Protection, Plasticity, and Physical Rehabilitation in Ischemic Injury

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 52226

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Guest Editor
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
Interests: stroke; neuroprotection; brain circulation; conditioning medicine; exercise; ischemia and reperfusion injury; stress; vascular diseases
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Special Issue Information

Dear Colleagues,

A new Special Issue on “Protection, Plasticity, and Physical Rehabilitation in Ischemic Injury” is under preparation. This issue will cover but not be limited to experimental, technical, and clinical studies related to health, ethical, and social issues of (1) cerebro- or cardiovascular disease, as well as its cause and pathology; (2) innovative treatment in stroke and ischemia/reperfusion injury, including thrombolysis and all non-drug treatments such as oxygen, hypothermia, and remote pre-, per- or post-ischemic preconditioning. Articles with clinical interest and implications will be given preference.

As we are aware of your interest in the fields of neuroscience, neurology, and neurotherapy, we would like to cordially invite you to submit your manuscripts for review and publication in Biomolecules.

Dr. Yuchuan Ding
Guest Editor

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Keywords

  • stroke
  • ischemia and reperfusion
  • stress and vascular injury
  • circulation
  • conditioning medicine
  • exercise

Published Papers (13 papers)

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Research

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17 pages, 2302 KiB  
Article
Neuroprotective Effects of Pharmacological Hypothermia on Hyperglycolysis and Gluconeogenesis in Rats after Ischemic Stroke
by Longfei Guan, Hangil Lee, Xiaokun Geng, Fengwu Li, Jiamei Shen, Yu Ji, Changya Peng, Huishan Du and Yuchuan Ding
Biomolecules 2022, 12(6), 851; https://doi.org/10.3390/biom12060851 - 19 Jun 2022
Cited by 7 | Viewed by 2457
Abstract
Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke, in which the temperature is decreased safely. The present study determined whether neuroprotective [...] Read more.
Stroke is a leading threat to human life. Metabolic dysfunction of glucose may play a key role in stroke pathophysiology. Pharmacological hypothermia (PH) is a potential neuroprotective strategy for stroke, in which the temperature is decreased safely. The present study determined whether neuroprotective PH with chlorpromazine and promethazine (C + P), plus dihydrocapsaicin (DHC) improved glucose metabolism in acute ischemic stroke. A total of 208 adult male Sprague Dawley rats were randomly divided into the following groups: sham, stroke, and stroke with various treatments including C + P, DHC, C + P + DHC, phloretin (glucose transporter (GLUT)-1 inhibitor), cytochalasin B (GLUT-3 inhibitor), TZD (thiazolidinedione, phosphoenolpyruvate carboxykinase (PCK) inhibitor), and apocynin (nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor). Stroke was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by 6 or 24 h of reperfusion. Rectal temperature was monitored before, during, and after PH. Infarct volume and neurological deficits were measured to assess the neuroprotective effects. Reactive oxygen species (ROS), NOX activity, lactate, apoptotic cell death, glucose, and ATP levels were measured. Protein expression of GLUT-1, GLUT-3, phosphofructokinase (PFK), lactate dehydrogenase (LDH), PCK1, PCK2, and NOX subunit gp91 was measured with Western blotting. PH with a combination of C + P and DHC induced faster, longer, and deeper hypothermia, as compared to each alone. PH significantly improved every measured outcome as compared to stroke and monotherapy. PH reduced brain infarction, neurological deficits, protein levels of glycolytic enzymes (GLUT-1, GLUT-3, PFK and LDH), gluconeogenic enzymes (PCK1 and PCK2), NOX activity and its subunit gp91, ROS, apoptotic cell death, glucose, and lactate, while raising ATP levels. In conclusion, stroke impaired glucose metabolism by enhancing hyperglycolysis and gluconeogenesis, which led to ischemic injury, all of which were reversed by PH induced by a combination of C + P and DHC. Full article
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17 pages, 41116 KiB  
Article
Transplantation of Human Umbilical Cord Mesenchymal Stem Cells-Derived Neural Stem Cells Pretreated with Neuregulin1β Ameliorate Cerebral Ischemic Reperfusion Injury in Rats
by Qiu-Yue Zhai, Yu-Qian Ren, Qin-Shuai Ni, Zhen-Hua Song, Ke-Li Ge and Yun-Liang Guo
Biomolecules 2022, 12(3), 428; https://doi.org/10.3390/biom12030428 - 10 Mar 2022
Cited by 15 | Viewed by 3190
Abstract
Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia [...] Read more.
Ischemic stroke is a common cerebrovascular disease and recovering blood flow as early as possible is essential to reduce ischemic damage and maintain neuronal viability, but the reperfusion process usually causes additional damage to the brain tissue in the ischemic area, namely ischemia reperfusion injury. The accumulated studies have revealed that transplantation of exogenous neural stem cells (NSCs) is an ideal choice for the treatment of ischemia reperfusion injury. At present, the source and efficacy of exogenous NSCs after transplantation is still one of the key issues that need to be resolved. In this study, human umbilical cord mesenchymal stem cells (hUC-MSCs) were obtained and induced into NSCs byadding growth factor and neuregulin1β (NRG1β) was introduced during the differentiation process of NSCs. Then, the rat middle cerebral artery occlusion/reperfusion (MCAO/R) models were established, and the therapeutic effects were evaluated among groups treated by NRG1β, NSCs and NSCs pretreated with 10 nM NRG1β (NSCs-10 nM NRG1β) achieved through intra-arterial injection. Our data show that the NSCs-10 nM NRG1β group significantly improves neurobehavioral function and infarct volume after MCAO/R, as well as cerebral cortical neuron injury, ferroptosis-related indexes and mitochondrial injury. Additionally, NSCs-10 nM NRG1β intervention may function through regulating the p53/GPX4/SLC7A11 pathway, and reducing the level of ferroptosis in cells, further enhance the neuroprotective effect on injured cells. Full article
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14 pages, 14341 KiB  
Article
Quantitative Proteomic Analysis of Plasma after Remote Ischemic Conditioning in a Rhesus Monkey Ischemic Stroke Model
by Siying Song, Linlin Guo, Di Wu, Jingfei Shi, Yunxia Duan, Xiaoduo He, Yunhuan Liu, Yuchuan Ding, Xunming Ji and Ran Meng
Biomolecules 2021, 11(8), 1164; https://doi.org/10.3390/biom11081164 - 06 Aug 2021
Cited by 7 | Viewed by 2146
Abstract
Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled [...] Read more.
Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes. Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week’s RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS). Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention. Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets. Full article
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Review

