain tissue and cells.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCurcumin regulates miR-7/RELA p65 axis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTherapeutic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eKim 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIschemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDay 7 and 31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eIschemia reperfusion-induced 2.1- to 3-fold decrease in miR-7 expression in the ipsilateral cortex of both young and aged rats of both sexes compared with the sham-operated controls.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003ePreischemic intracerebral administration of miR-7 mimics improved motor function recovery and decreased lesion volume in young male rats.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003ePostischemic intracerebral administration of miR-7 mimics decreased ischemic brain damage irrespective of sex and age in rats.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003ePostischemic intravenous administration of miR-7 mimic decreased the stroke-induced cognitive deficit and accelerated motor recovery but failed to do so in alpha syn knockout mice\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026alpha;-Synuclein regulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrevention, prognostication, and therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eDharap 2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIschemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e30 cases and 6 controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e3, 6, 12, 24, and 72 hr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eTransient focal ischemia in a rat model induced no change in miR 7-5P in the first 12 hours, followed by a sustained decrease.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePathobiology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eZhao 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIschemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eBrain tissue/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e24 hours after reperfusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p Exhibited High Expression in a Rat Model With Cerebral I/R Injury and OGD/RInduced SH-SY5Y Cells increasing progressively with time.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eSilence of miR-7-5p Impaired ischemia-reperfusion injury Caused Cerebral Injury.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eAttenuation of miR-7-5p Hindered I/R Caused Cerebral Inflammation.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eDepletion of miR-7-5p Impeded Neuronal Cell Apoptosis\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003emiR-7-5p Regulated Neuronal Cell Apoptosis by Targeting sirt1\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p Knockdown Blocked the NF-kB Pathway\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003esirt1 regulation\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrognosis and therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNi 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eHuman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eIschemic stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePlasma and brain tissue/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e8 human cases and controls\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003eBrain tissue: 24 h and 96 h after occlusion\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003ePlasma: within 48 h of stroke\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003emiR-7c-5p was significantly decreased in the plasma of ischemic stroke patients and experimental animals.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eThere was a significant decrease of let-7c-5p in the ipsilateral cortex and striatum in mice subjected to middle cerebral artery occlusion (MCAO) at 24 h reperfusion.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eOverexpression of let-7c-5p via ICV injection decreased the infarction volume and attenuated the neurological deficits.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003emiR-7c-5p directly targeted the 30-untranslated region of the caspase 3 mRNA to reduce caspase 3 levels, which may underline the miRNA\u0026ndash;modulated microglial activity.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eInhibition of microglia activation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrognosis and therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eYuan 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eRats\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:67.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCarotid injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:58.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eCarotid artery sample/invitro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:99.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:1.25in;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color:black;\"\u003eAfter 12 weeks of treatment\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:418.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p was downregulated, and NF-\u0026kappa;B p65 was up-regulated in injured carotid arteries in the rat model.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p relieves intimal hyperplasia in carotid artery injury rat model.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p attenuates the proliferation and migration of VSMCs\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/p\u003e\n \u003cdiv style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003cul style=\"margin-bottom:0in;list-style-type: disc;margin-left:-0.25in;\"\u003e\n \u003cli style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style='font-family:\"Times New Roman\",serif;'\u003eMiR-7-5p represses NF-\u0026kappa;B p65 in VSMCs and inhibits the proliferation and migration of VSMCs.\u003c/span\u003e\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:117.0pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003eNF-kB signaling.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:86.7pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.35pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003ePrognosis and therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"translational-stroke-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trsr","sideBox":"Learn more about [Translational Stroke Research](http://jcmr-online.biomedcentral.com)","snPcode":"12975","submissionUrl":"https://submission.nature.com/new-submission/12975/3","title":"Translational Stroke Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"acute ischemic stroke, miRNA, biomarker, micro-RNA, miR, large vessel occlusion, LVO, stroke biomarker","lastPublishedDoi":"10.21203/rs.3.rs-3754883/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3754883/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eIntroduction:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAcute ischemic stroke with large vessel occlusion (LVO) continues to present a considerable challenge to global health, marked by substantial morbidity and mortality rates. Although definitive diagnostic markers exist in the form of neuroimaging, their expense, limited availability, and potential for diagnostic delay can often result in missed opportunities for life-saving interventions. Despite several past attempts, research efforts to date have been fraught with challenges likely due to multiple factors such as inclusion of diverse stroke types, variable onset intervals, differing pathobiologies, and a range of infarct sizes, all contributing to inconsistent circulating biomarker levels. In this context, microRNAs (miRNAs) have emerged as a promising biomarker, demonstrating potential as biomarkers across various diseases, including cancer, cardiovascular conditions, and neurological disorders. These circulating miRNAs embody a wide spectrum of pathophysiological processes, encompassing cell death, inflammation, angiogenesis, neuroprotection, brain plasticity, and blood-brain barrier integrity. This pilot study explores the utility of circulating exosome-enriched extracellular vesicle (EV) miRNAs as potential biomarkers for anterior circulation LVO (acLVO) stroke.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn our longitudinal prospective cohort study, we collected data from acute large vessel occlusion (acLVO) stroke patients at four critical time intervals post-symptom onset: 0\u0026ndash;6 hours, 6\u0026ndash;12 hours, 12\u0026ndash;24 hours, and 5\u0026ndash;7 days. For comparative analysis, healthy individuals were included as control subjects. In this study, extracellular vesicles (EVs) were isolated from the plasma of participants, and the miRNAs within these EVs were profiled utilizing the NanoString nCounter system. Complementing this, a scoping review was conducted to examine the roles of specific miRNAs such as miR-140-5p, miR-210-3p, and miR-7-5p in acute ischemic stroke (AIS). This review involved a targeted PubMed search to assess their influence on crucial pathophysiological pathways in AIS, and their potential applications in diagnosis, treatment, and prognosis. The review also included an assessment of additional miRNAs linked to stroke.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWithin the first 6 hours of symptom onset, three specific miRNAs (miR-7-5p, miR-140-5p, and miR-210-3p) exhibited significant differential expression compared to other time points and healthy controls. These miRNAs have previously been associated with neuroprotection, cellular stress responses, and tissue damage, suggesting their potential as early markers of acute ischemic stroke.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study highlights the potential of circulating miRNAs as blood-based biomarkers for hyperacute acLVO ischemic stroke. However, further validation in a larger, risk-matched cohort is required. Additionally, investigations are needed to assess the prognostic relevance of these miRNAs by linking their expression profiles with radiological and functional outcomes.\u003c/p\u003e","manuscriptTitle":"MicroRNA Expression Profile in Acute Ischemic Stroke","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 14:49:28","doi":"10.21203/rs.3.rs-3754883/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-03-19T16:23:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"220ad77d-a6a5-439e-96f6-8e1a76a6c2e1","date":"2024-02-06T15:20:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-22T16:53:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"52ef279a-4818-427f-a44f-9b9723cf66f5","date":"2024-01-03T14:11:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-02T16:15:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-28T17:18:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-28T06:56:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Translational Stroke Research","date":"2023-12-14T17:52:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"translational-stroke-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trsr","sideBox":"Learn more about [Translational Stroke Research](http://jcmr-online.biomedcentral.com)","snPcode":"12975","submissionUrl":"https://submission.nature.com/new-submission/12975/3","title":"Translational Stroke Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dca7b79e-631f-4b7c-8a7a-f6c85cb46d02","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-04-04T07:28:19+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 14:49:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3754883","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3754883","identity":"rs-3754883","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}