Pathogenesis Of Stroke Research Articles

Identification of ribosome biogenesis genes and subgroups in ischaemic stroke.

Ischaemic stroke is a leading cause of death and severe disability worldwide. Given the importance of protein synthesis in the inflammatory response and neuronal repair and regeneration after stroke, and that proteins are acquired by ribosomal translation of mRNA, it has been theorised that ribosome biogenesis may have an impact on promoting and facilitating recovery after stroke. However, the relationship between stroke and ribosome biogenesis has not been investigated. In the present study, a ribosome biogenesis gene signature (RSG) was developed using Cox and least absolute shrinkage and selection operator (LASSO) analysis. We classified ischaemic stroke patients into high-risk and low-risk groups using the obtained relevant genes, and further elucidated the immune infiltration of the disease using ssGSEA, which clarified the close relationship between ischaemic stroke and immune subgroups. The concentration of related proteins in the serum of stroke patients was determined by ELISA, and the patients were divided into groups to evaluate the effect of the ribosome biogenesis gene on patients. Through bioinformatics analysis, we identified potential IS-RSGs and explored future therapeutic targets, thereby facilitating the development of more effective therapeutic strategies and novel drugs against potential therapeutic targets in ischaemic stroke. We obtained a set of 12 ribosome biogenesis-related genes (EXOSC5, MRPS11, MRPS7, RNASEL, RPF1, RPS28, C1QBP, GAR1, GRWD1, PELP1, UTP, ERI3), which play a key role in assessing the prognostic risk of ischaemic stroke. Importantly, risk grouping using ribosome biogenesis-related genes was also closely associated with important signaling pathways in stroke. ELISA detected the expression of C1QBP, RPS28 and RNASEL proteins in stroke patients, and the proportion of neutrophils was significantly increased in the high-risk group. The present study demonstrates the involvement of ribosomal biogenesis genes in the pathogenesis of ischaemic stroke, providing novel insights into the underlying pathogenic mechanisms and potential therapeutic strategies for ischaemic stroke.

Conformational Changes in DNA and Protein Biomolecules in Pathogenesis of Ischemic Stroke.

Conformational changes in DNA and protein biomolecules were studied in ischemic stroke (IS) cases varying severity by Raman spectroscopy. The conformational structure of hematoporphyrin was found to change in IS patients, leading to a higher (I1355/I1550)/(I1375/I1580) ratio (hemoglobin affinity of for ligands) and an increase in I1375/I1172 (a change in pyrrole conformation). Changes in genomic DNA spectra were observed at frequencies caused by stretching vibrations of primary amines (3400 cm-1), secondary amines and hydroxyls involved in hydrogen bonding (3100 cm-1), and CH2 groups of sugar phosphates (2900 cm-1) and vibrations of vibrational bonds between nitrogenous bases and sugars (1400 cm-1). The significant changes observed in genomic DNA and hemoglobin spectra were assumed to indicate conformational rearrangements of the molecules in IS. Severe IS was associated with maximum changes in DNA and hemoglobin spectra.

Study of serum gamma glutamyl transferase in acute stroke - a single centre experience

Background: Gamma-glutamyl transferase (GGT) is an enzyme involved in oxidative stress and inflammation, which are key mechanisms in the pathogenesis of stroke. Recent evidence suggests serum GGT levels may be associated with the risk and prognosis of acute ischemic stroke. This study aimed to investigate serum GGT levels in patients with acute stroke at a single center in India. Methods: This case-control study included 100 patients (50 with acute stroke and 50 age and sex-matched controls). Patients aged 40 to 80 years and diagnosed with acute stroke (encompassing first-time occurrences of intracerebral hemorrhage, ischemic stroke, and subarachnoid hemorrhage) were included in the study. Serum GGT levels were compared between stroke patients and controls. The association of GGT with various risk factors was also analyzed among cases. Results: The mean age of cases is 60.2±10.07 years. Hemorrhagic stroke was most common and found in 52% of cases. Mean serum GGT levels were significantly higher in stroke patients (55.2540±40.8909 U/l). Higher serum GGT levels were associated with male gender, presence of diabetes, hypertension, dyslipidemia and smoking and were found to be statistically significant (p<0.005). Age and stroke type were found to be not significantly associated with GGT levels. Conclusions: In conclusion, our study findings indicate that elevated serum GGT levels are associated with an increased risk of stroke, particularly in male patients and those with hypertension, dyslipidemia, and diabetes. Further prospective studies are needed to establish the predictive value of GGT for stroke.

