Search Results (19,132)

Background/Objectives: Systemic administration of recombinant cytokines for immunomodulation in cancer and chronic infection is limited by toxicity and poor spatial control. Messenger RNA (mRNA)-encoded cytokines offer a programmable alternative, but the immunological consequences of interferon-β (IFN-β) mRNA delivery in primary human immune cells, and its compatibility with co-delivered antigen-encoding mRNA, remain incompletely defined. This study evaluated whether nucleoside-modified, mRNA-encoded human IFN-β can function as a multifunctional immunomodulator with pro-apoptotic activity and timing-dependent immunostimulatory properties. Methods: N1-methylpseudouridine-modified IFN-β mRNA was transfected into HEK293T and HepG2 cell lines and into primary human monocyte-derived dendritic cells (MDDCs) and M2-polarized macrophages (MDMs) using Lipofectamine MessengerMAX, with OVA mRNA as a non-adjuvant control. Apoptosis, interferon-stimulated CXCL10 secretion, activation marker expression, and cytokine profiles were assessed by flow cytometry, ELISA, Western blot, and cytometric bead array. Adjuvant activity was evaluated in MDDCs co-transfected with IFN-β and antigen (EGFP or OVA) mRNA under four temporal delivery regimens. Results: IFN-β mRNA induced time-dependent apoptosis, most pronounced in HepG2 cells, and CXCL10 secretion in both cell lines. In primary immune cells, IFN-β mRNA activated MDDCs, increased pro-inflammatory cytokine secretion, and repolarized M2-like macrophages toward a pro-inflammatory phenotype. In co-transfection experiments, IFN-β mRNA enhanced MDDC activation across regimens, but antigen expression was preserved only when antigen mRNA was delivered before IFN-β mRNA. Conclusions: mRNA-encoded IFN-β combines direct pro-apoptotic activity with programmable, timing-dependent immunostimulatory effects, supporting its development as a component of next-generation mRNA-based immunotherapies and vaccines. Full article

Objective: Esophageal cancer (ESCA) has poor prognosis and lacks reliable biomarkers. This study aimed to construct a mitochondrial energy metabolism-related prognostic model and identify key regulatory genes. Methods: TCGA-ESCA and GSE53625 data were used as training and validation cohorts, respectively. Mitochondrial energy metabolism scores were calculated by ssGSEA. Differential expression analysis and WGCNA identified key genes, followed by consensus clustering, Cox/LASSO regression, enrichment analysis, immune infiltration, TIDE evaluation, and nomogram development. INHBA knockdown or overexpression was performed in KYSE-150 and TE-1 cells to assess malignant phenotypes, mitochondrial function, EMT markers, and Smad2/3 signaling, with SB431542 used for pathway blockade. Results: High mitochondrial energy metabolism scores predicted poorer overall survival. A total of 124 key genes were identified, and three molecular subtypes were established, with Cluster 2 showing the worst prognosis. A four-gene signature comprising COL11A1, INHBA, TNFAIP6, and POSTN stratified patients into high- and low-risk groups in both cohorts. High-risk tumors were enriched in extracellular matrix remodeling, cell adhesion, inflammatory response, hypoxia, angiogenesis, and PI3K-Akt signaling, whereas oxidative phosphorylation was more active in low-risk tumors. The high-risk group had higher TIDE scores, suggesting poorer immunotherapy response. The nomogram incorporating risk group and M stage showed limited discrimination after bootstrap correction. In vitro, INHBA promoted proliferation, migration, invasion, EMT, mitochondrial membrane potential, ATP production, and oxidative phosphorylation. SB431542 partially reversed these effects. Conclusions: This MEMRG-based model predicts ESCA prognosis and immune features. INHBA promotes ESCA progression by activating Smad2/3-mediated EMT and mitochondrial metabolic reprogramming, suggesting its potential as a prognostic biomarker and therapeutic target. Full article

