Search Results (7,629)

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD⁺ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine–ornithine metabolism, and tryptophan–kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy. Full article

Mesenchymal stromal cells are increasingly used for their immunomodulatory and regenerative properties, yet their interaction with the hemostatic system remains incompletely understood. This review examines the mechanisms through which these cells influence coagulation within the broader framework of immunothrombosis. Evidence from in vitro studies, animal models, and early clinical observations indicates that mesenchymal stromal cells can promote thrombin generation through tissue factor expression and phosphatidylserine exposure, while also engaging complement pathways, platelets, and innate immune responses. Counter-regulatory mechanisms, including adenosine-mediated platelet inhibition and immune reprogramming after cellular clearance, contribute to a context-dependent biological effect. Functional assays, rather than tissue factor expression alone, appear necessary to estimate the effective procoagulant potential of these products. Clinical data suggest that major thrombotic events remain uncommon, although subclinical activation of coagulation pathways may occur. The hemostatic impact of mesenchymal stromal cells depends on multiple variables, including cell source, dose, route of administration, and host inflammatory status. The available evidence supports a working model in which early coagulation and complement activation may be followed by immune modulation, supporting integrated strategies to optimise both safety and therapeutic efficacy. A central conclusion is that tissue factor, although mechanistically necessary for MSC-associated procoagulant activity, is not by itself an independent predictor of clinical thrombotic risk; the effective coagulation response also depends on phosphatidylserine exposure, membrane context, and host inflammatory conditions. Full article

Celiac disease (CD) is an immune-mediated enteropathy triggered by dietary gluten in genetically predisposed individuals. Although HLA-DQ2 and HLA-DQ8 are the primary genetic determinants of susceptibility, they are not sufficient to explain disease onset and progression. A key molecular event in CD pathogenesis is the post-translational modification of gluten peptides by transglutaminase 2 (TG2), which enhances their binding to HLA-DQ molecules and promotes CD4⁺ T cell activation. TG2 also acts as the principal autoantigen, driving the production of anti-TG2 autoantibodies through linked recognition mechanisms. Beyond its enzymatic activity, TG2 is tightly regulated by gene regulatory mechanisms, including cytokine-driven transcription, epigenetic modulation, and stress-responsive signaling pathways. These processes determine TG2 expression and activity in the intestinal mucosa, thereby influencing the efficiency of gluten peptide modification and antigen presentation. Here, we propose that TG2 operates at the interface between gene regulation and antigen processing, linking transcriptional control of TGM2 to HLA-restricted immune activation. In this framework, disease susceptibility arises from the coordinated interaction between HLA-dependent peptide presentation, TG2-mediated modification of gluten epitopes, and regulation of TG2 expression within the intestinal mucosa. This integrated model provides a mechanistic basis for disease heterogeneity and identifies TG2 as a central regulatory node and potential therapeutic target in CD. Full article

Background/Objectives: The STAT (Signal Transducer and Activator of Transcription) family of seven transcription factors mediates cytokine and growth-factor signaling, regulating proliferation, differentiation, and immunity. While STAT3/STAT5 are established oncogenes and STAT1/STAT2 are classically viewed as tumor suppressors, emerging evidence indicates context-dependent roles in tumorigenesis. This study aimed to integrate evolutionary analysis with bulk transcriptomic, regulon, single-cell, and exploratory chromatin-binding analyses of the STAT family in human solid tumors. Methods: Orthologs and paralogs of human STAT genes (81 sequences total) were retrieved across vertebrates and invertebrates; a phylogenetic tree was constructed using MUSCLE alignment and Neighbor-Joining in MEGA12. Differential expression was assessed in TCGA solid tumors versus GTEx normal tissues. Master-regulator activity was inferred using the corto algorithm. Single-cell RNA-seq datasets were used to compare malignant and non-malignant cell populations. STAT1 chromatin binding was examined via ChIP-seq in interferon-stimulated HeLa and K562 cells. Results: Phylogeny resolved seven conserved vertebrate clades, with endocrine-responsive STAT3/STAT5 showing higher conservation and immune-associated STAT1/STAT2/STAT4/STAT6 exhibiting faster divergence. The majority of STAT genes were frequently upregulated across multiple solid tumors, with activated regulons confirming functional transcriptional engagement. Single-cell analysis demonstrated tumor-cell-autonomous upregulation of STAT1 and STAT2 in the HNSCC dataset. STAT1 ChIP-seq revealed asymmetric forward/reverse-strand read density around peak summits, supporting non-canonical DNA recognition. Conclusions: The STAT family operates as an evolutionarily conserved, broadly activated transcriptional module in human solid cancers, combining quantitative upregulation with qualitative shifts in DNA-binding dynamics. These findings refine our understanding of JAK/STAT signaling in oncology and highlight opportunities for network-targeted therapies. Full article