Early and late gut microbiota signatures of stroke in high salt-fed stroke-prone spontaneously hypertensive rats

The high salt-fed stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable tool to study the mechanisms underlying stroke pathogenesis. Salt intake modifies the gut microbiota (GM) in rats and humans and alterations of the GM have previously been associated with increased stroke occurrence. We aimed to characterize the GM profile in SHRSPs fed a high-salt stroke-permissive diet (Japanese diet, JD), compared to the closely related stroke-resistant control (SHRSR), to identify possible changes associated with stroke occurrence. SHRSPs and SHRSRs were fed a regular diet or JD for 4 weeks (short-term, ST) or a maximum of 10 weeks (long-term, LT). Stroke occurred in SHRSPs on JD-LT, preceded by proteinuria and diarrhoea. The GM of JD-fed SHRSPs underwent early and late compositional changes compared to SHRSRs. An overrepresentation of Streptococcaceae and an underrepresentation of Lachnospiraceae were observed in SHRSPs JD-ST, while in SHRSPs JD-LT short-chain fatty acid producers, e.g. Lachnobacterium and Faecalibacterium, decreased and pathobionts such as Coriobacteriaceae and Desulfovibrio increased. Occludin gene expression behaved differently in SHRSPs and SHRSRs. Calprotectin levels were unchanged. In conclusion, the altered GM in JD-fed SHRSPs may be detrimental to gut homeostasis and contribute to stroke occurrence.

Assess the Serum Lipid Profile in Patient with Acute Ischemic Stroke at Tertiary Care Center in Nepal

Introduction: Ischemic stroke takes place when the blood flow cessation endures for more than a few minutes leading to brain tissue infarction. After ischemic heart disease, ischemic stroke is the second most common cause of death worldwide and one of the top five diseases based on DALYs (disability-adjusted life years) in Nepal. Though dyslipidemia is a major risk factor for coronary heart disease, it has an unclear role in the pathogenesis of ischemic stroke. In a patient with a previous ischemic stroke, statins reduce the risk of ischemic stroke. So, this study analyses the plasma prevalence of total cholesterol (TC), low-density lipoprotein (LDL), High-density lipoprotein (HDL), and triglyceride (TG) in patients with acute non-cardioembolic ischemic stroke and their association with different non-modifiable risk factors (age, gender & family history) and modifiable risk factors (diabetes, hypertension, obesity, smoking & alcohol intake).  Materials and Method: This is a descriptive and analytical cross-sectional hospital-based study carried out from December 5th, 2021 to December 4th, 2022 including 80 patients admitted to Chitwan Medical College, Chitwan, with a diagnosis of acute ischemic stroke. All the patients underwent a detailed history, physical examination, and baseline investigations including fasting lipid profile along with CT- scan/MRI head. The fasting lipid profile was done within the first 24 hours of hospitalization. Data was entered in MS Excel 2013 and converted it into SPSS 26 for statistical analysis.  Result: A total of 80 patients with the diagnosis of acute ischemic stroke were enrolled. Out of them, 37 (46.25%) were female and 43 (53.75%) were male. A total number of 71 (88.75%) patients were from more than or equal to 55 years of age group and 9 (11.25%) patients were from less than 55 years of age group. The mean age ± standard deviation of male and female patients was 66.69 ±9.14 years and 68.54 ±14.96 respectively. Overall, derangement in serum lipid profile (dyslipidemia) was present in 63.75% of the patients. Among the total cases, high TC is found in 18 patients (22.5%), TG in 24 patients (30%), high LDL is found in 16 patients (20%), and low HDL is found in 23 patients (28.75%).  Conclusion: The study highlights hypertriglyceridemia as the leading dyslipidemia in ischemic stroke patients, showing gender and age variations in prevalence. It confirms dyslipidemia's role in brain vascular changes, notably in the Middle Cerebral Artery, and its link to carotid artery stenosis severity. Despite common risk factors, their direct association with dyslipidemia remains statistically insignificant, stressing the need for focused lipid management to mitigate stroke risks.

