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Search Results (1,281)

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Keywords = stroke therapeutics

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13 pages, 1536 KiB  
Article
Gosha-Jinki-Gan Reduces Inflammation in Chronic Ischemic Stroke Mouse Models by Suppressing the Infiltration of Macrophages
by Mingli Xu, Kaori Suyama, Kenta Nagahori, Daisuke Kiyoshima, Satomi Miyakawa, Hiroshi Deguchi, Yasuhiro Katahira, Izuru Mizoguchi, Hayato Terayama, Shogo Hayashi, Takayuki Yoshimoto and Ning Qu
Biomolecules 2025, 15(8), 1136; https://doi.org/10.3390/biom15081136 - 6 Aug 2025
Abstract
Ischemic stroke is a primary cause of cerebrovascular diseases and continues to be one of the leading causes of death and disability among patients worldwide. Pathological processes caused by vascular damage due to stroke occur in a time-dependent manner and are classified into [...] Read more.
Ischemic stroke is a primary cause of cerebrovascular diseases and continues to be one of the leading causes of death and disability among patients worldwide. Pathological processes caused by vascular damage due to stroke occur in a time-dependent manner and are classified into three categories: acute, subacute, and chronic. Current treatments for ischemic stroke are limited to effectiveness in the early stages. In this study, we investigated the therapeutic effect of an oriental medicine, Gosha-jinki-gan (TJ107), on improving chronic ischemic stroke using the mouse model with middle cerebral artery occlusion (MCAO). The changes in the intracerebral inflammatory response (macrophages (F4/80), TLR24, IL-23, IL-17, TNF-α, and IL-1β) were examined using real-time RT-PCR. The MCAO mice showed the increased expression of glial fibrillary acidic protein (GFAP) and of F4/80, TLR2, TLR4, IL-1β, TNF-α, and IL-17 in the brain tissue from the MCAO region. This suggests that they contribute to the expansion of the ischemic stroke infarct area and to the worsening of the neurological symptoms of the MCAO mice in the chronic phase. On the other hand, the administration of TJ107 was proven to reduce the infarct area, with decreased GFAP expression, suppressed macrophage infiltration in the brain, and reduced TNF-α, IL-1β, and IL-17 production compared with the MCAO mice. This study first demonstrated Gosha-jinki-gan’s therapeutic effects on the chronic ischemic stroke. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Novel Treatments of Stroke)
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38 pages, 547 KiB  
Review
Sleep Disorders and Stroke: Pathophysiological Links, Clinical Implications, and Management Strategies
by Jamir Pitton Rissardo, Ibrahim Khalil, Mohamad Taha, Justin Chen, Reem Sayad and Ana Letícia Fornari Caprara
Med. Sci. 2025, 13(3), 113; https://doi.org/10.3390/medsci13030113 - 5 Aug 2025
Abstract
Sleep disorders and stroke are intricately linked through a complex, bidirectional relationship. Sleep disturbances such as obstructive sleep apnea (OSA), insomnia, and restless legs syndrome (RLS) not only increase the risk of stroke but also frequently emerge as consequences of cerebrovascular events. OSA, [...] Read more.
