Search Results (494)

Background: Long COVID is a heterogeneous post-viral condition in which persistent neurological, autonomic, cognitive, and psychometric symptoms often occur without clear isolated biomarker abnormalities. This mismatch suggests that disease persistence may be driven not only by changes in individual markers, but by longitudinal reorganization of biological and clinical interactions. Materials and Methods: This observational longitudinal study evaluated patients with persistent symptoms after confirmed SARS-CoV-2 infection at 3 and 6 months. Clinical assessment included neurological examination, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and COMPASS-31. Biomarkers representing hypoxia signaling, oxidative/redox stress, endothelial and renin–angiotensin system activity, glycation-related processes, and complement regulation were analyzed. Correlation analysis, association-level biomarker–clinical network modeling, and complementary Graphical LASSO-based sparse network estimation were used to compare network density, community organization, centrality, and edge rewiring between time points. Results: Conventional paired analysis identified HIF-1$\alpha$ as the only continuous variable with a statistically significant longitudinal change (Wilcoxon statistic = 610.0, $p=0.000350$), whereas association-level network analysis revealed a broader systems-level signal. The association-level biomarker–clinical network preserved a similar global size at 3 and 6 months, with 16 nodes, 27 versus 26 edges, and densities of 0.225 versus 0.217. However, this apparent stability concealed substantial rewiring: 19 edges were shared, 8 were lost, and 7 emerged. Complementary Graphical LASSO analysis with 1000 bootstrap resamples supported this pattern by identifying a conservative sparse conditional-dependency core, including seven shared conditional-dependency edges across time points and selective weakening of four early conditional dependencies. The C3–C4 relationship reversed from negative to positive correlation ($r=-0.618$ to $r=0.618$), indicating marked remodeling of complement-associated regulation. A psychometric–autonomic module involving Beck, HADS I, HADS II, and COMPASS-31 remained stable across both assessments. Conclusions: Long COVID progression was characterized by dynamic remodeling of immune, endothelial/RAS, oxidative-redox, hypoxia-related, autonomic, and psychometric interactions. Longitudinal network analysis identified a systems-level interaction structure that was not captured by isolated biomarker comparisons alone and that was further supported by complementary sparse conditional-dependency analysis. Full article

In this Perspective, we present a non-systematic narrative synthesis and propose a hypothesis-generating framework that links regional anesthesia, local anesthetic strategies, surgery-induced NETosis, and perioperative metastatic biology. Surgical tumor resection coincides with a biologically vulnerable perioperative period characterized by inflammatory activation, innate immune remodeling, and potential metastatic susceptibility. Preclinical evidence suggests that this interval may represent a transient metastatic window in which circulating tumor cells and host inflammatory responses overlap, potentially favoring metastatic implantation. Among the mechanisms implicated in this process, neutrophil extracellular traps (NETs) have been implicated in tumor-cell capture, endothelial interaction, immune evasion, and metastatic outgrowth. Experimental studies further suggest that surgery-induced NETosis may contribute to prometastatic signaling and tumor-cell metabolic adaptation during the postoperative period. Human evidence remains more limited and heterogeneous. Observational studies indicate that NET-related biology is active during oncologic surgery, with the presence of tissue NETs and circulating NET-associated biomarkers correlating with tumor stage, inflammatory context, or tumor burden in selected malignancies. Perioperative clinical studies also suggest that regional anesthesia and local anesthetic-based strategies, including intravenous lidocaine, may influence neutrophil activation and postoperative NET-associated biomarkers. However, robust evidence of clinical oncologic outcomes remains limited, and a clear distinction between surrogate perioperative endpoints and long-term clinical outcomes is still lacking. Within this context, we propose that regional anesthesia may influence pathways associated with perioperative tumor–host interactions not primarily through opioid sparing but through modulation of mechanisms related to surgery-induced NETosis during a short-lived biological window. The neutral results of large survival-based trials do not necessarily invalidate this hypothesis; rather, they underscore the limitations of conventional oncologic endpoints in capturing transient perioperative biological effects. This Perspective outlines a translational research agenda centered on biomarker-driven perioperative studies integrating NET-specific markers, circulating tumor cell dynamics, and temporally precise postoperative sampling. Full article