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25 pages, 458 KiB  
Review
Identification Markers of Carotid Vulnerable Plaques: An Update
by Yilin Wang, Tao Wang, Yumin Luo and Liqun Jiao
Biomolecules 2022, 12(9), 1192; https://doi.org/10.3390/biom12091192 - 28 Aug 2022
Cited by 10 | Viewed by 2139
Abstract
Vulnerable plaques have been a hot topic in the field of stroke and carotid atherosclerosis. Currently, risk stratification and intervention of carotid plaques are guided by the degree of luminal stenosis. Recently, it has been recognized that the vulnerability of plaques may contribute [...] Read more.
Vulnerable plaques have been a hot topic in the field of stroke and carotid atherosclerosis. Currently, risk stratification and intervention of carotid plaques are guided by the degree of luminal stenosis. Recently, it has been recognized that the vulnerability of plaques may contribute to the risk of stroke. Some classical interventions, such as carotid endarterectomy, significantly reduce the risk of stroke in symptomatic patients with severe carotid stenosis, while for asymptomatic patients, clinically silent plaques with rupture tendency may expose them to the risk of cerebrovascular events. Early identification of vulnerable plaques contributes to lowering the risk of cerebrovascular events. Previously, the identification of vulnerable plaques was commonly based on imaging technologies at the macroscopic level. Recently, some microscopic molecules pertaining to vulnerable plaques have emerged, and could be potential biomarkers or therapeutic targets. This review aimed to update the previous summarization of vulnerable plaques and identify vulnerable plaques at the microscopic and macroscopic levels. Full article
18 pages, 1598 KiB  
Review
The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease
by Yu Tian, Mengxi Zhao, Yiyi Chen, Mo Yang and Yilong Wang
Biomolecules 2022, 12(6), 748; https://doi.org/10.3390/biom12060748 - 25 May 2022
Cited by 22 | Viewed by 4703 | Correction
Abstract
There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, [...] Read more.
There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD. Full article
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13 pages, 5754 KiB  
Review
Factors Influencing Gallstone Formation: A Review of the Literature
by Hao Sun, Jonathan Warren, James Yip, Yu Ji, Shaolong Hao, Wei Han and Yuchuan Ding
Biomolecules 2022, 12(4), 550; https://doi.org/10.3390/biom12040550 - 06 Apr 2022
Cited by 29 | Viewed by 9381
Abstract
Gallstone disease is a common pathology of the digestive system with nearly a 10–20% incidence rate among adults. The mainstay of treatment is cholecystectomy, which is commonly associated with physical pain and may also seriously affect a patient’s quality of life. Clinical research [...] Read more.
Gallstone disease is a common pathology of the digestive system with nearly a 10–20% incidence rate among adults. The mainstay of treatment is cholecystectomy, which is commonly associated with physical pain and may also seriously affect a patient’s quality of life. Clinical research suggests that cholelithiasis is closely related to the age, gender, body mass index, and other basic physical characteristics of patients. Clinical research further suggests that the occurrence of cholelithiasis is related to obesity, diabetes, non-alcoholic fatty liver, and other diseases. For this reason, we reviewed the following: genetic factors; excessive liver cholesterol secretion (causing cholesterol supersaturation in gallbladder bile); accelerated growth of cholesterol crystals and solid cholesterol crystals; gallbladder motility impairment; and cardiovascular factors. Herein, we summarize and analyze the causes and mechanisms of cholelithiasis, discuss its correlation with the pathogenesis of related diseases, and discuss possible mechanisms. Full article
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10 pages, 623 KiB  
