Search Results (1,756)

Retinal neurovascular unit (RNVU) dysfunction underlies major blinding and neurodegenerative conditions including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal ischemia–reperfusion (RIR) injury, and Alzheimer’s disease (AD)-associated retinopathy. Within the RNVU, calcium ions coordinate neurotransmission, glial activation, vascular tone, and blood–retinal barrier maintenance, and calcium dysregulation is emerging as a unifying pathogenic hub across these conditions. Although upstream triggers differ, including mechanical stress in glaucoma, hyperglycemia in DR, oxidative damage in AMD, ischemic energy failure in RIR, and amyloid-β–driven endoplasmic reticulum stress in AD, all converge on disruption of intracellular calcium homeostasis, producing shared downstream consequences including excitotoxic injury of retinal ganglion cells (RGCs), Müller cell reactive gliosis, and pericyte hypercontraction. Broad-spectrum calcium channel blockade has shown limited clinical success, underscoring the need for cell-type-specific and pathway-selective approaches. This review therefore catalogs key interventional nodes, including transient receptor potential (TRP) channel antagonists, T-type calcium channel inhibitors, calcium/calmodulin-dependent protein kinase II (CaMKII) suppressors, and mitochondrial permeability transition pore (mPTP) inhibitors, and discusses how precision targeting of these pathways may restore RNVU homeostasis and open a therapeutic window into central nervous system (CNS) degenerative disorders. Full article

Background: Acute limb ischemia (ALI) is a vascular emergency characterized by abrupt limb hypoperfusion, ischemia–reperfusion injury, and a high risk of thromboinflammatory and organ complications. Complement activation has been implicated in endothelial dysfunction, glycocalyx injury, and ischemia–reperfusion damage, but the clinical relevance of ongoing terminal complement blockade in patients presenting with ALI remains unclear, highlighting a gap between mechanistic understanding and real-world clinical outcomes. Methods: A retrospective cohort study was performed using the TriNetX federated research network. Adult patients with ALI were identified and stratified according to ongoing treatment with the C5 inhibitors eculizumab or ravulizumab. Outcomes included ischemic stroke, venous thrombosis, pulmonary embolism, arterial embolism, thrombotic disorders, acute kidney injury (AKI), and the composite outcome major adverse cardiovascular events (MACE) within 31 days. Propensity score matching was performed for demographic characteristics, cardiovascular comorbidities, complement-associated diseases and medications. Results: After propensity score matching, 112 patients remained in each cohort. Compared with matched controls, patients receiving C5 inhibition had a significantly higher risk of venous thrombosis (27.9% vs. 13.7%; p < 0.001), AKI (18.9% vs. 9.4%; p = 0.001), MACE (50.0% vs. 35.1%; p = 0.001), and thrombotic disorders (46.7% vs. 31.3%; p = 0.001). Time-to-event analyses confirmed significantly lower event-free survival for venous thrombosis (HR 2.3), AKI (HR 2.1), MACE (HR 1.6), and thrombotic disorders (HR 1.7). No significant differences were observed for ischemic stroke, pulmonary embolism, or arterial embolism. Conclusions: In patients with ALI, ongoing treatment with eculizumab or ravulizumab was not associated with an apparent reduction in short-term thromboinflammatory or cardiovascular complications. Instead, the observed outcome pattern suggests persistent vulnerability in this clinically uncommon but increasingly relevant high-risk population, although substantial residual confounding by indication and disease severity remains likely. These findings support further investigation of complement-targeted therapy, endothelial injury, and short-term vascular outcomes in ALI, and emphasize the translational relevance of linking mechanistic insights with clinical data to inform risk stratification and management strategies in this population. Full article