Background: Periplaneta americana residue (PAR) has potential as a sustainable insect-derived feed ingredient. This study evaluated the effects of 3% dietary PAR on growth performance and ovarian function in finishing pigs and screened potential bioactive peptides. Methods: Thirty finishing pigs were assigned to a control diet or a diet containing 3% PAR. Growth traits, serum oxidative and inflammatory indicators, and ovarian histomorphology were assessed in vivo. Multi-omics profiling was integrated with quantitative real-time PCR, Western blotting, and immunofluorescence assays. The properties of selected peptides and their potential interactions with candidate proteins were assessed separately using in silico prediction, molecular docking, and molecular dynamics simulations. Results: PAR supplementation increased average daily gain and the ovary-to-body weight ratio and decreased serum malondialdehyde levels and follicular atresia, without significantly affecting feed intake, feed conversion ratio, or inflammatory cytokines. Multi-omics profiling associated PAR supplementation with changes in ovarian metabolism, antioxidant defense, immune regulation, and phosphorylation-related signaling. MGST2 and PPM1K were identified as candidate proteins, and their expression patterns were supported experimentally. Serum peptidomics identified GVSEIQQ as having higher abundance in the PAR group than in the control group, whereas GVEEHETL and PGIPT were detected only in the PAR group. In silico analyses predicted that these peptides were non-toxic, non-allergenic, and potentially antioxidant; these predictions require experimental validation. Molecular docking and molecular dynamics simulations suggested potential interactions of GVSEIQQ with MGST2 and GVEEHETL with PPM1K. However, these computational findings do not establish direct peptide–protein binding or functional effects in vivo. Conclusions: PAR shows potential as an alternative feed ingredient that may partially replace soybean meal while supporting growth and ovarian condition in finishing pigs. Further biochemical and in vivo studies are required to confirm the biological functions and mechanisms of the identified peptides. Full article

Acute stroke requires rapid diagnostic classification and prognostic assessment, yet clinical examination and neuroimaging do not fully characterize cerebral injury. This narrative review evaluated the diagnostic, prognostic, and pathophysiological relevance of circulating biomarkers in acute stroke, emphasizing emergency department applications. PubMed, Scopus, Web of Science, Embase, and Google Scholar were searched from January 2015 to August 2026, supplemented by landmark studies. Evidence on brain-specific and systemic biomarkers was synthesized narratively, including multimarker panels, point-of-care testing, and artificial intelligence-based models. Glial fibrillary acidic protein has shown consistent evidence for early differentiation of intracerebral hemorrhage from ischemic stroke. Combinations of glial fibrillary acidic protein and D-dimer showed potential for large-vessel occlusion detection and prehospital triage. Neurofilament light chain, S100B, neuron-specific enolase, matrix metalloproteinase-9, inflammatory indices, hemostatic markers, cardiac biomarkers, and metabolic signatures were associated with severity, neurological deterioration, hemorrhagic transformation, mortality, functional outcome, or recurrence. Clinical translation remains limited by heterogeneity in populations, sampling times, analytical platforms, thresholds, and external validation. Circulating biomarkers are most likely to be useful as adjuncts to established stroke assessment. Multimarker strategies, point-of-care platforms, and integration with clinical scales, neuroimaging, and artificial intelligence may require standardization, multicenter validation, and demonstration of additional clinical value. Full article