Sleep disorders and stroke are intricately linked through a complex, bidirectional relationship. Sleep disturbances such as obstructive sleep apnea (OSA), insomnia, and restless legs syndrome (RLS) not only increase the risk of stroke but also frequently emerge as consequences of cerebrovascular events. OSA, in particular, is associated with a two- to three-fold increased risk of incident stroke, primarily through mechanisms involving intermittent hypoxia, systemic inflammation, endothelial dysfunction, and autonomic dysregulation. Conversely, stroke can disrupt sleep architecture and trigger or exacerbate sleep disorders, including insomnia, hypersomnia, circadian rhythm disturbances, and breathing-related sleep disorders. These post-stroke sleep disturbances are common and significantly impair rehabilitation, cognitive recovery, and quality of life, yet they remain underdiagnosed and undertreated. Early identification and management of sleep disorders in stroke patients are essential to optimize recovery and reduce the risk of recurrence. Therapeutic strategies include lifestyle modifications, pharmacological treatments, medical devices such as continuous positive airway pressure (CPAP), and emerging alternatives for CPAP-intolerant individuals. Despite growing awareness, significant knowledge gaps persist, particularly regarding non-OSA sleep disorders and their impact on stroke outcomes. Improved diagnostic tools, broader screening protocols, and greater integration of sleep assessments into stroke care are urgently needed. This narrative review synthesizes current evidence on the interplay between sleep and stroke, emphasizing the importance of personalized, multidisciplinary approaches to diagnosis and treatment. Advancing research in this field holds promise for reducing the global burden of stroke and improving long-term outcomes through targeted sleep interventions. Full article
17 pages, 5839 KiB  
Article
Salvianolic Acid A Activates Nrf2-Related Signaling Pathways to Inhibit Ferroptosis to Improve Ischemic Stroke
by Yu-Fu Shang, Wan-Di Feng, Dong-Ni Liu, Wen-Fang Zhang, Shuang Xu, Dan-Hong Feng, Guan-Hua Du and Yue-Hua Wang
Molecules 2025, 30(15), 3266; https://doi.org/10.3390/molecules30153266 - 4 Aug 2025
Abstract
Ischemic stroke is a serious disease that frequently occurs in the elderly and is characterized by a complex pathophysiology and a limited number of effective therapeutic agents. Salvianolic acid A (SAL-A) is a natural product derived from the rhizome of Salvia miltiorrhiza, [...] Read more.
Ischemic stroke is a serious disease that frequently occurs in the elderly and is characterized by a complex pathophysiology and a limited number of effective therapeutic agents. Salvianolic acid A (SAL-A) is a natural product derived from the rhizome of Salvia miltiorrhiza, which possesses diverse pharmacological activities. This study aims to investigate the effect and mechanisms of SAL-A in inhibiting ferroptosis to improve ischemic stroke. Brain injury, oxidative stress and ferroptosis-related analysis were performed to evaluate the effect of SAL-A on ischemic stroke in photochemical induction of stroke (PTS) in mice. Lipid peroxidation levels, antioxidant protein levels, tissue iron content, nuclear factor erythroid 2-related factor 2 (Nrf2), and mitochondrial morphology changes were detected to explore its mechanism. SAL-A significantly attenuated brain injury, reduced malondialdehyde (MDA) and long-chain acyl-CoA synthase 4 (ACSL4) levels. In addition, SAL-A also amplified the antioxidative properties of glutathione (GSH) when under glutathione peroxidase 4 (GPX4), and the reduction in ferrous ion levels. In vitro, brain microvascular endothelial cells (b.End.3) exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to investigate whether the anti-stroke mechanism of SAL-A is related to Nrf2. Following OGD/R, ML385 (Nrf2 inhibitor) prevents SAL-A from inhibiting oxidative stress, ferroptosis, and mitochondrial dysfunction in b.End.3 cells. In conclusion, SAL-A inhibits ferroptosis to ameliorate ischemic brain injury, and this effect is mediated through Nrf2. Full article
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15 pages, 1825 KiB  
Article
Entropy Analysis of Electroencephalography for Post-Stroke Dysphagia Assessment
by Adrian Velasco-Hernandez, Javier Imaz-Higuera, Jose Luis Martinez-de-Juan, Yiyao Ye-Lin, Javier Garcia-Casado, Marta Gutierrez-Delgado, Jenny Prieto-House, Gemma Mas-Sese, Araceli Belda-Calabuig and Gema Prats-Boluda
Entropy 2025, 27(8), 818; https://doi.org/10.3390/e27080818 - 31 Jul 2025
Viewed by 221
Abstract
Affecting over 50% of stroke patients, dysphagia is still challenging to diagnose and manage due to its complex multifactorial nature and can be the result of disruptions in the coordination of cortical and subcortical neural activity as reflected in electroencephalographic (EEG) signal patterns. [...] Read more.
