Search Results (1,920)

Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, vaso-occlusion, and systemic inflammation. Epidemiological studies identified an increased risk of leukemia, especially acute myeloid leukemia (AML), in individuals with SCD, whereas data regarding other tumors are conflicting. SCD-associated AMLs frequently display high-risk features with unfavorable karyotypes and a dismal prognosis. SCD is associated with multiple phenomena linked to carcinogenesis in other contexts, including chronic inflammation, oxidative stress, ineffective erythropoiesis, accelerated hematopoietic aging, impaired tumor immunosurveillance, and increased clonal hematopoiesis. The role and respective contribution of these disease-intrinsic mechanisms in SCD remain to be studied. Although therapies used in SCD could theoretically modulate the risk of malignancies, no data exist to support an increased or reduced risk associated with their use. The most notable exception is hematopoietic stem cell transplantation and, to a lesser extent, gene therapy, for which the conditioning and/or procedure itself is known to increase the risk of leukemia. In sum, the effect of SCD on carcinogenesis is an emerging area of investigation with data supporting specificities in SCD-associated AML. Future research is required to determine the role of treatments to mitigate the increased risk and improve the outcome of SCD-associated AML. Full article

Prorocentrum lima is a widely distributed and major source of diarrhetic shellfish toxins (DSTs); the ecological impact of diol-estered DSTs (eDSTs) compounds on benthic systems is still inadequate. In this study, the acute toxicity of eDSTs was evaluated in Caenorhabditis elegans, and their accumulation capacity and toxic effects were examined in Mytilus galloprovincialis for an ecological risk assessment. The results indicated that larvae 1 (L1) was more sensitive than larvae 4 (L4) of C. elegans, and the eDSTs in P. lima extract lysate were more toxic than the okadaic acid (OA) standard solution. The lowest LC₅₀ values were 0.293 and 0.469 μg/mL for L1 and L4, respectively. The growth, productivity, and intestinal permeability of C. elegans were impaired, and the effect of P. lima extract lysate on C. elegans was greater than that of the OA standard solution. The total toxin concentration in the digestive gland of mussels reached 3230 μg/kg, with esterified DSTs accounting for 76.7–97.1% of total toxins and inducing marked oxidative stress. Diol-estered DSTs exert direct toxic effects, including oxidative damage and growth inhibition, while exhibiting a high accumulation potential. This study revealed the toxicity of eDSTs, necessitating a focused investigation to comprehensively assess their toxicological impact and ecological risks. Full article

Excessive oxidative stress drives pathological ventricular remodeling after acute myocardial infarction (AMI), yet adaptive cardiomyocyte mechanisms are poorly understood. We analyzed 64,510 human cardiomyocytes from five integrated single-cell datasets to delineate oxidative stress heterogeneity. Using quartile thresholds of a composite oxidative stress score, cells were stratified into three distinct subpopulations: high oxidative stress (HOX, score > 2.608), dynamic transient oxidative stress (DTOX), and low oxidative stress (LOX, score < 2.061). Paradoxically, HOX cells exhibited severe oxidative stress alongside significantly higher cellular plasticity than DTOX and LOX cells (p < 0.001), as confirmed by CytoTRACE and pseudotime trajectory analyses. This subpopulation demonstrated a unique “metabolic activation–immune suppression” signature and served as a central communication hub. An integrative machine-learning framework incorporating six distinct algorithms and independent cohort validation identified five core marker genes (TRIM63, ETFDH, TXNIP, CKMT2, and PDK4). These genes demonstrated stable diagnostic capability for AMI in independent validation cohorts (AUCs 0.688–0.721, all p < 0.001) and were specifically enriched in HOX cells. Our work reveals a previously unrecognized adaptive state in post-infarction cardiomyocytes, offering promising new targets for precision diagnosis and intervention. Full article

Postoperative delirium is a frequent and serious neurocognitive complication in older surgical patients, characterized by acute impairments in attention, awareness, and cognition. It is associated with increased morbidity, prolonged hospitalization, and persistent cognitive decline. In this narrative review, we synthesize translational research on biological mechanisms underlying delirium and emerging targeted interventions. We conducted a comprehensive search of major biomedical databases, with no date restrictions but prioritizing publications from 2018 to 2025. The multifactorial pathophysiology involves dysregulated cholinergic and dopaminergic signaling, systemic and neuroinflammation, oxidative stress, and metabolic disturbances. Pre-existing cognitive impairment and frailty emerge as key clinical risk factors linked to these mechanisms. Aged rodent models replicate delirium-like cognitive deficits and validate mechanistic pathways, while human neuroimaging studies demonstrate disrupted functional connectivity in attentional and consciousness networks. Genomic and proteomic analyses have identified candidate biomarkers for early detection and risk stratification, and genetic variants associated with inflammation and neurodegeneration contribute to individual vulnerability. Emerging therapies targeting inflammation, microglial activation, mitochondrial function, and neurotransmitter balance show promise in preclinical studies, although clinical trials report mixed results. We advocate integrating basic science with clinical care through thorough preoperative assessment, multicomponent non-pharmacological strategies, and mechanism-based preventive measures to reduce the burden of postoperative delirium. Full article