This narrative review synthesizes evidence linking periodontal dysbiosis with Alzheimer’s disease, all-cause dementia, and dementia-relevant mechanisms, focusing on the red complex pathogens P. gingivalis, T. denticola, and T. forsythia and on the translational meaning of periodontal therapy. A PubMed-centered literature search up to May 2026 informed this synthesis (a narrative review, not a registered systematic review or meta-analysis) of 46 periodontal-scope sources, supplemented by five contextual references identified outside the periodontal search (51 references in total). P. gingivalis shows the strongest mechanistic support, including gingipains, lipopolysaccharide, outer membrane vesicles, endothelial stress, and neuroinflammatory signaling; T. denticola shows moderate biological plausibility; and T. forsythia remains mainly hypothesis-generating. Human studies associate periodontitis, tooth loss, oral-hygiene indicators, and periodontal-care exposure with dementia-relevant outcomes, but residual confounding, reverse causation, dental-care access, and heterogeneous endpoints preclude causal inference. Notably, direct targeting of a single periodontal pathogen has not shown clinical benefit, as the gingipain inhibitor atuzaginstat failed in the GAIN trial, contrasting with the modest success of amyloid-targeting therapies. Current evidence supports graded plausibility rather than causal certainty, and a registered multi-database systematic review with neurological endpoints is needed before meta-analytic clinical claims can be made. Full article

Microplastics (MPs) and nanoplastics (NPs) have become pervasive environmental contaminants, raising growing concern regarding their potential accumulation within the human body and associated health risks. MP particles can translocate into systemic circulation and multiple organs, necessitating a comprehensive evaluation of current human biomonitoring data. This comprehensive review aimed to synthesize current evidence on the occurrence, distribution, detection technologies, exposure reduction and potential health implications of microplastics in human biological samples. The reviewed literature confirms the presence of microplastics in blood, placenta, amniotic fluid, umbilical cord blood, breast milk, semen, urine, and selected tissues including cardiovascular, renal, and reproductive samples. Detection frequencies in some matrices exceeded 70–90%, with polymer types such as polyethylene, polypropylene, polystyrene, and polyethylene terephthalate most commonly identified. Reported particle sizes ranged from nanometer-scale fragments to particles over 100 µm, indicating both systemic circulation and potential tissue retention. Spectroscopic techniques such as μFTIR and μRaman dominate polymer identification, while thermoanalytical approaches such as Py-GC/MS provide quantitative polymer confirmation. Emerging evidence suggests associations with oxidative stress, inflammatory responses, endothelial dysfunction, and impaired reproductive parameters, although causal relationships remain uncertain due to methodological heterogeneity and limited longitudinal data. This review provides an integrated overview of current human exposure evidence, identifies analytical gaps, and highlights the urgent need for harmonized detection frameworks and longitudinal risk assessment studies to inform public health policy and future biomonitoring strategies. Full article

Osteoradionecrosis of the jaw (ORNJ) remains one of the most severe late complications of head and neck radiotherapy. Current evidence suggests that ORNJ is a progressive and biologically heterogeneous disorder driven by microvascular injury, chronic hypoxia, oxidative stress, fibro-atrophic remodeling, impaired bone turnover, immune dysregulation, and systemic susceptibility factors. Within this complex pathogenic network, heat shock protein 27 (HSP27) emerges as a biologically plausible but unexplored mediator. HSP27 regulates multiple stress-response pathways, including redox homeostasis, cytoskeletal stabilization, endothelial protection, apoptosis control, fibroblast activation, and osteoblast–osteoclast function, all of which overlap with key mechanisms implicated in ORNJ. However, no studies have directly investigated HSP27 expression, activation, or functional significance in irradiated mandibular tissues or ORNJ-specific cohorts. This review summarizes current knowledge of ORNJ pathobiology, examines potential mechanistic links with HSP27, and outlines future research priorities involving biomarker development, tissue-level characterization, preclinical modeling, and therapeutic targeting. Integrating HSP27 into ORNJ research may improve understanding of pathogenesis, risk stratification, and the development of novel preventive and therapeutic strategies. Full article