Background: Cardiovascular magnetic resonance (CMR) is the reference non-invasive imaging modality for evaluating cardiomyopathies, providing comprehensive assessment of cardiac morphology, function, and tissue characterization. Radiomics has recently emerged as an advanced image analysis technique that extracts quantitative imaging biomarkers from routine CMR images, potentially enhancing disease characterization beyond conventional visual assessment. This systematic review summarizes current evidence on the role of CMR-based radiomics in the diagnosis, phenotypic characterization and risk stratification of cardiomyopathies. Methods: A structured search identified English-language, peer-reviewed studies published up to August 2026 investigating CMR-based radiomics in hypertrophic, dilated, arrhythmogenic, and infiltrative cardiomyopathies, including cardiac amyloidosis, Fabry disease, and cardiac sarcoidosis. Study selection followed PRISMA 2020 guidelines. Methodological quality was assessed using the Methodological Index for Non-Randomized Studies (MINORS) and the Radiomics Quality Score 2.0 (RQS 2.0) The authors have reviewed and edited the output and take full responsibility for the content of this publication. Results: Current evidence indicates that CMR radiomics provides incremental diagnostic information beyond conventional CMR by quantifying myocardial tissue heterogeneity. Radiomic features derived from cine imaging, late gadolinium enhancement, native T1/T2 mapping, and extracellular volume maps showed promising performance in differentiating cardiomyopathy subtypes, distinguishing pathological from physiological remodeling, and identifying infiltrative and inflammatory myocardial diseases. Multiparametric radiomic models generally outperformed individual imaging biomarkers, with preliminary evidence supporting applications in risk stratification and outcome prediction. However, studies were predominantly retrospective, involved small cohorts, used heterogeneous imaging and radiomics workflows, and rarely included external validation. RQS 2.0 assessment demonstrated low-to-moderate methodological quality. Conclusions: CMR-based radiomics shows considerable potential for improving diagnosis and phenotypic characterization of cardiomyopathies. However, methodological standardization, multicenter prospective validation, and demonstration of incremental clinical value are required before routine clinical implementation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a leading cause of advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma. The disease develops through the interaction of multiple interconnected pathophysiological mechanisms, including insulin resistance, dysregulated lipid metabolism, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, chronic inflammation, gut–liver axis disruption, and progressive fibrogenesis. Betaine, a naturally occurring methyl donor, has been investigated as a potential therapeutic agent because of its diverse metabolic and cytoprotective effects. This review summarizes current knowledge on the mechanisms by which betaine may influence MASLD development and progression. Preclinical studies indicate that betaine improves insulin sensitivity and hepatic lipid homeostasis, reduces oxidative and endoplasmic reticulum stress, preserves mitochondrial function, mitigates inflammatory signaling, and limits hepatic fibrosis. In addition, growing evidence suggests that betaine contributes to the maintenance of gut–liver axis homeostasis, further supporting its beneficial effects on liver function. Although these findings are consistent across preclinical models, clinical evidence remains limited, and the therapeutic efficacy of betaine in patients with MASLD has not yet been established. Further well-designed clinical trials are required to determine its clinical value, optimal therapeutic strategy, and potential role in the management of MASLD. Full article

Background: Dietary factors may influence psychosocial outcomes through inflammatory pathways, but evidence in adolescents remains limited. The aim was to examine whether dietary inflammatory potential is associated with psychosocial functioning among Spanish adolescents. Methods: This cross-sectional study is based on a subsample from the Eating Healthy and Daily Life Activities (EHDLA) project, conducted in the Region of Murcia (Spain). Dietary inflammatory potential was assessed using a dietary inflammatory index (DII)-informed Food Frequency Questionnaire (FFQ)-derived inflammatory score based on a validated 45-item food frequency questionnaire. Behavioral functioning was evaluated using the Strengths and Difficulties Questionnaire (SDQ). Associations between DII-informed FFQ-derived inflammatory scores and SDQ outcomes were examined using robust linear regression models adjusted for sociodemographic, lifestyle, and anthropometric factors. Results: The analysis included 674 adolescents (57.1% girls; age: 14.0 [13.0–15.0] years). Higher DII-informed FFQ-derived inflammatory score (more pro-inflammatory diet) was associated with greater total behavioral difficulties (unstandardized beta coefficient [B] = 0.058; 95% confidence interval [CI]: 0.005–0.111; standardized β = 0.099), conduct problems (B = 0.025; 95% CI: 0.011–0.039; β = 0.148), hyperactivity/inattention (B = 0.032; 95% CI: 0.013–0.052; β = 0.154), and externalizing problems (B = 0.056; 95% CI: 0.028–0.084; β = 0.181), and with lower prosocial behavior (B = −0.029; 95% CI: −0.045 to −0.014; β = −0.149). Multiple imputation sensitivity analyses yielded estimates in a similar direction, although the associations did not reach statistical significance. No significant associations were observed for emotional symptoms, peer relationship problems, or internalizing difficulties. Conclusions: Higher dietary inflammatory potential was associated with a less favorable psychosocial functioning profile among adolescents, particularly in externalizing domains. Longitudinal studies and anti-inflammatory dietary interventions are needed to determine whether the observed associations translate into meaningful changes in psychosocial functioning. Full article