The gastrointestinal (GI) tract contributes significantly to the pathogenesis of acute respiratory distress syndrome (ARDS) by influencing systemic inflammation and sepsis, which are key factors in the development of multiple organ dysfunction syndrome (MODS), while the significant impact of gut microbiota in critically ill patients, including those with sepsis and ARDS, further underscores its importance. The intestinal microbiota is vital to immune system function, responsible for triggering around 80% of immune responses. Therefore, it may be hypothesized that modifying fecal microbiota, such as through fecal microbiota transplantation (FMT), could serve as a valuable therapeutic approach for managing inflammatory diseases like lung injury (LI)/ARDS. Indeed, emerging experimental research suggests that FMT may have beneficial effects in ARDS models by improving inflammation, oxidative stress, LI, and oxygenation. However, well-designed randomized clinical trials in patients with ARDS are still lacking. Our study seeks to examine how therapeutic interventions such as FMT might benefit LI/ARDS patients by exploring the interactions between the gut and lungs in this context. Full article

The coronavirus disease 2019 (COVID-19) pandemic has revealed a close and multifaceted relationship between viral infection, systemic inflammation, and cardiovascular health. Among the cardiac complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), atrial fibrillation (AF)—especially new-onset atrial fibrillation (NOAF)—has emerged as a major determinant of disease severity and prognosis. Clinical studies and meta-analyses show that 5–10% of hospitalized COVID-19 patients develop AF, with markedly higher rates in critically ill individuals. Both pre-existing and NOAF are independently associated with increased risks of intensive care admission, mechanical ventilation, thromboembolic events, and mortality. The underlying mechanisms involve a combination of cytokine-mediated inflammation, endothelial dysfunction, microvascular injury, and dysregulation of the renin–angiotensin–aldosterone system (RAAS). Viral downregulation of angiotensin-converting enzyme 2 (ACE2) receptors contributes to myocardial fibrosis, while hypoxia, oxidative stress, and autonomic imbalance further promote electrical remodeling and arrhythmogenesis. Post-infectious studies indicate that atrial structural changes and autonomic dysfunction may persist for months, predisposing survivors to recurrent arrhythmias. Technological advances in telecardiology and digital medicine have provided new tools for early detection and long-term monitoring. Wearable electroencephalography (ECG) devices, implantable loop recorders (ILRs), and artificial intelligence (AI)-based diagnostic algorithms enable continuous rhythm surveillance and individualized management, improving outcomes in post-COVID patients. This review summarizes current evidence on the epidemiology, pathophysiology, clinical implications, and monitoring strategies of AF in COVID-19. It underscores the importance of integrating telemedicine and AI-assisted diagnostics into cardiovascular care to mitigate the long-term arrhythmic and systemic consequences of SARS-CoV-2 infection. Full article

Aortic aneurysms are complex, predominantly asymptomatic vascular diseases with distinct incidence patterns depending on anatomical localisation. The incidence of thoracic aortic aneurysms (TAAs) has moderately increased, whereas that of abdominal aortic aneurysms has declined, primarily due to public health measures. Undiagnosed or poorly managed aneurysms are at significant risk of progression to acute aortic syndrome, with high associated mortality. The embryological origins of the aorta may have a substantial impact on its structural, cellular, and functional heterogeneity. Specifically, smooth-muscle cells (SMCs) in the thoracic aorta are derived from cardiac neural crest and mesodermal cells, whereas abdominal aortic SMCs originate from the paraxial and splanchnic mesoderm. To explore these developmental and regional distinctions, we conducted a narrative review based on targeted literature retrieval and expert curation, highlighting how these distinctions might potentially influence susceptibility to aneurysms and their clinical presentation. Histological differences, such as the number of lamellar units and the presence or absence of vasa vasorum, could further explain regional vulnerability. Molecular mechanisms underlying aneurysm formation include inflammation, oxidative stress, extracellular matrix degradation, phenotypic switching, and dysregulated signalling pathways, notably transforming growth factor-beta (TGF-β) and angiotensin II. Genetic mutations significantly contribute to TAAs, with genes involved in the elastin–contractile unit and TGF-β signalling pathways playing pivotal roles. However, the complex interplay between genetic susceptibility and risk factors explains why some patients develop aneurysms while others do not. Clinical management strategies have evolved, emphasising early risk stratification, surveillance, and timely surgical intervention, guided increasingly by genetic profiling and segment-specific molecular understanding. Advances in genomic technologies, biomarker identification, and computational modelling promise to enhance individualised care. Bridging developmental biology, molecular genetics, and clinical practice is crucial for improving outcomes in patients with aortic aneurysms, thereby reinforcing a multidisciplinary approach to patient-centred cardiovascular medicine. Full article

