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Quinlan M, Arora R, Cho SM. Postoperative Brain Attack: Current Perspectives and Future Directions. Semin Thorac Cardiovasc Surg 2025:S1043-0679(25)00016-4. [PMID: 40081610 DOI: 10.1053/j.semtcvs.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/10/2024] [Accepted: 02/12/2025] [Indexed: 03/16/2025]
Abstract
The incidence of stroke after cardiac surgery poses significant challenges. This expert review piece explores current knowledge, challenges, future directions, and offers insights into improving patient outcomes through optimal prevention, early recognition, and management strategies. By addressing the challenges and opportunities in this area, we can enhance patient care, reduce long-term disabilities, and improve the overall quality of life for affected individuals. This expert review aims to provide a comprehensive framework for managing postoperative stroke: mechanisms, risk factors, diagnosis, treatment, systems of care, and ethical considerations.
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Affiliation(s)
- Miriam Quinlan
- Division of Neurosciences Critical Care, Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Case Western Reserve University, Department of Surgery, Cleveland, Ohio
| | - Rakesh Arora
- Case Western Reserve University, Department of Surgery, Cleveland, Ohio.; Harrington Heart and Vascular Institute, Division of Cardiac Surgery, University Hospitals, Cleveland, Ohio
| | - Sung Min Cho
- Division of Neurosciences Critical Care, Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.; Case Western Reserve University, Department of Surgery, Cleveland, Ohio.; Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland..
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Borończyk M, Zduńska A, Węgrzynek-Gallina J, Grodzka O, Lasek-Bal A, Domitrz I. Migraine and stroke: correlation, coexistence, dependence - a modern perspective. J Headache Pain 2025; 26:39. [PMID: 39979846 PMCID: PMC11844069 DOI: 10.1186/s10194-025-01973-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/04/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Migraine is a chronic neurological condition that has a well-documented, yet not fully understood connection to stroke, particularly in patients who experience migraine with aura (MA). Although migraine can rarely be directly related to stroke, in the form of migrainous infarction, it serves as an independent risk factor, particularly when combined with other factors such as smoking or hypertension. This study will thoroughly review and summarize the existing literature regarding the relationship between migraine and stroke. MAIN TEXT Several key processes are common to both stroke and migraine. These include cortical spreading depression, particularly in MA, endothelial dysfunction, which activates local inflammatory responses, and vasculopathy, which often appears as white matter hyperintensities on neuroimaging. Furthermore, microRNAs also play a significant role in the pathogenesis of both migraine and stroke by targeting genes such as CALCA, which regulates calcitonin gene-related peptide, a factor involved in the pathophysiology of both conditions. There are also several genetic links between migraine and stroke, including both monogenic diseases and common risk loci. Moreover, various conditions are linked to both migraine and stroke, including patent foramen ovale (PFO), atrial fibrillation, carotid artery dissection, platelet dysfunction, dyslipidemia, obesity, hyperhomocysteinemia, and elevated estrogen levels, such as in combined hormonal contraceptives. Notably, PFO is often found in patients who have experienced a cryptogenic stroke, as well as in those with MA. While microemboli associated with PFO may provoke ischemic events and migraine attacks, the effectiveness of PFO closure in alleviating migraine symptoms has produced varying results. Migraine is linked to worse outcomes after ischemic stroke, including larger stroke volumes and poorer functional outcomes, while the connection between migraines and hemorrhagic stroke is less understood. Furthermore, migraine may serve as a stroke mimic (condition presenting with symptoms similar to ischemic stroke) or a stroke chameleon (unrecognized stroke misdiagnosed as migraine), leading to significant diagnostic and treatment errors. CONCLUSIONS The interplay between migraine and stroke is complex, involving shared pathophysiology and overlapping risk factors. While migraine can serve as both a cause and a risk factor for stroke, the precise mechanisms remain unclear, warranting further research to clarify their connection and enhance clinical management.
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Affiliation(s)
- Michał Borończyk
- Department of Neurology, Faculty of Health Sciences in Katowice, Medical University of Silesia in Katowice, Ziołowa 45/47, Katowice, 40-635, Poland.
- Department of Neurology, Upper-Silesian Medical Centre in Katowice, Ziołowa 45/47, Katowice, 40-635, Poland.
| | - Anna Zduńska
- Department of Neurology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Bielanski Hospital, Cegłowska 80, Warsaw, 01-809, Poland
| | - Julia Węgrzynek-Gallina
- Department of Neurology, Faculty of Medical Sciences, University Clinical Centre of Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland
| | - Olga Grodzka
- Department of Neurology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Bielanski Hospital, Cegłowska 80, Warsaw, 01-809, Poland
- Doctoral School, Medical University of Warsaw, Żwirki i Wigury 61, Warsaw, 02-091, Poland
| | - Anetta Lasek-Bal
- Department of Neurology, Faculty of Health Sciences in Katowice, Medical University of Silesia in Katowice, Ziołowa 45/47, Katowice, 40-635, Poland
- Department of Neurology, Upper-Silesian Medical Centre in Katowice, Ziołowa 45/47, Katowice, 40-635, Poland
| | - Izabela Domitrz
- Department of Neurology, Faculty of Medicine and Dentistry, Medical University of Warsaw, Bielanski Hospital, Cegłowska 80, Warsaw, 01-809, Poland
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He GD, Sun S, Huang YQ. Association of Circulating, Inflammatory Response Exosomal Long RNAs with Ischemic Stroke. FRONT BIOSCI-LANDMRK 2025; 30:25355. [PMID: 40018923 DOI: 10.31083/fbl25355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 03/01/2025]
Abstract
BACKGROUND The expression profiles and function of exosomal long RNAs (exoLRs) in ischemic stroke remain unknown. This study aimed to investigate the pathophysiologic responses reflected by exoLRs. METHODS The expression profile of exosomal messenger RNA, long non-coding RNA and circular RNA in 9 patients with ischemic stroke and 12 healthy individuals were analyzed by sequencing. We assessed the immune cell landscape to reveal the pathophysiologic responses reflected by exoLRs and performed biological process and pathway enrichment analyses. Competing endogenous RNA networks were constructed to explore the molecular functions of exoLRs. RESULTS A total of 321 up- and 187 down-regulated messenger RNAs, 31 up- and 9 down-regulated long non-coding RNAs, and 67 up- and 48 down-regulated circular RNAs were identified. The immune cell landscape analysis identified that the proportions of exhausted and gamma delta T cells were statistically higher in patients with ischemic stroke. Bioinformatics analyses, including enrichment and competing endogenous RNA network analyses, also indicated that exoLRs were associated with T- cell-mediated inflammatory responses. CONCLUSIONS The expression patterns of exoLRs highlighted the association between ischemic stroke and inflammatory responses mediated by T cells.
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Affiliation(s)
- Guo-Dong He
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
- Institute of Medical Research, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
| | - Shuo Sun
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
| | - Yu-Qing Huang
- Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080 Guangzhou, Guangdong, China
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Al-Jehani HM, Mousa AH, Alhamid MA, Al-Mufti F. Role of microRNA in the risk stratification of ischemic strokes. Front Neurol 2025; 16:1499493. [PMID: 40012999 PMCID: PMC11860075 DOI: 10.3389/fneur.2025.1499493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/29/2025] [Indexed: 02/28/2025] Open
Abstract
Background Ischemic stroke is a major cause of death and morbidity, and risk classification is essential for predicting therapeutic outcomes. MicroRNAs may be useful indicators for risk stratification, as they control gene expression and influence physiological and pathological processes. Methodology A systematic strategy was developed to search relevant material using databases like PubMed, Scopus, and Web of Science. Selection criteria included human research, a certain date, or categories of studies. Data extraction, synthesis, and analysis were carried out to find trends, similarities, and differences among the chosen studies. The study's design, sample size, methodology, statistical analysis, and any potential biases or restrictions from the selected reference papers were also taken into account. Results and findings MicroRNA is an important biomarker for risk stratification in Ischemic Strokes. It can be used to identify Stroke-Specific microRNA Signatures, identify diagnostic and prognostic values, and regulate Vascular Inflammation, Endothelial Dysfunction, and Thrombus Formation and Resolution. It also has potential therapeutic applications. Conclusion MicroRNAs have emerged as promising biomarkers for predicting stroke risk, severity of strokes, and clinical outcomes. They can be used to predict the severity of a stroke and aid clinicians in making treatment decisions.
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Affiliation(s)
- Hosam M. Al-Jehani
- Department of Neurosurgery and Interventional Neuroradiology and Critical Care Medicine, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia
- Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
- Department of Neurosurgery, Houston Methodist Hospital, Weill Cornell University, Houston, TX, United States
- Department of Neurosurgery and Interventional Neuroradiology, King Fahd Hospital Specialist Hospital, Dammam, Saudi Arabia
| | - Ahmed Hafez Mousa
- Department of Neurosurgery and Interventional Neuroradiology, King Fahd Hospital Specialist Hospital, Dammam, Saudi Arabia
- Neurosciences, Dubai Health, Dubai, United Arab Emirates
- Department of Neurosurgery, Graduate Medical Education, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Department of Neurosurgery and Interventional Neuroradiology, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia
| | - May Adel Alhamid
- Department of Neurology and Interventional Neuroradiology, King Fahad Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Fawaz Al-Mufti
- Department of Neurology and Neurosurgery, Westchester Medical Center at New York Medical College, Valhalla, NY, United States
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Saha P, Yarra SS, Arruri V, Mohan U, Kumar A. Exploring the role of miRNA in diabetic neuropathy: from diagnostics to therapeutics. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:1129-1144. [PMID: 39249503 DOI: 10.1007/s00210-024-03422-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/29/2024] [Indexed: 09/10/2024]
Abstract
Diabetic neuropathy (DN) is one of the major microvascular complications of diabetes mellitus affecting 50% of the diabetic population marred by various unmet clinical needs. There is a need to explore newer pathological mechanisms for designing futuristic regimens for the management of DN. There is a need for post-transcriptional regulation of gene expression by non-coding RNAs (ncRNAs) to finetune different cellular mechanisms with significant biological relevance. MicroRNAs (miRNAs) are a class of small ncRNAs (~ 20 to 24 nucleotide length) that are known to regulate the activity of ~ 50% protein-coding genes through repression of their target mRNAs. Differential expression of these miRNAs is associated with the pathophysiology of diabetic neuropathy via regulating various pathways such as neuronal hyperexcitability, inflammation, axonal growth, regeneration, and oxidative stress. Of note, the circulating and extracellular vesicular miRNAs serve as potential biomarkers underscoring their diagnostic potential. Recent pieces of evidence highlight the potential of miRNAs in modulating the initiation and progression of DN and the possibility of developing miRNAs as treatment options for DN. In this review, we have elaborated on the role of different miRNAs as potential biomarkers and emphasized their druggable aspects for promising future therapies for the clinical management of DN.
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Affiliation(s)
- Priya Saha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) SAS Nagar, Sec 67, Mohali, Punjab, 160062, India
| | - Sai Sumanjali Yarra
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Kolkata, Maniktala Main Road, Kolkata, West Bengal, India
| | - Vijay Arruri
- Department of Neurological Surgery, University of Wisconsin, Madison, USA
| | - Utpal Mohan
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Kolkata, Maniktala Main Road, Kolkata, West Bengal, India
| | - Ashutosh Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) SAS Nagar, Sec 67, Mohali, Punjab, 160062, India.
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Mainali S, Nepal G, Shumilov K, Webb A, Fadda P, Mirebrahimi D, Hamed M, Nana-Sinkam P, Worrall BB, Woo D, Johnson N. MicroRNA Expression Profile in Acute Ischemic Stroke. Int J Mol Sci 2025; 26:747. [PMID: 39859461 PMCID: PMC11765720 DOI: 10.3390/ijms26020747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/23/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
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 the 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. In our longitudinal prospective cohort study, we collected data from acLVO stroke patients at four critical time intervals post-symptom onset: 0-6 h, 6-12 h, 12-24 h, 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. Within the first 6 h 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. 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.
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Affiliation(s)
- Shraddha Mainali
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Gaurav Nepal
- Department of Internal Medicine, Maharajgunj Medical Campus, Tribhuvan University, Kathmandu 44600, Nepal;
| | - Kirill Shumilov
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Amy Webb
- Biomedical Informatics Shared Resources, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Paolo Fadda
- Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
| | - Darya Mirebrahimi
- College of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Mohammad Hamed
- Department of Neurology, Division of Stroke and Neurocritical Care, The Ohio State University, Columbus, OH 43210, USA
| | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Disease and Critical Care Medicine, VCU School of Medicine, Richmond, VA 23298, USA
| | - Bradford B. Worrall
- Department of Neurology, University of Virginia, Charlottesville, VA 22903, USA
| | - Daniel Woo
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Nicholas Johnson
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
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Ahmed S, Adnan H, Khawaja MA, Butler AE. Novel Micro-Ribonucleic Acid Biomarkers for Early Detection of Type 2 Diabetes Mellitus and Associated Complications-A Literature Review. Int J Mol Sci 2025; 26:753. [PMID: 39859467 PMCID: PMC11765584 DOI: 10.3390/ijms26020753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/11/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most widespread chronic diseases globally, with its prevalence expected to rise significantly in the years ahead. Previous studies on risk stratification for T2DM identify certain biomarkers, including glycated hemoglobin (HbA1c), oral glucose tolerance testing (OGTT), fructosamine, and glycated albumin, as key indicators for predicting the onset and progression of T2DM. However, these traditional markers have been shown to lack sensitivity and specificity and their results are difficult to analyze due to non-standardized interpretation criteria, posing significant challenges to an accurate and definitive diagnosis. The strict measures of these traditional markers may not catch gradual increases in blood sugar levels during the early stages of diabetes evolution, as these might still fall within acceptable glycemic parameters. Recent advancements in research have suggested novel micro ribonucleic acid (miRNA) as circulatory molecules that can facilitate the early detection of prediabetic conditions in high-risk groups and potentially enable prevention of the progression to T2DM. This capability makes them a very powerful tool for potentially improving population health, enhancing outcomes for many patients, and reducing the overall burden of T2DM. These promising biomarkers are small, noncoding RNA involved in the regulation of many cellular functions that have a hand in the metabolic activities of cells, making them a very useful and relevant biomarker to explore for the diagnosis and risk stratification of T2DM. This review analyzes the current literature, outlining the occurrence of miRNAs in prediabetic and diabetic individuals and their implications in predicting dysglycemic disorders.
