Search Results (5,215)

Frailty is a geriatric syndrome involving inflammation, oxidative stress, mitochondrial dysfunction, and metabolic disturbances. Metabolomics can systematically elucidate metabolic pathways and identify actionable biomarkers. This study systematically reviews the progress and evolutionary trends of metabolomics applications in frailty research from 2006 to 2025. Based on 1924 publications retrieved from the Web of Science Core Collection, systematic analyses were performed using CiteSpace, VOSviewer, SCImago Graphica, and the R package “bibliometrix”, focusing on pathway-level research hotspots and collaboration networks. The United States and China are the leading contributors. Research hotspots have shifted from macro-level biomarkers such as inflammation and protein–energy wasting to specific metabolic pathways including amino acid metabolism, energy metabolism, lipid metabolism, and tryptophan degradation. Key metabolites include sphingomyelin, butyrate, and trimethylamine-N-oxide. Emerging frontiers focus on the association between gut microbiota-derived metabolites and frailty phenotypes, as well as intervention strategies targeting these metabolites. This study provides the first systematic overview of global research progress in metabolomics and frailty, establishes a reproducible evaluation framework integrating physiology, nutrition, geriatrics, and computational biology, and identifies butyrate, trimethylamine-N-oxide, and tryptophan metabolites as potential metabolic targets for early identification and intervention. Full article

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and are traditionally considered acute and self-limited conditions. However, growing evidence suggests that recurrent or persistent UTIs may contribute to chronic kidney disease (CKD) progression through complex interactions between uropathogens and host responses. This review examines the pathophysiological links of UTIs caused by uropathogenic Escherichia coli, Klebsiella spp., and Enterococcus spp. and the development of chronic renal injury. Pathogen-specific persistence mechanisms, including intracellular survival, biofilm formation, and chronic colonization, may promote sustained inflammation, oxidative stress, and maladaptive repair responses. These processes are associated with tubular injury and progressive fibrotic remodeling. In addition, host-related factors such as diabetes, immune dysfunction, and antimicrobial resistance may further influence disease progression. Emerging biomarkers of inflammation, tubular injury, and fibrosis may improve early detection and risk stratification in patients with recurrent or complicated UTIs. Collectively, these findings support the concept that recurrent UTIs may represent potential contributors to CKD progression in susceptible individuals and highlight the importance of early recognition, pathogen-oriented management, and improved diagnostic strategies. Full article

Background: Patent foramen ovale (PFO) is associated with cryptogenic stroke, but mechanisms beyond paradoxical embolism remain unclear. Inflammation, fibrosis-related remodeling, and nitrosative stress may contribute to vascular vulnerability in these patients. The aim of this study was to evaluate inflammatory, fibrotic, and nitrosative biomarker profiles in patients with PFO and prior cryptogenic stroke and to determine whether these patients exhibit coupled inflammatory fibrotic nitrosative activation. Methods: This prospective, observational, single-center study included 92 patients aged <55 years with PFO and prior cryptogenic stroke and 56 age-matched controls without PFO and cerebrovascular events. Circulating interleukin-18 (IL-18), galectin-3, and 3-nitrotyrosine (3-NT) levels were measured using ELISA assays. Correlation and linear regression analyses were performed. Results: Compared with controls, patients with PFO had higher galectin-3 (11.87 vs. 10.36 ng/mL; p = 0.015), IL-18 (268.0 vs. 121.0 pg/mL; p < 0.001), and 3-NT (48.5 vs. 41.8 ng/mL; p = 0.046). Significant correlations were observed between IL-18 and galectin-3 (r = 0.565), IL-18 and 3-NT (r = 0.425), and galectin-3 and 3-NT (r = 0.292) (all p ≤ 0.002). Conclusions: Patients with PFO and prior cryptogenic stroke exhibit a distinct biomarker profile consistent with coupled inflammatory–fibrotic–nitrosative activation, suggesting a potential non-mechanical component of stroke susceptibility. Full article

Myalgic encephalomyelitis (ME) is characterized by profound fatigue, post-exertional malaise (PEM), and cognitive dysfunction. Despite its clinical significance, the pathophysiology of PEM and disease heterogeneity remain unclear, and no validated biomarkers are available for rapid diagnosis or monitoring. We aimed to develop a screening approach combining label-free Raman spectroscopy (RS) and machine learning modeling (ML) to detect biomolecular changes in blood plasma and differentiate patients with ME from sedentary healthy controls. Blood plasma was collected from 115 patients with ME and 45 controls at rest (T0) and 90 min after a standardized, non-invasive stress test designed to induce PEM. Plasma samples were analyzed by RS, and ML models were developed independently at each time point to differentiate patients with ME and controls. The RS-ML models identified spectral features consistent with contributions from proteins, lipids, and low-molecular-weight metabolites. At T0 and T90, the area under the receiver operating characteristic curve, accuracy, specificity and sensitivity were 0.85 and 0.83, 79% and 84%, 82% and 90%, and 73% and 69%, respectively. RS-ML provides a rapid, low-cost approach to detect ME-associated biomolecular signatures in plasma and capture biochemical alterations associated with standardized stress. Full article