Genome−wide association analysis to search for new loci associated with stroke risk in Northwestern Chinese population

Background and PurposeGenetic factors play an important role in the pathogenesis of stroke(S). This study aimed to screen the loci associated with S risk in northwestern Chinese population by genome-wide association analysis (GWAS). MethodsA total of 1394 subjects, including 682 S patients and 692 controls, were enrolled in this study. SPSS 25.0 software was used for statistical analysis, and the independent sample t-test as well as Chi-square test were used to analyze the differences in age and gender between the case and control groups. The Precision Medicine Diversity Array (PMDA) genotyping chip was used in this study. The genotyping platform was the Gene Titan multi-channel instrument, and the Axiom Analysis Suite 6.0 software was used for the data analyzing. Besides, the LASSO analysis, SNP-SNP and GO/KEGG analysis were conducted to analyze the association between significant loci and S risk. ResultsA total of 30 SNPs were found to be associated with the S risk based on additive model (p < 5 × 10-8). After the LASSO screening, 22 SNPs showed the diagnostic value in S. The SNPs interaction analysis further screened the SNP-SNP interaction groups associated with the S risk(p < 0.05). Finally, the GO/KEGG analysis discovered the suggestive significance loci could be involved in the S development mainly by immune-related functions and pathways. ConclusionThis study discovered 30 S related SNPs and analyzed the potential pathways associated with genes located on the 30 SNPs, which were beneficial for enriching the genetic mechanism analysis of S in northwestern Chinese population.

The SWELL1 Channel Promotes Ischemic Brain Damage by Mediating Neuronal Swelling and Glutamate Toxicity.

Cytotoxic neuronal swelling and glutamate excitotoxicity are two hallmarks of ischemic stroke. However, the underlying molecular mechanisms are not well understood. Here, it is reported that SWELL1, the essential subunit of the volume-regulated anion channel (VRAC), plays a dual role in ischemic injury by promoting neuronal swelling and glutamate excitotoxicity. SWELL1 expression is upregulated in neurons and astrocytes after experimental stroke in mice. The neuronal SWELL1 channel is activated by intracellular hypertonicity, leading to Cl- influx-dependent cytotoxic neuronal swelling and subsequent cell death. Additionally, the SWELL1 channel in astrocytes mediates pathological glutamate release, indicated by increases in neuronal slow inward current frequency and tonic NMDAR current. Pharmacologically, targeting VRAC with a new inhibitor, an FDA-approved drug Dicumarol, attenuated cytotoxic neuronal swelling and cell death, reduced astrocytic glutamate release, and provided significant neuroprotection in mice when administered either before or after ischemia. Therefore, these findings uncover the pleiotropic effects of the SWELL1 channel in neurons and astrocytes in the pathogenesis of ischemic stroke and provide proof of concept for therapeutically targeting it in this disease.

The role of LCN2 in exacerbating ferroptosis levels in acute ischemic stroke injury

Due to the complex pathogenesis of acute ischemic stroke (AIS), further investigation into its underlying mechanisms is necessary. Presently, existing literature indicates a close association between ferroptosis and AIS injury; however, the precise mechanism and molecular target of ferroptosis in AIS injury remain elusive. By RNA sequencing, we found a significant increase in LCN2 expression in the ischemic cortex. In order to investigate the potential role of LCN2 in modulating AIS injury through the regulation of ferroptosis, we utilized RNA interference (RNAi) knockdown and gene overexpression experiments. The findings from experiments conducted both in vitro and in vivo revealed a marked increase in ferroptosis levels within the AIS model group. Suppression of the LCN2 gene resulted in a significant reduction in ferroptosis levels in OGD/R cells. Conversely, upregulation of LCN2 exacerbated ferroptosis levels in OGD/R cells. The results suggest that elevated levels of ferroptosis may result from heightened expression of LCN2, thereby exacerbating ischemia/reperfusion injury. This study indicates the involvement of ferroptosis in the pathogenesis of AIS and highlights LCN2 as a regulator of ferroptosis in AIS-induced injury, suggesting a potential therapeutic target for ischemic stroke.