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Affiliation(s)
- Sara Ahmed
- School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen 15503, Bahrain; (S.A.); (H.A.); (M.A.K.)
| | - Haroon Adnan
- School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen 15503, Bahrain; (S.A.); (H.A.); (M.A.K.)
| | - Maryam A. Khawaja
- School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Busaiteen 15503, Bahrain; (S.A.); (H.A.); (M.A.K.)
| | - Alexandra E. Butler
- Research Department, Royal College of Surgeons in Ireland-Bahrain, Busaiteen 15503, Bahrain
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Zhang H, Wang J, Qu Y, Yang Y, Guo ZN. Brain injury biomarkers and applications in neurological diseases. Chin Med J (Engl) 2025; 138:5-14. [PMID: 38915214 PMCID: PMC11717530 DOI: 10.1097/cm9.0000000000003061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Indexed: 06/26/2024] Open
Abstract
ABSTRACT Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
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Affiliation(s)
- Han Zhang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Jing Wang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yang Qu
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Yi Yang
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Zhen-Ni Guo
- Stroke Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
- Neuroscience Research Center, Department of Neurology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
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Pir GJ, Zahid MA, Akhtar N, Ayadathil R, Pananchikkal SV, Joseph S, Morgan DM, Babu B, Ty Ui R, Sivasankaran S, Francis R, Own A, Shuaib A, Parray A, Agouni A. Differentially expressed miRNA profiles of serum derived extracellular vesicles from patients with acute ischemic stroke. Brain Res 2024; 1845:149171. [PMID: 39168264 DOI: 10.1016/j.brainres.2024.149171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 08/13/2024] [Accepted: 08/17/2024] [Indexed: 08/23/2024]
Abstract
BACKGROUND MicroRNAs (miRNAs) participate in diverse cellular changes following acute ischemic stroke (AIS). Circulating miRNAs, stabilized and delivered to target cells via extracellular vesicles (EVs), are potential biomarkers to facilitate diagnosis, prognosis, and therapeutic modulation. We aimed to identify distinctive expression patterns of circulating EV-miRNAs in AIS patients. METHODS miRNA profiles from EVs, isolated from plasma samples collected within 24 h following AIS diagnosis, were examined between a dataset of 10 age-, gender- and existing comorbidities-matched subjects (5 AIS and 5 healthy controls, HC). We measured 2578 miRNAs and identified differentially expressed miRNAs between AIS and HC. An enrichment analysis was conducted to delineate the networks and biological pathways implicated by differentially expressed microRNAs. An enrichment analysis was conducted to delineate the networks and biological pathways implicated by differentially expressed microRNAs. RESULTS Five miRNAs were differentially expressed between stroke (AIS) versus control (HC). hsa-let-7b-5p, hsa-miR-16-5p, and hsa-miR-320c were upregulated, whereas hsa-miR-548a-3p and hsa-miR-6808-3p, with no previously reported changes in stroke were downregulated. The target genes of these miRNAs affect various cellular pathways including, RNA transport, autophagy, cell cycle progression, cellular senescence, and signaling pathways like mTOR, PI3K-Akt, and p53. Key hub genes within these networks include TP53, BCL2, Akt, CCND1, and NF-κB. These pathways are crucial for cellular function and stress response, and their dysregulation can have significant implications for the disease processes. CONCLUSION Our findings reveal distinct circulating EV-miRNA expression patterns in AIS patients from Qatar, highlighting potential biomarkers that could aid in stroke diagnosis and therapeutic strategies. The identified miRNAs are involved in critical cellular pathways, offering novel insights into the molecular mechanisms underlying stroke pathology. Circulating EV-miRNAs differentially expressed in AIS may have a pathophysiological role and may guide further research to elucidate their precise mechanisms.
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Affiliation(s)
- Ghulam Jeelani Pir
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Muhammad Ammar Zahid
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Naveed Akhtar
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Raheem Ayadathil
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sajitha V Pananchikkal
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sujata Joseph
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Deborah M Morgan
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Blessy Babu
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ryan Ty Ui
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shobhna Sivasankaran
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Reny Francis
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ahmed Own
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ashfaq Shuaib
- Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada
| | - Aijaz Parray
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Abdelali Agouni
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar.
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Lan H, Yuan S, Song Y, Liu T, Agarwal G, Li X, Liang L, Wei G. Differential analysis of microRNAs in plasma exosomes in patients with cerebral ischemic stroke. Medicine (Baltimore) 2024; 103:e40677. [PMID: 39612450 DOI: 10.1097/md.0000000000040677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2024] Open
Abstract
The high incidence, disability, mortality, and recurrence rates of cerebral infarction impose a heavy burden on both the Chinese and global populations. It is essential for the early diagnosis, prevention, and protection against brain cell injury. To identify differentially expressed microRNAs (miRNAs) in plasma exosomes of patients with cerebral ischemic stroke, determine relevant biomarkers, and explore their potential signaling pathways. High-throughput sequencing was used to detect the expression of plasma exosomal miRNAs in patients with cerebral ischemic stroke and in a control group. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment, and target gene network analyses were performed to investigate the target genes and signaling pathways of the differentially expressed miRNAs. The sequencing results identified 95 differentially expressed miRNAs, with 40 upregulated and 55 downregulated miRNAs. Among these, hsa-miR-1303, hsa-miR-125b-1-3p, and hsa-miR-548ab were significantly upregulated in the stroke group and downregulated in the normal control group, whereas hsa-miR-1289 was downregulated in the stroke group and upregulated in the normal group. Gene Ontology, Kyoto Encyclopedia of Genes, and genomes enrichment analyses indicated that the differentially expressed miRNAs and their target genes were mainly concentrated in the PI3K-AKt, mitogen-activated protein kinase, calcium, Ras, Rap1, and cAMP signaling pathways. The expression of plasma exosomal hsa-miR-1303, hsa-miR-125b-1-3p, and hsa-miR-1289 was significantly different in stroke patients than in the control group. These miRNAs may be involved in various signaling pathways related to cerebral infarction, providing a reference for further experimental research.
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Affiliation(s)
- Haifang Lan
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
| | - Shengshan Yuan
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yanlun Song
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
| | - Tingjun Liu
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
| | - Gautam Agarwal
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
| | - Xuebin Li
- Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Modern Industrial College of Biomedicine and Great Health, Youjiang Medical University for Nationalities, Guangxi, China
| | - Lina Liang
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
| | - Guijiang Wei
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
- Baise Key Laboratory for Research and Development on Clinical Molecular Diagnosis for High-Incidence Diseases, Guangxi, China
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi, Guangxi, China
- Modern Industrial College of Biomedicine and Great Health, Youjiang Medical University for Nationalities, Guangxi, China
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11
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Zhang Z, Hua J, Chen L. The causal association between COVID-19 and ischemic stroke: a mendelian randomization study. Virol J 2024; 21:280. [PMID: 39506873 PMCID: PMC11542230 DOI: 10.1186/s12985-024-02548-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/18/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Current observational data indicates that ischemic stroke (IS) affects a significant proportion of people with COVID-19. The current study sought to evaluate the causal relationship between COVID-19 and IS. METHODS A two-sample Mendelian randomization (2 S-MR) approach was used to probe the relationship between genetic determinants of three COVID-19 parameters (SARS-CoV-2 infection, COVID-19 hospitalization, and severe COVID-19) and the incidence of IS based on genome-wide association studies (GWAS) data. Using this 2 S-MR technique, expression quantitative trait loci (eQTL) and GWAS studies were further assessed for overlap to identify common causative genes associated with severe COVID-19 and IS. RESULTS IVW approaches indicated the genetic variants linked to COVID-19 hospitalization (OR 1.04, 95% CI 1.01-1.08, p = 0.023) and severe COVID-19 (OR 1.03, 95% CI 1.01-1.05, p = 0.007) were both significantly linked to greater odds of IS. In contrast, there was no causal association between genetic SARS-CoV-2 infection susceptibility and the occurrence of IS (OR 0.99, 95% CI 0.92-1.06, p = 0.694). Ten shared causal genes (TNFSF8, CFL2, TPM1, C15orf39, LHFPL6, FAM20C, SPAG9, KCNJ2, PELI1, and HLA-L) were established as possible mediators of the interplay between severe COVID-19 and the development of IS, with these genes primarily being enriched in immune-related and renin-angiotensin-aldosterone system pathways. CONCLUSION These findings indicate a possible causative relationship between IS risk and COVID-19 severity, offering crucial new information for managing COVID-19 patients. Promising options for therapeutic therapies for severe COVID-19 complicated by IS include the common genes found in the present study.
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Affiliation(s)
- Zhaojie Zhang
- Department of Critical Care Medicine, Zhongda Hospital Lishui Branch, Nanjing Lishui People's Hospital, Southeast University, Nanjing, 211200, China
| | - Jie Hua
- Department of Gastroenterology, Jiangsu Province People' s Hospital, Nanjing, 211029, China
| | - Liang Chen
- Department of Infectious Diseases, Taikang Xianlin Drum Tower Hospital, Affiliated Hospital of Medical College of Nanjing University, NO 188 Lingshan North Road, Qixia District, Nanjing, 210046, China.
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12
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Diamantopoulos MA, Adamopoulos PG, Scorilas A. Small non-coding RNAs as diagnostic, prognostic and predictive biomarkers of gynecological cancers: an update. Expert Rev Mol Diagn 2024; 24:979-995. [PMID: 39390687 DOI: 10.1080/14737159.2024.2408740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 09/22/2024] [Indexed: 10/12/2024]
Abstract
INTRODUCTION Non-coding RNAs (ncRNAs) comprise a heterogeneous cluster of RNA molecules. Emerging evidence suggests their involvement in various aspects of tumorigenesis, particularly in gynecological malignancies. Notably, ncRNAs have been implicated as mediators within tumor signaling pathways, exerting their influence through interactions with RNA or proteins. These findings further highlight the hypothesis that ncRNAs constitute therapeutic targets and point out their clinical potential as stratification biomarkers. AREAS COVERED The review outlines the use of small ncRNAs, including miRNAs, tRNA-derived small RNAs, PIWI-interacting RNAs and circular RNAs, for diagnostic, prognostic, and predictive purposes in gynecological cancers. It aims to increase our knowledge of their functions in tumor biology and their translation into clinical practice. EXPERT OPINION By leveraging interdisciplinary collaborations, scientists can decipher the riddle of small ncRNA biomarkers as diagnostic, prognostic and predictive biomarkers of gynecological tumors. Integrating small ncRNA-based assays into clinical practice will allow clinicians to provide cure plans for each patient, reducing the likelihood of adverse responses. Nevertheless, addressing challenges such as standardizing experimental methodologies and refining diagnostic assays is imperative for advancing small ncRNA research in gynecological cancer.
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Affiliation(s)
- Marios A Diamantopoulos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis G Adamopoulos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
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13
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Barbo M, Glavač D, Jezernik G, Ravnik-Glavač M. MicroRNAs as Biomarkers in Spinal Muscular Atrophy. Biomedicines 2024; 12:2428. [PMID: 39594995 PMCID: PMC11592373 DOI: 10.3390/biomedicines12112428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/28/2024] Open
Abstract
Spinal muscular atrophy (SMA) is a severe neurodegenerative disease caused by the loss of the survival motor neuron (SMN) protein, leading to degeneration of anterior motor neurons and resulting in progressive muscle weakness and atrophy. Given that SMA has a single, well-defined genetic cause, gene-targeted therapies have been developed, aiming to increase SMN production in SMA patients. The SMN protein is likely involved in the synthesis of microRNAs (miRNAs), and dysregulated miRNA expression is increasingly associated with the pathophysiology of SMA. Currently, there is a lack of reliable biomarkers to monitor SMA; therefore, the search for novel SMA biomarkers, including miRNAs, is crucial as reliable tools are needed to track disease progression, predict the response to therapy and understand the different clinical outcomes of available treatments. In this review, we compile data on miRNAs associated with SMA pathogenesis and their potential use as biomarkers. Based on current knowledge, the most frequently deregulated miRNAs between SMA patients and controls, as well as pre- and post-treatment in SMA patients, include miR-1-3p, miR-133a-3p, miR-133b, and miR-206. These findings offer promising possibilities for improving patient classification and monitoring disease progression and response to treatment. Additionally, these findings provide insights into the broader molecular mechanisms and networks of SMA that could inform the development of future therapeutic strategies.