Affecting over 50% of stroke patients, dysphagia is still challenging to diagnose and manage due to its complex multifactorial nature and can be the result of disruptions in the coordination of cortical and subcortical neural activity as reflected in electroencephalographic (EEG) signal patterns. Sample Entropy (SampEn), a signal complexity or predictability measure, could serve as a tool to identify any abnormalities associated with dysphagia. The present study aimed to identify quantitative dysphagia biomarkers using SampEn from EEG recordings in post-stroke patients. Sample entropy was calculated in the theta, alpha, and beta bands of EEG recordings in a repetitive swallowing task performed by three groups: 22 stroke patients without dysphagia (controls), 36 stroke patients with dysphagia, and 21 healthy age-matched individuals. Post-stroke patients, both with and without dysphagia, exhibited significant differences in SampEn compared to healthy subjects in the alpha and theta bands, suggesting widespread alterations in brain dynamics. These changes likely reflect impairments in sensorimotor integration and cognitive control mechanisms essential for effective swallowing. A significant cluster was identified in the left parietal region during swallowing in the beta band, where dysphagic patients showed higher entropy compared to healthy individuals and controls. This finding suggests altered neural dynamics in a region crucial for sensorimotor integration, potentially reflecting disrupted cortical coordination associated with dysphagia. The precise quantification of these neurophysiological alterations offers a robust and objective biomarker for diagnosing neurogenic dysphagia and monitoring therapeutic interventions by means of EEG, a non-invasive and cost-efficient technique. Full article
(This article belongs to the Section Multidisciplinary Applications)
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22 pages, 8824 KiB  
Article
Pro-Inflammatory Microglia Exacerbate High-Altitude-Induced Cognitive Impairment by Driving Lipid Droplet Accumulation in Astrocytes
by Xiaoyang Fan, Sitong Cao, Yujie Fang, Li Zhu and Xueting Wang
Antioxidants 2025, 14(8), 918; https://doi.org/10.3390/antiox14080918 - 26 Jul 2025
Viewed by 545
Abstract
High-altitude cognitive impairment (HACI) results from acute or chronic exposure to hypoxic conditions. Brain lipid homeostasis is crucial for cognitive function, and lipid droplet (LD) accumulation in glia cells is linked to cognitive decline in aging and stroke. However, whether high-altitude exposure affects [...] Read more.
High-altitude cognitive impairment (HACI) results from acute or chronic exposure to hypoxic conditions. Brain lipid homeostasis is crucial for cognitive function, and lipid droplet (LD) accumulation in glia cells is linked to cognitive decline in aging and stroke. However, whether high-altitude exposure affects brain lipid homeostasis is unclear. Microglia, key regulators of brain homeostasis and inflammation, play a significant role in pathological cognitive impairment and are implicated in LD formation. This study investigates whether lipid dysregulation contributes to HACI and explores microglia-driven mechanisms and potential interventions. Mice were exposed to a simulated 7000 m altitude for 48 h, followed by a week of recovery. Cognitive function and LD accumulation in brain cells were assessed. Microglia were depleted using PLX5622, and mice were exposed to hypoxia or lipopolysaccharide (LPS) to validate microglia’s role in driving astrocytic LD accumulation and cognitive decline. Minocycline was used to inhibit inflammation. In vitro, co-culture systems of microglia and astrocytes were employed to confirm microglia-derived pro-inflammatory factors’ role in astrocytic LD accumulation. Hypobaric hypoxia exposure induced persistent cognitive impairment and LD accumulation in hippocampal astrocytes and microglia. Microglia depletion alleviated cognitive deficits and reduced astrocytic LD accumulation. Hypoxia or LPS did not directly cause LD accumulation in astrocytes but activated microglia to release IL-1β, inducing astrocytic LD accumulation. Microglia depletion also mitigated LPS-induced cognitive impairment and astrocytic LD accumulation. Minocycline reduced hypoxia-induced LD accumulation in co-cultured astrocytes and improved cognitive function. Hypoxia triggers pro-inflammatory microglial activation, leading to LD accumulation and the release of IL-1β, which drives astrocytic LD accumulation and neuroinflammation, exacerbating HACI. Minocycline effectively restores brain lipid homeostasis and mitigates cognitive impairment. This study provides novel insights into HACI mechanisms and suggests potential therapeutic strategies. Full article
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16 pages, 956 KiB  
Review
The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases
by Francesco D’Egidio, Housem Kacem, Giorgia Lombardozzi, Michele d’Angelo, Annamaria Cimini and Vanessa Castelli
Appl. Sci. 2025, 15(15), 8239; https://doi.org/10.3390/app15158239 - 24 Jul 2025
Viewed by 266
Abstract
Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. [...] Read more.
