Search Results (1,137)

Cerebrovascular diseases, encompassing a spectrum of conditions affecting the blood vessels supplying the brain, represent a significant global health burden. Among the diverse mechanisms implicated in cerebrovascular pathology, emerging evidence highlights the role of ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation. The review also elucidates the molecular mechanisms underlying ferroptosis, emphasizing the pivotal role of iron, the intracellular antioxidant system, and lipid metabolism. Subsequently, it explores the growing body of literature implicating ferroptosis in the pathogenesis of various cerebrovascular diseases, including atherosclerosis, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Special attention is given to the interplay between ferroptosis and other established mechanisms, such as oxidative stress, and inflammation. Moreover, pharmacological interventions and therapeutic strategies aimed at modulating key players in the ferroptosis cascade are explored, with a focus on their translational potential for clinical application. Finally, the review addresses current gaps in knowledge and proposes future research directions, emphasizing the need for a deeper understanding of the specific roles of ferroptosis in the pathogenesis of cerebrovascular diseases. The elucidation of these aspects holds promise for advancing our comprehension of cerebrovascular pathology and opening new avenues for therapeutic intervention in these debilitating conditions. Full article

Mitochondria serve as an essential component in the maintenance of cardiac function, and targeting them may represent a promising approach to handling heart failure (HF). HF in this review refers to various etiologies, including ischemic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy, unless otherwise specified. Mitochondrial dysfunction, a distinctive feature of HF, leads to a progressive decrease in bioenergetic reserves due to switching of energy production from oxidation of fatty acids in mitochondria to glycolytic pathways. The main problem in developing methods to improve mitochondrial function lies in the fact that protein preparations injected through the bloodstream cannot enter cells through the plasma membrane. Modern gene therapy involving the delivery of missing genes to cells using adeno-associated virus (AAV) vectors has the potential to improve the function of cardiomyocytes (CMCs). This type of therapy aims to target proteins that have been lost, damaged, or altered due to pathological conditions in the myocardium. This review summarizes pathophysiological mechanisms associated with mitochondrial dysfunction, which is mainly caused by increased oxidative stress and impaired mitochondrial biodynamics under HF progression. It also addresses possible ways to modulate these processes using gene therapy. Special attention is paid to modern characteristics of AAVs that can be used as vectors for the efficient delivery of desired genes to CMCs. Full article

Ocular diseases, including glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), remain major global causes of irreversible vision loss. Despite advances in clinical management, current therapies insufficiently address the shared metabolic, inflammatory, vascular, and neurodegenerative mechanisms underlying these conditions. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for type 2 diabetes and obesity, have emerged as multi-target candidates for ocular therapeutics due to their pleiotropic anti-inflammatory, antioxidant, vasculoprotective, and neuroprotective properties. Preclinical studies consistently demonstrate that GLP-1RAs preserve blood–retina barrier integrity, suppress pathological angiogenesis, mitigate oxidative and inflammatory stress, and protect retinal neurons from degeneration. Complementary clinical and real-world evidence shows a robust and reproducible reduction in glaucoma risk among GLP-1RA users across diabetic and non-diabetic populations. By contrast, findings for DR and AMD are more heterogeneous and appear context-dependent, with potential benefits most evident in early or non-exudative disease stages. Emerging safety considerations—including reports of nonarteritic anterior ischemic optic neuropathy and early DR worsening in the setting of rapid glycemic improvement—highlight the need for careful interpretation, individualized risk assessment, and appropriate ophthalmic monitoring. This review synthesizes molecular mechanisms, experimental data, clinical and pharmacoepidemiologic evidence, and safety signals to critically evaluate the therapeutic potential of GLP-1RAs in ocular disease. We also outline key translational challenges, including the need for ocular-targeted delivery strategies, prospective ophthalmology-specific trials, and precision-medicine approaches to determine when and how GLP-1RAs can be safely advanced as disease-modifying treatments in ophthalmology. Full article