Background: Long-term exposure to ambient air pollution during pregnancy has been strongly associated with oxidative-stress-mediated adverse maternal and fetal outcomes. Aim: The present study aimed to evaluate systemic oxidative stress and antioxidant capacity in pregnant women residing in a highly polluted area (Kozani) compared with a less polluted region (Grevena) in Western Macedonia, Greece. Methods: Oxidative stress was assessed using derivatives of reactive oxygen metabolites (d-ROMs), while antioxidant capacity was evaluated through biological antioxidant potential (BAP). Results: The findings of the study demonstrated that pregnant women in the polluted area exhibited elevated d-ROMs levels and significantly reduced BAP levels compared with controls. Although unadjusted oxidative stress differences were not statistically significant, adjusted analyses revealed significantly higher oxidative stress in the exposed group. These results suggest that air pollution exposure is associated with systemic redox homeostasis, primarily through depletion of antioxidant defenses. Conclusions: This study provides novel biomonitoring evidence linking environmental exposure to redox imbalance during pregnancy. As Western Macedonia transitions to a post-lignite era, the decrease in air pollution is anticipated to lead to significant improvements in public health, while these findings establish an important baseline for evaluating the effectiveness of environmental and public health interventions. Full article

Background: Soccer match play induces substantial mechanical, metabolic, inflammatory, and neuromuscular stress, yet post-match monitoring in applied settings often relies on isolated markers, venous sampling, or limited time points. This observational repeated-measures study aimed to describe whether capillary-derived biomarkers, neuromuscular performance, and perceptual measures showed asynchronous recovery during the first 48 h after a standardised soccer match in elite players. Methods: Twenty-two elite male outfield soccer players completed a standardised 90 min match. Capillary blood biomarkers, countermovement jump (CMJ), 20 m sprint performance, maximal voluntary contraction (MVC), and delayed onset muscle soreness (DOMS) were assessed before the match, immediately post-match, and at 24 and 48 h post-match. Time effects were analysed using repeated-measures mixed-effects models, and associations between biochemical and functional responses were examined descriptively. Results: Match play induced clear but domain-specific disturbances. IL-6 and cortisol rose rapidly immediately post-match, whereas hsCRP, CK, LDH, myoglobin, and DOMS showed delayed peaks during early recovery. CK, LDH, myoglobin, and soreness remained above baseline at 48 h. CMJ and sprint performance were impaired after the match but largely recovered by 48 h, whereas MVC showed its greatest decrement at 24 h. Exploratory associations indicated that larger muscle damage responses tended to co-occur with greater strength and jump decrements and higher soreness, but these analyses were not causal. Conclusions: Recovery after a standardised elite soccer match was multidimensional and non-synchronous across physiological, neuromuscular, and perceptual domains. A capillary-based, multi-domain assessment strategy may provide a feasible descriptive perspective for field-based observation of post-match fatigue. Full article