Background: Echinacea purpurea (L.) Moench (EP) and Onopordum acanthium (L.) (OA) are promising medicinal plants with diverse biological activities but there is no information on the effects of their combinations. To harness the therapeutic potential of both while minimizing the risk of adverse effects, we prepared two combinations (CE1 and CE2) of EP and OA in ratios 1:1 and 3:1, respectively. Methods: Oxygen radical absorbance capacity (ORAC), hydroxyl radical absorbance capacity (HORAC), and an electrochemical assay were used to determine the antioxidant activity of the extracts in vitro. The anxiolytic and immunomodulatory properties were studied in rats. Animals were subjected to acute cold stress and anxiety-like behavior was evaluated by the elevated plus maze (EPM) and social interaction test (SIT). Serum IFN-γ, TNF-α and IL-10 levels were measured by ELISA. Results: CE2 demonstrated the highest antioxidant activity (1841.7 μmolTE/g by ORAC, 277.2 GAE/g by HORAC, and 39.6 by electrochemical method). Moreover CE2 produced anxiolytic-like effects—significantly increasing the open arms entries ratio (OAER; p < 0.001), open arms time ratio (OATR; p < 0.01) in the EPM, and prolonging the social interaction time (p < 0.05) versus the stressed control. OA increased OAER (p < 0.01) and OATR (p < 0.001), while EP increased only OAER (p < 0.01). CE1 showed no significant behavioral consequences. CE2 significantly reduced IFN-γ (p < 0.05), and IL-10 levels were elevated in OA and CE2 groups (p < 0.01). No significant changes in TNF-α levels were observed across groups. Conclusions: These findings indicate that CE2 and OA attenuate anxiety-like behavior and modulate the immune response primarily by stimulating IL-10 production. Full article

Stroke is the leading cause of death and long-term disability worldwide, with ischemic stroke accounting for nearly 87% of all cases. Vascular occlusion, a key pathological event in ischemic stroke, has been reliably reproduced in preclinical studies using permanent ischemic stroke models. This study demonstrated the neuroprotective effect of NXC736, a functional antagonist of sphingosine-1-phosphate receptor 4 (S1P₄, currently in phase II clinical trials for alopecia areata), against acute injury in mice with permanent middle cerebral artery occlusion (pMCAO). pMCAO-challenged mice received oral NXC736 1 h after occlusion. NXC736 demonstrated substantial therapeutic activity against permanent ischemic stroke by attenuating pMCAO-induced acute brain infarction, neurological deficits, and apoptosis. Additionally, NXC736 reduced blood–brain barrier disruption and edema in the injured brain. Moreover, NXC736 reduced microglial activation and proliferation, oxidative stress, and suppressed pro-inflammatory cytokine expression, suggesting that the efficacy of NXC736 in permanent ischemic stroke is associated with the suppression of neuroinflammatory responses. Mechanistically, we found that NXC736-mediated neuroprotective effects were dependent on the inactivation of NF-κB and MAPKs, including ERK1/2, JNK, and p38. Collectively, our findings indicate that NXC736 is an effective neuroprotective drug for permanent ischemic brain stroke, highlighting S1P₄ as a promising therapeutic target for ischemic stroke. Full article