Group 2 innate lymphoid cells (ILC2s) are tissue-resident immune cells that play a central role in type 2 immunity. Beyond cytokine signaling, they integrate inputs from lipids, nutrients, neuroendocrine mediators, and local metabolic cues, establishing cellular metabolism as a key regulator of their function. Immunometabolism provides a framework to understand how ILC2s adapt to diverse tissue environments such as the lung, adipose tissue, gut, skin, and brain, each defined by distinct nutrient availability, oxygen tension, and inflammatory conditions. Unlike many immune cells that primarily rely on glycolysis, ILC2s dynamically balance glycolysis, fatty acid oxidation (FAO), and oxidative phosphorylation (OXPHOS) depending on activation state and tissue context. Lipids not only serve as energy substrates but also regulate membrane organization, lipid raft–dependent signaling, and the generation of bioactive mediators, including eicosanoids, oxysterols, and sphingolipids. Emerging evidence linking cholesterol biosynthesis, steroid metabolism, and sphingolipid signaling to ILC2 function underscores the importance of lipid-dependent immune regulation. Dysregulation of these pathways contributes to chronic inflammatory diseases such as asthma, metabolic disorders, and fibrosis. Targeting metabolic pathways and checkpoints may therefore offer new strategies to modulate ILC2-driven pathology. This review summarizes current insights into metabolic programs governing ILC2 activation, survival, and plasticity and highlights emerging therapeutic opportunities. Full article

Vogt–Koyanagi–Harada syndrome (VKH) is a rare granulomatous autoimmune disease characterised by a systemic immune response directed against melanocytes. This multisystem condition primarily affects organs that are rich in melanocytes, such as the eyes, inner ear, meninges and skin. VKH might be responsible for the development of chronic uveitis and permanent visual impairment, particularly in cases where a diagnosis is delayed and treatment is not administered in a timely manner. A key factor in its pathogenesis is the loss of immune tolerance to melanocytes, driven by a T-cell–mediated immune response and genetic susceptibility, including the presence of HLA-DRB1*04 antigens. In recent years, immune checkpoint inhibitors (ICIs) have become the standard treatment in oncology, including non-small cell lung cancer and unresectable melanoma. However, it should be noted that their utilisation carries with it the potential for immune-related adverse events, including rare cases of VKH-like uveitis. The objective of this review is to outline the clinical features of VKH syndrome, examine current diagnostic and treatment approaches, and emphasise the immunopathological mechanisms associated with drug-induced forms of VKH, with a particular focus on programmed cell death protein 1 (PD-1) inhibitors. The article also includes an analysis of the genetic, epigenetic, and environmental factors that predispose individuals to the disease. This analysis facilitates a deeper understanding of the pathogenesis of the disease and assists in the identification of patients at increased risk of drug-induced VKH manifestations. Full article

Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sjögren’s syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5^CreERT2; R26^tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16^INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5⁺ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5⁺ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy. Full article