Background: Low-dose aspirin (LDA) reduces preeclampsia (PE) risk by up to 40%, yet its molecular effects on chorion trophoblast cells (CTCs), a fetal membrane lineage at the feto-maternal interface, remain obscure. CTCs form a structural and immunoregulatory barrier whose dysfunction drives inflammation-associated membrane pathology in PE. Extracellular vesicles (EVs) released by CTCs may encode cellular stress and adaptation states, offering a molecular window into aspirin’s timing-dependent effects on PE risk modification. Methods: Human CTCs were challenged with cigarette smoke extract (CSE) to model oxidative stress-driven PE pathology. Two paradigms were tested: (1) prophylactic aspirin (4 and 40 µg/mL) before and/or flanking the CSE, and (2) therapeutic aspirin after the CSE challenge. The EVs were isolated via ultracentrifugation and size-exclusion chromatography, characterized by nanoparticle tracking and immunoblotting, and profiled by quantitative mass spectrometry. A network pathway analysis and machine learning biomarker selection defined the EV-encoded molecular states. Results: The CTC-derived EVs from the CSE-exposed cells carried a PE-like proteomic signature marked by suppressed VEGF/ECM remodeling, activated TNF-p53 apoptotic signaling, and heightened inflammation. Prophylactic low-dose aspirin shifted the EV cargo toward an EV-encoded signature consistent with preserved angiogenic potential (enrichment of VEGFA, COL1A1, and MMP14) and predicted attenuation of apoptotic and NF-κB pathway activity by an Ingenuity Pathway Analysis. High-dose aspirin produced broad transcriptional suppression without an accompanying pro-angiogenic EV signature. Therapeutic (post-injury) aspirin partially attenuated the injury-associated EV cargo but did not restore the angiogenic EV signature. An exploratory machine learning analysis of EV proteomes identified a candidate prophylactic biomarker panel anchored by HSPA8, SERPINF2, COL4A1, and PLOD1, mapped to the predicted angiogenic recovery and redox-balance pathways. These EV cargo readouts represent the predicted molecular states and require functional validation before clinical interpretation. Conclusions: The CTC-derived EV proteomic signatures capture the dose- and timing-dependent aspirin effects in this in vitro CTC model, positioning the chorion as a candidate pharmacological “secondary responder” favoring cellular resilience over classical anti-inflammatory suppression. As an exploratory hypothesis-generating study, EV-based molecular profiling could provide a foundation for future investigations aimed at stratifying aspirin responders from non-responders, although clinical validation in maternal plasma cohorts will be required before any translational application. Full article

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by epithelial barrier disruption, oxidative stress, immune dysregulation, and defective mucosal healing. Recent studies have identified ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, as a key mechanism linking these processes. This review summarizes the current progress in understanding the role of ferroptosis in colitis. Available evidence shows that ferroptosis occurs in both human UC and experimental colitis models, with intestinal epithelial cells representing the best-established target compartment. Recent studies have further expanded this concept to reparative immune cells, particularly type 2 (M2) macrophages, thereby indicating that ferroptosis contributes not only to barrier injury but also to impaired mucosal healing. Mechanistically, colitis-associated ferroptosis is governed by interconnected networks involving solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) failure, acyl-CoA synthetase long chain family member 4 (ACSL4)-dependent lipid remodeling, iron overload, mitochondrial reactive oxygen species (ROS) amplification, inflammatory signaling, and N6-methyladenosine (m6A)-mediated post-transcriptional regulation. In parallel, microbiota-derived metabolites and dietary factors can either suppress or exacerbate ferroptotic injury. Therapeutically, ferroptosis-targeted strategies, including iron chelation, nutrient-based interventions, natural products, exosomes, and nanoplatforms show promising preclinical efficacy. Overall, ferroptosis provides a connected framework for understanding colitis pathogenesis and provides new opportunities for biomarker development and mechanism-based therapies. Full article

Microbiome dysbiosis has become recognized as an important interface connecting environmental exposures to chronic inflammatory and degenerative diseases. Although prior research has largely considered heavy metals as biomarkers of exposure and toxicity, their function as ecological modulators of host-associated microbial communities remains underexplored. The oral cavity is a distinct exposome–microbiome interface where environmental, behavioral, and intraoral metal sources converge and interact with structured biofilms and mucosal immunity. This review adopts an ecological systems perspective, interpreting chronic low-dose exposure to metals such as cadmium, lead, mercury, nickel, chromium, arsenic, and aluminum as a sustained selective force on oral microbial networks. A resilience–threshold model is proposed in which cumulative metal pressure progressively diminishes microbial community stability, alters network topology, and drives transitions toward persistent dysbiosis. These modifications are further reinforced by oxidative–inflammatory feedback loops at the host–microbiome interface, facilitating a self-sustaining ecological imbalance. Sketching on insights from microbial ecology, environmental toxicology, and host response biology, this review presents a framework that links metallomic patterns to microbial restructuring, redox imbalance, immune activation, and regulatory adaptation. The analysis emphasizes ecological perturbations from stable dysbiotic states and identifies key methodological limitations that currently restrict causal inference. By conceptualizing heavy metals as active ecological drivers rather than passive exposure indicators, this work establishes a foundation for understanding microbiome-mediated disease susceptibility within an exposome-informed systems biology framework. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder linked to cardio-kidney–metabolic (CKM) syndrome, early vascular injury and redox imbalance. Inflammatory adipokines such as retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) may contribute to this hepatic–vascular interplay by integrating metabolic inflammation, oxidative stress and endothelial dysfunction. Therefore, the present study aimed to investigate the contribution of the inflammatory adipokines retinol-binding protein 4 (RBP4) and lipocalin-2 (LCN2) to the hepatic–vascular interplay in MASLD within the cardio-kidney–metabolic (CKM) syndrome. Materials and Methods: We performed a systematic review and meta-analysis of studies evaluating circulating RBP4 and LCN2 levels in MASLD. PubMed, Scopus, and Web of Science were searched. Twenty studies were included in the qualitative synthesis, and ten in the quantitative meta-analysis. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Vascular findings were synthesized narratively because of heterogeneity in outcomes. Results: Circulating RBP4 levels were significantly higher in MASLD patients than in controls (SMD = 0.64, 95% CI: 0.08 to 1.20, p = 0.026; I² = 91.2%). LCN2 levels were also significantly elevated (SMD = 1.92, 95% CI: 0.83 to 3.00, p < 0.001; I² = 98.0%). Compared with RBP4, LCN2 showed a larger pooled effect size, although heterogeneity remained very high. In the qualitative synthesis, adipokines, particularly LCN2, were associated with markers of vascular injury, including carotid intima–media thickness, plaque burden, arterial stiffness, endothelial dysfunction, coronary severity, and cardiovascular events. Conclusions: Both RBP4 and LCN2 were elevated in MASLD, supporting a link between adipokine dysregulation and hepatic metabolic dysfunction within the broader cardio-kidney–metabolic (CKM) syndrome. LCN2 appeared to better reflect the inflammatory, metabolic, and vascular burden of disease. These findings support the view of MASLD as a systemic disorder within the CKM syndrome and highlight the potential of inflammatory adipokines as non-invasive biomarkers of integrated hepatic, metabolic, and vascular dysfunction. Full article