Accurate segmentation of ischemic stroke lesions from multimodal magnetic resonance imaging (MRI) is fundamental for quantitative assessment, treatment planning, and outcome prediction; yet, it remains challenging due to highly heterogeneous lesion morphology, low lesion–background contrast, and substantial variability across scanners and protocols. This work introduces Tri-UNetX-2D, a large-kernel and scale-aware 2D convolutional network with explicit boundary refinement for automated ischemic stroke lesion segmentation from DWI, ADC, and FLAIR MRI. The architecture is built on a compact U-shaped encoder–decoder backbone and integrates three key components: first, a Large-Kernel Inception (LKI) module that employs factorized depthwise separable convolutions and dilation to emulate very large receptive fields, enabling efficient long-range context modeling; second, a Scale-Aware Fusion (SAF) unit that learns adaptive weights to fuse encoder and decoder features, dynamically balancing coarse semantic context and fine structural detail; and third, a Boundary Refinement Head (BRH) that provides explicit contour supervision to sharpen lesion borders and reduce boundary error. Squeeze-and-Excitation (SE) attention is embedded within LKI and decoder stages to recalibrate channel responses and emphasize modality-relevant cues, such as DWI-dominant acute core and FLAIR-dominant subacute changes. On the ISLES 2022 multi-center benchmark, Tri-UNetX-2D improves Dice Similarity Coefficient from 0.78 to 0.86, reduces the 95th-percentile Hausdorff distance from 12.4 mm to 8.3 mm, and increases the lesion-wise F1-score from 0.71 to 0.81 compared with a plain 2D U-Net trained under identical conditions. These results demonstrate that the proposed framework achieves competitive performance with substantially lower complexity than typical 3D or ensemble-based models, highlighting its potential for scalable, clinically deployable stroke lesion segmentation. Full article

Background/Objectives: In severe peripheral artery disease (PAD) with limb ischemia, hypercholesterolemia (HC) is associated with impaired neovascularization. Extracellular vesicles (EVs) are present within ischemic muscles, and they contain microRNAs (miRs) involved in several biological functions, including angiogenesis and neovascularization. Methods: We used a mouse model of PAD and compared the response to hindlimb ischemia in hypercholesterolemic ApoE^−/− vs. normocholesterolemic mice. Next-generation sequencing (NGS) was used to perform full miR expression profiling in ischemic skeletal muscles and in EVs of varying sizes—large EVs (lEVs) and small EVs (sEVs)—within these muscles. Results: We identified several miRs with potential pro-angiogenic effects (angiomiRs) that are reduced by HC in lEVs (Let-7b-5p, miR-151-3p, Let-7c-5p) or sEVs (miR-21a-5p, miR-196b-5p, miR-340-5p). As proof of principle, we showed that the overexpression of Let-7b-5p in lEVs, or miR-21a-5p in sEVs, can significantly increase the angiogenic capacity of these EVs in vitro. HC also impaired the enrichment of specific angiomiRs in lEVs (miR-100-5p), sEVs (miR-142a-3p), or in both lEVs and sEVs (miR-146b-5p). In silico approaches, including the prediction of miR targets, pathway unions, and gene unions, identified the resulting predictive effects of HC-modulated miRs in EVs on processes with key roles in the modulation of angiogenesis and neovascularization, such as the regulation of the actin cytoskeleton and focal adhesion and the HIF-1, MAPK, AMPK, and PI3K-Akt signaling pathways. Conclusions: Our results constitute an important first step towards the identification of specific miRs that could be targeted to improve EV angiogenic function in hypercholesterolemic conditions and reduce tissue ischemia in patients with severe PAD. Full article