Bruton Tyrosine Kinase (BTK) has emerged as a critical mediator in the pathophysiology of neuroinflammation associated with neurodegenerative diseases. BTK, a non-receptor tyrosine kinase predominantly expressed in cells of the hematopoietic lineage, modulates B-cell receptor signaling and innate immune responses, including microglial activation. Recent evidence implicates aberrant BTK signaling in the exacerbation of neuroinflammatory cascades contributing to neuronal damage in disorders such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, and Huntington’s disease. Pharmacological inhibition of BTK has shown promise in attenuating microglial-mediated neurotoxicity, reducing pro-inflammatory cytokine release, and promoting neuroprotection in preclinical models. BTK inhibitors, originally developed for hematological malignancies, demonstrate favorable blood–brain barrier penetration and immunomodulatory effects relevant to central nervous system pathology. This therapeutic approach may counteract detrimental neuroimmune interactions without broadly suppressing systemic immunity, thus preserving host defense. Ongoing clinical trials are evaluating the safety and efficacy of BTK inhibitors in patients with neurodegenerative conditions, with preliminary results indicating potential benefits in slowing disease progression and improving neurological outcomes. This review consolidates current knowledge on BTK signaling in neurodegeneration and highlights the rationale for BTK inhibition as a novel, targeted therapeutic strategy to modulate neuroinflammation and mitigate neurodegenerative processes. Full article
(This article belongs to the Section Applied Biosciences and Bioengineering)
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12 pages, 459 KiB  
Article
Effects of Air Splints on Sensorimotor Disturbances of the Affected Upper Extremity and Trunk Control in Adult Post-Stroke Patients
by Ana Isabel Useros-Olmo, Roberto Cano-de-la-Cuerda, Jesús Rodríguez-Herranz, Alfonso Gil-Martínez and Alicia Hernando-Rosado
J. Clin. Med. 2025, 14(15), 5185; https://doi.org/10.3390/jcm14155185 - 22 Jul 2025
Viewed by 193
Abstract
Background: The present study aimed to determine whether the protocolized use of pneumatic splints within neurodevelopmental therapeutic approaches produces a positive effect on sensorimotor impairments of the hemiplegic upper extremity in patients. Methods: A randomized clinical single-blind trial was conducted. Stroke patients were [...] Read more.
Background: The present study aimed to determine whether the protocolized use of pneumatic splints within neurodevelopmental therapeutic approaches produces a positive effect on sensorimotor impairments of the hemiplegic upper extremity in patients. Methods: A randomized clinical single-blind trial was conducted. Stroke patients were recruited and randomized into an experimental group, which completed a treatment protocol of splinting plus physiotherapy for 45 min per session, two sessions per week for four weeks; or a control group, which received the same type of conventional physiotherapy treatment for the same period of time. The patients were evaluated by Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) and the Trunk Control Scale. Secondary variables were Mini-BEStest, the modified Ashworth scale for ankle flexors, and computerized measurements of upper limb functional parameters performed by Armeo Spring® robotic systems and Amadeo®. All variables were measured pre- and post-treatment. Results: Twenty stroke patients with subacute and chronic stroke completed the protocol. Mann–Whitney U tests showed statistically significant differences between groups for the FM sensation variable (Z = −2.19; p = 0.03). The rest of the variables studied in the comparison between the two study groups did not present statistically significant differences (p > 0.05). Conclusions: The use of air splints in combination with physiotherapy treatment produced improvements in exteroceptive and proprioceptive sensitivity in post-stroke adult patients in the subacute and chronic phases. Full article
(This article belongs to the Section Clinical Rehabilitation)
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16 pages, 2628 KiB  
Article
Astrocyte-Conditioned Medium Induces Protection Against Ischaemic Injury in Primary Rat Neurons
by Ayesha Singh and Ruoli Chen
Neuroglia 2025, 6(3), 27; https://doi.org/10.3390/neuroglia6030027 - 17 Jul 2025
Viewed by 266
Abstract
Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to [...] Read more.