This study investigated the individual and combined effects of mercury (as HgCl₂) and Bisphenol S (BPS) on the blue crab Callinectes sapidus, focusing on biomarkers measured in hemolymph, gills, and hepatopancreas and ultrastructure (transmission electron microscopy, TEM) observations. Adult males were exposed for seven days to environmentally relevant concentrations of each contaminant, alone and in mixture. Results revealed clear tissue-specific responses. In hemolymph, both contaminants reduced total hemocyte count and affected immune-related parameters, including hemocyte proliferation and enzymatic activities. In gills, mercury significantly decreased total antioxidant capacity, while both contaminants increased lipid peroxidation, indicating oxidative stress. BPS and the mixture stimulated catalase activity, whereas electron transport system activity increased only under combined exposure. In contrast, the hepatopancreas showed limited biochemical alterations, suggesting a higher resilience to medium-term exposure. TEM observations revealed a general decrease in granularity of hemocytes from crabs exposed to BPS and mixture, suggesting cell degranulation. In addition, infiltration of hemocytes into gills was observed in crabs exposed to experimental conditions, suggesting migration of hemocytes from hemolymph to peripheral tissues, while alterations of the microvilli arrangement were detected in digestive cells of BPS-treated crabs. Overall, the findings suggested that hemolymph and gills were more sensitive to contaminant exposure, while the hepatopancreas appears more resistant, at least under the experimental conditions tested. The study also suggests potential non-additive interactions between mercury and BPS. Full article

Vaquejada (VQ) is a traditional Brazilian sport demanding high performance from Quarter Horse (QH) athletes. This study aimed to identify modifications in hematological, biochemical, inflammatory, and oxidative stress biomarkers associated with VQ training, comparing conditioned and non-conditioned horses. Blood samples were collected at rest from 70 healthy QH horses: 60 athletes (VQ-conditioned athlete group—AG) and 10 sedentary controls (breeding horses—CG). Using Linear Mixed Models alongside comprehensive hematological and biochemical analyses, the study found that AG horses exhibited an altered homeostatic profile, characterized by significant reductions in erythrocytes (7.0 [2.7] vs. 8.0 [1.6]; p = 0.021), lymphocytes (33.0 [21.0] vs. 41.0 [25.0]; p = 0.028), and the antioxidant enzymes catalase (1.5 [0.5] vs. 2.4 [1.4]; p = 0.026) and myeloperoxidase (141.5 [53.9] vs. 235.6 [30.4]; p = 0.022) relative to CG. Conversely, marked increases were observed in band neutrophils (59.0 [16.0] vs. 49.0 [27.0]; p = 0.028), platelets (276.0 [115.0] vs. 160.0 [113.6]; p = 0.026), and malondialdehyde levels (177.5 [211.8] vs. 1475.0 [802.5]; p < 0.001), evidencing lipid peroxidation. These findings indicate that VQ induces severe oxidative stress and compromises immune functions, with horses presenting oxidative rather than inflammatory damage. Dietary monitoring is therefore recommended to mitigate such effects at 96 h post-exercise. Full article