Review
The Role of the lncRNA MALAT1 in Neuroprotection against Hypoxic/Ischemic Injury
by Liping Wang, Sijie Li, Sara Saymuah Stone, Na Liu, Kerui Gong, Changhong Ren, Kai Sun, Chunyang Zhang and Guo Shao
Biomolecules 2022, 12(1), 146; https://doi.org/10.3390/biom12010146 - 17 Jan 2022
Cited by 8 | Viewed by 3025
Abstract
Hypoxic and ischemic brain injury can cause neurological disability and mortality, and has become a serious public health problem worldwide. Long-chain non-coding RNAs are involved in the regulation of many diseases. Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) is a type of long non-coding [...] Read more.
Hypoxic and ischemic brain injury can cause neurological disability and mortality, and has become a serious public health problem worldwide. Long-chain non-coding RNAs are involved in the regulation of many diseases. Metastasis-related lung adenocarcinoma transcript 1 (MALAT1) is a type of long non-coding RNA (lncRNA), known as long intergenic non-coding RNA (lincRNA), and is highly abundant in the nervous system. The enrichment of MALAT1 in the brain indicates that it may be associated with important functions in pathophysiological processes. Accordingly, the role of MALAT1 in neuronal cell hypoxic/ischemic injury has been gradually discovered over recent years. In this article, we summarize recent research regarding the neuroprotective molecular mechanism of MALAT1 and its regulation of pathophysiological processes of brain hypoxic/ischemic injury. MALAT1 may function as a regulator through interaction with proteins or RNAs to perform its role, and may therefore serve as a therapeutic target in cerebral hypoxia/ischemia. Full article
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15 pages, 1273 KiB  
Review
Potential Role of Exosomes in Ischemic Stroke Treatment
by Lingling Jiang, Weiqi Chen, Jinyi Ye and Yilong Wang
Biomolecules 2022, 12(1), 115; https://doi.org/10.3390/biom12010115 - 11 Jan 2022
Cited by 18 | Viewed by 4483
Abstract
Ischemic stroke is a life-threatening cerebral vascular disease and accounts for high disability and mortality worldwide. Currently, no efficient therapeutic strategies are available for promoting neurological recovery in clinical practice, except rehabilitation. The majority of neuroprotective drugs showed positive impact in pre-clinical studies [...] Read more.
Ischemic stroke is a life-threatening cerebral vascular disease and accounts for high disability and mortality worldwide. Currently, no efficient therapeutic strategies are available for promoting neurological recovery in clinical practice, except rehabilitation. The majority of neuroprotective drugs showed positive impact in pre-clinical studies but failed in clinical trials. Therefore, there is an urgent demand for new promising therapeutic approaches for ischemic stroke treatment. Emerging evidence suggests that exosomes mediate communication between cells in both physiological and pathological conditions. Exosomes have received extensive attention for therapy following a stroke, because of their unique characteristics, such as the ability to cross the blood brain–barrier, low immunogenicity, and low toxicity. An increasing number of studies have demonstrated positively neurorestorative effects of exosome-based therapy, which are largely mediated by the microRNA cargo. Herein, we review the current knowledge of exosomes, the relationships between exosomes and stroke, and the therapeutic effects of exosome-based treatments in neurovascular remodeling processes after stroke. Exosomes provide a viable and prospective treatment strategy for ischemic stroke patients. Full article
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14 pages, 1512 KiB  
Review
Effect of Bariatric Surgery on Metabolic Diseases and Underlying Mechanisms
by Yu Ji, Hangil Lee, Shawn Kaura, James Yip, Hao Sun, Longfei Guan, Wei Han and Yuchuan Ding