Background: Edwardsiella piscicida is a significant intracellular pathogen of channel catfish (Ictalurus punctatus) and a major threat to U.S. aquaculture. A recently developed recombinant attenuated vaccine strain (χ16016) uses arabinose-regulated murA expression to trigger delayed cell wall lysis in vivo, ensuring biological containment while conferring strong protection against virulent challenge. Although its efficacy has been demonstrated, the host immune programs underlying protection remain incompletely defined. Methods: We used RNA sequencing to characterize tissue-specific transcriptomic responses in the intestines and kidneys of channel catfish at 7 days post-vaccination. Fish were vaccinated with χ16016 by either bath immersion or intracoelomic (IC) injection, and differentially expressed genes and enriched immune pathways were analyzed to determine how the vaccine delivery route shapes systemic and mucosal immune responses. Results: Across comparisons, 19,101 differentially expressed genes revealed pronounced route- and tissue-dependent immune remodeling. As aquaculture vaccination strategies increasingly prioritize scalability and practical deployment, understanding how the delivery route shapes immune outcomes is critical. Here, IC vaccination induced broader systemic transcriptional changes, particularly in the intestine, whereas bath immunization elicited a more focused yet coordinated mucosal response. Overall, intestinal tissue exhibited greater transcriptional responsiveness than kidney tissue, underscoring its central role in early vaccine-induced immunity. Functional enrichment analyses identified the activation of innate recognition pathways, MAPK and calcium signaling cascades, complement components, antigen processing machinery, and cell adhesion networks. Notably, bath immunization enriched the intestinal immune network for IgA production pathway, which represents an orthology-based mapping of conserved mucosal immune components, alongside the upregulation of IL-6, CXCL12–CXCR4, integrins (α4β7), MHC class II, complement C3, and polymeric immunoglobulin receptor (pIgR). Given that catfish rely primarily on IgM in mucosal immunity, these findings indicate the induction of IgM-mediated mucosal defense rather than classical mammalian IgA responses. Concurrent complement and scavenger receptor signatures suggest a transition toward efficient opsonophagocytic clearance with controlled inflammation at this subacute stage. Conclusions: This study provides the first systems-level view of host transcriptomic responses to a regulated-lysis E. piscicida vaccine in channel catfish. The findings demonstrate that immersion vaccination, although transcriptionally less expansive than injection, effectively activates coordinated mucosal innate and adaptive immune programs, supporting its practical use as a scalable vaccination strategy for aquaculture. Full article

The Hippo, as a central pathway regulating cell proliferation, apoptosis, stem cell homeostasis and organ development, is closely associated with the onset and progression of tumors, metabolic reprogramming, drug resistance and immune evasion when it is abnormally inactivated. The Hippo not only directly promotes tumor cell proliferation, maintains cancer stem cell properties, and mediates metabolic reprogramming and treatment resistance, but also reshapes the tumor microenvironment(TME) by regulating the formation, heterogeneity and function of cancer-associated fibroblasts (CAFs). Furthermore, it mediates tumor immunosuppression and immune evasion by modulating programmed death-ligand 1(PD-L1) expression, T-cell function, macrophage polarization and cytokine secretion. At the same time, inflammatory cytokines, growth factors, metabolites and physical signals within the TME can negatively regulate the activity of the Hippo, creating a pro-tumor positive feedback loop. This article provides a systematic review of the composition and regulation of the Hippo , its mechanisms of action in the biological behavior of tumor cells and interactions within the tumor microenvironment, as well as progress in the development of drugs targeting this pathway. It offers a theoretical basis for a deeper understanding of the role of the Hippo in tumors and for the development of novel anti-tumor therapeutic strategies. Full article

Eosinophils are multifunctional granulocytes that reside constitutively within mucosal tissues, where they engage in bidirectional communication with the epithelial cells lining the respiratory and gastrointestinal (GI) tracts. Once regarded solely as terminal effectors of the type 2 immunity, eosinophils are now recognized as key regulators of epithelial homeostasis and barrier integrity. Epithelial cells initiate crosstalk by releasing the alarm cytokines such as interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and IL-25, which drive eosinophil recruitment, activation, and tissue retention. Conversely, eosinophils modulate epithelial function through the release of granule proteins, cytokines, and growth factors with both damaging and reparative consequences. In the airway, this crosstalk underpins the pathogenesis of eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), in part via eosinophil-derived mediators that disrupt tight junction integrity and fuel remodeling. In the GI tract, homeostatic eosinophils support villous architecture, epithelial turnover, and goblet cell differentiation through microbiota-driven IL-33 signals and neuropeptide-mediated neuroimmune pathways, whereas dysregulated crosstalk promotes eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). This review synthesizes recent research to delineate the molecular mechanisms of eosinophil–epithelial crosstalk across mucosal compartments, highlight tissue-specific differences and shared mechanistic themes, and discuss the implications of these findings for targeted therapy. Full article