Epilepsy is increasingly conceptualized as a disorder of dynamic network instability rather than a static imbalance between excitation and inhibition. However, substantial variability in seizure occurrence, clinical expression, and treatment response remains insufficiently explained by existing models. This narrative review examines how neurotransmitter systems contribute to seizure dynamics within a state-dependent framework, in which factors such as sleep–wake cycles, stress, inflammation, and metabolic conditions modulate network excitability. The review identified four key findings: neurotransmitter function in epilepsy is state-dependent rather than fixed; multiple physiological state modifiers shape seizure susceptibility; seizure termination is an active state-sensitive process; and biomarker performance depends on the prevailing brain state. Evidence from experimental and clinical studies indicates that neurotransmitter function is context-sensitive and interacts with molecular pathways, including ion channel function, synaptic plasticity, and neuromodulatory signaling. These interactions influence key stages of seizure dynamics, including initiation, propagation, and termination, and may differ across etiological categories of epilepsy. This perspective also helps explain the limited performance of static biomarkers, as they do not capture temporal variability in network states. Instead, state-sensitive markers and context-aware interpretations of electrophysiological and clinical data may provide more informative insights. Overall, integrating neurotransmitter mechanisms with dynamic brain states offers a more precise perspective on seizure variability and may support the development of individualized, state-aware approaches to epilepsy management. Full article

Breast cancer remains the most frequently diagnosed malignancy among women worldwide, while metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease, reflecting a global burden of metabolic dysfunction. Increasing evidence suggests that MASLD is associated with breast cancer development and progression; however, whether this relationship reflects an independent effect of hepatic metabolic dysfunction or the broader metabolic environment remains uncertain. This review synthesizes current epidemiological, clinical, and mechanistic data linking hepatic metabolic dysfunction to breast carcinogenesis. Population-based studies consistently demonstrate an association between hepatic steatosis and increased breast cancer incidence, particularly in postmenopausal and metabolically vulnerable populations, as well as poorer oncological outcomes. Mechanistically, MASLD promotes a systemic pro-tumorigenic environment through interconnected pathways, including insulin resistance, hormonal dysregulation with increased estrogen bioavailability, chronic inflammation, oxidative stress, lipid metabolic reprogramming, and gut–liver axis disruption. Hepatokines, particularly fibroblast growth factor 21 (FGF21), emerge as key mediators of tumor progression and potential biomarkers of metabolic vulnerability, while Fetuin-A and angiopoietin-like protein 8 (ANGPTL8) further support the liver’s endocrine role in oncogenic signaling. Preclinical evidence highlights fatty acid oxidation as a metabolic dependency in aggressive breast cancer subtypes, suggesting novel therapeutic targets. Despite consistent associations, causality remains unproven. Future prospective studies are needed to determine whether targeting metabolic dysfunction can improve breast cancer prevention and outcomes. Full article

Sepsis is a systemic disorder in which infection-induced inflammation progressively disrupts vascular homeostasis and drives organ dysfunction. This review reframes septic pathophysiology as a sequential and self-amplifying process centered on endothelial failure. Early activation of innate immune pathways by pathogen- and damage-associated molecular patterns promotes cytokine release, oxidative stress, and enzymatic degradation of the endothelial glycocalyx. Loss of this protective surface layer exposes endothelial cells to unbuffered inflammatory and mechanical injury, impairing mechanotransduction, increasing leukocyte and platelet adhesion, and destabilizing vascular barrier function. Subsequent disruption of intercellular junctions promotes capillary leakage, tissue edema, and impaired oxygen diffusion, while mitochondrial dysfunction and redox imbalance reduce endothelial repair capacity. In parallel, complement activation, neutrophil extracellular trap formation, platelet–leukocyte interactions, and loss of anticoagulant signaling shift the microvasculature toward a prothrombotic and proinflammatory state. These interconnected mechanisms culminate in microvascular incoherence, characterized by heterogeneous capillary flow, regional hypoxia, impaired oxygen extraction, and progressive organ failure despite apparent restoration of systemic hemodynamics. Within this framework, biomarkers such as syndecan-1, soluble thrombomodulin, angiopoietin-2, von Willebrand factor, and plasminogen activator inhibitor-1 are best interpreted as mechanistic readouts of glycocalyx shedding, endothelial injury, permeability imbalance, and thromboinflammatory activation. Understanding sepsis as an evolving endothelial pathophysiological process provides a coherent framework for integrating inflammation, vascular leakage, hypoxia, coagulation, and organ dysfunction while identifying mechanistic biomarkers that reflect distinct stages of microvascular collapse. Full article