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Affiliation(s)
- Maruša Barbo
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Damjan Glavač
- Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (D.G.); (G.J.)
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Gregor Jezernik
- Center for Human Genetics & Pharmacogenomics, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (D.G.); (G.J.)
| | - Metka Ravnik-Glavač
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
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14
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Aderinto N, Olatunji G, Kokori E, Sanker V, Yusuf IA, Adefusi TO, Egbunu E, Aboje JE, Apampa OO, Ogieuhi IJ, Obasanjo OM, Awuah WA. miR-210 in ischaemic stroke: biomarker potential, challenges and future perspectives. Eur J Med Res 2024; 29:432. [PMID: 39180099 PMCID: PMC11342498 DOI: 10.1186/s40001-024-02029-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/17/2024] [Indexed: 08/26/2024] Open
Abstract
Ischaemic stroke, a leading cause of global morbidity and mortality, necessitates effective biomarkers for enhanced diagnostic and prognostic stratification. MicroRNAs (miRNAs), particularly miR-210, have emerged as promising candidates due to their intricate regulatory roles in cellular responses to hypoxia and neuroprotective effects. This study explores the potential of miR-210 as a biomarker for ischaemic stroke, considering its expression patterns, regulatory functions and diagnostic/prognostic implications. A literature search was conducted on PubMed, Scopus, Google Scholar and Web of Science to identify studies focusing on miR-210 in ischaemic stroke. Inclusion criteria comprised reports on miR-210 expression in ischaemic stroke patients, excluding non-English studies, reviews, commentaries and conference abstracts lacking primary data. Studies investigating miR-210 levels in ischaemic stroke patients revealed significant alterations in expression patterns compared to healthy controls. Diagnostic potential was explored, indicating miR-210's sensitivity and specificity in distinguishing ischaemic stroke from other neurological conditions. Prognostic value was evident through associations with infarct size, functional outcomes and long-term survival. Challenges included variability in miR-210 levels, limited diagnostic specificity, absence of standardised assays and concerns regarding cost-effectiveness and accessibility. While miR-210 holds promise as an ischaemic stroke biomarker, challenges must be addressed for its successful integration into clinical practice. Standardised reference ranges, validation studies in diverse populations and collaborative efforts for assay standardisation are crucial. Despite challenges, miR-210's diagnostic and prognostic potential, particularly in predicting therapeutic responses, suggests a significant role in advancing ischaemic stroke management.
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Affiliation(s)
- Nicholas Aderinto
- Department of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
- Department of Medicine and Surgery, Ladoke Akintola University of Technology, Ogbomoso, Nigeria.
| | - Gbolahan Olatunji
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Emmanuel Kokori
- Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria
| | - Vivek Sanker
- Department of Neurosurgery, Trivandrum Medical College, Thiruvananthapuram, Kerala, India
| | - Ismaila Ajayi Yusuf
- Department of Medicine and Surgery, Obafemi Awolowo University Teaching Hospital, Ife, Nigeria
| | | | | | - John Ehi Aboje
- College of Health Sciences, Benue State University, Benue, Nigeria
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15
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Xiao X, Luo Z, Peng M, Yan H, Yi D, Du Z, Liu J. Expression profile of circulating miRNAs in patients with atrial fibrillation-dominated cardioembolic stroke: A systematic review and bioinformatics analysis. Heliyon 2024; 10:e35201. [PMID: 39166047 PMCID: PMC11334639 DOI: 10.1016/j.heliyon.2024.e35201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/22/2024] Open
Abstract
Background Cardioembolic stroke is a type of ischemic stroke with high disability and mortality, a high recurrence rate and poor prognosis. miRNAs have been explored as potential noninvasive biomarkers in atrial fibrillation and ischemic stroke, but their expression profile in cardioembolic stroke still needs to be explored. This study will explore the differences in miRNA expression between cardioembolic stroke patients and healthy people through meta-analysis and attempt to analyze the target genes by bioinformatics analysis. Methods Literature databases and gene expression databases were searched from the inception date to June 2022. The study reported the circulating miRNA expression profiles in cardioembolic stroke patients and healthy controls. miRNAs with significantly differential expression and their target genes were analyzed. Results Three articles and one gene expression dataset were included in the analysis. The results showed that miR-21-5p (SMD: 2.16; 95 % CI: 1.57, 2.75; p < 0.001), miR-943, miR-145-3p, and miR-3148 were upregulated in cardioembolic stroke patients compared with controls. The downregulated miRNAs included miR-3136-5p, miR-2277-5p, and miR-2277-3p. The area under the receiver operating characteristic curve of miR-21-5p for cardioembolic stroke was 0.975 (0.933-0.989). For the enrichment results, the target genes of upregulated miRNAs were enriched in the MAPK signaling pathway, Ras signaling pathway, etc. The target genes of downregulated miRNAs were also enriched in the Ras signaling pathway. Conclusions This study suggested that circulating miR-21-5p is upregulated in cardioembolic stroke patients compared to healthy controls. The Ras signaling pathway plays an important role in pathogenesis according to enrichment analysis.
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Affiliation(s)
- Xiangbin Xiao
- Corresponding author. No. 196, Hospital Road, Jianyang City, Sichuan Province, 641400, China.
| | | | - Minjian Peng
- Cardiovascular Department, The People's Hospital of Jianyang City, Chengdu, Sichuan Province, China
| | - Hui Yan
- Cardiovascular Department, The People's Hospital of Jianyang City, Chengdu, Sichuan Province, China
| | - Dengliang Yi
- Cardiovascular Department, The People's Hospital of Jianyang City, Chengdu, Sichuan Province, China
| | - Zigang Du
- Cardiovascular Department, The People's Hospital of Jianyang City, Chengdu, Sichuan Province, China
| | - Ji Liu
- Cardiovascular Department, The People's Hospital of Jianyang City, Chengdu, Sichuan Province, China
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16
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Gasecka A, Błażejowska E, Pluta K, Gajewska M, Rogula S, Filipiak KJ, Kochman J, Siller-Matula JM, Postuła M, Eyileten C. Ticagrelor downregulates the expression of proatherogenic and proinflammatory miR125-b compared to clopidogrel: A randomized, controlled trial. Int J Cardiol 2024; 406:132073. [PMID: 38643804 DOI: 10.1016/j.ijcard.2024.132073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.
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Affiliation(s)
- Aleksandra Gasecka
- 1(st) Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland.
| | - Ewelina Błażejowska
- 1(st) Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Kinga Pluta
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Gajewska
- 1(st) Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Sylwester Rogula
- 1(st) Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof J Filipiak
- Maria Sklodowska-Curie Medical Academy in Warsaw, Warsaw, Poland; Department of Hypertensiology, Angiology and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Janusz Kochman
- 1(st) Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | | | - Marek Postuła
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
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17
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Wicik Z, Eyileten C, Nowak A, Keshwani D, Simões SN, Martins DC, Klos K, Wlodarczyk W, Assinger A, Soldacki D, Chcialowski A, Siller-Matula JM, Postula M. Alteration of circulating ACE2-network related microRNAs in patients with COVID-19. Sci Rep 2024; 14:13573. [PMID: 38866792 PMCID: PMC11169442 DOI: 10.1038/s41598-024-58037-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/25/2024] [Indexed: 06/14/2024] Open
Abstract
Angiotensin converting enzyme 2 (ACE2) serves as the primary receptor for the SARS-CoV-2 virus and has implications for the functioning of the cardiovascular system. Based on our previously published bioinformatic analysis, in this study we aimed to analyze the diagnostic and predictive utility of miRNAs (miR-10b-5p, miR-124-3p, miR-200b-3p, miR-26b-5p, miR-302c-5p) identified as top regulators of ACE2 network with potential to affect cardiomyocytes and cardiovascular system in patients with COVID-19. The expression of miRNAs was determined through qRT-PCR in a cohort of 79 hospitalized COVID-19 patients as well as 32 healthy volunteers. Blood samples and clinical data of COVID-19 patients were collected at admission, 7-days and 21-days after admission. We also performed SHAP analysis of clinical data and miRNAs target predictions and advanced enrichment analyses. Low expression of miR-200b-3p at the seventh day of admission is indicative of predictive value in determining the length of hospital stay and/or the likelihood of mortality, as shown in ROC curve analysis with an AUC of 0.730 and a p-value of 0.002. MiR-26b-5p expression levels in COVID-19 patients were lower at the baseline, 7 and 21-days of admission compared to the healthy controls (P < 0.0001). Similarly, miR-10b-5p expression levels were lower at the baseline and 21-days post admission (P = 0.001). The opposite situation was observed in miR-124-3p and miR-302c-5p. Enrichment analysis showed influence of analyzed miRNAs on IL-2 signaling pathway and multiple cardiovascular diseases through COVID-19-related targets. Moreover, the COVID-19-related genes regulated by miR-200b-3p were linked to T cell protein tyrosine phosphatase and the HIF-1 transcriptional activity in hypoxia. Analysis focused on COVID-19 associated genes showed that all analyzed miRNAs are strongly affecting disease pathways related to CVDs which could be explained by their strong interaction with the ACE2 network.
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Affiliation(s)
- Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, 02-957, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
- Doctoral School, Medical University of Warsaw, 02-091, Warsaw, Poland
- Department of Diabetology and Internal Medicine, University Clinical Centre, Medical University of Warsaw, Warsaw, Poland
| | - Disha Keshwani
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland
| | - Sérgio N Simões
- Federal Institute of Education, Science and Technology of Espírito Santo, Serra, Espírito Santo, 29056-264, Brazil
| | - David C Martins
- Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo Andre, 09606-045, Brazil
| | - Krzysztof Klos
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Wojciech Wlodarczyk
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Dariusz Soldacki
- Department of Clinical Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Chcialowski
- Department of Infectious Diseases and Allergology - Military Institute of Medicine, Warsaw, Poland
| | - Jolanta M Siller-Matula
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, 1090, Vienna, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology CEPT, Medical University of Warsaw, 02-097, Warsaw, Poland.
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18
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Gorgani L, Mohammadi M, Najafpour Darzi G, Raoof JB. Metal-organic framework (MOF)-based biosensors for miRNA detection. Talanta 2024; 273:125854. [PMID: 38447342 DOI: 10.1016/j.talanta.2024.125854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/31/2023] [Accepted: 02/28/2024] [Indexed: 03/08/2024]
Abstract
MicroRNAs (miRNAs) play several crucial roles in the physiological and pathological processes of the human body. They are considered as important biomarkers for the diagnosis of various disorders. Thus, rapid, sensitive, selective, and affordable detection of miRNAs is of great importance. However, the small size, low abundance, and highly similar sequences of miRNAs impose major challenges to their accurate detection in biological samples. In recent years, metal-organic frameworks (MOFs) have been applied as promising sensing materials for the fabrication of different biosensors due to their distinctive characteristics, such as high porosity and surface area, tunable pores, outstanding adsorption affinities, and ease of functionalization. In this review, the applications of MOFs and MOF-derived materials in the fabrication of fluorescence, electrochemical, chemiluminescence, electrochemiluminescent, and photoelectrochemical biosensors for the detection of miRNAs and their detection principle and analytical performance are discussed. This paper attempts to provide readers with a comprehensive knowledge of the fabrication and sensing mechanisms of miRNA detection platforms.
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Affiliation(s)
- Leila Gorgani
- Biotechnology Research Laboratory, Faculty of Chemical Engineering, Babol Noshirvani University of Technology, Babol, 47148-71167, Iran
| | - Maedeh Mohammadi
- Biotechnology Research Laboratory, Faculty of Chemical Engineering, Babol Noshirvani University of Technology, Babol, 47148-71167, Iran; School of Chemical Engineering, Universiti Sains Malaysia, 14300, Nibong Tebal, Pulau Pinang, Malaysia.
| | - Ghasem Najafpour Darzi
- Biotechnology Research Laboratory, Faculty of Chemical Engineering, Babol Noshirvani University of Technology, Babol, 47148-71167, Iran
| | - Jahan Bakhsh Raoof
- Electroanalytical Chemistry Research Laboratory, Department of Analytical Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, Iran
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Ullah A, Ullah M, Lim SI. Recent advancements in nanotechnology based drug delivery for the management of cardiovascular disease. Curr Probl Cardiol 2024; 49:102396. [PMID: 38266693 DOI: 10.1016/j.cpcardiol.2024.102396] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 01/14/2024] [Indexed: 01/26/2024]
Abstract
Cardiovascular diseases (CVDs) constitute a predominant cause of both global mortality and morbidity. To address the challenges in the early diagnosis and management of CVDs, there is growing interest in the field of nanotechnology and nanomaterials to develop innovative diagnostic and therapeutic approaches. This review focuses on the recent advancements in nanotechnology-based diagnostic techniques, including cardiac immunoassays (CIA), cardiac circulating biomarkers, cardiac exosomal biomarkers, and molecular Imaging (MOI). Moreover, the article delves into the exciting developments in nanoparticles (NPs), biomimetic NPs, nanofibers, nanogels, and nanopatchs for cardiovascular applications. And discuss how these nanoscale technologies can improve the precision, sensitivity, and speed of CVD diagnosis and management. While highlighting their vast potential, we also address the limitations and challenges that must be overcome to harness these innovations successfully. Furthermore, this review focuses on the emerging opportunities for personalized and effective cardiovascular care through the integration of nanotechnology, ultimately aiming to reduce the global burden of CVDs.