Background: Pulmonary infarction (PI) is the result of the occlusion of distal pulmonary arteries resulting in damage to downstream lung areas that become ischemic, hemorrhagic, or necrotic, and it is often a complication of an underlying condition such as pulmonary embolism (PE). Since in most of cases it is located peripherally, lung ultrasound (LUS) can be a good evaluation tool. The typical radiological features of PI are well-known; however, there are limited data on its sonographic characteristics and its evolution. Methods: The aim of this study is to evaluate, using LUS, a convenience sample of patients with acute PE with computed tomography (CT) consolidation findings consistent with PI. Patients’ clinical characteristics were collected and LUS findings at baseline and their short-term progression was assessed. LUS was performed within 72 h of PE diagnosis (T0) and repeated after one (T1) and four weeks (T2). Each procedure started with a focused examination of the areas of lesions based on CT findings, followed by an exploration of the other posterior and lateral lung fields. The convex probe was used for initial evaluation integrating LUS evaluation with the linear one was employed for smaller and more superficial lesions and when appropriate. Color Doppler mode was added to study vascularization. Results: From June to October 2023, 14 consecutive patients were enrolled at the Respiratory Unit of the University Hospital of Pisa. The main population characteristics included the absence of respiratory failure and prognostic high-risk PE (100%), the absence of significant comorbidities (79%), and the presence of typical symptoms, such as chest pain (57%) and dyspnea (50%). The average number of consolidations per patient was 1.4 ± 0.6. Follow-up LUS showed the disappearance of some consolidations and some morphological changes in the remaining lesions: the presence of hypoechoic consolidation with a central hyperechoic area (“bubbly consolidation”) was more typical at T1 while the presence of a small pleural effusion often persisted both at T1 and T2. A decrease in wedge/triangular-shaped consolidations was observed (82% at T0, 67% at T1, 24% at T2), as was an increase in elongated shapes, representing a residual pleural thickening over time (9% at T0, 13% at T1, 44% at T2). A reduction in size was also observed by comparing the mean diameter, long axis, and short axis measurements of each consolidation at the three different studied time points: the average of the short axes and the median of the mean diameters showed a statistically significant reduction after four weeks. Additionally, a correlation between lesion size and pleuritic pain was described, although it did not achieve statistical significance. Conclusions: Patients’ clinical characteristics and ultrasound features are consistent with previous studies studying PI at PE diagnosis. Most consolidations detected by LUS change over time regarding size and form, but a minority of them do not differ. LUS is a safe and non-invasive exam that could help to improve patients’ clinical approach in emergency rooms as well as medical and pulmonology settings, clinically contextualized for cases of chest pain and dyspnea. Future studies could expand the morphological study of PI. Full article

The heart exhibits inherently nonlinear and chaotic electrical dynamics, making the early detection of myocardial ischemia (MI) challenging using traditional electrocardiography (ECG) or standard magnetocardiography (MCG). In this study, we propose an engineering-oriented framework that integrates classical nonlinear dynamics with machine-learning-based analysis, termed the Magnetocardiography Chaotic Dynamics Map (MCDM), to reconstruct nonlinear phase-space trajectories from 36-channel MCG recordings and capture differences in reconstructed nonlinear dynamics associated with ischemic conditions. Morphological and quantitative analyses of the MCDM patterns reveal marked differences between healthy and ischemic subjects. Using a machine-learning classifier trained on HOG and LBP descriptors, the proposed MCDM-based model achieved an accuracy of 92.19%, a sensitivity of 88.75%, a specificity of 95.63%, an F1-score of 91.91%, and an AUC of 89.80%, demonstrating effective discriminative capability for early ischemia screening. Owing to its computational simplicity and noninvasive nature, the proposed MCDM framework represents a promising tool for scalable screening of ischemic heart disease. Full article