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic relapsing intestinal inflammatory disorder driven by complex interactions among host genetics, immune dysregulation, and gut microbiota dysbiosis. The functional contribution of microbial metabolites beyond short-chain fatty acids and bile acids remains incompletely understood. A critical and unresolved question is whether microbiota-associated amino acid metabolites are merely passive indicators of dysbiosis or active drivers of intestinal inflammation and tissue repair. In this review, we summarize recent advances in the roles of microbiota-associated amino acid metabolites and their derivatives in IBD, highlighting that amino acid metabolites constitute a functionally distinct class of bioactive signaling molecules that operate through four representative metabolic networks: tryptophan metabolism, aspartate-related metabolism, branched-chain amino acid (BCAA) metabolism, and arginine–polyamine metabolism. We synthesize recent clinical metabolomic data and identify reductions in tryptophan-derived indoles, glutamate, histidine, and selected BCAAs across IBD clinical cohorts and sample matrices, whereas metabolites such as serine, proline, and polyamine degradation products are frequently elevated or associated with disease activity or therapeutic response. Mechanistically, microbiota-associated amino acid metabolites are implicated in intestinal homeostasis and IBD pathogenesis through multifaceted pathways, including modulation of intestinal epithelial barrier integrity (e.g., cell–cell junction, mucus secretion, and stem cell-driven mucosal repair), innate and adaptive immune responses, host–pathogen interactions, and extraintestinal inflammatory signaling (e.g., systemic inflammation, and brain–gut axis communication). Finally, we highlight current challenges and limitations in achieving a causal understanding of microbiota-associated amino acid metabolic alterations in IBD, particularly regarding their origin, spatial distribution, and functional relevance, as well as their potential utility for disease stratification and treatment-response assessment, and discuss how these insights may inform the future development of next-generation biomarkers and precision therapeutic strategies tailored to individual metabolic phenotypes in IBD. Full article

Background/Objectives: In myelodysplastic neoplasms, autoinflammatory syndromes result from dysregulated innate immunity and cause severe, organ-dominant inflammation. Interleukin-1 signaling through the NLRP3 inflammasome is implicated in the pathogenesis of myelodysplastic disease and related inflammatory complications, especially in the context of RAS-pathway activation. Reports describing therapy-related myelodysplastic syndrome with pulmonary autoinflammatory syndromes are rare, and the efficacy of interleukin-1 blockade in this setting has not been previously documented. Results: A man in his 60s with therapy-related myelodysplastic syndrome (del 5q) following rectal chemoradiation developed a recurrent, lung-predominant autoinflammatory syndrome refractory to corticosteroids and Janus kinase inhibition. Next-generation sequencing identified gain-of-function mutations in NRAS, PTPN11, SF3B1, and ASXL1. On two separate occasions, anakinra produced rapid clinical improvement with normalization of inflammatory biomarkers and radiographic resolution; on both occasions, discontinuation of anakinra led to prompt relapse within days, with ferritin rising to above 5500 ng/mL and C-reactive protein exceeding 300 mg/L. Conclusions: This case demonstrates that interleukin-1-mediated inflammation can drive pulmonary complications in therapy-related myelodysplastic syndrome. Targeted cytokine blockade with anakinra produced reproducible and measurable clinical improvement when conventional therapies were insufficient. The recurrence of symptoms following anakinra withdrawal, and rapid improvement upon re-administration, underscores the functional link between interleukin-1-driven inflammation and clinical outcomes. The RAS/MAPK mutational context and the observed on–off response to anakinra further support an interleukin-1-driven mechanism that merits further investigation. Full article