Chronic low-grade systemic inflammation is increasingly recognized as a key mediator linking stress, pain sensitivity, and cognitive decline. Central to this process are the acute-phase reactants interleukin-6 (IL-6) and C-reactive protein (CRP), which serve as biomarkers of systemic inflammation while promoting neuroimmune dysregulation. Emerging evidence implicates the IL-6–CRP axis in the amplification of pain perception, central sensitization, and stress hypersensitivity, ultimately promoting neurodegenerative processes such as those observed in Alzheimer’s disease (AD) and vascular dementia. Monomeric CRP (mCRP), a proinflammatory isoform generated under mechanical or oxidative stress, can trigger histone modifications (e.g., H3 citrullination), activate endothelial and immune cells, and exacerbate inflammatory pain pathways. These mechanisms are further modulated by genetic and epigenetic factors, including IL-6/CRP/NR3C1 gene variant expression; promoter methylation; and stress-responsive microRNAs, which intersect with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, impairing immune resolution and neurocognitive resilience. Psychosocial stressors, such as the burden of caregiving or perfectionistic cognitive patterns, amplify IL-6 and CRP levels, particularly when pain is present, suggesting a synergistic interaction between emotional distress and somatic inflammation. Specifically, elevated CRP is associated with increased pain sensitivity, lower pain thresholds, and cognitive decline even in subclinical populations, providing a feedforward model in which chronic stress and pain potentiate systemic inflammation, disrupt neuroendocrine feedback, and accelerate neurodegenerative pathology. However, in this model, the potentially critical mechanistic and pathological role of mCRP remains to be discovered. This review addresses the missing elements of these overlapping pathways and discusses the therapeutic potential of targeting IL-6–CRP signaling, stress regulation, and epigenetic modifiers as strategies to ameliorate inflammation-driven cognitive decline and enhance stress resistance in chronic disease contexts. We propose that plasma mCRP or more likely the isoform-aware metric, the mCRP/CRP ratio, will provide a biologically anchored, potentially more discriminative approach to vascular-neuroimmune risk and capture the propensity for local effector signaling, likely outperforming hs-CRP or IL-6 alone for risk stratification across neurovascular and stress-sensitized pain phenotypes. Full article

Mitochondria are crucial for energy metabolism and the regulation of apoptosis and the inflammatory response in acute myeloid leukemia (AML). This study examined key mitochondrial characteristics in apoptosis-resistant AML cells during in vitro aseptic pro-inflammatory activation utilizing spectrofluorimetry, quantitative reverse transcription PCR, Western blotting, differential gene expression analysis, flow cytometry, transmission electron microscopy, and cellular respiration analysis. Under conditions of aseptic inflammation simulated in three-dimensional high-density cultures, apoptosis-resistant AML cells exhibited a significant reduction in the transcriptional activity of genes linked to oxidative phosphorylation and the tricarboxylic acid cycle; demonstrated diminished mitochondrial respiration activity; and decreased levels of the mitophagy regulatory proteins PINK1 and Parkin. Furthermore, pathogenic alterations in mitochondrial morphology were observed. These cells demonstrated enhanced intracellular generation of reactive oxygen species, lactate accumulation in the culture media, elevated levels of DRP1 protein, and an increased fraction of small and medium-sized mitochondria. The acquired data demonstrate that aseptic pro-inflammatory activation results in metabolic remodelling of acute myeloid leukemia cells, integrating characteristics of mitochondrial dysfunction. This condition may facilitate the persistence of leukemic cells during inflammatory stress and potentially contribute to the development of an apoptosis-resistant phenotype. The established in vitro model is crucial for examining both the characteristics of energy metabolism and the anti-apoptotic mechanisms in leukemic cells. Full article

Nanoparticles (NPs), which possess unique physicochemical qualities such as large surface area and reactivity, have brought about a revolution in a variety of sectors, including medicine and electronics. The growing ubiquity of these substances, on the other hand, has given rise to worries over the toxicological effects they have on human health and ecosystems. The condition known as oxidative stress, which is caused by an imbalance between the formation of reactive oxygen species (ROS) and antioxidant defenses, is one of the key processes that contribute to the toxicity of NPs. An excessive amount of ROS may cause damage to cellular components such as lipids, proteins, and DNA, which can result in detrimental consequences such as inflammation, apoptosis, and the development of cancer. NP-induced oxidative stress is investigated in this work, which focuses on the molecular mechanisms that are responsible for it. These processes include mitochondrial dysfunction, catalytic redox cycling, and the release of metal ions from particle disintegration. On top of that, we investigate how the features of NPs, such as their size, shape, surface charge, and composition, affect their capacity to produce ROS. Additionally, the consequences of oxidative stress for both acute and chronic health effects are examined, in addition to the function that it plays in the toxicity of the environment. The use of antioxidants and alterations to the surface of NPs are two examples of mitigation measures that are discussed in this article. The findings of this study highlight the significance of gaining knowledge of the processes behind oxidative stress to ensure the safe design and deployment of NPs. Full article