Background: Astrocytes are not only structural cells but also play a pivotal role in neurogenesis and neuroprotection by secreting a variety of neurotrophic factors that support neuronal survival, growth, and repair. This study investigates the time-dependent responses of primary rat cortical astrocytes to oxygen–glucose deprivation (OGD) and evaluates the neuroprotective potential of astrocyte-conditioned medium (ACM). Methods: Primary rat cortical astrocytes and neurons were obtained from postnatal Sprague Dawley rat pups (P1–3) and embryos (E17–18), respectively. Astrocytes exposed to 6, 24, and 48 h of OGD (0.3% O2) were assessed for viability, metabolic function, hypoxia-inducible factor 1 and its downstream genes expression. Results: While 6 h OGD upregulated protective genes such as Vegf, Glut1, and Pfkfb3 without cell loss, prolonged OGD, e.g., 24 or 48 h, led to significant astrocyte death and stress responses, including elevated LDH release, reduced mitochondrial activity, and increased expression of pro-apoptotic marker Bnip3. ACM from 6 h OGD-treated astrocytes significantly enhanced neuronal survival following 6 h OGD and 24 h reperfusion, preserving dendritic architecture, improving mitochondrial function, and reducing cell death. This protective effect was not observed with ACM from 24 h OGD astrocytes. Furthermore, 6 h OGD-ACM induced autophagy in neurons, as indicated by elevated LC3b-II and decreased p62 levels, suggesting autophagy as a key mechanism in ACM-mediated neuroprotection. Conclusions: These findings demonstrate that astrocytes exhibit adaptive, time-sensitive responses to ischemic stress and secrete soluble factors that can confer neuroprotection. This study highlights the therapeutic potential of targeting astrocyte-mediated signalling pathways to enhance neuronal survival following ischemic stroke. Full article
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25 pages, 432 KiB  
Review
Targeting CX3CR1 Signaling Dynamics: A Critical Determinant in the Temporal Regulation of Post-Stroke Neurorepair
by Quan He, Tong Zhou and Quanwei He
Brain Sci. 2025, 15(7), 759; https://doi.org/10.3390/brainsci15070759 - 17 Jul 2025
Viewed by 566
Abstract
Ischemic stroke ranks among the top global causes of disability and mortality, with a highly dynamic pathological process. Post-stroke neuroinflammation, mediated by microglia, demonstrates a dual role in both injury and repair. The CX3CR1/CX3CL1 signaling axis, highly expressed in microglia, acts as a [...] Read more.
Ischemic stroke ranks among the top global causes of disability and mortality, with a highly dynamic pathological process. Post-stroke neuroinflammation, mediated by microglia, demonstrates a dual role in both injury and repair. The CX3CR1/CX3CL1 signaling axis, highly expressed in microglia, acts as a key regulator. This review examines the spatiotemporal dynamics of the axis across the stroke process and its involvement in neural repair. Crucially, this signaling pathway demonstrates stage-dependent functional duality: its cellular sources, receptor expression profiles, and functional consequences undergo temporally orchestrated shifts, manifesting coexisting or interconverting protective and damaging properties. Ignoring this dynamism compromises the therapeutic efficacy of targeted interventions. Thus, we propose a triple precision strategy of “stroke phase—biomarker—targeted intervention”. It uses specific biomarkers for precise staging and designs interventions based on each phase’s signaling characteristics. Despite challenges like biomarker validation, mechanistic exploration, and cross-species differences, integrating cutting-edge technologies such as spatial metabolomics and AI-driven dynamic modeling promises to shift stroke therapy toward personalized spatiotemporal programming. Temporally targeting CX3CR1 signaling may offer a key basis for developing next-generation precision neural repair strategies for stroke. Full article
13 pages, 569 KiB  
Systematic Review
Combining Visual Feedback and Noninvasive Brain Stimulation for Lower Limb Motor Rehabilitation in Stroke: A Systematic Review of the Current Evidence
by Leonardo Di Cosmo, Santiago Nieto Cuervo, Francesca Pellicanò, Francesca Romana Centini, Jad El Choueiri, Chiara Learmonth, Filippo Emanuele Colella, Lorenzo De Rossi, Delia Cannizzaro and Alessio Baricich
J. Clin. Med. 2025, 14(14), 5027; https://doi.org/10.3390/jcm14145027 - 16 Jul 2025
Viewed by 312
Abstract
Background and Objectives: Recent technological advances have introduced new interventions in the field of stroke rehabilitation. Among them, visual feedback (VF) and non-invasive brain stimulation (NIBS) have gained considerable attention, with growing evidence supporting their efficacy. However, their combined application in lower limb [...] Read more.