Aims: Coronary heart disease (CHD) associated with rheumatoid arthritis (RA) is a primary driver of mortality in RA patients. In this study, we sought to establish a combined rat model of CHD and RA by integrating cardiac ischemia/reperfusion (I/R), high-fat diet (HFD), and intradermal administration of bovine type II collagen emulsified in complete Freund’s adjuvant. The aim of constructing this model is to investigate and analyze the pathogenesis of RA-induced CHD under the modulation of HFD and cardiac I/R exposure. Methods and Results: Sixty-four male Sprague–Dawley rats were randomly categorized into eight groups (n = 8 per group): control, I/R, HFD, collagen-induced arthritis (CIA), I/R + CIA, HFD + CIA, I/R + HFD, and I/R + HFD + CIA groups (n = 8 per group). We applied Synchrotron radiation-based X-ray micro-computed tomography (micro-CT) to observe the structural changes within the model over time. To further elucidate molecular mechanisms, transcriptome RNA-seq analysis was carried out to identify key signaling pathways, with particular emphasis on the homeostasis of Toll-like receptor 4 (TLR4)/Myd88 signaling in the ischemic myocardium. Furthermore, we conducted in vivo shRNA-mediated knockdown of polymerase I and transcription release factor (PTRF) and evaluated the co-localization of PTRF and TLR4 through immunofluorescence experiments. It is worth mentioning that our rat model of RA-induced (CHD) under a high-fat diet effectively manifested the relevant pathological features that align with the Traditional Chinese Medicine (TCM) definition of “bi” syndrome. The results indicate that the combined stimulation of HFD and CIA significantly elevated cardiac injury markers (CK-MB, LDH, CRP, and c-TNT) and was accompanied by a more severe expansion of the infarct area and increased cardiomyocyte apoptosis compared to the I/R group alone. In addition, the histopathological evaluation revealed significantly aggravated myocardial inflammation and fibrosis deposition, accompanied by extensive areas of tissue damage, further indicating a state of heightened inflammation and severe cardiac degenerative changes. Consistently, myocardial tissues from rats in the I/R + CIA + HFD group exhibited robust activation of the TLR4/MyD88 signaling pathway and a pronounced elevation in the p-JNK/JNK ratio. Moreover, pronounced co-localization between PTRF and TLR4 was evident in small vessels surrounding the infarcted myocardium. Importantly, AAV-mediated knockdown of PTRF attenuated the HFD- and CIA-induced exacerbation of myocardial injury in I/R rats. Conclusions: We successfully established a rat model of CHD with rheumatic syndrome using I/R in combination with RA and HFD. The present findings suggest that the PTRF-related TLR4/MyD88-JNK signaling pathway may act as an important regulatory mechanism underlying myocardial injury aggravated by combined HFD and CIA stimulation. Full article

Background: Spinal cord ischemia (SCI) is a severe complication of thoracoabdominal aortic aneurysm (TAAA) repair, associated with substantial morbidity and mortality. Despite advances in operative techniques, its pathophysiology remains incompletely understood, with no reliable biomarkers available for early detection or risk stratification. Methods: This narrative review synthesizes current evidence on the pathophysiology of SCI following aortic intervention, integrating insights from ischemic stroke and traumatic spinal cord injury to identify key mechanistic pathways and potential biomarker targets. Results: SCI results from multifactorial impairment of spinal cord perfusion pressure (SCPP) driven by extensive aortic coverage, disruption of segmental arterial inflow, hypotension, and impaired collateral circulation. While acute hypoperfusion initiates injury, secondary processes—including excitotoxicity, oxidative stress, and neuroinflammation—drive progression. Cytokine signaling and immune activation contribute to blood–spinal cord barrier disruption and vasogenic edema, with Aquaporin-4 playing a central role in delayed injury. Candidate biomarkers, including neuron-specific enolase, S100β, and glial fibrillary acidic protein, reflect neuronal damage but lack sufficient sensitivity and temporal resolution for clinical use. Emerging evidence supports a multimodal biomarker approach incorporating inflammatory, structural, and Aquaporin-4-dependent edema-related pathways. Conclusions: Spinal cord ischemia following thoracoabdominal aortic aneurysm repair is a dynamic and multifactorial process in which reduced spinal cord perfusion pressure represents a final common pathway linking diverse perioperative factors to ischemic injury. Secondary mechanisms, particularly neuroinflammation and Aquaporin-4-driven vasogenic edema, play a central role in injury propagation and represent promising targets for biomarker development. Future strategies should focus on longitudinal, multimodal biomarker approaches to improve early detection, risk stratification, and therapeutic intervention. Full article