Biomolecules 2021, 11(11), 1582; https://doi.org/10.3390/biom11111582 - 26 Oct 2021
Cited by 22 | Viewed by 5565
Abstract
Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated with obesity such as the development of type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, and nonalcoholic fatty liver disease [...] Read more.
Obesity is a highly prevalent public health concern, attributed to multifactorial causes and limited in treatment options. Several comorbidities are closely associated with obesity such as the development of type 2 diabetes mellitus (T2DM), cardiovascular and cerebrovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Bariatric surgery, which can be delivered in multiple forms, has been remarked as an effective treatment to decrease the prevalence of obesity and its associated comorbidities. The different types of bariatric surgery create a variety of new pathways for food to metabolize in the body and truncate the stomach’s caliber. As a result, only a small quantity of food is tolerated, and the body mass index noticeably decreases. This review describes the improvements of obesity and its comorbidities following bariatric surgery and their mechanism of improvement. Additionally, endocrine function improvements after bariatric surgery, which contributes to the patients’ health improvement, are described, including the role of glucagon-like peptide-1 (GLP-1), fibroblast growth factors 19 and 21 (FGF-19, FGF-21), and pancreatic peptide YY (PYY). Lastly, some of the complications of bariatric surgery, including osteoporosis, iron deficiency/anemia, and diarrhea, as well as their potential mechanisms, are described. Full article
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37 pages, 888 KiB  
Review
Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke
by Reed Berlet, Stefan Anthony, Beverly Brooks, Zhen-Jie Wang, Nadia Sadanandan, Alex Shear, Blaise Cozene, Bella Gonzales-Portillo, Blake Parsons, Felipe Esparza Salazar, Alma R. Lezama Toledo, Germán Rivera Monroy, Joaquín Vega Gonzales-Portillo and Cesario V. Borlongan
Biomolecules 2021, 11(9), 1316; https://doi.org/10.3390/biom11091316 - 06 Sep 2021
Cited by 14 | Viewed by 5576
Abstract
Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new [...] Read more.
Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke. Full article
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15 pages, 630 KiB  
Review
Role of White Matter Hyperintensities and Related Risk Factors in Vascular Cognitive Impairment: A Review
by Yiyi Chen, Xing Wang, Ling Guan and Yilong Wang
Biomolecules 2021, 11(8), 1102; https://doi.org/10.3390/biom11081102 - 27 Jul 2021
Cited by 20 | Viewed by 5172
Abstract
White matter hyperintensities (WMHs) of presumed vascular origin are one of the imaging markers of cerebral small-vessel disease, which is prevalent in older individuals and closely associated with the occurrence and development of cognitive impairment. The heterogeneous nature of the imaging manifestations of [...] Read more.
White matter hyperintensities (WMHs) of presumed vascular origin are one of the imaging markers of cerebral small-vessel disease, which is prevalent in older individuals and closely associated with the occurrence and development of cognitive impairment. The heterogeneous nature of the imaging manifestations of WMHs creates difficulties for early detection and diagnosis of vascular cognitive impairment (VCI) associated with WMHs. Because the underlying pathological processes and biomarkers of WMHs and their development in cognitive impairment remain uncertain, progress in prevention and treatment is lagging. For this reason, this paper reviews the status of research on the features of WMHs related to VCI, as well as mediators associated with both WMHs and VCI, and summarizes potential treatment strategies for the prevention and intervention in WMHs associated with VCI. Full article
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Other