Background and Objectives: Recent technological advances have introduced new interventions in the field of stroke rehabilitation. Among them, visual feedback (VF) and non-invasive brain stimulation (NIBS) have gained considerable attention, with growing evidence supporting their efficacy. However, their combined application in lower limb recovery remains to be established. This systematic review aims to evaluate the current evidence on the therapeutic effect of combining VF and NIBS for lower limb motor rehabilitation in stroke patients. Methods: Following PRISMA guidelines, PubMed, Embase, Scopus, and Cochrane databases were searched for randomized controlled trials and observational studies comparing VF and NIBS interventions with either their monotherapy, placebo, or standard treatment. The outcomes evaluated for lower limb function included balance, gait, and motor performance. Results: From 997 studies screened, 5 studies (3 RCTs and 2 cohort studies) were included. Despite heterogeneity in the immersion level, NIBS protocols, and outcome measures, evidence emerged supporting the efficacy of combined VF and NIBS across multiple outcomes. However, the degree to which these interventions outperform standard therapies remains uncertain, primarily due to a limited number of comparator studies and the quality of the existing data. Conclusions: This review provides preliminary insights into the potential of combining VF and NIBS in stroke patients affected by lower limb motor impairments. Future research should focus on standardizing protocols and addressing demographic variability to enhance the reliability and comparability of findings. Full article
(This article belongs to the Special Issue Innovations in Neurorehabilitation)
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13 pages, 1838 KiB  
Systematic Review
Antiplatelet Resumption After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis
by Sarah Yahya Alharthi, Sarah Abdulaziz Alsheikh, Dawood Salman Almousa, Saud Samer A. Alsedrah, Nouf Mohammed Alshammari, Mariam Mostafa Elsayed, Rahaf Ali Hamed AlShamrani, Mohammed Ahmed Yaslam Bellahwal, Abdulrahman Alnwiji, Raed A. Albar and Ayman M. A. Mohamed
Diagnostics 2025, 15(14), 1780; https://doi.org/10.3390/diagnostics15141780 - 15 Jul 2025
Viewed by 691
Abstract
Background: Intracerebral hemorrhage management presents clinicians with a significant therapeutic challenge. Maintaining antiplatelet therapy potentially increases the risk of recurrent bleeding, while discontinuation heightens susceptibility to ischemic stroke, particularly during the critical first month after hemorrhage. In contemporary practice, physicians demonstrate considerable hesitancy [...] Read more.
Background: Intracerebral hemorrhage management presents clinicians with a significant therapeutic challenge. Maintaining antiplatelet therapy potentially increases the risk of recurrent bleeding, while discontinuation heightens susceptibility to ischemic stroke, particularly during the critical first month after hemorrhage. In contemporary practice, physicians demonstrate considerable hesitancy regarding early antiplatelet reinitiation, complicated by the absence of clear evidence-based treatment guidelines. Aim: This meta-analysis assesses the safety of early antiplatelet resumption following ICH. Methods: We conducted a systematic review by searching Web of Science, Scopus, PubMed, and Cochrane Library from inception to April 2025. Articles were independently screened and data extracted by two reviewers who also assessed study quality. The inclusion criteria are enrollment of adults (≥18 years) with imaging-confirmed intracerebral hemorrhage surviving >24 h, comparing early vs. delayed or withheld antiplatelet therapy. Randomized trials underwent separate evaluation using Cochrane’s Risk of Bias. Statistical analysis was performed using R software (version 4.4.2), with categorical outcomes pooled as risk ratios (RRs) with 95% confidence intervals. Statistical significance was established at p < 0.05. The evidence is limited by the availability of few RCTs, variable antiplatelet regiments, male predominance, and other confounding factors. The review was registered in SFO. Results: Our meta-analysis included 10 studies (8 observational, 2 RCTs) with 5554 patients. Early antiplatelet therapy significantly reduced recurrent intracerebral hemorrhage by 46% (RR 0.54, 95% CI 0.37–0.78, p = 0.001). All-cause mortality showed a non-significant difference (RR 0.81, 95% CI 0.65–1.01, p = 0.06). No significant differences were found for ischemic stroke (RR 0.99, 95% CI 0.60–1.63, p = 0.96), major hemorrhagic events (RR 0.75, 95% CI 0.49–1.13, p = 0.17), or ischemic vascular outcomes (RR 0.71, 95% CI 0.49–1.02, p = 0.60). Conclusions: Our meta-analysis reveals that early antiplatelet therapy following intracerebral hemorrhage significantly reduces recurrent hemorrhagic events (46% reduction) without increasing major ischemic or hemorrhagic complications. Full article
(This article belongs to the Special Issue Pathology and Diagnosis of Neurological Disorders, 2nd Edition)
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27 pages, 2375 KiB  
Review
Pulmonary Embolism in Acute Ischaemic Stroke: Evolving Evidence, Diagnostic Challenges, and a Novel Thromboinflammatory Axis Hypothesis
by Darryl Chen and Sonu M. M. Bhaskar
Int. J. Mol. Sci. 2025, 26(14), 6733; https://doi.org/10.3390/ijms26146733 - 14 Jul 2025
Viewed by 527
Abstract
Pulmonary embolism (PE) is an under-recognised yet serious complication in patients with acute ischaemic stroke (AIS), contributing significantly to morbidity and mortality. The interplay of traditional risk factors—such as immobility, endothelial dysfunction, and hypercoagulability—with AIS-specific conditions, including atrial fibrillation, malignancy, and reperfusion therapies, [...] Read more.