Pterostilbene (Pts), a small molecule stilbenoid and a dimethyl analogue of the star molecule resveratrol, exerts significant blood–brain barrier protection on cerebral ischemia-reperfusion injury and has received extensive attention. This study performed structural optimizations on Pts to obtain a series of derivatives and investigated their anti-ischemic activities both in vitro and in vivo, aiming to identify candidates with high safety and improved efficacy compared with Pts. The ADMET method was used to predict the drug-likeness of a series of Pts derivatives, and in vitro MTT cell viability analysis was conducted on neuroblastoma cells (SH-SY5Y) and brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation/reperfusion (OGD/R) injury. On the basis of the cytotoxicity results, four derivatives (NO. 1, NO. 3, NO. 5, and NO. 7) were selected for subsequent in vitro and in vivo biological activities evaluation. These compounds exhibited significantly higher TI values (18.29–30.61) in OGD/R-injured hBMECs compared with Pts (7.63) and effectively suppressed apoptosis, promoted cell migration, and enhanced tube formation capacity. In vivo, NO. 3 (5 mg/kg, ip., 7 d) demonstrated superior efficacy compared to Pts in improving cerebral blood flow, reducing infarction volume, enhancing neurological function, and modulating serum biomarker levels in middle cerebral artery occlusion/reperfusion (MCAO/R) rats, whereas NO. 1 and NO. 7 showed comparable efficacy to Pts. The acute intraperitoneal toxicity of NO. 3 was conducted and showed that the LD₅₀ of NO. 3 was estimated to be more than 300 mg/kg. In this study, the rational design and comprehensive evaluation of Pts derivatives were reported. Compound NO. 3 demonstrated superior pharmacological efficacy to Pts both in vitro and in vivo, and it may be a promising therapeutic candidate for ischemic stroke intervention. Full article

Calycosin-7-O-β-D-glucoside (CG), a bioactive compound extracted from the traditional Chinese herb Astragalus (AR), exhibits diverse biological activities, including anti-oxidative and anti-inflammatory effects, and has shown protective properties in ischemia–reperfusion (I/R) injury. While previous studies have demonstrated that CG mitigates I/R injury primarily through its anti-oxidative and anti-inflammatory actions, its potential role in promoting neuroregeneration—a critical process for stroke recovery—remains unclear, and the underlying mechanisms have yet to be elucidated. In this study, an ischemic stroke model was established in rats via middle cerebral artery occlusion (MCAO). Seven days after CG treatment, cerebral infarct volume was assessed using triphenyltetrazolium chloride (TTC) staining, while neurological function was evaluated through behavioral tests. Nissl staining and Bielschowsky silver staining were employed to examine neuronal damage and axonal loss, and immunofluorescence was used to assess axonal regeneration. The expression of key proteins in the Rho/ROCK signaling pathway was analyzed by Western blotting (WB) and quantitative real-time PCR (qRT-PCR). CG treatment significantly reduced infarct volume, promoted axonal regeneration, improved neurological outcomes, and modulated the expression of RGMa, Rho, ROCK, and CRMP2. Collectively, these findings provide the first evidence that CG facilitates axonal regeneration and neurological recovery after cerebral ischemia, at least in part by inhibiting activation of the Rho/ROCK pathway, highlighting its potential as a therapeutic agent for ischemic stroke. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Mesenchymal stromal cells (MSCs) are multipotent cells characterized by their regenerative capacity and strong immunomodulatory properties. In recent years, MSC-based therapy has attracted significant attention as a potential treatment for a wide range of immune-mediated and degenerative diseases. The therapeutic effects of MSCs are primarily mediated through paracrine signaling and secretion of cytokines that regulate immune responses and promote tissue repair. This review focuses on five key cytokines involved in MSC immunomodulation: interleukin-6 (IL-6), interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). These cytokines interact within a complex signaling network that allows MSCs to suppress excessive inflammation and restore immune balance. The role of MSC therapy is examined in several clinically relevant conditions, including systemic lupus erythematosus, systemic sclerosis, ischemic stroke, spinal cord injury, diabetes mellitus, and female infertility. Across these diseases, MSCs demonstrate the ability to inhibit pro-inflammatory immune cell activity, promote regulatory immune phenotypes, reduce oxidative stress, and stimulate regeneration through the secretion of growth factors and extracellular vesicles. Despite promising experimental and early clinical findings, several limitations remain, including variability in MSC sources, limited cell survival after transplantation, and the need for optimized dosing strategies. Overall, MSC therapy represents a multifunctional therapeutic approach combining immunomodulation, anti-inflammatory activity, and regenerative support. Further research is required to better understand cytokine interactions, improve standardization of MSC-based treatments, and enhance clinical efficacy across diverse pathological conditions. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Background/Objectives: Birth asphyxia is a frequent neonatal complication in humans. Its outcome is variable, and the factors underlying this variability remain incompletely understood. Maternal gut microbiome impairment has been proposed as one factor that may influence offspring neurodevelopment, especially when the immature brain is exposed to additional vulnerability such as perinatal asphyxia (PA). Building on our previous maternal microbiome disruption model and on our prior observation that electroencephalography (EEG) reactivity to photic stimulation under deep anesthesia detects functional impairment two months after PA, we assessed whether this reactivity was further impaired after prolonged gestational antibiotic administration and whether probiotics modulated this effect. Methods: Wistar dams received antibiotics, probiotics, antibiotics with probiotics, or control treatment, and offspring underwent PA. Adult EEG reactivity to photic stimulation was assessed during chloral hydrate-induced burst suppression. Burst count reactivity (BCR) was used as the primary event-based readout of stimulus-evoked burst recruitment and was compared with the suppression-ratio-based burst-suppression reactivity index (BSRi). Results: Burst suppression remained reactive to photic stimulation in all groups. BCR was lower after gestational antibiotic treatment than in controls. The magnitude of the effect was attenuated by probiotics coadministration. BSRi showed the same overall pattern. Conclusions: Prolonged gestational antibiotic exposure increased the severity of perinatal asphyxia as measured by EEG reactivity in the adult offspring. The converging BCR and BSRi results support burst-suppression reactivity as a functional neurophysiological readout in this PA model and support further methodological development of EEG reactivity measures for translational studies of hypoxic–ischemic brain injury. Full article