Intersecting Pathways: The Role of Metabolic Dysregulation, Gastrointestinal Microbiome, and Inflammation in Acute Ischemic Stroke Pathogenesis and Outcomes.

Acute ischemic stroke (AIS) remains a major cause of mortality and long-term disability worldwide, driven by complex and multifaceted etiological factors. Metabolic dysregulation, gastrointestinal microbiome alterations, and systemic inflammation are emerging as significant contributors to AIS pathogenesis. This review addresses the critical need to understand how these factors interact to influence AIS risk and outcomes. We aim to elucidate the roles of dysregulated adipokines in obesity, the impact of gut microbiota disruptions, and the neuroinflammatory cascade initiated by lipopolysaccharides (LPS) in AIS. Dysregulated adipokines in obesity exacerbate inflammatory responses, increasing AIS risk and severity. Disruptions in the gut microbiota and subsequent LPS-induced neuroinflammation further link systemic inflammation to AIS. Advances in neuroimaging and biomarker development have improved diagnostic precision. Here, we highlight the need for a multifaceted approach to AIS management, integrating metabolic, microbiota, and inflammatory insights. Potential therapeutic strategies targeting these pathways could significantly improve AIS prevention and treatment. Future research should focus on further elucidating these pathways and developing targeted interventions to mitigate the impacts of metabolic dysregulation, microbiome imbalances, and inflammation on AIS.

Sex differences in the association between plasma branched-chain amino acids and risk of ischemic stroke: A nested case-control study from China

ObjectivesThe aim of this study was to investigate the prospective associations between plasma branched-chain amino acids (BCAAs) and the risk of ischemic stroke in men and women. MethodsWe conducted a nested case-control study within a community-based cohort in China. The cohort consisted of 15,926 participants in 2013-2018. A total of 321 ischemic stroke cases were identified during the follow up and individually matched with 321 controls by date of birth (±1 year) and sex. Females accounted for 55.8% (n = 358, 179 cases vs 179 controls) of the study population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between plasma BCAAs and ischemic stroke risk by conditional logistic regression. ResultsElevated plasma isoleucine was associated with a higher risk of ischemic stroke in women. The OR for the highest compared to the lowest quartile was 2.22 (95% CI: 1.11-4.44, P trend = 0.005) after adjustment for body mass index, education attainment, smoking, hypertension, renal function, menopause and physical activity. A similar association was found for total BCAAs (adjusted OR = 2.03, 95% CI: 1.05-3.95, P trend = 0.04). In contrast, no significant association of plasma BCAAs with ischemic stroke risk was observed in men. ConclusionsPlasma isoleucine and total BCAAs were significantly associated with ischemic stroke risk in women, but not in men, highlighting sex differences in BCAAs metabolism and stroke pathogenesis.

Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but regulates neurorepair processes after experimental ischemic stroke.

Inflammation is a key contributor to stroke pathogenesis and exacerbates brain damage leading to poor outcome. Interleukin-1 (IL-1) is an important regulator of post-stroke inflammation, and blocking its actions is beneficial in pre-clinical stroke models and safe in the clinical setting. However, the distinct roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, and the specific role of IL-1α in ischemic stroke remain largely unknown. Here we show that IL-1α and IL-1β have different spatio-temporal expression profiles in the brain after experimental stroke, with early microglial IL-1α expression (4 h) and delayed IL-1β expression in infiltrated neutrophils and a small microglial subset (24-72 h). We examined for the first time the specific role of microglial-derived IL-1α in experimental permanent and transient ischemic stroke through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Microglial IL-1α deletion did not influence acute brain damage, cerebral blood flow, IL-1β expression, neutrophil infiltration, microglial nor endothelial activation after ischemic stroke. However, microglial IL-1α knock out (KO) mice showed reduced peri-infarct vessel density and reactive astrogliosis at 14 days post-stroke, alongside long-term impaired functional recovery. Our study identifies for the first time a critical role for microglial IL-1α on neurorepair and functional recovery after stroke, highlighting the importance of targeting specific IL-1 mechanisms in brain injury to develop more effective therapies.