Ischemic heart disease (IHD) remains a leading cause of morbidity and mortality worldwide. Myocardial ischemia–reperfusion injury (MIRI) is a significant contributor to cardiac tissue damage, resulting from an abrupt reduction in blood flow that leads to a reduction in the supply of oxygen and nutrients. The resulting hypoxia triggers severe cellular injury and impairs organ function. Hypoxia-inducible factors (HIFs) play a central role in maintaining oxygen homeostasis in mammalian tissues. As primary oxygen sensors, HIFs trigger the transcriptional activation of a wide range of genes that facilitate cellular adaptation to reduced oxygen availability and assist in minimizing ischemic damage. Mitochondria are particularly vulnerable to hypoxic stress and are a major source of reactive oxygen species (ROS) during I/R injury. Stabilization of HIFs has been shown to reduce loss of cardiomyocytes under these conditions, highlighting the importance of HIF-dependent pathways in preserving mitochondrial integrity and promoting cell survival. Collectively, these observations suggest that hypoxia, HIF signaling, and mitochondrial dysfunction are tightly interconnected processes in the pathogenesis of IHD. This review, therefore, focuses on the interaction between hypoxia-driven HIF responses and mitochondrial regulation, emphasizing their implications for therapeutic strategies in managing IHD. Full article

Objective: Cerebral ischemia–reperfusion injury (IRI) is a distinct pathological phase that differs from permanent ischemia (IR) in that it triggers secondary damage despite the restoration of blood flow. The primary objective of this study is to comprehensively characterize and compare the molecular signatures—such as differential gene expression, protein activation, and metabolic alterations—between IRI and IR. By doing so, we aim to identify key pathways and biomarkers that specifically drive IRI and IR pathology, thereby providing novel therapeutic targets to mitigate reperfusion-induced damage in stroke and related neurological conditions. Methods: We employed an integrated transcriptomic and proteomic approach to compare a permanent ischemia model (IR, 24 h ischemia) with a reperfusion model (IRI, 1 h ischemia + 24 h reperfusion), using SHAM-operated animals as controls. Results: Our results demonstrate a profound decoupling between the transcriptome and proteome in IRI. While IRI induced extensive proteomic alterations (160 changed proteins in IRI vs. IR), transcriptional changes were minimal (3 genes), indicating dominant post-transcriptional regulation. Both IR and IRI activated shared inflammatory responses (e.g., Saa3, upregulated 14.33-fold in IRI/SHAM) and metabolic shifts (Gapdh, downregulated 4.03-fold). However, IRI uniquely upregulated neuroprotective genes (Arc, Npas4), activated a specific set of reperfusion-related pathways (72 proteins), and exhibited distinct extracellular matrix remodeling (Mmp3, upregulated 11.24-fold in IR/SHAM). The overall correlation between transcriptomic and proteomic dynamics was remarkably low (r = 0.014), underscoring the importance of translation and protein decay mechanisms. Conclusions: This study redefines IRI not merely as an exacerbation of ischemic damage but as a unique adaptive molecular trajectory. We identify Pisd-ps3 and Saa3 as potential therapeutic targets and show that proteomic signatures can stratify injury phases. These findings advance the prospects of precision therapeutics aimed at neuroprotection and immunomodulation in ischemic stroke. Full article

Microglia play a key role in the development of neuroinflammation induced by cerebral ischemia. On the other hand, these cells participate in neurorepair processes. This dual role of microglia stems from the ability to shift their phenotype from pro-inflammatory M1 to protective M2. Histone deacetylase inhibitors (HDACis) are a group of agents that exhibit neuroprotective effects in some models of ischemia, among others, by modulation of signaling pathways that regulate microglial activation. This study aimed to examine the effect of HDACis—sodium butyrate and Givinostat—on polarization of microglia and their potential mechanism of action in a model of ischemia in vitro (oxygen and glucose deprivation, OGD). We examined the expression of pro- and anti-inflammatory markers in the BV2 microglial cell line after OGD and HDACis treatment by qPCR; polarization of microglia by flow cytometry; and the activation/phosphorylation of ERK and AKT in BV2 cells by Western blot and ELISA. Our findings demonstrate a divergent impact of HDACis on the phenotype of microglial cells. Sodium butyrate significantly suppressed the mRNA expression of pro-inflammatory markers (IL-1β, TNF-α, CD86) and increased the level of anti-inflammatory factors in BV2 microglial cells after OGD, whereas Givinostat failed to attenuate these inflammatory responses. Our findings demonstrate that sodium butyrate, but not Givinostat, promotes a shift in microglia toward an anti-inflammatory M2 phenotype under ischemic conditions. This effect is associated with suppression of pro-inflammatory gene expression and activation of the PI3K/AKT signaling pathway. These results identify sodium butyrate as a potential modulator of microglial responses following ischemic injury. Full article