This review demonstrates that the diagnostic and prognostic significance of glial fibrillary acidic protein (GFAP) is not limited to its use as a marker of astrocytic damage but should also be considered in the context of the diversity of GFAP isoforms, their heterogeneous tissue-specific expression and their pronounced association with extracellular vesicles (EVs). The data presented in this review indicate that GFAP-positive (GFAP+) EVs possess broad clinical relevance in both acute and chronic pathologies of the nervous system, including ischemic stroke, traumatic brain injury, glioblastoma, and potentially diabetic and drug-induced polyneuropathy. Particular attention is given to the critical analysis of methodological approaches for studying GFAP+ EVs, including discussion of their proposed biogenesis, mechanisms of intravesicular incorporation of cytoskeletal fragments, and the hypothetical sorption of GFAP within the vesicular protein corona. A principal conclusion of this work is that, despite the high translational potential of GFAP+ vesicles as a novel liquid biopsy platform, further implementation of this approach in clinical practice will require standardization of EV isolation protocols, harmonization of phenotyping methodologies in accordance with MISEV 2023 recommendations, and large-scale prospective studies aimed at validating the biological nature, origin, and clinical reproducibility of identified GFAP-associated vesicular subpopulations. Full article

Ischemic stroke, a major cause of global disability, is characterized by the blockage of an artery leading to reduced cerebral blood flow and subsequent brain injury. Automatic segmentation of ischemic stroke lesions in Computed Tomography Perfusion (CTP) maps is critical for accurate diagnosis, treatment planning, and outcome assessment. However, the accuracy of traditional methods remains limited, with Dice Similarity Coefficient (DSC) values around 68%. To address this challenge, we propose a deep learning-based model inspired by biological systems and brain mechanisms, which emulates natural information processing to enhance ischemic stroke lesion segmentation. The proposed network architecture consists of five graph convolutional layers that automatically extract and classify features from CTP images. We evaluated the model using the ISLES 2018 database, achieving a DSC of 75.41% and a Jaccard Index of 74.52%, representing significant improvements over previous methods. Notably, the proposed approach performs robustly in noisy environments, maintaining accuracy above 60% even at SNR = −4. These results demonstrate the potential of biomimetic-inspired networks for automatic ischemic stroke segmentation. Full article