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Affiliation(s)
- Aziz Ullah
- Department of Chemical Engineering, Pukyong National University, Yongso-ro 45, Nam-gu, Engineering Bldg#1, Rm1108, Busan 48513, Republic of Korea
| | - Muneeb Ullah
- College of Pharmacy, Pusan National University, Busandaehak-ro 63 beon-gil 2, Geumjeong-gu, Busan 46241, Republic of Korea
| | - Sung In Lim
- Department of Chemical Engineering, Pukyong National University, Yongso-ro 45, Nam-gu, Engineering Bldg#1, Rm1108, Busan 48513, Republic of Korea.
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20
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Gendosz de Carrillo D, Kocikowska O, Rak M, Krzan A, Student S, Jędrzejowska-Szypułka H, Pawletko K, Lasek-Bal A. The Relevance of Reperfusion Stroke Therapy for miR-9-3p and miR-9-5p Expression in Acute Stroke-A Preliminary Study. Int J Mol Sci 2024; 25:2766. [PMID: 38474013 DOI: 10.3390/ijms25052766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
Reperfusion stroke therapy is a modern treatment that involves thrombolysis and the mechanical removal of thrombus from the extracranial and/or cerebral arteries, thereby increasing penumbra reperfusion. After reperfusion therapy, 46% of patients are able to live independently 3 months after stroke onset. MicroRNAs (miRNAs) are essential regulators in the development of cerebral ischemia/reperfusion injury and the efficacy of the applied treatment. The first aim of this study was to examine the change in serum miRNA levels via next-generation sequencing (NGS) 10 days after the onset of acute stroke and reperfusion treatment. Next, the predictive values of the bioinformatics analysis of miRNA gene targets for the assessment of brain ischemic response to reperfusion treatment were explored. Human serum samples were collected from patients on days 1 and 10 after stroke onset and reperfusion treatment. The samples were subjected to NGS and then validated using qRT-PCR. Differentially expressed miRNAs (DEmiRNAs) were used for enrichment analysis. Hsa-miR-9-3p and hsa-miR-9-5p expression were downregulated on day 10 compared to reperfusion treatment on day 1 after stroke. The functional analysis of miRNA target genes revealed a strong association between the identified miRNA and stroke-related biological processes related to neuroregeneration signaling pathways. Hsa-miR-9-3p and hsa-miR-9-5p are potential candidates for the further exploration of reperfusion treatment efficacy in stroke patients.
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Affiliation(s)
- Daria Gendosz de Carrillo
- Department of Physiology, Faculty of Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
- Department of Histology and Cell Pathology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Olga Kocikowska
- Department of Physiology, Faculty of Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
- Department of Engineering and Systems Biology, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Małgorzata Rak
- Department of Physiology, Faculty of Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Aleksandra Krzan
- Department of Neurology, School of Health Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
- Department of Neurology, Upper-Silesian Medical Center of the Silesian Medical University, 40-752 Katowice, Poland
| | - Sebastian Student
- Department of Engineering and Systems Biology, Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, 44-100 Gliwice, Poland
- Biotechnology Centre, Silesian University of Technology, 44-100 Gliwice, Poland
| | - Halina Jędrzejowska-Szypułka
- Department of Physiology, Faculty of Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Katarzyna Pawletko
- Department of Physiology, Faculty of Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
- Department for Experimental Medicine, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
| | - Anetta Lasek-Bal
- Department of Neurology, School of Health Sciences, Medical University of Silesia in Katowice, 40-752 Katowice, Poland
- Department of Neurology, Upper-Silesian Medical Center of the Silesian Medical University, 40-752 Katowice, Poland
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Mainali S, Nepal G, Webb A, Fadda P, Mirebrahimi D, Nana-Sinkam P, Worrall B, Woo D, Johnson N, Hamed M. MicroRNA Expression Profile in Acute Ischemic Stroke. RESEARCH SQUARE 2024:rs.3.rs-3754883. [PMID: 38260305 PMCID: PMC10802726 DOI: 10.21203/rs.3.rs-3754883/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
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.
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Affiliation(s)
| | | | | | | | | | | | | | - Daniel Woo
- University of Cincinnati College of Medicine
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22
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MicroRNA miR-188-5p enhances SUMO2/3 conjugation by targeting SENP3 and alleviates focal cerebral ischemia/reperfusion injury in rats. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:1260-1267. [PMID: 39229582 PMCID: PMC11366937 DOI: 10.22038/ijbms.2024.76165.16485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 01/16/2024] [Indexed: 09/05/2024]
Abstract
Objectives Expression of miR-188-5p changes upon experiencing cerebral I/R injury. SENP3 is a predicted target of miR-188-5p. The study aimed to examine the potential mechanism underlying the miR-188-5p mediated enhancement of SUMO2/3 conjugation via targeting SENP3 and alleviation against cerebral I/R injury. Materials and Methods Focal cerebral I/R was established in Sprague-Dawley rats using the MCAO model. The expression of miR-188-5p was modulated through intracerebroventricular (ICV) administration of its mimics or inhibitors. The expression of miR-188-5p, SENP3, and SUMO2/3 was detected using RT-qPCR or western blot analysis. Dual luciferase reporter assays were conducted to demonstrate the targeting effect of miR-188-5p on SENP3 in N2a cells. HE staining and TUNEL staining were performed to evaluate neurocellular morphological changes and detect neurocellular apoptosis, respectively. The extent of neurological deficits was evaluated using mNSS. TTC staining was used to evaluate the infarct area. Results In the cerebral ischemic penumbra, the expression of miR-188-5p declined and SENP3 levels increased following I/R. Dual luciferase reporter assays confirmed that miR-188-5p directly acted on SENP3 in N2a cells. As a self-protective mechanism, SUMO2/3 conjugation increased after reperfusion. After ICV administration of miR-188-5p inhibitor, the expression of miR-188-5p was down-regulated, the expression of SENP3 was up-regulated, the SUMO2/3 conjugation decreased, and cerebral I/R injury was exacerbated. However, ICV administration of small hairpin RNA targeting SENP3 partially reversed the effects of the miR-188-5p inhibitor. Conclusion MiR-188-5p mitigated cerebral I/R injury by down-regulating SENP3 expression and consequently enhancing SUMO2/3 conjugation in rats.
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23
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Abdel-Reheim MA, Nomier Y, Zaki MB, Abulsoud AI, Mohammed OA, Rashad AA, Oraby MA, Elballal MS, Tabaa MME, Elazazy O, Abd-Elmawla MA, El-Dakroury WA, Abdel Mageed SS, Abdelmaksoud NM, Elrebehy MA, Helal GK, Doghish AS. Unveiling the regulatory role of miRNAs in stroke pathophysiology and diagnosis. Pathol Res Pract 2024; 253:155085. [PMID: 38183822 DOI: 10.1016/j.prp.2023.155085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 12/28/2023] [Accepted: 12/30/2023] [Indexed: 01/08/2024]
Abstract
Stroke, a major global cause of mortality, leads to a range of problems for those who survive. Besides its brutal events, stroke also tends to have a characteristic of recurrence, making it a complex disease involving intricate regulatory networks. One of the major cellular regulators is the non-coding RNAs (ncRNA), specifically microRNAs (miRNAs), thus the possible functions of miRNAs in the pathogenesis of stroke are discussed as well as the possibility of using miRNA-based therapeutic approaches. Firstly, the molecular mechanisms by which miRNAs regulate vital physiological processes, including synaptic plasticity, oxidative stress, apoptosis, and the integrity of the blood-brain barrier (BBB) are reviewed. The miRNA indirectly impacts stroke outcomes by regulating BBB function and angiogenesis through the targeting of transcription factors and angiogenic factors. In addition, the tendency for some miRNAs to be upregulated in response to hypoxia, which is a prevalent phenomenon in stroke and various neurological disorders, highlights the possibility that it controls hypoxia-inducible factor (HIF) signaling and angiogenesis, thereby influencing the integrity of the BBB as examples of the discussed mechanisms. Furthermore, this review explores the potential therapeutic targets that miRNAs may offer for stroke recovery and highlights their promising capacity to alleviate post-stroke complications. This review provides researchers and clinicians with valuable resources since it attempts to decipher the complex network of miRNA-mediated mechanisms in stroke. Additionally, the review addresses the interplay between miRNAs and stroke risk factors as well as clinical applications of miRNAs as diagnostic and prognostic markers.
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Affiliation(s)
- Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Yousra Nomier
- Department of Pharmacology and Clinical Pharmacy, College of Medicine and health sciences, Sultan Qaboos University, Muscat, Oman
| | - Mohamed Bakr Zaki
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ahmed A Rashad
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mamdouh A Oraby
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Manar Mohammed El Tabaa
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City 32897, Menoufia, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mai A Abd-Elmawla
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | | | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Gouda Kamel Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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Jarosz-Popek J, Eyileten C, Gager GM, Nowak A, Szwed P, Wicik Z, Palatini J, von Lewinski D, Sourij H, Siller-Matula JM, Postula M. The interaction between non-coding RNAs and SGLT2: A review. Int J Cardiol 2023; 398:131419. [PMID: 39492411 DOI: 10.1016/j.ijcard.2023.131419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 09/19/2023] [Accepted: 10/03/2023] [Indexed: 11/05/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2, SLC5A2) is a promising target for a new class of drug primarily established as kidney-targeting as well as emerging class of glucose-lowering drugs in diabetes. Studies showed that SGLT2 inhibitors also have a systemic impact via indirectly targeting the heart and kidneys which exerts broad cardio- and nephroprotective effects. Additionally, as cancer cells tightly require glucose supply, studies also questioned how SGLT2 inhibitors impact molecular pathology and cellular metabolism in cancer hallmarks. However, the exact molecular mechanisms responsible for those benefits have not been fully discovered. MicroRNAs (miRNA) and circularRNAs (circRNAs) are endogenous, single-stranded, non-coding RNAs (ncRNAs) that can control protein-coding genes, affecting significant molecular and cellular processes regulating homeostasis. CircRNAs particularly regulate gene expression at the transcriptional and post-transcriptional level by sponging to miRNAs and by altering interactions between proteins.
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Affiliation(s)
- Joanna Jarosz-Popek
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Gloria M Gager
- Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria; Department of Clinical Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Anna Nowak
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Szwed
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego 9 Street, Warsaw 02-957, Poland
| | - Jeff Palatini
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | - Jolanta M Siller-Matula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna 1090, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, Warsaw, Poland.
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Kamyshnikova LA, Gorbachevskaya KS, Efremova OA, Obolonkova NI, Bolkhovitina OA. Biomarkers of Adverse Cardiovascular Events in Kidney Disease. THE RUSSIAN ARCHIVES OF INTERNAL MEDICINE 2023; 13:253-262. [DOI: 10.20514/2226-6704-2023-13-4-253-262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Based on domestic and international literature the review refers to the analysis of the research data on risk factors and biomarkers for the development of adverse cardiovascular events in patients with chronic kidney disease and acute kidney injury. Biomarker studies are important, especially in the early stages of chronic kidney disease, that is, in patients with creatinine clearance above 60 ml/min/1.73 m2, when preventive and therapeutic measures work more effectively. Among the potential predictors of adverse cardiovascular events, the biomarkers related to the following pathological processes (conditions) should be noted: oxidative stress (malondialdehyde, ischemic-modified albumin; superoxide dismutase), inflammation (interleukin-6, interleukin-18), acute kidney injury (kidney injury molecule 1; neutrophil gelatinase-associated lipocalin), cardiospecific biomarkers (highly sensitive troponin) and circulating microribonucleic acids (specific miRNA-133a, miRNA-21), as well as the prospects for further study of some biomarkers in cardionephrology are discussed. A separate emphasis is placed on the need to establish threshold values for various molecules in chronic kidney disease, depending on the degree of decline in kidney function, which will allow these indicators to be effectively used in clinical practice as diagnostic and prognostic biomarkers for cardiovascular diseases, since their usual reference values are used in the general population, will be higher in kidney disease. Currently, only for troponin and natriuretic peptides, certain reference values are established, which are less clear-cut in the population with chronic kidney disease than in the general population, and for all other biomarkers, cut-off values are not yet known.
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Goyal S, Rani J, Bhat MA, Vanita V. Genetics of diabetes. World J Diabetes 2023; 14:656-679. [PMID: 37383588 PMCID: PMC10294065 DOI: 10.4239/wjd.v14.i6.656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/13/2023] [Accepted: 04/17/2023] [Indexed: 06/14/2023] Open
Abstract
Diabetes mellitus is a complicated disease characterized by a complex interplay of genetic, epigenetic, and environmental variables. It is one of the world's fastest-growing diseases, with 783 million adults expected to be affected by 2045. Devastating macrovascular consequences (cerebrovascular disease, cardiovascular disease, and peripheral vascular disease) and microvascular complications (like retinopathy, nephropathy, and neuropathy) increase mortality, blindness, kidney failure, and overall quality of life in individuals with diabetes. Clinical risk factors and glycemic management alone cannot predict the development of vascular problems; multiple genetic investigations have revealed a clear hereditary component to both diabetes and its related complications. In the twenty-first century, technological advancements (genome-wide association studies, next-generation sequencing, and exome-sequencing) have led to the identification of genetic variants associated with diabetes, however, these variants can only explain a small proportion of the total heritability of the condition. In this review, we address some of the likely explanations for this "missing heritability", for diabetes such as the significance of uncommon variants, gene-environment interactions, and epigenetics. Current discoveries clinical value, management of diabetes, and future research directions are also discussed.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Jyoti Rani
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| | - Mohd Akbar Bhat
- Department of Ophthalmology, Georgetown University Medical Center, Washington DC, DC 20057, United States
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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Siracusa C, Vono N, Morano MB, Sabatino J, Leo I, Eyileten C, Cianflone E, Postula M, Torella D, De Rosa S. Clinical Application of Circular RNAs as Biomarkers in Acute Ischemic Stroke. J Pers Med 2023; 13:jpm13050839. [PMID: 37241009 DOI: 10.3390/jpm13050839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/12/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
Despite the substantial improvement in diagnosis and treatment within the last decades, ischemic stroke still represents a challenge, responsible still for a high burden of morbidity and mortality. Among the unmet clinical needs are the difficulties in identifying those subjects with the greatest risk of developing a stroke, the challenges in obtaining a timely diagnosis, the prompt recognition of the different clinical forms of stroke, the assessment of the response to treatments and the prognostic assessment. All these issues might be improved with appropriate smart biomarkers that could better inform clinical management. The present article offers an overview of the potential role of circular RNAs as disease biomarkers in stroke. A systematic approach was adopted to gather all potentially relevant information in order to provide a panoramic view on this class of promising molecules.