Glutamate-related excitotoxicity represents a fundamental pathological process underlying both acute and chronic disorders of the central nervous system. Excessive stimulation of ionotropic and metabotropic glutamate receptors induces ionic dysregulation, mitochondrial dysfunction, and oxidative stress, which can activate necrotic and apoptotic pathways, processes further amplified by defective glutamate clearance and astrocytic impairment. These mechanisms are recognized as key contributors to neuronal damage in ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, identifying excitotoxicity as a convergent hallmark of neurodegeneration. Despite considerable progress in elucidating its molecular mechanisms, clinical translation of excitotoxicity-targeted interventions remains limited, largely due to the difficulty of selectively attenuating pathological glutamatergic activity while preserving physiological neurotransmission. Recent advances in nanotechnology, particularly the development of graphene-based materials (GBMs), have offered innovative approaches for neuroprotection. Owing to their unique physicochemical properties and compatibility with neural tissue, GBMs have been investigated as platforms for neural interfacing, regenerative scaffolds, drug delivery platforms, and direct modulators of glutamatergic transmission. In particular, small graphene oxide nanosheets exhibit the capacity to downregulate glutamate release and confer anti-inflammatory and neuroprotective effects. These findings suggest that GBMs may represent a promising class of neuromodulatory tools for mitigating excitotoxic injury, warranting further preclinical and translational investigations. Full article

Alcohol use disorder (AUD) predisposes individuals to pneumonia, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, yet the mechanisms underlying alcohol-related lung disease (ARLD) remain unclear. Alveolar type II (AT2) epithelial cells play a central role in ethanol (EtOH) metabolism, surfactant production, alveolar repair, and pulmonary innate immunity. To examine EtOH-mediated effects, immortalized human AT2 cells were treated with 22–130 mM EtOH for 6 h (concentration-dependent) and 65 mM EtOH for 6–72 h (time-dependent). Cytotoxicity, inflammation, surfactant lipid/protein dysregulation, fatty acid ethyl ester (FAEE) formation, cellular stress responses, AMP-activated protein kinase (AMPKα) signaling, and mitochondrial function were analyzed. EtOH disrupted surfactant homeostasis by reducing dipalmitoylphosphatidylcholine and surfactant protein C (SP-C). Importantly, EtOH inactivated AMPKα, downregulated CPT1A (involved in β-oxidation of fatty acids), and upregulated lipogenic proteins ACC1 and FAS, accompanied by increased ER stress markers (GRP78, p-eIF2α, and CHOP). Expression of carboxyl ester lipase (FAEE-synthesizing enzyme) and FAEE levels increased with EtOH exposure, further exacerbating oxidative and ER stress, impairing mitochondrial energetics, ATP production, and AT2 cell function. These findings suggest that EtOH-induced FAEE formation, dysregulation of AMPKα-CPT1A signaling, and surfactant contribute to AT2 cell dysfunction and play a critical role in the pathogenesis of ARLD. Full article

Acute kidney injury (AKI) is characterized by rapid loss of renal function due to oxidative stress, inflammation, and apoptosis, with limited targeted therapies. Alpha-mangostin (AM), a natural compound from Garcinia mangostana, exhibits antioxidant and anti-inflammatory properties in preclinical studies, but its efficacy in AKI has not been reviewed. This systematic review and meta-analysis, registered on the Open Science Framework and adhering to PRISMA guidelines, analyzed in vivo and in vitro studies on AM’s effects in AKI models through searches of PubMed, Scopus, Embase, and Web of Science. Primary outcomes included serum creatinine and cell viability, while secondary outcomes encompassed oxidative stress markers (malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS)), inflammatory cytokines, apoptosis indicators, and histopathology. Data were extracted independently and assessed using the Toxicological Data Reliability Assessment Tool (ToxRTool). AM significantly reduced serum creatinine (mean difference (MD) = −0.67 mg/dL; 95% confidence interval (CI): −1.28 to −0.06; p = 0.03) and improved cell viability (MD = 28.26%; 95% CI: 17.25 to 39.26; p < 0.0001). It markedly decreased MDA and ROS, increased GSH, and enhanced antioxidant enzymes (glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD)). In vivo, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were lowered, and histopathology showed reduced tubular necrosis and structural damage. Subgroup analyses indicated dose- and model-dependent effects, with lower doses often yielding greater benefits. Sensitivity analyses confirmed robustness despite heterogeneity. Preclinical evidence supports AM’s nephroprotective potential and underscores the need for dose optimization, mechanistic validation, and clinical translation. Full article