Healthcare-associated infections (HAIs) are clinically relevant complications in critically ill stroke patients, particularly in neurological intensive care settings, where severe neurological injury, dysphagia, immobilization, invasive device exposure, and prolonged hospitalization increase infection susceptibility. Romanian data focused on deceased stroke patients admitted to neurological intensive care units remain limited. This retrospective descriptive single-center hospital-based study, supported by focused literature contextualization, was conducted in the Neurological Intensive Care Unit of the Brașov County Emergency Clinical Hospital, Romania. Adult stroke patients who died during hospitalization over a six-year observation period were included. Clinical data were extracted from a working hospital database and analyzed descriptively after data cleaning and harmonization. The final cohort comprised 190 deceased stroke patients; ischemic stroke was documented in 69.5% and hemorrhagic stroke in 28.9%. Hypertension (73.7%) and ischemic heart disease and/or previous myocardial infarction (60.0%) were the most frequently recorded comorbidities. Pneumonia was the dominant documented infectious complication, recorded in 52.6% of patients, followed by urinary tract infection (11.6%), pressure sore-related infection (4.7%), and sepsis-related coding (6.8%). The median in-hospital survival interval was 6 days (IQR 3.0–10.75). Because year-by-year stratification was not sufficiently robust, the temporal component was interpreted only in aggregate form. These findings provide a descriptive hospital-based profile of documented infectious complications in a fatal stroke ICU cohort and support the need for more standardized infection documentation and better linkage between clinical and microbiological data in neurocritical care settings. Full article

Isovitexin (ISOV) is an active component identified in the traditional Tibetan medicine Tsantan Sumtang, which is commonly used for treating myocardial ischemia. Although previous studies have suggested the protective effect of ISOV on cardiomyocytes, the in vivo anti-ischemic efficacy and underlying mechanisms of ISOV remain unclear. This study aimed to systematically evaluate the therapeutic effects of ISOV on myocardial ischemia in rats and to elucidate its molecular mechanism of action. An acute myocardial infarction model was established in rats by ligating the left anterior descending branch (LADL) of the coronary artery. The protective effects of ISOV were assessed by measuring infarct size, serum cardiac injury biomarkers, and oxidative stress levels. Chemical proteomics using photoaffinity magnetic beads was employed to identify potential target proteins of ISOV. Molecular docking, pull-down western blotting, and cellular thermal shift assay (CETSA) western blotting were applied to validate the interaction between ISOV and target. Knockdown of the target was used to verify the mechanism of ISOV on anti-myocardial ischemia effect. ISOV treatment significantly reduced myocardial infarct size, decreased serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), malondialdehyde (MDA), and enhanced superoxide dismutase (SOD) activity in myocardial ischemia rats. Furthermore, ISOV improved mitochondrial function, as evidenced by increased ATP content and enhanced activities of mitochondrial complexes I and IV. Chemical proteomics and bioinformatic analysis identified SLC25A4 as a direct target of ISOV. Molecular docking revealed a high-affinity binding (binding energy: −8.3 kcal/mol), which was further confirmed by pull-down assays and CETSA. In SLC25A4-knockdown H9c2 cells under hypoxic conditions, ISOV upregulated SLC25A4 expression, promoted the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and upregulated the expression of proliferator-activated receptor gamma coactivator-1$\alpha$ (PGC-1$\alpha$). ISOV exerts cardioprotective effects against myocardial ischemia by directly binding to SLC25A4 and activating the AMPK/PGC-1$\alpha$ pathway, highlighting its potential as a therapeutic agent for myocardial ischemia. Full article

Ischemic heart disease (IHD) remains the leading cause of chronic heart failure (HF) worldwide, yet the biological processes underlying this transition are not fully elucidated. Growing evidence indicates that chronic, low-grade inflammation acts as a pivotal link between ischemic injury and progressive myocardial dysfunction. Our review is the most up-to-date and structured synthesis on the pathophysiological pathways, biomarkers, and therapeutic implications of subclinical inflammation in patients with IHD at risk of developing HF. Following acute or repetitive ischemic episodes, persistent immune activation—mediated through interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)—promotes endothelial dysfunction, microvascular instability, and extracellular matrix remodeling. These mechanisms culminate in ventricular stiffness, diastolic impairment, and adverse structural remodeling, even when left ventricular ejection fraction is preserved. Biomarkers such as Galectin-3, cancer antigen 125 (CA125), and high-sensitivity C-reactive protein (hsCRP) provide valuable insight into the interplay between fibrosis, congestion, and systemic inflammatory load, supporting early detection of subclinical myocardial injury. Advanced imaging modalities, including strain echocardiography and cardiac magnetic resonance imaging (MRI) mapping, enhance the phenotypic characterization of inflammatory cardiomyopathy. Understanding and targeting these inflammatory pathways may open new avenues for precision-based prevention and treatment, ultimately improving outcomes across the IHD–HF continuum. Full article