Ultrasound-assisted deep eutectic solvent (DES) extraction has emerged as a promising green and intensified strategy for recovering natural polysaccharides from plant, algal, fungal, and other biological matrices. By coupling acoustic cavitation with tunable solvent microenvironments, this approach can enhance cell-wall disruption, solvent penetration, mass transfer, and polysaccharide solubilization while reducing reliance on harsh acidic, alkaline, or organic solvents. However, extraction efficiency alone is insufficient to define process quality because ultrasound-assisted DES systems may also reshape the molecular weight distribution, monosaccharide composition, uronic acid or sulfate content, substitution pattern, charge density, conformation, surface morphology, and physicochemical behavior. These structural consequences directly influence downstream bioactivities, including antioxidant, hypoglycemic, prebiotic, anti-inflammatory, and anti-ulcerative colitis effects. This review critically summarizes the mechanistic foundations of ultrasound–DES synergy, analyzes how extraction conditions determine polysaccharide structural outcomes, and highlights the importance of linking structure with functionality. Emerging data-driven approaches, including solvent prescreening, COSMO-RS, and machine learning-assisted process optimization, are also discussed as supporting tools for navigating the multidimensional extraction space. However, their current application to the direct prediction of polysaccharide structural outcomes remains limited. Future progress will require standardized datasets, advanced structural characterization, causal structure–activity validation, and scalable process engineering. Overall, ultrasound-assisted DES extraction should be viewed as a structure-sensitive extraction platform whose performance depends on the coordinated control of solvent properties, acoustic conditions, biomass characteristics, and downstream processing. Full article

Cardiovascular autonomic failure arises from lesions across central nuclei, peripheral nerves, and autonomic ganglia. This review examines whether dysfunction of the neurovascular unit and neural barriers contributes to that failure. The clearest evidence comes from rodent models of hypertension and heart failure. Increased permeability in the PVN, NTS, and RVLM develops alongside sympathetic activation and impaired baroreflex control. Angiotensin II and inflammation appear to affect endothelial transport and junctional integrity. Exercise and interventions directed at these pathways improve barrier function together with autonomic control. Peripheral evidence is less direct. Diabetes and inflammatory neuritis alter the blood–nerve barrier, but most experiments examine somatic or sensory nerves and do not establish causation in cardiovascular autonomic neuropathy. Autonomic ganglia also differ in normal vascular permeability, which precludes treating them as uniform extensions of the blood–nerve barrier. Human studies show altered barrier measurements in heart failure and synucleinopathies, yet rarely pair regional permeability with validated autonomic tests. Neural barrier dysfunction may contribute to dysautonomia in defined anatomical and clinical settings. Its importance remains uncertain outside the pathways examined directly, and future studies should relate regional barrier changes to autonomic function over time. Full article

Extracellular vesicles (EVs) have emerged as fundamental mediators of intercellular communication during infectious diseases, acting as vehicles for proteins, lipids, and nucleic acids that profoundly influence host–pathogen interactions. In recent years, accumulating evidence has revealed that pathogens from distinct biological kingdoms, including protozoan parasites, viruses, and bacteria, either release their own EVs or exploit host-derived EVs to manipulate immune responses, promote infection, and sustain chronic disease. This review provides a comprehensive and integrative overview of the roles of EVs in infectious diseases, with particular emphasis on immune modulation, immune evasion, pathogenesis, and translational applications. We summarize current knowledge on EV-mediated communication in infections caused by major protozoan parasites (Trypanosoma cruzi, Plasmodium spp., Toxoplasma gondii, and Leishmania spp.), highlighting how parasite- and host-derived EVs regulate inflammatory responses, facilitate intracellular survival, and shape disease outcomes. We further examine viral infections, including HIV, HPV, HCV, and airborne respiratory viruses such as SARS-CoV-2, where EVs contribute to viral persistence, immune dysfunction, oncogenesis, and long-term sequelae. In addition, we discuss bacterial infections, focusing on Mycobacterium tuberculosis, Streptococcus pneumoniae, and Helicobacter pylori, illustrating how EVs can function both as vectors of virulence factors and as components of host defense mechanisms. Finally, we explore the emerging translational potential of EVs as non-invasive biomarkers for disease diagnosis and prognosis, as well as their application as therapeutic and vaccine platforms. By integrating findings across diverse pathogens, this review highlights extracellular vesicles as widely implicated and dynamic contributors of infectious disease biology and underscores their relevance as targets and tools for next-generation diagnostic and therapeutic strategies. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several accessory proteins that modulate host cellular pathways and contribute to immune evasion and disease severity. Among them, ORF8 has emerged as a key immunomodulatory factor; however, its impact on host post-transcriptional regulatory networks remains poorly defined. In this study, we investigated how ORF8 expression reshapes the microRNA (miRNA) landscape of lung epithelial cells and how these changes translate into functional proteomic alterations. Using A549 cells transduced with ORF8 and control cells, we performed small RNA sequencing to identify differentially expressed miRNAs, followed by integrative analysis with quantitative proteomic data. ORF8 expression induces extensive remodeling of the miRNA profile, with coordinated upregulation and downregulation of miRNAs involved in inflammatory signaling, interferon regulation, apoptosis, autophagy and epithelial homeostasis. Integration of miRNA and proteomic datasets revealed inverse regulatory relationships linking ORF8-associated miRNAs to proteins involved in immune defense, stress responses and epithelial integrity. Selected miRNA alterations were validated by RT–qPCR, and the junctional protein plakoglobin (JUP) was experimentally confirmed as a representative downregulated target. Collectively, our findings identify ORF8 as a factor associated with coordinated miRNA-mediated post-transcriptional reprogramming in lung epithelial cells. This network-based regulatory framework provides new insight into how SARS-CoV-2 accessory proteins may influence host responses and highlights miRNA networks as potential contributors to viral pathogenesis and host immune dysregulation. Full article