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1 pages, 161 KiB  
Correction
Correction: Tian et al. The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease. Biomolecules 2022, 12, 748
by Yu Tian, Mengxi Zhao, Yiyi Chen, Mo Yang and Yilong Wang
Biomolecules 2023, 13(4), 705; https://doi.org/10.3390/biom13040705 - 21 Apr 2023
Cited by 2 | Viewed by 712
Abstract
In the published publication [...] Full article
17 pages, 3887 KiB  
Systematic Review
A Systematic Review and Meta-Analysis of Serum Concentrations of Ischaemia-Modified Albumin in Acute Ischaemic Stroke, Intracerebral Haemorrhage, and Subarachnoid Haemorrhage
by Arduino A. Mangoni and Angelo Zinellu
Biomolecules 2022, 12(5), 653; https://doi.org/10.3390/biom12050653 - 29 Apr 2022
Cited by 5 | Viewed by 2194
Abstract
The identification of robust circulating biomarkers of stroke may improve outcomes. We conducted a systematic review and meta-analysis of serum concentrations of ischaemia-modified albumin (IMA) in subjects with or without acute ischaemic stroke (AIS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). We searched [...] Read more.
The identification of robust circulating biomarkers of stroke may improve outcomes. We conducted a systematic review and meta-analysis of serum concentrations of ischaemia-modified albumin (IMA) in subjects with or without acute ischaemic stroke (AIS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). We searched PubMed, Web of Science, Scopus, and Google Scholar from inception to March 2022. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 17 studies, IMA concentrations were significantly higher in patients with AIS (standard mean difference, SMD = 2.52, 95% CI 1.92 to 3.12; p < 0.001), ICH (SMD = 3.13, 95% CI 1.00 to 5.25; p = 0.004), and SAH (SMD = 4.50, 95% CI 0.91 to 7.01; p = 0.014) vs. controls (very low certainty of evidence). In AIS, the effect size was associated with the male gender, and was relatively larger in studies conducted in Egypt and India and those using enzyme-linked immunosorbent assays. IMA concentrations were progressively higher, by direct comparison, in SAH, ICH, and AIS. In sensitivity analysis, the pooled SMDs were not altered when individual studies were sequentially removed. Our meta-analysis suggests that IMA concentrations might be useful to diagnose stroke and discriminate between AIS, ICH, and SAH (PROSPERO registration number: CRD42021320535). Full article
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