Stroke remains one of the leading causes of death and disability worldwide, yet its clinical management is constrained by substantial biological heterogeneity that single-biomarker and single-omics approaches fail to resolve. The integration of multiple molecular data layers, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and immunomics, offers a transformative framework for investigating the underlying neuroinflammatory mechanisms of different stroke subtypes and endotypes. In this review, we synthesize the current multi-omics evidence in stroke by examining how genetic variants propagate through regulatory and immune pathways and generate measurable molecular signatures and clinically relevant biomarkers. We investigate the roles of microglia, infiltrating monocyte-derived macrophages, astrocytes, neutrophils, T cells, and endothelial cells as interacting nodes in the neuroimmune network after stroke, and analyze how spatially resolved single-cell transcriptomics illuminate state-specific programs previously undetectable in bulk tissue analyses. We discuss how proteomics and metabolomics translate these cellular programs into actionable circulating biomarkers and examine emerging evidence on blood–brain barrier disruption and neurovascular unit remodeling as multi-omics-defined targets. We then explore AI and machine learning frameworks enabling the integration of heterogeneous, high-dimensional datasets for endotype classification, patient stratification, and therapeutic response prediction. Finally, we address translational barriers, including analytical standardization, multi-ancestry generalizability, and regulatory readiness, and propose a roadmap for precision stroke medicine based on systems immunology. The core conceptual point of this review is the shift from describing omics findings in stroke cases to redefining biologically meaningful neuroinflammatory endotypes and using multi-omics to enable precision cerebrovascular medicine. Full article

The vascular endothelial glycocalyx (EGX) is a gel-like, negatively charged mesh of membrane-bound proteoglycans, glycosaminoglycans, glycoproteins and adsorbed plasma proteins that covers the luminal surface of the endothelium and orchestrates vascular homeostasis through regulation of permeability, leukocyte trafficking, mechanotransduction and anti-thrombotic signalling. Progressive thinning, heterogeneous remodelling and accelerated shedding of the EGX are now recognised as hallmarks of vascular ageing and early drivers of age-related cardiovascular disease. Here, we synthesise current evidence linking EGX integrity to biological ageing, with emphasis on age-dependent remodelling of heparan-sulfate proteoglycans, endothelial progenitor-cell dysfunction, and the heightened susceptibility of the aged EGX to oxidative, inflammatory and infectious insults. We discuss signalling pathways driving EGX shedding—including the IQGAP1/PAR1-2/PI3K/Akt axis—and clinical correlates such as vulnerable coronary plaque in older patients with coronary artery disease and microvascular endotheliopathy in severe COVID-19. Finally, we review emerging anti-ageing strategies targeting the EGX, including direct oral anticoagulants, glycocalyx-mimetic and nitric-oxide-releasing biomaterials, bioinspired antithrombogenic surfaces and microbiome-based modulation, and consider their translational potential for extending cardiovascular healthspan. Full article

Background: Vitamin D is involved not only in calcium–phosphate homeostasis but also in immune and endothelial regulation. Vitamin D deficiency has been suggested to worsen disease activity in systemic lupus erythematosus (SLE). Environmental and lifestyle factors, including seasonal sun exposure, smoking, diet, and supplementation, may influence vitamin D status and disease manifestations. This study aimed to evaluate the association between serum 25-hydroxyvitamin D [25(OH)D] levels, disease activity, and anti-double-stranded DNA (anti-dsDNA) antibody titers in patients with SLE, taking selected lifestyle and environmental factors into account. Methods: Serum 25(OH)D concentrations, SLE disease activity assessed by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, and anti-dsDNA antibody titers were measured in patients with SLE and healthy controls. Blood samples were collected during sunny (April–September) and non-sunny (October–March) months. Information on vitamin D supplementation, smoking status, and dietary habits was obtained using a structured questionnaire. Associations between vitamin D status, disease activity, anti-dsDNA seropositivity, season of blood collection, supplementation, smoking, and diet were analyzed statistically. Results: Patients with SLE had significantly higher mean serum 25(OH)D levels than controls, mainly due to frequent vitamin D supplementation. No significant associations were observed between serum 25(OH)D levels and SLEDAI-2K scores or anti-dsDNA antibody positivity. Seasonality, smoking status, and adherence to special diets were not significantly related to disease activity or anti-dsDNA seropositivity. Vitamin D supplementation was strongly associated with sufficient 25(OH)D levels but did not translate into reduced disease activity or lower anti-dsDNA prevalence. Conclusions: Serum 25(OH)D concentration was not associated with clinical or immunological activity of SLE in this cross-sectional study, despite effective correction of deficiency through supplementation. These findings likely reflect the heterogeneity of SLE and the limitations of single time-point assessments, although regular monitoring and individualized vitamin D supplementation may still be considered in SLE care, particularly in the context of recommended photoprotection. Full article