Lipoprotein (a) and cerebrovascular disease.

The role of lipoprotein (a) [Lp(a)] in cerebrovascular disease is a topic of importance. In this narrative review, pertinent studies have been leveraged to comprehensively examine this relationship from diverse perspectives.Lp(a) shares structural traits with low-density lipoprotein cholesterol. Lp(a) is synthesized by hepatocytes, and its plasma levels are genetically determined by the LPA gene, which produces apolipoprotein (a).Numerous epidemiological studies have confirmed the positive correlation between elevated serum Lp(a) levels and the occurrence or recurrence of cerebrovascular events, especially ischemic strokes, in adults. It should be noted that the correlation strength varies among studies and is marginal in Mendelian randomization studies.Regarding pediatric patients, screening is currently limited to those with a relevant medical history. Lp(a) seems to play a significant role in the pathogenesis of arterial ischemic stroke in children because environmental thrombotic and atherogenic factors are generally not present.Phase 3 trials of novel Lp(a) targeting agents, such as pelacarsen and olpasiran, are anticipated to demonstrate their efficacy in reducing the incidence of stroke. Given the richness of the literature, new guidelines regarding Lp(a) screening and management in targeted populations are warranted to provide more effective primary and secondary prevention.

Cardiovascular Risk Factors and Disparities in Management of Embolic Stroke: A Western Sydney Perspective

Ischaemic stroke remains one of the leading causes of death and disability worldwide. The population of Western Sydney has a unique demographic with lower socioeconomic status and a culturally and linguistically diverse population. This study aims to investigate the demographics and cardiovascular risk factors of patients in Western Sydney, focusing on the prevalence and profile of cardioembolic (CE) strokes and embolic strokes of undetermined source (ESUS). Prospective data were collected in 463 patients with ischaemic stroke presenting to a tertiary centre in Western Sydney, who underwent predischarge transthoracic echocardiography. Patients with haemorrhagic strokes or unclear stroke diagnosis were excluded. Analysis of stroke subtype (CE, ESUS, or non-embolic) and clinical characteristics was performed based on age, gender, and prior atrial fibrillation (AF) prevalence. Of the 463 patients, 147 (32%) had CE strokes, and 147 (32%) had ESUS. Cardioembolic (CE) strokes were associated with older age (≥65 years) and a history of congestive cardiac failure. Older patients had higher rates of hypertension, ischaemic heart disease, AF, and congestive heart failure. History of AF was present in 67 patients (14.5%); however, only 51% received anticoagulation before admission despite a low bleeding risk. The transthoracic echocardiography characteristics of ESUS/non-embolic strokes differed from those of CE strokes; 20% of patients with ESUS had an enlarged left atrium, suggesting a subset of patients with ESUS with a left atrial myopathy. Patients with ischaemic stroke in Western Sydney have a high prevalence of cardiovascular risk factors which were often undertreated. Half of the patients with prior AF did not receive anticoagulation despite low bleeding risk, indicating a gap in optimal stroke prevention. There were distinct echocardiographic characteristics among stroke subtypes. Further analysis of left atrium parameters may provide greater insights into the pathogenesis and prevention of embolic strokes.