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Affiliation(s)
- Chiara Siracusa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Niccolò Vono
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Maria Benedetta Morano
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Jolanda Sabatino
- Department of Children and Woman's Health, University of Padua, 35121 Padua, Italy
| | - Isabella Leo
- Royal Brompton and Harefield Hospitals, Guy's and St Thomas' NHS Foundation Trust, London SW3 5NP, UK
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Ceren Eyileten
- Centre for Preclinical Research and Technology, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 02-097 Warsaw, Poland
- Genomics Core Facility, Center of New Technologies, University of Warsaw, 00-927 Warsaw, Poland
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Marek Postula
- Centre for Preclinical Research and Technology, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
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Deng L, Zhang J, Chen S, Wu Y, Fan X, Zuo T, Hu Q, Jiang L, Yang S, Dong Z. miR-671-5p Upregulation Attenuates Blood-Brain Barrier Disruption in the Ischemia Stroke Model Via the NF-кB/MMP-9 Signaling Pathway. Mol Neurobiol 2023; 60:3824-3838. [PMID: 36949221 DOI: 10.1007/s12035-023-03318-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 03/14/2023] [Indexed: 03/24/2023]
Abstract
Blood-brain barrier (BBB) disruption can induce further hemorrhagic transformation in ischemic stroke (IS). miR-671-5p, a micro-RNA, is abundant in the cortex of mammalian brains. Herein, we investigated the roles and potential mechanisms for the effects of miR-671-5p on BBB permeability in IS. Results showed that miR-671-5p levels were significantly downregulated in the cerebral cortex of middle cerebral artery occlusion/reperfusion (MCAO/R) C57/BL6 mice in vivo. miR-671-5p agomir administration via right intracerebroventricular injection significantly reduced infarct volume, improved neurological deficits, the axon of neurons and nerve fiber, attenuated cell injury and apoptosis, as well as reduced BBB permeability in MCAO/R mice. Treatment with miR-671-5p agomir alleviated tight junction proteins degradation, including claudin, occludin, and ZO-1 in MCAO/R mice, and these effects were reversed following NF-κB overexpression. Bend.3 brain endothelial cells were subjected to oxygen and glucose deprivation/reoxygenation (OGD/R) treatment in vivo, and then miR-671-5p agomir was transfected into the cells. This resulted in reduction of cytotoxicity, improved cell viability, trans-endothelial electrical resistance, reduced fluorescein sodium permeability, and inhibited tight junction degradation in Bend.3 OGD/R cells. However, these effects were reversed following NF-κB overexpression. These results demonstrated that upregulation of miR-671-5p in IS models in vivo and in vitro alleviated BBB permeability by targeting NF-κB/MMP-9. In summary, miR-671-5p is a potential therapeutic target for protecting BBB permeability in IS to minimize cerebral hemorrhage transformation.
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Affiliation(s)
- Ling Deng
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Jiyu Zhang
- Pain Department, Traditional Chinese Medicine Hospital of Jiulongpo District in Chongqing, Chongqing, 400050, China
| | - Sha Chen
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Yu Wu
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Xiaomei Fan
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Tianrui Zuo
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Qingwen Hu
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Lu Jiang
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Shaonan Yang
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China
| | - Zhi Dong
- College of Pharmacology, The Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, 400016, China.
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Toor SM, Aldous EK, Parray A, Akhtar N, Al-Sarraj Y, Abdelalim EM, Arredouani A, El-Agnaf O, Thornalley PJ, Pananchikkal SV, Pir GJ, Ayadathil R, Shuaib A, Alajez NM, Albagha OME. Circulating MicroRNA Profiling Identifies Distinct MicroRNA Signatures in Acute Ischemic Stroke and Transient Ischemic Attack Patients. Int J Mol Sci 2022; 24:108. [PMID: 36613546 PMCID: PMC9820644 DOI: 10.3390/ijms24010108] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
Transient ischemic attack (TIA) refers to a momentary neurologic deficit caused by focal cerebral, spinal or retinal ischemic insult. TIA is associated with a high risk of impending acute ischemic stroke (AIS), a neurologic dysfunction characterized by focal cerebral, spinal or retinal infarction. Understanding the differences in molecular pathways in AIS and TIA has merit for deciphering the underlying cause for neuronal deficits with long-term effects and high risks of morbidity and mortality. In this study, we performed comprehensive investigations into the circulating microRNA (miRNA) profiles of AIS (n = 191) and TIA (n = 61) patients. We performed RNA-Seq on serum samples collected within 24 hrs of clinical diagnosis and randomly divided the study populations into discovery and validation cohorts. We identified a panel of 11 differentially regulated miRNAs at FDR < 0.05. Hsa-miR-548c-5p, -20a-5p, -18a-5p, -484, -652-3p, -486-3p, -24-3p, -181a-5p and -222-3p were upregulated, while hsa-miR-500a-3p and -206 were downregulated in AIS patients compared to TIA patients. We also probed the previously validated gene targets of our identified miRNA panel to highlight the molecular pathways affected in AIS. Moreover, we developed a multivariate classifier with potential utilization as a discriminative biomarker for AIS and TIA patients. The underlying molecular pathways in AIS compared to TIA may be explored further in functional studies for therapeutic targeting in clinical translation.
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Affiliation(s)
- Salman M. Toor
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Eman K. Aldous
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Aijaz Parray
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Naveed Akhtar
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Yasser Al-Sarraj
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Qatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation (QF), Doha P.O. Box 5825, Qatar
| | - Essam M. Abdelalim
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Abdelilah Arredouani
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Omar El-Agnaf
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Paul J. Thornalley
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Sajitha V. Pananchikkal
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Ghulam Jeelani Pir
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Raheem Ayadathil
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Ashfaq Shuaib
- Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Department of Neurology, Hamad Medical Corporation (HMC), Doha P.O. Box 3050, Qatar
| | - Nehad M. Alajez
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Translational Cancer and Immunity Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
| | - Omar M. E. Albagha
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar
- Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK
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Li W, Shao C, Zhou H, Du H, Chen H, Wan H, He Y. Multi-omics research strategies in ischemic stroke: A multidimensional perspective. Ageing Res Rev 2022; 81:101730. [PMID: 36087702 DOI: 10.1016/j.arr.2022.101730] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/23/2022] [Accepted: 09/03/2022] [Indexed: 01/31/2023]
Abstract
Ischemic stroke (IS) is a multifactorial and heterogeneous neurological disorder with high rate of death and long-term impairment. Despite years of studies, there are still no stroke biomarkers for clinical practice, and the molecular mechanisms of stroke remain largely unclear. The high-throughput omics approach provides new avenues for discovering biomarkers of IS and explaining its pathological mechanisms. However, single-omics approaches only provide a limited understanding of the biological pathways of diseases. The integration of multiple omics data means the simultaneous analysis of thousands of genes, RNAs, proteins and metabolites, revealing networks of interactions between multiple molecular levels. Integrated analysis of multi-omics approaches will provide helpful insights into stroke pathogenesis, therapeutic target identification and biomarker discovery. Here, we consider advances in genomics, transcriptomics, proteomics and metabolomics and outline their use in discovering the biomarkers and pathological mechanisms of IS. We then delineate strategies for achieving integration at the multi-omics level and discuss how integrative omics and systems biology can contribute to our understanding and management of IS.
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Affiliation(s)
- Wentao Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Chongyu Shao
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Huifen Zhou
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Haixia Du
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Haiyang Chen
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Haitong Wan
- School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yu He
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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31
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Eyileten C, Skrobucha A, Starczyński M, Boszko M, Jarosz-Popek J, Fitas A, Filipiak KJ, Kochman J, Huczek Z, Rymuza B, Wilimski R, Kuśmierczyk M, Siller-Matula JM, Postula M, Gąsecka A. Expression of miR-223 to predict outcomes after transcatheter aortic valve implantation. Cardiol J 2022; 31:111-123. [PMID: 36200549 PMCID: PMC10919566 DOI: 10.5603/cj.a2022.0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 07/14/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Transcatheter aortic valve implantation (TAVI) is an established treatment for aortic stenosis (AS) in patients at increased surgical risk. Up to 29% of patients annually experience major adverse cardiac and cerebrovascular events (MACCE) after TAVI. MicroRNAs (miRNA) are currently widely investigated as novel cardiovascular biomarkers. The aim of this study was to determine the influence of TAVI on the expressions of selected miRNAs associated with platelet function (miR-125a-5p, miR-125b and miR-223), and evaluate the predictive value of these miRNAs for MACCE in 65 patients undergoing TAVI. METHODS Venous blood samples for miRNA expression analysis were collected 1 day before TAVI and at hospital discharge. The expression of miR-223, miR-125a-5p, miR-125b was evaluated in platelet-depleted plasma. RESULTS The expression of miR-223 and miR-125b increased after TAVI, compared to the measurement before (p = 0.020, p = 0.003, respectively). Among 63 patients discharged from the hospital, 18 patients experienced MACCE (29%) during the median 15 months of observation. Baseline low miR-223 expression was a predictor of MACCE in univariate Cox regression analysis (hazard ratio [HR]: 2.71, 95% confidence interval [CI]: 1.04-7.01; p = 0.041). After inclusion of covariates, age, gender (male), New York Heart Association class and diabetes into the multivariate Cox regression model, miR-223 did not reach statistical significance (HR: 2.56, 95% CI: 0.79-8.33; p = 0.118). CONCLUSIONS To conclude, miR-223 might improve risk stratification after TAVI. Further studies are required to confirm the clinical applicability of this promising biomarker.
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Affiliation(s)
- Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology, Medical University of Warsaw, Poland
| | - Alicja Skrobucha
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Miłosz Starczyński
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Maria Boszko
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Joanna Jarosz-Popek
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology, Medical University of Warsaw, Poland
| | - Alex Fitas
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology, Medical University of Warsaw, Poland
| | - Krzysztof J Filipiak
- Department of Clinical Sciences, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland
| | - Janusz Kochman
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Zenon Huczek
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Bartosz Rymuza
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
| | - Radosław Wilimski
- Department of Cardiac Surgery, Medical University of Warsaw, Poland.
| | | | - Jolanta M Siller-Matula
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology, Medical University of Warsaw, Poland
- Department of Cardiology, Medical University of Vienna, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Center for Preclinical Research and Technology, Medical University of Warsaw, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland
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Rogula S, Pomirski B, Czyżak N, Eyileten C, Postuła M, Szarpak Ł, Filipiak KJ, Kurzyna M, Jaguszewski M, Mazurek T, Grabowski M, Gąsecka A. Biomarker-based approach to determine etiology and severity of pulmonary hypertension: Focus on microRNA. Front Cardiovasc Med 2022; 9:980718. [PMID: 36277769 PMCID: PMC9582157 DOI: 10.3389/fcvm.2022.980718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/12/2022] [Indexed: 11/25/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is characterized by remodeling of the pulmonary arteries, and defined by elevated pulmonary arterial pressure, measured during right heart catheterization. There are three main challenges to the diagnostic and therapeutic process of patients with PAH. First, it is difficult to differentiate particular PAH etiology. Second, invasive diagnostic is required to precisely determine the severity of PAH, and thus to qualify patients for an appropriate treatment. Third, the results of treatment of PAH are unpredictable and remain unsatisfactory. MicroRNAs (miRNAs) are small non-coding RNAs that regulate post transcriptional gene-expression. Their role as a prognostic, and diagnostic biomarkers in many different diseases have been studied in recent years. MiRNAs are promising novel biomarkers in PAH due to their activity in various molecular pathways and processes underlying PAH. Lack of biomarkers to differentiate between particular PAH etiology and evaluate the severity of PAH, as well as paucity of therapeutic targets in PAH open a new field for the possibility to use miRNAs in these applications. In our article, we discuss the potential of miRNAs use as diagnostic tools, prognostic biomarkers and therapeutic targets in PAH.