Ischemic vascular diseases remain a leading cause of morbidity and mortality worldwide and are frequently associated with irreversible tissue damage. Although stem cell-based therapies have shown promise for vascular regeneration, their clinical translation has been limited by poor survival, insufficient engraftment, functional heterogeneity, and immune rejection. Recent advances in genome-editing technologies, including CRISPR/Cas9, base editing, and prime editing, have provided powerful tools for overcoming these limitations through precise genetic modification of stem cells. Gene editing can enhance angiogenic potential, improve resistance to ischemic stress, augment paracrine activity, promote endothelial maturation, and reduce immunogenicity. In this review, we outline the current genome-editing toolbox and its application to stem cell engineering for vascular regeneration in ischemic disease. We also examine emerging therapeutic concepts, universal donor cell platforms, and key issues in safety and ethics, with a focus on translational pathways. Taken together, advances at the interface of genome editing and stem cell biology are likely to accelerate the development of regenerative therapies that deliver more durable vascular repair in ischemic vascular disease. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and fibrosis involving the skin and internal organs. Interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and cardiac involvement remain major causes of morbidity and mortality, yet prediction of disease progression and therapeutic responsiveness remains difficult. Methods: This narrative review summarizes studies of circulating blood biomarkers in SSc, with emphasis on literature published since 2020 and on Japanese multicenter longitudinal cohort studies. Disease-specific autoantibodies were intentionally excluded from the main scope, and the review focuses on soluble biomarkers measurable in peripheral blood that reflect inflammation, endothelial injury, and fibrotic remodeling. Results: Multiple cytokines, chemokines, adhesion molecules, endothelial markers, extracellular vesicle-associated molecules, and extracellular matrix (ECM)-related molecules have been associated with disease activity, organ involvement, prognosis, and therapeutic response in SSc. Clinically established biomarkers such as KL-6 and surfactant protein-D (SP-D) for SSc-associated interstitial lung disease (ILD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for pulmonary arterial hypertension (PAH), are already used as adjunctive tools in routine clinical assessment, whereas many other candidate biomarkers, including interleukin (IL)-6, CCL2, CXCL8, CXCL4, intercellular adhesion molecule-1 (ICAM-1), CCL18, periostin, endostatin, endothelin-1, extracellular vesicle signatures, and ECM turnover markers remain at varying stages of clinical validation. In particular, Japanese multicenter longitudinal studies have demonstrated the prognostic significance of circulating chemokines and adhesion molecules in early SSc and, more recently, identified biomarker-based clusters associated with distinct pulmonary trajectories. Recent multidimensional proteomic and transcriptomic approaches further support biologically based patient stratification in SSc. Conclusions: Blood biomarkers may contribute to risk stratification, prediction of organ progression, and future precision medicine in SSc. Integrated biomarker signatures may better capture the biological heterogeneity of SSc than single biomarkers alone. However, most candidate biomarkers still require external validation, assay standardization, and demonstration of incremental value over conventional clinical variables before routine clinical implementation. Full article

Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies. Full article

Coronary artery disease (CAD) is increasingly recognized as a thromboinflammatory disorder in which innate immune activation and coagulation are tightly coupled within the plaque microenvironment. Emerging single-cell and spatial technologies have refined this paradigm by demonstrating that these processes are not diffusely distributed but instead concentrated within discrete cellular niches. This narrative review critically evaluates mechanistic and translational studies integrating single-cell RNA sequencing, spatial transcriptomics, and ligand–receptor modeling to characterize cell–cell communication networks driving immunothrombosis in CAD. Converging evidence from single-cell and spatial studies indicates substantial heterogeneity among macrophages, neutrophils, and smooth muscle cells, with functionally distinct subpopulations contributing differentially to inflammation, matrix remodeling, and thrombogenicity. Spatial analyses further demonstrate that procoagulant and inflammatory programs converge in anatomically defined high-risk regions, particularly at the plaque shoulder and sites of endothelial dysfunction. However, whether these transcriptional states represent causal drivers or epiphenomena remains unresolved. Many insights are derived from murine models or dissociated tissues, raising concerns regarding translational relevance and loss of spatial context. Additionally, computational inference of intercellular communication remains indirect and requires functional validation. In conclusion, immunothrombosis in CAD should be interpreted as an emergent property of spatially organized cellular networks rather than a uniform inflammatory state. While these approaches identify candidate therapeutic nodes, their clinical translation and the central challenge is to distinguish causal regulatory nodes from transcriptional correlates generated by high-dimensional profiling. Full article