Correlation between Mean Platelet Volume, Fibrinogen and D-dimer with NIHSS Score

Introduction: Stroke is a clinical syndrome that develops rapidly due to focal or global brain disorders with symptoms last for &gt;24 hours and potentially cause death. Due to the consideration that this Mean Platelet Volume (MPV) marker is not invasive, easy to do and is in line with the pathogenesis of stroke, researchers are interested in carrying out this research. And hopefully this research can provide information for the world of education and health about changes in MPV, fibrinogen and D-dimer in ischemic stroke patients. So it can be taken as consideration in the early management of ischemic stroke patients. Subject and Methods: This research was an observational study with a cross-sectional design at Haji Adam Malik General Hospital from October to November 2023. The research subjects were stroke patients who were treated in emergency room and met inclusion criteria. This research was to study about correlation of MPV, fibrinogen, and D-dimer with NIHSS scores of ischemic stroke patients. The method used in this research is the Pearson correlation test where data was normally distributed. All statistical tests with a p value &lt; 0.05 were considered significant. Results: The mean MPV was 10.4 ± 1.6, while the mean NIHSS value was 19.9 ± 8.7, and there was a statistically significant correlation between the MPV value and the NIHSS score (p&lt;0.05). The mean fibrinogen was 421.9 ± 109.3, while mean NIHSS value was 19.9 ± 8.7, and there was a statistically significant correlation between fibrinogen values and NIHSS scores (p&lt;0.001). The mean D-Dimer was 8.0 ± 11.3, while the mean NIHSS value was 19.9 ± 8.7, and showed a statistically significant correlation between D-Dimer value and NIHSS score (p&lt;0.05). The r value of MPV, fibrinogen, and D-dimer on NIHSS score was 0.494; 0.495; and 0.504. The regression coefficient for MPV variable is 0.093, therefore MPV variable influence on NIHSS variable is positive. Conclusion: There is a strong correlation between D-dimer and the NIHSS score, and a moderate correlation between MPV and fibrinogen with NIHSS score.

MicroRNA-195-5p Attenuates Intracerebral-Hemorrhage-Induced Brain Damage by Inhibiting MMP-9/MMP-2 Expression.

Intracerebral hemorrhage (ICH) remains a devastating disease with high mortality, and there is a lack of effective strategies to improve functional outcomes. The primary injury of ICH is mechanical damage to brain tissue caused by the hematoma. Secondary injury, resulting from inflammation, red cell lysis, and thrombin production, presents a potential target for therapeutic intervention. Inflammation, crucial in secondary brain injury, involves both cellular and molecular components. MicroRNAs (miRNAs) are vital regulators of cell growth, differentiation, and apoptosis. Their deregulation may lead to diseases, and modulating miRNA expression has shown therapeutic potential, especially in cancer. Recent studies have implicated miRNAs in the pathogenesis of stroke, affecting endothelial dysfunction, neurovascular integrity, edema, apoptosis, inflammation, and extracellular matrix remodeling. Preclinical and human studies support the use of miRNA-directed gene modulation as a therapeutic strategy for ICH. Our study focused on the effects of miR-195 in ICH models. Neurological tests, including the corner turn and grip tests, indicated that miR-195 treatment led to improvements in motor function impairments caused by ICH. Furthermore, miR-195-5p significantly reduced brain edema in the ipsilateral hemisphere and restored blood-brain barrier (BBB) integrity, as shown by reduced Evans blue dye extravasation. These results suggest miR-195-5p's potential in attenuating ICH-induced apoptosis, possibly related to its influence on MMP-9 and MMP-2 expression, enzymes associated with secondary brain injury. The anti-apoptotic effects of miR-195-5p, demonstrated through TUNEL assays, further underscore its therapeutic promise in addressing the secondary brain injury and apoptosis associated with ICH. In conclusion, miR-195-5p demonstrates a significant neuroprotective effect against ICH-induced neural damage, brain edema, and BBB disruption, primarily through the downregulation of MMP-9 and MMP-2. Our findings indicate that miR-195-5p holds therapeutic potential in managing cerebral cell death following ICH.

Downregulation of Ripk1 and Nsf mediated by CRISPR-CasRx ameliorates stroke volume and neurological deficits after ischemia stroke in mice.