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Affiliation(s)
- Sylwester Rogula
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland,*Correspondence: Sylwester Rogula,
| | - Bartosz Pomirski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Norbert Czyżak
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland,Genomics Core Facility, Center of New Technologies (CeNT), University of Warsaw, Warsaw, Poland
| | - Marek Postuła
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Łukasz Szarpak
- Department of Outcomes Research, Maria Skłodowska-Curie Medical Academy in Warsaw, Warsaw, Poland
| | - Krzysztof J. Filipiak
- Institute of Clinical Sciences, Maria Skłodowska-Curie Medical Academy in Warsaw, Warsaw, Poland
| | - Marcin Kurzyna
- Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Otwock, Poland
| | - Miłosz Jaguszewski
- 1st Department of Cardiology, Medical University of Gdańsk, Gdańsk, Poland
| | - Tomasz Mazurek
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Grabowski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
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Upregulation of MiRNA-149-5p Reduces the Infract Volume in Middle Cerebral Artery Occlusion Rats by Modulating Cation-Chloride Cotransporters Expressions. IRANIAN BIOMEDICAL JOURNAL 2022; 26:357-65. [PMID: 35871268 PMCID: PMC9763874 DOI: 10.52547/ibj.3759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Brain ischemia often leads to the chloride gradient alternations, which affects volume regulation and neuronal survival. Increase in NKCC1 expression and reduction in KCC2 level under ischemic condition results in inflammation and neuronal death. In this study, we investigated the effect of mimic miRNA and coenzyme Q10 (CoQ10) on the expression of cation-chloride cotransporters (CCCs) (NKCC1 and KCC2) after cerebral ischemia. Methods In this study, cerebral ischemia was modeled using the middle cerebral artery occlusion method. Rats were randomly divided into six groups: sham, model, negative control, vehicle, and the first and second treatments. In the Sham group, ischemia was not induced, and no treatment was performed. In the Model group, ischemia induction was performed, and other groups, in addition to ischemia induction, received Scramble miRNA, Ethanol, mimic miRNA-149-5p and CoQ10, respectively. Each group was divided into three subgroups to assess the volume of the tissue damage and neurological deficits scores (NDS) in subgroup 1, brain water content in subgroup 2, level of miRNA-149-5p and CCC expressions in subgroup 3. Results Our data suggested that the use of mimic miRNA and Q10 increased the level of miRNA-149 and KCC2 expression and decreased NDS, NKCC1 expression, brain water content, and infract volume. Conclusion Findings of this study suggest that the mimic miRNA and Q10 may have neuroprotective effects through reducing infract volume and brain water content and modulating the expression of CCCs after brain ischemia.
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Ma HP, Fu M, Masula M, Xing CS, Zhou Q, Tan JT, Wang J. miR-3064-5p and miR-4745-5p affect heparin sensitivity in patients undergoing cardiac surgery by regulating AT-III and factor X mRNA levels. Front Physiol 2022; 13:914333. [PMID: 36035472 PMCID: PMC9412912 DOI: 10.3389/fphys.2022.914333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Subject: Perioperative regulation of coagulation function through heparin in patients undergoing cardiac surgery with cardiopulmonary bypass is an important part of performing cardiac surgery, and postoperative bleeding due to abnormal coagulation function caused by differences in heparin sensitivity in different individuals is an independent risk factor for postoperative complications and death.Method: Using an online database, 10 miRNAs interacting with AT-III and FX genes were predicted. Patients were divided into three groups according to the difference in activated clotting time (ACT) after the first dose of heparin (2.5 mg kg−1): group A: hyposensitive group (ACT < 480 s); group B: sensitive group (480 s ≤ ACT ≤ 760 s); and group C: hypersensitive group (ACT > 760 s). Perioperative and 24 h postoperative blood loss and other clinical data of patients in the three groups were recorded. Blood samples were collected before surgery, and RT-PCR was used to detect the levels of AT-III and FX gene mRNA and the levels of predicted 10 miRNAs.Result: Heparin sensitivity was positively correlated with AT-III mRNA levels and negatively correlated with FX gene mRNA levels in the three groups, and the blood loss in group B was significantly lower than that in groups A and C, which was statistically significant (p < 0.05). miR-3064-5p and miR-4745-5p expression levels were significantly different among group A, group B, and group C (p < 0.05) and were closely correlated with AT-III and FX gene mRNA expression levels, respectively.Conclusion: Differences in heparin sensitivity in patients undergoing cardiac surgery were associated with the mRNA expression of AT-III and FX genes, and the expression levels of miR-3064-5p and miR-4745-5p were found to be closely related to the AT-III and FX gene mRNA, respectively, indicating that miR-3064-5p and miR-4745-5p affect the differences in heparin sensitivity among different individuals by regulating the mRNA expression levels of AT-III and FX genes.Clinical Trial Registration:http://www.chictr.org.cn/abouten.aspx, identifier registration number: ChiCTR-2100047348
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Stopic B, Medic-Brkic B, Savic-Vujovic K, Davidovic Z, Todorovic J, Dimkovic N. Biomarkers and Predictors of Adverse Cardiovascular Events in Different Stages of Chronic Kidney Disease. Dose Response 2022; 20:15593258221127568. [PMID: 36118679 PMCID: PMC9478703 DOI: 10.1177/15593258221127568] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Chronic kidney disease (CKD) is an important factor that contributes to the
increase of all-cause morbidity and mortality in the group of non-communicable
diseases, and it is also recognized as a strong and independent risk factor that
contributes to cardiovascular disease (CVD). CVDs are a consequence of the
action of a large number of risk factors among which are traditional and
non-traditional. These risk factors have been the subject of a large number of
studies which partially explained the unfavorable cardiovascular (CV) outcome of
CKD patients. Therefore, valid studies about clinical and biohumoral predictors
are of particular importance, especially in the early stages of renal disease,
that is, in patients with creatinine clearance below
60 ml/min/1.73 m2 when preventive measures are most effective.
Among potential predictors of adverse CV outcome are biomarkers of inflammation
(Interleukin-18—IL-18), oxidative stress (ischemia-modified albumin—IMA;
superoxide dismutase—SOD), acute kidney injury (kidney injury
molecule-1—KIM-1; neutrophil gelatinase–associated
lipocalin—NGAL), and microribonucleic acids (specific microRNA-133a). In this
review, we tried to confirm the relationship between risk factors of CKD and CVD
and newer, less frequently examined biomarkers with the occurrence of incidental
CV events in renal patients.
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Affiliation(s)
- Bojan Stopic
- Clinical Department for Nephrology, Zvezdara University Medical Center, Belgrade, Serbia
| | - Branislava Medic-Brkic
- Faculty of Medicine, Department of Pharmacology, University of Belgrade, Belgrade, Serbia
| | - Katarina Savic-Vujovic
- Faculty of Medicine, Department of Pharmacology, University of Belgrade, Belgrade, Serbia
| | - Zeljko Davidovic
- Clinical Department for Nephrology, Zvezdara University Medical Center, Belgrade, Serbia
| | - Jovana Todorovic
- Faculty of Medicine, Institute of Social Medicine, University of Belgrade, Belgrade, Serbia
| | - Nada Dimkovic
- Clinical Department for Nephrology, Zvezdara University Medical Center, Belgrade, Serbia
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36
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Kadir RRA, Alwjwaj M, Bayraktutan U. MicroRNA: An Emerging Predictive, Diagnostic, Prognostic and Therapeutic Strategy in Ischaemic Stroke. Cell Mol Neurobiol 2022; 42:1301-1319. [PMID: 33368054 PMCID: PMC9142420 DOI: 10.1007/s10571-020-01028-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 12/09/2020] [Indexed: 02/07/2023]
Abstract
Stroke continues to be the third-leading cause of death and disability worldwide. The limited availability of diagnostic tools approved therapeutics and biomarkers that help monitor disease progression or predict future events remain as the major challenges in the field of stroke medicine. Hence, attempts to discover safe and efficacious therapeutics and reliable biomarkers are of paramount importance. MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. Since miRNAs also play important roles in key mechanisms associated with the pathogenesis of stroke, including energy failure, inflammation and cell death, it is possible that miRNAs may serve as reliable blood-based markers for risk prediction, diagnosis and prognosis of ischaemic stroke. Discovery of better neurological outcome and smaller cerebral infarcts in animal models of ischaemic stroke treated with miRNA agomirs or antagomirs indicate that miRNAs may also play a cerebrovascular protective role after an ischaemic stroke. Nonetheless, further evidences on the optimum time for treatment and route of administration are required before effective translation of these findings into clinical practice. Bearing these in mind, this paper reviews the current literature discussing the involvement of miRNAs in major pathologies associated with ischaemic stroke and evaluates their value as reliable biomarkers and therapeutics for ischaemic stroke.
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Affiliation(s)
- Rais Reskiawan A Kadir
- Stroke, Division of Clinical Neuroscience, School of Medicine, The University of Nottingham, Clinical Sciences Building, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Mansour Alwjwaj
- Stroke, Division of Clinical Neuroscience, School of Medicine, The University of Nottingham, Clinical Sciences Building, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Ulvi Bayraktutan
- Stroke, Division of Clinical Neuroscience, School of Medicine, The University of Nottingham, Clinical Sciences Building, Hucknall Road, Nottingham, NG5 1PB, UK.
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37
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Wang Y, Jin X, Fan Q, Li C, Zhang M, Wang Y, Wu Q, Li J, Liu X, Wang S, Wang Y, Li L, Ling J, Li C, Wang Q, Liu Y. Deciphering the Active Compounds and Mechanisms of HSBDF for Treating ALI via Integrating Chemical Bioinformatics Analysis. Front Pharmacol 2022; 13:879268. [PMID: 35721141 PMCID: PMC9201258 DOI: 10.3389/fphar.2022.879268] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/06/2022] [Indexed: 01/08/2023] Open
Abstract
The Huashi Baidu Formula (HSBDF), a key Chinese medical drug, has a remarkable clinical efficacy in treating acute lung injury (ALI), and it has been officially approved by the National Medical Products Administration of China for drug clinical trials. Nevertheless, the regulated mechanisms of HSBDF and its active compounds in plasma against ALI were rarely studied. Based on these considerations, the key anti-inflammatory compounds of HSBDF were screened by molecular docking and binding free energy. The key compounds were further identified in plasma by LC/MS. Network pharmacology was employed to identify the potential regulatory mechanism of the key compounds in plasma. Next, the network pharmacological prediction was validated by a series of experimental assays, including CCK-8, EdU staining, test of TNF-α, IL-6, MDA, and T-SOD, and flow cytometry, to identify active compounds. Molecular dynamic simulation and binding interaction patterns were used to evaluate the stability and affinity between active compounds and target. Finally, the active compounds were subjected to predict pharmacokinetic properties. Molecular docking revealed that HSBDF had potential effects of inhibiting inflammation by acting on IL-6R and TNF-α. Piceatannol, emodin, aloe-emodin, rhein, physcion, luteolin, and quercetin were key compounds that may ameliorate ALI, and among which, there were five compounds (emodin, aloe-emodin, rhein, luteolin, and quercetin) in plasma. Network pharmacology results suggested that five key compounds in plasma likely inhibited ALI by regulating inflammation and oxidative damage. Test performed in vitro suggested that HSBDF (0.03125 mg/ml), quercetin (1.5625 μM), emodin (3.125 μM), and rhein (1.5625 μM) have anti-inflammatory function against oxidative damage and decrease apoptosis in an inflammatory environment by LPS-stimulation. In addition, active compounds (quercetin, emodin, and rhein) had good development prospects, fine affinity, and stable conformations with the target protein. In summary, this study suggested that HSBDF and its key active components in plasma (quercetin, emodin, and rhein) can decrease levels of pro-inflammatory factors (IL-6 and TNF-α), decrease expression of MDA, increase expression of T-SOD, and decrease cell apoptosis in an inflammatory environment. These data suggest that HSBDF has significant effect on anti-inflammation and anti-oxidative stress and also can decrease cell apoptosis in treating ALI. These findings provided an important strategy for developing new agents and facilitated clinical use of HSBDF against ALI.
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Affiliation(s)
- Yanru Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiaojie Jin
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China.,College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qin Fan
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Chenghao Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Min Zhang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yongfeng Wang
- Gansu University of Chinese Medicine, Lanzhou, China
| | - Qingfeng Wu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jiawei Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Xiuzhu Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Siyu Wang
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yu Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Ling Li
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jia Ling
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Chaoxin Li
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qianqian Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian, China
| | - Yongqi Liu
- Gansu University Key Laboratory for Molecular Medicine and Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, China.,Key Laboratory of Dunhuang Medical and Transformation, Ministry of Education of The People's Republic of China, Lanzhou, China
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Cullell N, Soriano-Tárraga C, Gallego-Fábrega C, Cárcel-Márquez J, Torres-Águila NP, Muiño E, Lledós M, Llucià-Carol L, Esteller M, Castro de Moura M, Montaner J, Fernández-Sanlés A, Elosua R, Delgado P, Martí-Fábregas J, Krupinski J, Roquer J, Jiménez-Conde J, Fernández-Cadenas I. DNA Methylation and Ischemic Stroke Risk: An Epigenome-Wide Association Study. Thromb Haemost 2022; 122:1767-1778. [PMID: 35717949 DOI: 10.1055/s-0042-1749328] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND Ischemic stroke (IS) risk heritability is partly explained by genetics. Other heritable factors, such as epigenetics, could explain an unknown proportion of the IS risk. The objective of this study is to evaluate DNA methylation association with IS using epigenome-wide association studies (EWAS). METHODS We performed a two-stage EWAS comprising 1,156 subjects. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were assessed using the Infinium 450K and EPIC BeadChip in the discovery cohort (252 IS and 43 controls). Significant DMPs were replicated in an independent cohort (618 IS and 243 controls). Stroke subtype associations were also evaluated. Differentially methylated cell-type (DMCT) was analyzed in the replicated CpG sites using EpiDISH. We additionally performed pathway enrichment analysis and causality analysis with Mendelian randomization for the replicated CpG sites. RESULTS A total of 957 CpG sites were epigenome-wide-significant (p ≤ 10-7) in the discovery cohort, being CpG sites in the top signals (logFC = 0.058, p = 2.35 × 10-22; logFC = 0.035, p = 3.22 × 10-22, respectively). ZFHX3 and MAP3K1 were among the most significant DMRs. In addition, 697 CpG sites were replicated considering Bonferroni-corrected p-values (p < 5.22 × 10-5). All the replicated DMPs were associated with risk of cardioembolic, atherothrombotic, and undetermined stroke. The DMCT analysis demonstrated that the significant associations were driven by natural killer cells. The pathway enrichment analysis showed overrepresentation of genes belonging to certain pathways including oxidative stress. ZFHX3 and MAP3K1 methylation was causally associated with specific stroke-subtype risk. CONCLUSION Specific DNA methylation pattern is causally associated with IS risk. These results could be useful for specifically predicting stroke occurrence and could potentially be evaluated as therapeutic targets.