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na⁺-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity. Full article

Background: Acute necrotizing esophagitis (ANE), also known as “black esophagus,” is a rare but life-threatening condition typically occurring in critically ill patients with profound systemic disturbances. Extreme hyperglycemic crises represent an underrecognized precipitating factor, capable of inducing severe metabolic, inflammatory, and microvascular injury. Case Presentation: We report the case of a 54-year-old male admitted with altered mental status and severe dehydration, in whom initial laboratory evaluation revealed extreme hyperglycemia (serum glucose ~1000 mg/dL), metabolic acidosis, and early multiorgan dysfunction. During intensive care unit hospitalization, the patient developed anemia and severe thrombocytopenia, followed by evidence of upper gastrointestinal bleeding. Urgent upper gastrointestinal endoscopy demonstrated diffuse circumferential black necrosis of the distal esophageal mucosa with abrupt demarcation at the gastroesophageal junction, consistent with acute necrotizing esophagitis, along with associated erosive hemorrhagic gastritis. Comprehensive laboratory evaluation documented marked inflammatory activation and hematologic instability. Management and Outcome: Treatment consisted of aggressive metabolic correction, strict glycemic control, hemodynamic stabilization, infection management, and supportive gastrointestinal care. Progressive clinical and biological improvement was observed, with resolution of bleeding and partial recovery of hematologic parameters. Conclusions: This case highlights a severe hyperglycemic crisis as a major contributing factor within a multifactorial ischemic and inflammatory cascade leading to acute necrotizing esophagitis. Full article

MicroRNAs (miRNAs) are small non-coding RNA molecules approximately 20–22 nucleotides in length that regulate gene expression at the post-transcriptional level. By binding to target messenger RNAs (mRNAs), miRNAs inhibit translation or induce degradation, thus influencing a wide array of biological processes including development, inflammation, apoptosis, and tissue remodeling. Owing to their remarkable stability and tissue specificity, miRNAs have emerged as promising biomarkers in both clinical and forensic settings. In recent years, increasing evidence has demonstrated their utility in cardiovascular diseases, where they may serve as diagnostic, prognostic, and therapeutic tools. This systematic review aims to comprehensively summarize the role of miRNAs in cardiovascular pathology, focusing on their diagnostic potential in myocardial infarction, sudden cardiac death (SCD), and cardiomyopathies, and their applicability in post-mortem investigations. Following PRISMA guidelines, we screened PubMed, Scopus, and Web of Science databases for studies up to December 2024. The results highlight several miRNAs—including miR-1, miR-133a, miR-208b, miR-499a, and miR-486-5p—as robust markers for ischemic injury and sudden death, even in degraded or formalin-fixed autopsy samples. The high stability of miRNAs under extreme post-mortem conditions reinforces their potential as molecular tools in forensic pathology. Nevertheless, methodological heterogeneity and limited standardization currently hinder their routine application. Future studies should aim to harmonize analytical protocols and validate diagnostic thresholds across larger, well-characterized cohorts to fully exploit miRNAs as reliable molecular biomarkers in both clinical cardiology and forensic medicine. Full article