Pulmonary embolism (PE) is an under-recognised yet serious complication in patients with acute ischaemic stroke (AIS), contributing significantly to morbidity and mortality. The interplay of traditional risk factors—such as immobility, endothelial dysfunction, and hypercoagulability—with AIS-specific conditions, including atrial fibrillation, malignancy, and reperfusion therapies, complicates both diagnosis and management. Despite available prophylactic strategies, including low-molecular-weight heparin and intermittent pneumatic compression, their use remains limited by bleeding concerns and a lack of tailored guidelines. This review synthesises the current evidence on the incidence, risk factors, pathophysiology, diagnostic approaches, and preventive strategies for PE in AIS, identifying critical gaps in risk stratification and clinical decision-making. We propose a novel mechanistic framework—the Brain–Lung Thromboinflammatory Axis Hypothesis—which posits that stroke-induced systemic inflammation, neutrophil extracellular trap (NET) formation, and pulmonary endothelial activation may drive in situ pulmonary thrombosis independent of deep vein thrombosis. This conceptual model highlights new diagnostic and therapeutic targets and underscores the need for stroke-specific VTE risk calculators, biomarker-guided prophylaxis, and prospective trials to optimise prevention and outcomes in this vulnerable population. Full article
(This article belongs to the Special Issue New Therapies, Pathogenetic and Inflammatory Mechanisms in Thrombosis)
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21 pages, 1099 KiB  
Review
The Roles of E3 Ubiquitin Ligases in Cerebral Ischemia–Reperfusion Injury
by Man Li, Xiaoxiao Yu, Qiang Liu, Zhi Fang and Haijun Wang
Int. J. Mol. Sci. 2025, 26(14), 6723; https://doi.org/10.3390/ijms26146723 - 13 Jul 2025
Viewed by 342
Abstract
The temporary or permanent occlusion of cerebral blood vessels results in ischemic stroke (IS). Ischemia per se causes focal neuronal damage, and the subsequent ischemia–reperfusion injury that occurs after blood flow restoration further compromises brain tissue and cells in the neurovascular unit, significantly [...] Read more.
The temporary or permanent occlusion of cerebral blood vessels results in ischemic stroke (IS). Ischemia per se causes focal neuronal damage, and the subsequent ischemia–reperfusion injury that occurs after blood flow restoration further compromises brain tissue and cells in the neurovascular unit, significantly contributing to poor patient outcomes and functional impairments. Current research indicates that the ubiquitin–proteasome system (UPS) plays a crucial role in the pathological processes associated with cerebral ischemia–reperfusion injury (CIRI). Notably, E3 ubiquitin (Ub) ligases, which are essential in the UPS, have garnered increasing attention as potential novel therapeutic targets for treating ischemia–reperfusion damage in the brain. This review focuses primarily on the background of E3 Ub ligases and explores their intricate relationships with the pathological processes of CIRI. Full article
(This article belongs to the Special Issue Latest Advances in Oxidative Stress and Brain Injury)
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19 pages, 3181 KiB  
Article
Overexpression of BDNF and uPA Combined with the Suppression of Von Hippel–Lindau Tumor Suppressor Enhances the Neuroprotective Activity of the Secretome of Human Mesenchymal Stromal Cells in the Model of Intracerebral Hemorrhage
by Stalik S. Dzhauari, Alexandra L. Primak, Nataliya A. Basalova, Natalia I. Kalinina, Anna O. Monakova, Kirill D. Bozov, Arkadiy Ya. Velichko, Maria E. Illarionova, Olga A. Grigorieva, Zhanna A. Akopyan, Vladimir S. Popov, Pavel G. Malkov, Anastasia Yu. Efimenko, Vsevolod A. Tkachuk and Maxim N. Karagyaur
Int. J. Mol. Sci. 2025, 26(14), 6697; https://doi.org/10.3390/ijms26146697 - 12 Jul 2025
Viewed by 377
Abstract
Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat [...] Read more.