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Affiliation(s)
- Natalia Cullell
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain.,Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain.,Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
| | - Carolina Soriano-Tárraga
- Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain.,Department of Psychiatry, NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, Missouri, United States
| | | | - Jara Cárcel-Márquez
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
| | - Nuria P Torres-Águila
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain.,Evolutionary Developmental Genomics Research Group, The Scottish Oceans Institute, University of St Andrews, St Andrews, United Kingdom
| | - Elena Muiño
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
| | - Miquel Lledós
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain
| | - Laia Llucià-Carol
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain.,Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Manel Esteller
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain.,Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.,Centro de Investigación Biomédica en Red Cancer, Barcelona, Spain
| | | | - Joan Montaner
- Department of Neurology, Hospital Universitario Virgen Macarena, Institute of Biomedicine of Seville/Hospital Universitario Virgen del Rocío/CSIC/University of Seville, Seville, Spain
| | - Alba Fernández-Sanlés
- Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain.,Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
| | - Roberto Elosua
- Cardiovascular Epidemiology and Genetics Research Group, IMIM, Barcelona, Spain.,CIBER Cardiovascular Diseases, Instituto Carlos III, Barcelona, Spain.,School of Medicine, University of Vic-Central University of Catalonia, Barcelona, Spain
| | - Pilar Delgado
- Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain
| | - Joan Martí-Fábregas
- Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Jerzy Krupinski
- Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain.,Centre for Bioscience, School of HealthCare Science, Manchester Metropolitan University, Manchester, England
| | - Jaume Roquer
- Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
| | - Jordi Jiménez-Conde
- Neurovascular Research Group, Department of Neurology, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra, Barcelona, Spain
| | - Israel Fernández-Cadenas
- Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí, Barcelona, Spain.,Department of Neurology, Hospital Universitari MútuaTerrassa/Fundacio Docència i Recerca MútuaTerrassa, Barcelona, Spain
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Zu J, Zuo L, Zhang L, Wang Z, Shi Y, Gu L, Zhang Z. Circular RNA FUNDC1 for Prediction of Acute Phase Outcome and Long-Term Survival of Acute Ischemic Stroke. Front Neurol 2022; 13:846198. [PMID: 35720103 PMCID: PMC9203888 DOI: 10.3389/fneur.2022.846198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/04/2022] [Indexed: 11/25/2022] Open
Abstract
Circular RNAs (CircRNAs) have shown promising potential in the diagnosis and the prediction of outcomes of stroke. This study aimed to explore the potential value of circRNAs for identifying acute neurological deterioration and estimating long-term survival for acute ischemic stroke (AIS). One hundred healthy controls and 200 patients with AIS within 72 h were recruited, 140 of whom were admitted within 24 h after onset. CircRNA levels in peripheral blood were measured by quantitative polymerase chain reaction (qPCR). Compared to the controls, the levels of three circRNAs were significantly increased in three subgroups of patients, including large artery atherosclerosis (LAA) stroke, small artery occlusion (SAO) stroke, and cardioembolism (CE) stroke (all P < 0.001). Among, LAA stroke patients had higher levels of circular RNA FUNDC1 (circFUNDC1) compared to SAO stroke patients (P = 0.015). CircFUNDC1 levels were positively correlated with National Institutes of Health Stroke Scale (NIHSS) scores on the 7th day only in LAA patients (P = 0.048, r = 0.226). It should be noted that the levels of circFUNDC1 in patients with early neurological deterioration (END), admitted within 24 h after onset, were significantly higher than those without END (P = 0.013). In addition, circFUNDC1 levels positively correlated with baseline NIHSS scores (P = 0.016, r = 0.203) or the 7th day NIHSS scores (P = 0.001, r = 0.289) in patients within 24 h after onset. Importantly, after 18 months of follow-up, a significant difference was observed on survival Kaplan-Meier curves (P = 0.042) between AIS patients with low (below cut-off) or high circFUNDC1 levels (above cut-off). Circulating circFUNDC1 could be a potential biomarker for predicting acute-phase outcome and long-term survival in AIS.
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Affiliation(s)
- Juan Zu
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Lei Zuo
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Lin Zhang
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Zan Wang
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Yachen Shi
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Lihua Gu
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
| | - Zhijun Zhang
- Department of Neurology, Key Laboratory of Developmental Genes and Human Disease, Affiliated Zhongda Hospital, School of Medicine, Institution of Neuropsychiatry, Southeast University, Nanjing, China
- Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- *Correspondence: Zhijun Zhang
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Stroke and Etiopathogenesis: What Is Known? Genes (Basel) 2022; 13:genes13060978. [PMID: 35741740 PMCID: PMC9222702 DOI: 10.3390/genes13060978] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 02/05/2023] Open
Abstract
Background: A substantial portion of stroke risk remains unexplained, and a contribution from genetic factors is supported by recent findings. In most cases, genetic risk factors contribute to stroke risk as part of a multifactorial predisposition. A major challenge in identifying the genetic determinants of stroke is fully understanding the complexity of the phenotype. Aims: Our narrative review is needed to improve our understanding of the biological pathways underlying the disease and, through this understanding, to accelerate the identification of new drug targets. Methods: We report, the research in the literature until February 2022 in this narrative review. The keywords are stroke, causes, etiopathogenesis, genetic, epigenetic, ischemic stroke. Results: While better risk prediction also remains a long-term goal, its implementation is still complex given the small effect-size of genetic risk variants. Some authors encourage the use of stroke genetic panels for stroke risk assessment and further stroke research. In addition, new biomarkers for the genetic causes of stroke and new targets for gene therapy are on the horizon. Conclusion: We summarize the latest evidence and perspectives of ischemic stroke genetics that may be of interest to the physician and useful for day-to-day clinical work in terms of both prevention and treatment of ischemic stroke.
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The role of non-coding RNAs in neuroinflammatory process in multiple sclerosis. Mol Neurobiol 2022; 59:4651-4668. [PMID: 35589919 DOI: 10.1007/s12035-022-02854-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 04/23/2022] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.
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Zhou X, Xu C, Chao D, Chen Z, Li S, Shi M, Pei Y, Dai Y, Ji J, Ji Y, Ji Q. Acute Cerebral Ischemia Increases a Set of Brain-Specific miRNAs in Serum Small Extracellular Vesicles. Front Mol Neurosci 2022; 15:874903. [PMID: 35571371 PMCID: PMC9094043 DOI: 10.3389/fnmol.2022.874903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
Small extracellular vesicles (sEVs) miRNAs are promising diagnosis and prognosis biomarkers for ischemic stroke (IS). This study aimed to determine the impact of IS on the serum sEVs miRNA profile of IS patients and a transient middle cerebral artery occlusion (tMCAO) mouse model. Small RNAseq was used to define the serum sEVs miRNA profile in IS patients and healthy controls (HC), and tMCAO mice and sham controls. Among the 1,444 and 1,373 miRNAs identified in human and mouse serum sEVs, the expression of 424 and 37 miRNAs was significantly altered in the IS patients and tMCAO mice, respectively (| Log2FC| ≥ 1, p < 0.01). Notably, five of the top 25 upregulated miRNAs in IS patients were brain-specific or enriched, including hsa-miR-9-3p, hsa-miR-124-3p, hsa-miR-143-3p, hsa-miR-98-5p, and hsa-miR-93-5p. Upregulation of these four miRNAs was further validated by qPCR. Nine of the 20 upregulated miRNAs in tMCAO mice were also brain-specific or enriched miRNAs. Temporal analysis indicated that the dynamics of mmu-miR-9-5p, mmu-miR-124-3p, mmu-miR-129-5p, and mmu-miR-433-3p were closely correlated with the evolution of ischemic brain injury, as their expression increased at 0.5 days after the onset of ischemia, peaked at day 1 or 3, and returned to normal levels at day 7 and 14. Notably, with the exceptions of mmu-miR-128-3p, the expression of the other eight miRNAs in the mouse serum sEVs was unaffected in the lipopolysaccharide (LPS)-induced neuroinflammation model. Together, in this study, we provided a comprehensive view of the influences of IS on the serum sEVs miRNA profile of IS patients and tMCAO mice and demonstrated the increment of a set of brain-specific miRNAs in serum sEVs after acute cerebral ischemia, which could be promising candidates directly reflecting the ischemic brain injury.
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Affiliation(s)
- Xin Zhou
- College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
- The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chenxue Xu
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Dachong Chao
- College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
| | - Zixin Chen
- College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
| | - Shuyuan Li
- College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
| | - Miaomiao Shi
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuqiang Pei
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yujuan Dai
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Yuhua Ji
- College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong, China
- Yuhua Ji,
| | - Qiuhong Ji
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
- *Correspondence: Qiuhong Ji,
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Diagnostic Performance of Circulating miRNAs and Extracellular Vesicles in Acute Ischemic Stroke. Int J Mol Sci 2022; 23:ijms23094530. [PMID: 35562921 PMCID: PMC9102701 DOI: 10.3390/ijms23094530] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Background: Increased inflammation activates blood coagulation system, higher platelet activation plays a key role in the pathophysiology of ischemic stroke (IS). During platelet activation and aggregation process, platelets may cause increased release of several proinflammatory, and prothrombotic mediators, including microRNAs (miRNAs) and extracellular vesicles (EVs). In the current study we aimed to assess circulating miRNAs profile related to platelet function and inflammation and circulating EVs from platelets, leukocytes, and endothelial cells to analyse their diagnostic and predictive utility in patients with acute IS. Methods: The study population consisted of 28 patients with the diagnosis of the acute IS. The control group consisted of 35 age- and gender-matched patients on acetylsalicylic acid (ASA) therapy without history of stroke and/or TIA with established stable coronary artery disease (CAD) and concomitant cardiovascular risk factors. Venous blood samples were collected from the control group and patients with IS on ASA therapy (a) 24 h after onset of acute IS, (b) 7-days following index hospitalization. Flow cytometry was used to determine the concentration of circulating EVs subtypes (from platelets, leukocytes, and endothelial cells) in platelet-depleted plasma and qRT-PCR was used to determine several circulating plasma miRNAs (miR-19a-3p, miR-186-5p and let-7f). Results: Patients with high platelet reactivity (HPR, based on arachidonic acid-induced platelet aggregometry) had significantly elevated platelet-EVs (CD62+) and leukocyte-EVs (CD45+) concentration compared to patients with normal platelet reactivity at the day of 1 acute-stroke (p = 0.012, p = 0.002, respectively). Diagnostic values of baseline miRNAs and EVs were evaluated with receiver operating characteristic (ROC) curve analysis. The area under the ROC curve for miR-19a-3p was 0.755 (95% CI, 0.63–0.88) p = 0.004, for let-7f, it was 0.874 (95% CI, 0.76–0.99) p = 0.0001; platelet-EVs was 0.776 (95% CI, 0.65–0.90) p = 0.001, whereas for leukocyte-EVs, it was 0.715 (95% CI, 0.57–0.87) p = 0.008. ROC curve showed that pooling the miR-19a-3p expressions, platelet-EVs, and leukocyte-EVs concentration yielded a higher AUC than the value of each individual biomarker as AUC was 0.893 (95% CI, 0.79–0.99). Patients with moderate stroke had significantly elevated miR-19a-3p expression levels compared to patients with minor stroke at the first day of IS. (AUC: 0.867, (95% CI, 0.74–0.10) p = 0.001). Conclusion: Combining different biomarkers of processes underlying IS pathophysiology might be beneficial for early diagnosis of ischemic events. Thus, we believe that in the future circulating biomarkers might be used in the prehospital phase of IS. In particular, circulating plasma EVs and non-coding RNAs including miRNAs are interesting candidates as bearers of circulating biomarkers due to their high stability in the blood and making them highly relevant biomarkers for IS diagnostics.