Stroke is a leading cause of death and long-term disability worldwide, with ischemic stroke accounting for approximately 62.4% of all cases. This condition often results in persistent motor dysfunction, significantly reducing patients’ productivity. The effectiveness of rehabilitation therapy is crucial for post-stroke motor recovery. However, limited access to rehabilitation services particularly in low- and middle-income countries remains a major barrier due to a shortage of experienced professionals. This challenge also affects home-based rehabilitation, an alternative to conventional therapy, which primarily relies on standard evaluation methods that are heavily dependent on expert interpretation. Electromyography (EMG) offers an objective and alternative approach to assessing muscle activity during stroke therapy in home environments. Recent advancements in deep learning (DL) have opened new avenues for automating the classification of EMG data, enabling differentiation between post-stroke patients and healthy individuals. This study introduces a novel methodology for transforming EMG signals into time–frequency representation (TFR) spectrograms, which serve as input for a convolutional neural network (CNN) model. The proposed Tri-CCNN model achieved the highest classification accuracy of 93.33%, outperforming both the Shallow CNN and the classic LeNet-5 architecture. Furthermore, an in-depth analysis of spectrogram amplitude distributions revealed distinct patterns in stroke patients, demonstrating the method’s potential for objective stroke assessment. These findings suggest that the proposed approach could serve as an effective tool for enhancing stroke classification and rehabilitation procedures, with significant implications for automating rehabilitation monitoring in home-based rehabilitation (HBR) settings. Full article

Background: Irisin, an exercise-induced myokine, has emerged as a potent neuroprotective factor, though a systematic synthesis of its role across neurological disorders is lacking. This review systematically evaluates clinical and preclinical evidence on irisin’s association with neurological diseases and its underlying mechanisms. Methods: Following PRISMA 2020 guidelines, a systematic search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane Library was conducted. The review protocol was prospectively registered in PROSPERO. Twenty-one studies were included, comprising predominantly preclinical evidence (n = 14), alongside clinical observational studies (n = 6), and a single randomized controlled trial (RCT) investigating irisin in cerebrovascular diseases, Parkinson’s disease (PD), Alzheimer’s disease (AD), and other neurological conditions. Eligible studies were original English-language research on irisin or FNDC5 and their neuroprotective effects, excluding reviews and studies without direct neuronal outcomes. Risk of bias was independently assessed using SYRCLE, the Newcastle–Ottawa Scale, and RoB 2, where disagreements between reviewers were resolved through discussion and consensus. Results were synthesized narratively, integrating mechanistic, pre-clinical, and clinical evidence to highlight consistent neuroprotective patterns of irisin across disease categories. Results: Clinical studies consistently demonstrated that reduced circulating irisin levels predict poorer outcomes. Lower serum irisin was associated with worse functional recovery and post-stroke depression after ischemic stroke, while decreased plasma irisin in PD correlated with greater motor severity, higher α-synuclein, and reduced dopamine uptake. In AD, cerebrospinal fluid irisin levels were significantly correlated with global cognitive efficiency and specific domain performance, and correlation analyses within studies suggested a closer association with amyloid-β pathology than with markers of general neurodegeneration. However, diagnostic accuracy metrics (e.g., AUC, sensitivity, specificity) for irisin as a standalone biomarker are not yet established. Preclinical findings revealed that irisin exerts neuroprotection through multiple mechanisms: modulating microglial polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, suppressing NLRP3 inflammasome activation, enhancing autophagy, activating integrin αVβ5/AMPK/SIRT1 signaling, improving mitochondrial function, and reducing neuronal apoptosis. Irisin administration improved outcomes across models of stroke, PD, AD, postoperative cognitive dysfunction, and epilepsy. Conclusions: Irisin represents a critical mediator linking exercise to brain health, with consistent neuroprotective effects across diverse neurological conditions. Its dual ability to combat neuroinflammation and directly protect neurons, demonstrated in preclinical models, positions it as a promising therapeutic candidate for future investigation. Future research must prioritize the resolution of fundamental methodological challenges in irisin measurement, alongside investigating pharmacokinetics and sex-specific effects, to advance irisin toward rigorous clinical evaluation. Full article