Crohn’s disease and ulcerative colitis, the principal forms of inflammatory bowel disease (IBD), are chronic inflammatory disorders characterized by recurrent intestinal injury, impaired mucosal healing, and substantial disease burden. Despite significant therapeutic advances, many patients fail to achieve sustained remission, highlighting the need for a better understanding of the molecular mechanisms driving intestinal inflammation. Nitric oxide (NO) is a key regulator of intestinal homeostasis, influencing epithelial barrier integrity, vascular function, host defense, and immune responses. In IBD, dysregulated production of NO, largely attributable to inducible nitric oxide synthase (NOS2), has been associated with both protective and pathogenic effects. Accumulating evidence indicates that the biological consequences of NOS2 activation depend on the cellular source of NO, local microenvironmental signals, and disease context. This review summarizes current knowledge on the transcriptional, epigenetic, post-transcriptional, translational, and post-translational mechanisms regulating NOS2 expression and activity in the intestine. Particular emphasis is placed on cell-specific regulation in epithelial, stromal, endothelial, neural, and immune-cell populations, as well as emerging insights from single-cell and spatial transcriptomic studies. Collectively, available evidence supports a context-dependent role for NOS2 in IBD and highlights the importance of cell-specific approaches for future biomarker development and therapeutic targeting. Full article

Neuroinflammation is a coordinated response to central nervous system injury and disease involving resident glia, neurons, the neurovascular unit, and infiltrating immune cells. Although transient inflammatory signaling supports host defense, debris clearance, and repair, persistent activation contributes to synaptic dysfunction, demyelination, blood–brain barrier disruption, and neuronal loss. Neuregulin-1 (NRG1), a pleiotropic epidermal growth factor family ligand, has emerged as a potential regulator of this balance. Through ErbB receptor complexes, particularly ErbB4-containing dimers, NRG1 influences neural development, myelination, synaptic function, cell survival, and inflammatory signaling. Experimental evidence indicates that NRG1 can restrain NF-κB-dependent transcription, alter microglial activation states, enhance alpha7 nicotinic acetylcholine receptor-associated anti-inflammatory signaling, support oligodendroglial lineage cells, and stabilize neurovascular integrity. However, these actions are context-dependent; in spinal nociceptive circuits, ErbB2-linked signaling can promote microglial activation and pain hypersensitivity. This review examines NRG1 isoform biology, ErbB receptor architecture, cellular targets, and disease-specific evidence across demyelinating disease, stroke, traumatic brain injury, neurodegeneration, cerebral malaria, sickle cell disease, and neuropathic pain. Translation will require isoform-specific, receptor-biased, and anatomically targeted approaches supported by rigorous in vivo validation and verified biomarkers. Full article