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Circulating Non-coding RNAs as Potential Biomarkers for Ischemic Stroke: A Systematic Review. J Mol Neurosci 2022; 72:1572-1585. [DOI: 10.1007/s12031-022-01991-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/25/2022] [Indexed: 12/14/2022]
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Wang H, Yang H, Chang M, Sun F, Qi H, Li X. Long non-coding RNA TTTY15 sponges miR-520a-3p to exacerbate neural apoptosis induced by cerebral ischemia/reperfusion via targeting IRF9 in vivo and in vitro. Biomed J 2022; 46:100530. [PMID: 35439640 DOI: 10.1016/j.bj.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 03/17/2022] [Accepted: 04/07/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Studies have proven that as competing endogenous RNAs (ceRNAs), long non-coding RNAs (lncRNAs) play vital roles in regulating RNA transcripts in ischemic stroke. It has been reported that TTTY15, a lncRNA, is dysregulated in cardiomyocytes after ischemic injury. We intended to explore the potential regulating mechanism of TTTY15 in ischemic stroke. METHODS TTTY15 and miR-520a-3p levels in vivo were measured in the cerebral ischemia/reperfusion (I/R) model. Cell apoptosis was measured by flow cytometry. To manifest TTTY15 functions in I/R injury, Neuro 2a (N2a) cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) and treated with si-NC, pcDNA3.1-NC, si-TTTY15 or pcDNA3.1-TTTY15. RESULTS TTTY15 expression was elevated and miR-520a-3p expression was declined in mouse brains exposed to I/R and in N2a cells exposed to OGD/R. Bioinformatics analyses predicted the binding sites of miR-520a-3p in the 3'-UTRs of interferon regulatory factor 9 (IRF9) and TTTY15. Luciferase reporter assay exhibited that TTTY15 bound to miR-520a-3p directly and IRF9 was targeted by miR-520a-3p. MiR-520a-3p overexpression diminished N2a cell apoptosis caused by OGD/R. TTTY15 overexpression antagonized the inhibitory impacts of miR-520a-3p on IRF9 expression and apoptosis after OGD/R, while TTTY15 knockdown enhanced the inhibitory impacts of miR-520a-3p. Additionally, TTTY15 knockdown alleviated brain damages and neurological deficits induced by I/R in vivo. Our results revealed that TTTY15 modulated IRF9 via acting as a ceRNA for miR-520a-3p. CONCLUSION The study revealed the roles of TTTY15/miR-520a-3p/IRF9 signaling pathway in regulating cerebral ischemia/reperfusion injury.
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Affiliation(s)
- Huan Wang
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China
| | - Hui Yang
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China
| | - Mingxiu Chang
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China
| | - Feifei Sun
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China
| | - Huiping Qi
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China
| | - Xuling Li
- Department of Neurology, The Fourth Affiliated Hospital, Harbin Medical University, Harbin City, Heilongjiang Province, PR China.
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Sun P, Hamblin MH, Yin KJ. Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders. Fluids Barriers CNS 2022; 19:27. [PMID: 35346266 PMCID: PMC8959280 DOI: 10.1186/s12987-022-00317-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/17/2022] [Indexed: 12/26/2022] Open
Abstract
The blood–brain barrier (BBB) is an essential component of the neurovascular unit that controls the exchanges of various biological substances between the blood and the brain. BBB damage is a common feature of different central nervous systems (CNS) disorders and plays a vital role in the pathogenesis of the diseases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs), are important regulatory RNA molecules that are involved in almost all cellular processes in normal development and various diseases, including CNS diseases. Cumulative evidences have demonstrated ncRNA regulation of BBB functions in different CNS diseases. In this review, we have summarized the miRNAs, lncRNAs, and circRNAs that can be served as diagnostic and prognostic biomarkers for BBB injuries, and demonstrated the involvement and underlying mechanisms of ncRNAs in modulating BBB structure and function in various CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), Alzheimer's disease (AD), vascular cognitive impairment and dementia (VCID), brain tumors, brain infections, diabetes, sepsis-associated encephalopathy (SAE), and others. We have also discussed the pharmaceutical drugs that can regulate BBB functions via ncRNAs-related signaling cascades in CNS disorders, along with the challenges, perspective, and therapeutic potential of ncRNA regulation of BBB functions in CNS diseases.
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Wicik Z, Czajka P, Eyileten C, Fitas A, Wolska M, Jakubik D, von Lewinski D, Sourij H, Siller-Matula JM, Postula M. The role of miRNAs in regulation of platelet activity and related diseases - a bioinformatic analysis. Platelets 2022; 33:1052-1064. [DOI: 10.1080/09537104.2022.2042233] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
| | - Pamela Czajka
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
| | - Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
| | - Alex Fitas
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
| | - Marta Wolska
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
- Doctoral School of Medical University of Warsaw, Poland
| | - Daniel Jakubik
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
| | - Dirk von Lewinski
- Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria
| | - Harald Sourij
- Division of Endocrinology and Diabetology, Interdisciplinary Metabolic Medicine Trials Unit, Medical University of Graz, Graz, Austria
| | - Jolanta M. Siller-Matula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
- Department of Cardiology, Medical University of Vienna, Vienna, Austria
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology Cept, Warsaw, Poland
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Zhao X, Liu J, Yang L, Niu Y, Ren R, Su C, Wang Y, Chen J, Ma X. Beneficial effects of mijianchangpu decoction on ischemic stroke through components accessing to the brain based on network pharmacology. JOURNAL OF ETHNOPHARMACOLOGY 2022; 285:114882. [PMID: 34848358 DOI: 10.1016/j.jep.2021.114882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 11/24/2021] [Accepted: 11/25/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE To explore the effective components, potential targets and neuroprotective related mechanisms of Mijianchangpu decoction (MJCPD), a well-known TCM used by the Chinese Hui minorities to treat stroke, on the prevention and treatment of ischemic stroke (IS) by using experimental models combined with network pharmacology. MATERIALS AND METHODS The neuroprotective efficacy of MJCPD was estimated by applying the middle cerebral artery occlusion (MCAO) induced cerebral ischemia rats, and the neurological deficits score, TTC and HE staining as well as behavioral evaluation tests were employed to evaluate the beneficial effects. Meanwhile, the bioactive components of MJCPD responsible for the neuroprotective effects were identified by detecting the constituents in the brain of the MCAO rats with UHPLC-QTOF-MS/MS techniques, and these compounds were then underwent for network pharmacology analysis. Firstly, the targets of the bioactive compounds of MJCPD were predicted using Pharmmapper database, and simultaneously, the targets of IS disease were obtained from disease databases including DisGenet, OMIM, and GeneCards. Secondly, the protein-protein interaction (PPI) network between the targets and diseases were established to give the possible therapeutic targets for IS. Thirdly, the go function and KEGG pathway enrichment analysis were carried out and the compound-target-pathway network was constructed by Cytoscape software. Finally, the effective compounds, core targets and possible pathways were obtained by analyzing the connectivity of the network. More importantly, the core targets were verified by western blot experiments to validate the reliability of this study. RESULTS MJCPD exhibited significant neuroprotective effect on IS, and 16 bioactive components of MJCPD were identified in the brain of the MCAO rats. 59 and 1982 targets related with IS disease were explored from Pharmapper and disease databases, respectively, and 32 intersecting targets were obtained as hypothetical therapeutic targets. Based on the results of the compound-target-pathway and PPI network with the degree was greater than the median, 8 effective compounds (suberic acid, epishyobunone, crocetin monomethyl ester, sfaranal, (Z)-6-octadccenoic acid, nerolidol and gurjunene) and 5 hub targets (SRC, MAPK8, MAPK14, EGFR and MAPK1) as well as 12 pathways were predicted. Western blot results showed that EGFR, p38, ERK and SRC proteins were expressed significantly different after MJCPD treatment as compared with the model group. CONCLUSION The present study employed network pharmacology, pharmacodynamics and molecular biology techniques to predict and validate the core potential targets and signaling pathways as well as the bioactive components of MJCPD responsible for the treatment of IS. All of which are very helpful to clarify the neuroprotective mechanism of MJCPD, and obviously, the active compounds and targets in this study can also provide clues for the treatment of IS.
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Affiliation(s)
- Xiaojun Zhao
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Jingjing Liu
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China; School of Pharmacy, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, China.
| | - Lingling Yang
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Yang Niu
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Ruru Ren
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Chao Su
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Yingli Wang
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
| | - Jianyu Chen
- Fujian University of Traditional Chinese Medicine, No. 1, Huatuo Road, Minhoushangjie, Fuzhou, 350122, China.
| | - Xueqin Ma
- Department of Pharmaceutical analysis, School of Pharmacy, Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education, Ningxia Medical University, 1160 Shenli Street, Yinchuan, 750004, China.
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Li J, Wang N, Nie H, Wang S, Jiang T, Ma X, Liu W, Tian K. Long Non-coding RNA RMST Worsens Ischemic Stroke via MicroRNA-221-3p/PIK3R1/TGF-β Signaling Pathway. Mol Neurobiol 2022; 59:2808-2821. [PMID: 35217983 DOI: 10.1007/s12035-021-02632-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/01/2021] [Indexed: 11/26/2022]
Abstract
Much efforts have been made to probe the mechanism underlying ischemic stroke (IS). This study was proposed to uncover the role of long non-coding RNA rhabdomyosarcoma 2 related transcript (RMST) in IS through microRNA-221-3p (miR-221-3p)/phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1)/transforming growth factor-β (TGF-β) axis. Neurological behavioral function, pathological changes in brain tissue, oxidative stress, and inflammation responses in middle cerebral artery occlusion (MCAO) mice were tested. RMST, miR-221-3p, PIK3R1, and TGF-β signaling-related protein expression in brain tissues of MCAO mice were detected. RMST and PIK3R1 were elevated, miR-221-3p was downregulated, and TGF-β pathway was activated in mice after MCAO. Restored miR-221-3p or depleted RMST improved neurological behavioral functions, relieved pathological injury in brain tissue, and repressed oxidative stress and inflammation in mice after MCAO. Depleted PIK3R1 or restored miR-221-3p offsets the negative effects of overexpressed RMST on mice with MCAO. The present work highlights that RMST augments IS through reducing miR-221-3p-mediated regulation of PIK3R1 and activating TGF-β pathway.
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Affiliation(s)
- Jie Li
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Ning Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Huan Nie
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Shan Wang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Tongtong Jiang
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Xuehan Ma
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China
| | - Wenjuan Liu
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China.
| | - Kuo Tian
- Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150081, China.
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Eyileten C, Wicik Z, Fitas A, Marszalek M, Simon JE, De Rosa S, Wiecha S, Palatini J, Postula M, Malek LA. Altered Circulating MicroRNA Profiles After Endurance Training: A Cohort Study of Ultramarathon Runners. Front Physiol 2022; 12:792931. [PMID: 35145424 PMCID: PMC8824535 DOI: 10.3389/fphys.2021.792931] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/21/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Despite the positive effects of endurance training on the cardiovascular (CV) system, excessive exercise induces not only physiological adaptations but also adverse changes in CV system, including the heart. We aimed to evaluate the selected miRNAs expression based on bioinformatic analysis and their changes before and after an ultramarathon run. MATERIALS AND METHODS Cardiac tissue-specific targets were identified with the Tissue 2.0 database. Gene-gene interaction data were retrieved from the STRING app for Cytoscape. Twenty-three endurance athletes were recruited to the study. Athletes ran to completion (100 km) or exhaustion (52-91 km, median 74 km). All participants completed pre- and post-run testing. miRNAs expressions were measured both before and after the race. RESULTS Enrichment analysis of the signaling pathways associated with the genes targeted by miRNAs selected for qRT-PCR validation (miR-1-3p, miR-126, miR-223, miR-125a-5p, miR-106a-5p, and miR-15a/b). All selected miRNAs showed overlap in regulation in pathways associated with cancer, IL-2 signaling, TGF-β signaling as well as BDNF signaling pathway. Analysis of metabolites revealed significant regulation of magnesium and guanosine triphosphate across analyzed miRNA targets. MiR-1-3p, miR-125a-5p, miR-126, and miR-223 expressions were measured in 23 experienced endurance athletes, before and after an ultramarathon wherein athletes ran to completion (100 km) or exhaustion (52-91 km, median 74 km). The expressions of miR-125a-5p, miR-126, and miR-223 were significantly increased after the race (p = 0.007, p = 0.001, p = 0.014, respectively). MiR-1-3p expression post-run showed a negative correlation with the post-run levels of high-sensitivity C-reactive protein (hs-CRP) (r = -0.632, p = 0.003). Higher miR-1-3p expression was found in runners, who finished the race under 10 h compared to runners who finished over 10 h (p = 0.001). Post-run miR-125a-5p expression showed a negative correlation with the peak lactate during the run (r = -0.576, p = 0.019). CONCLUSION Extreme physical activity, as exemplified by an ultramarathon, is associated with changes in circulating miRNAs' expression related to inflammation, fibrosis, and cardiac muscle function. In particular, the negative correlations between miR-125a-5p and lactate concentrations, and miR-1-3p and hs-CRP, support their role in specific exercise-induced adaptation. Further studies are essential to validate the long-term effect of these observations.
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Affiliation(s)
- Ceren Eyileten
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Zofia Wicik
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Alex Fitas
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Mikolaj Marszalek
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Jenny E. Simon
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Salvatore De Rosa
- Division of Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Szczepan Wiecha
- Department of Physical Education and Health in Biala Podlaska, Józef Pilsudski University of Physical Education in Warsaw, Biala Podlaska, Poland
| | - Jeffrey Palatini
- Genomics Core Facility, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Marek Postula
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Lukasz A. Malek
- Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion, National Institute of Cardiology, Warsaw, Poland
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