Nerve tissue damage is an unsolved problem in modern neurology and neurosurgery, which prompts the need to search for approaches to stimulate neuroprotection and regeneration of neural tissue. Earlier we have shown that the secretome of human mesenchymal stromal cells (MSCs) stimulates rat survival, reduces the severity of neurological deficits, and decreases the volume of brain damage in a hemorrhagic stroke model. A significant disadvantage of using the MSC secretome is the need to concentrate it (at least 5–10 fold) to achieve appreciable pharmacological activity. This increases the cost of obtaining clinically applicable amounts of secretome and slows down the clinical translation of this technology. Here, we created a number of genetically modified human MSC cultures, including immortalized MSCs and those with hyperexpression of brain-derived neurotrophic factor (BDNF) and urokinase-type plasminogen activator (uPA) and with suppressed expression of Von Hippel–Lindau tumor suppressor (VHL), and we evaluated the pharmacological activity of their secretomes in a model of intracerebral hemorrhage (ICH) in rats. The secretome of MSCs immortalized by hyperexpression of the catalytic subunit of human telomerase (hTERT) revealed neuroprotective activity indistinguishable from that of primary MSC cultures, yet it still required 10-fold concentration to achieve neuroprotective efficacy. The secretome of MSC culture with combined hyperexpression of BDNF and uPA and suppressed expression of Von Hippel–Lindau tumor suppressor even without additional concentration reduced the severity of neurological disorders and decreased brain lesion volume in the ICH model. The secretomes of MSCs with separate overexpression of BDNF and uPA or suppression of VHL had no such effect or, on the contrary, revealed a toxic effect in the ICH model. Presumably, this may be due to an imbalance in the representation of individual growth factors in the secretome of genetically modified MSCs, which individually may lead to undesirable effects in damaged nervous tissue, such as increased permeability of the blood–brain barrier (under the influence of pro-angiogenic factors) or neural cell apoptosis (due to an excess of neurotrophic factors). The obtained data show that genetic modification of MSC cultures can enhance or alter the therapeutic activity of their secretomes, which can be used in the creation of promising sources of biopharmaceutical substances. Full article
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39 pages, 1388 KiB  
Review
Neuroprotective Effects of Metformin Through the Modulation of Neuroinflammation and Oxidative Stress
by Sarah Reed, Equar Taka, Selina Darling-Reed and Karam F. A. Soliman
Cells 2025, 14(14), 1064; https://doi.org/10.3390/cells14141064 - 11 Jul 2025
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Abstract
Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, [...] Read more.
Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, two significant factors in neurodegenerative diseases. This review examines the mechanisms by which metformin mitigates neuronal damage. Metformin reduces neuroinflammation by inhibiting microglial activation and suppressing proinflammatory cytokines. It also triggers the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway to combat oxidative stress, an essential regulator of antioxidant defenses. These outcomes support the possible neuroprotective roles of metformin in type 2 diabetes-related cognitive decline and conditions like Alzheimer’s disease. Metformin’s therapeutic potential is further supported by its capacity to strengthen the blood–brain barrier’s (BBB’s) integrity and increase autophagic flux. Metformin also offers several neuroprotective effects by targeting multiple pathological pathways. Moreover, metformin is being studied for its potential benefits beyond glycemic control, particularly in the areas of cognition, Alzheimer’s disease, aging, and stroke management. Evidence from both clinical and preclinical studies indicates a complex and multifaceted impact, with benefits varying among populations and depending on underlying disease conditions, making it an appealing candidate for managing several neurodegenerative diseases. Full article
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