Necroptosis is implicated in the pathogenesis of ischemic stroke. However, the mechanism underlying the sequential recruitment of receptor-interacting protein kinase 1 (RIPK1) and N-ethylmaleimide-sensitive fusion ATPase (NSF) in initiating necroptosis remains poorly understood, and the role of NSF in ischemic stroke is a subject of controversy. Here, we utilized a recently emerging RNA-targeting CRISPR system known as CasRx, delivered by AAVs, to knockdown Ripk1 mRNA and Nsf mRNA around the ischemic brain tissue. This approach resulted in a reduction in infarct and edema volume, as well as an improvement in neurological deficits assessed by Bederson score, RotaRod test, and Adhesive removal test, which were achieved by RIPK1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein signaling pathway involved in neuronal necroptosis. In conclusion, the downregulation of Ripk1 mRNA and Nsf mRNA mediated by CRISPR-CasRx holds promise for future therapeutic applications aimed at ameliorating cerebral lesions and neurological deficits following the ischemic stroke.

CEBPD aggravates apoptosis and oxidative stress of neuron after ischemic stroke by Nrf2/HO-1 pathway

CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.

Molecular Pathogenesis of Ischemic and Hemorrhagic Strokes: Background and Therapeutic Approaches.

Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies.

Research progress of neurovascular units involved in ischemic stroke

AbstractIschemic stroke is the most prevalent cerebrovascular disorder in the clinical setting. It results in associated neurological abnormalities due to a variety of factors, including disruption of cerebral arterial blood flow, hypoxia, and ischemic necrosis of local brain tissues. The neurovascular unit (NVU) is a dynamic structural complex that consists of neurons, glial cells, pericytes, vascular endothelial cells, and the extracellular matrix. Many cells work together to preserve the integrity of the central nervous system (CNS) under physiological conditions. However, following ischemic stroke, NVU homeostasis is disrupted along with the development of tissue ischemia and hypoxia, as well as impaired interactions between various components of the NVU. Collectively, the changes result in increased blood–brain barrier permeability, neuronal dysfunction, and functional destruction of nerve conduction bundles, ultimately leading to the clinical manifestation of neurological deficits including motor, cognitive, and speech impairments that hinder the rehabilitation process. In recent years, with continuously expanding research on ischemic cerebrovascular disease, the role of interconnections between different cells in the NVU in ischemic stroke has received increasing attention. To describe new concepts for the prevention and treatment of ischemic cerebrovascular illnesses, this article reviews the interplay between NVU in the pathogenesis of ischemic stroke.

Effects of a novel regimen of repetitive transcranial magnetic stimulation (rTMS) on neural remodeling and motor function in adult male mice with ischemic stroke

AbstractNeuroinflammation caused by excessive microglial activation plays a key role in the pathogenesis of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulatory technique that has recently been reported to regulate microglial functions and exert anti‐inflammatory effects. The intermittent burst stimulation (iTBS) regimen in rTMS improves neuronal excitability. However, whether iTBS exerts its anti‐inflammatory effects by stimulating neurons and thereby modulating microglial polarization remains unclear. Motor function was assessed after 1 week of rTMS (iTBS regimen) treatment in adult male mice with occlusion/reperfusion of the middle cerebral artery (MCAO/r) injury. We also investigated the molecular biological alterations associated with microglial polarization using a cell proliferation assay, multiplex cytokine bioassays, and immunofluorescence staining. iTBS regimen can improve balance and motor coordination function, increase spontaneous movement, and improve walking function in mice with early cerebral ischemia injury. Expression levels of IL‐1β, TNF‐α, and IL‐10 increased significantly in mice with MCAO injury. Especially, rTMS significantly increased the number of proliferating cells in the infarcted cortex. The fluorescence intensity of MAP2 in the peri‐infarct area of MCAO injured mice was low, but the signal was broader. Compared with MCAO group, the fluorescence intensity of MAP2 in rTMS group was significantly increased. rTMS inhibited pro‐inflammatory M1 activation (Iba1+/CD86+) and improved anti‐inflammatory M2 activation (Iba1+/CD206+) in the peri‐infarct zone, thus significantly changing the phenotypic ratio M1/M2. rTMS improves motor dysfunction and neuroinflammation after cerebral I/R injury in mice by regulating microglial polarization.