Background/Objectives: Perioperative brain injury arises from interacting pathways including excitotoxicity, neuroinflammation, and endothelial dysfunction, with limited effective pharmacological neuroprotection. Magnesium sulphate has multimodal biological effects that may address these pathways, but its translational role remains unclear. We aimed to map the translational evidence landscape of perioperative magnesium sulphate and evaluate its translational evidence profile across mechanistic, indirect, and direct clinical domains with respect to potential neuroprotective signalling. Methods: A scoping review was conducted following PRISMA ScR. The literature from PubMed, Scopus, the Cochrane Library, and ProQuest was screened using a Population–Concept–Context framework. Eligible studies included randomised trials, observational studies, and evidence syntheses evaluating perioperative magnesium sulphate. Evidence was categorised into direct neurological outcomes, indirect clinical outcomes, biomarker evidence, and mechanistic domains. Results: Eighteen studies were included, comprising randomised trials, observational studies, and reviews. Magnesium was consistently associated with reductions in postoperative pain and opioid consumption and improvements in recovery characteristics and shivering prevention. In contrast, direct neuroprotective outcomes such as cognitive function, cerebral oxygenation, and neurovascular events showed limited and heterogeneous evidence. Mechanistic mapping suggested effects on NMDA receptor modulation, calcium regulation, sympathetic tone, and endothelial stability. Conclusions: Perioperative magnesium sulphate demonstrates consistent indirect benefits related to analgesia and recovery but lacks robust evidence for direct neuroprotection. Its role is best conceptualised as a multimodal modulator of perioperative neural stress rather than a definitive neuroprotective agent. Future studies should adopt multidomain outcome frameworks integrating mechanistic and clinical endpoints to better define its translational impact. Full article

Carotid body tumors (CBTs) exhibit pronounced clinical heterogeneity, particularly in fibrotic progression, yet the underlying cellular mechanisms remain poorly defined. Here, we performed single-cell RNA sequencing on 64,944 cells from three fibrotic CBT (FCBT) and three non-fibrotic CBT (nFCBT) specimens to construct a high-resolution cellular atlas of CBT fibrosis. Integrated analyses revealed that FCBTs are distinguished by a FOXP2+ chief cell subpopulation exhibiting a metabolic shift toward mitochondrial respiration and enhanced MIF signaling, which may facilitate macrophage recruitment. Endothelial cells expanded in FCBTs and acquired pro-angiogenic signatures driven by macrophage-derived CXCL signaling. Notably, CXCL14+ fibroblasts emerged as the principal effectors of extracellular matrix deposition, with lineage inference suggesting their origin from smooth muscle cells. Immune cells, including T/NK and mast cells, further modulated the fibrotic niche through cytokine interactions. This study provides the first comprehensive single-cell dissection of CBT fibrosis, identifies FOXP2+ chief cells as initiators of stromal remodeling, and highlights CXCL14+ fibroblasts as key matrix-producing effectors. These findings nominate FOXP2 and CXCL14 as potential therapeutic targets for mitigating fibrosis in CBT patients. Full article

Background and Clinical Significance: Cardiac and mediastinal angiosarcomas are rare, aggressive malignancies that often present with nonspecific symptoms and pose significant diagnostic challenges. Tumor heterogeneity and necrosis may lead to false-negative biopsy results; Case Presentation: We report a 64-year-old man who initially presented with cardiac tamponade of unclear etiology. Despite an extensive workup, the patient remained asymptomatic for five months before re-presenting with dyspnea and a large mediastinal mass compressing the right heart, along with a lytic rib lesion. Initial ultrasound-guided biopsy of the rib lesion demonstrated a benign vascular proliferation consistent with Masson tumor (intravascular papillary endothelial hyperplasia), which was discordant with aggressive imaging findings. Further evaluation with positron emission tomography–computed tomography (PET-CT) revealed peripheral metabolic activity, and cardiac magnetic resonance imaging (MRI) demonstrated a heterogeneous mass with central necrosis and peripheral enhancement. A repeat CT-guided biopsy targeting the metabolically active region confirmed angiosarcoma, with immunohistochemical staining demonstrating diffuse positivity for ERG, CD31, and CD34. The patient was treated with palliative radiation and paclitaxel-based chemotherapy but experienced rapid clinical decline and transitioned to comfort-focused care; Conclusions: This case highlights the importance of correlating imaging with pathology and emphasizes the risk of sampling error in necrotic tumors. PET-guided biopsy targeting viable tumor regions is essential in cases with discordant findings. Full article