Dietary antioxidants and phytochemicals are believed to support cognitive health, but evidence on composite dietary indices remains limited. This cross-sectional study of 1845 community-dwelling older adults in China investigated the associations of the composite dietary antioxidant index (CDAI) and dietary phytochemical index (DPI) with cognitive function and mild cognitive impairment (MCI). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA; Beijing version). MCI was diagnosed through a two-stage procedure: MoCA-based preliminary screening (with education-stratified cutoffs: 13/14 for illiterate, 19/20 for 1–6 years, 24/25 for ≥7 years) followed by neurologist confirmation. CDAI was calculated as the sum of the standardized intakes of six antioxidants (selenium, zinc, carotenoids, vitamin A, vitamin C, vitamin E); DPI was defined as the percentage of the total energy intake from phytochemical-rich foods (fruits, vegetables excluding potatoes, legumes including soy products, nuts, seeds, and whole grains). Multivariable linear regression, logistic regression, and receiver operating characteristic (ROC) curve analyses were performed. The basal metabolic rate (BMR) and systemic immune-inflammation index (SII; platelets × neutrophils/lymphocytes) were tested as potential statistical mediators. Each one-unit increase in CDAI was associated with a 0.068-point higher MoCA score (95% CI: 0.012–0.123), and each one-unit increase in DPI was associated with a 0.029-point higher MoCA score (95% CI: 0.008–0.050). BMR and SII partially mediated the association between CDAI and MoCA score, but temporal ordering remains unclear due to the cross-sectional design. When both CDAI and DPI were in the highest quartile, participants had a 46.3% lower risk of MCI compared with those with both indices in the lowest quartile (OR = 0.537, 95% CI: 0.308–0.935). A predictive model incorporating CDAI, inflammatory markers, and red blood cell parameters showed moderate discriminatory ability in this study sample (apparent AUC = 0.731, bootstrap-corrected AUC = 0.728). These findings suggest that a higher combined dietary antioxidant and phytochemical intake may be jointly associated with better cognitive function, although the cross-sectional design precludes causal inference. Full article

Type II toxin–antitoxin (TA) systems are significantly expanded in the Mycobacterium tuberculosis complex; however, the functional role of the VapBC40 system in Mycobacterium bovis(M. bovis) pathogenesis remains poorly characterized. This study aimed to investigate the role of VapBC40 in mycobacterial virulence and evaluate its potential as a target for rational vaccine attenuation. We performed evolutionary analysis and yeast two-hybrid assays to characterize VapBC40 system specificity, conducted in vitro macrophage infection models and in vivo murine studies to assess virulence contribution, and evaluated the immunoprotective efficacy of a VapC40 knockout strain. Evolutionary analysis revealed progressive sequence conservation and stringent homologous pairing specificity within the VapBC40 system. The VapC40 toxin correlates with enhanced intracellular bacterial survival, increased host cell death, and more severe pulmonary pathology with systemic dissemination. Based on these findings, we evaluated the vaccine potential of a vapC40 knockout strain. Immunization with this attenuated strain elicited a Th1 cellular immune response, characterized by enhanced IFN-γ production and increased frequency of CD4⁺IFN-γ⁺ T cells. Upon challenge with virulent M. bovis, the knockout strain conferred superior protection compared to the conventional BCG vaccine, significantly reducing lung pathology and restricting extrapulmonary bacterial dissemination. Although the molecular mechanisms underlying VapC40-mediated effects remain to be fully elucidated, our findings suggest an important role of the VapBC40 system in mycobacterial-host interactions and support its potential as a target for next-generation tuberculosis vaccine development. Full article

Functional antibody-dependent enhancement (ADE) represents a fundamental and context-dependent characteristic of antiviral antibody responses, reflecting the dual capacity of antibodies to mediate both the neutralization and Fc receptor-dependent enhancement of infection. In flavivirus research, this duality complicates the interpretation of conventional serological metrics and limits the reliability of single-parameter correlates of immunity, particularly in populations with complex exposure histories. Over the past decade, functional ADE assays have evolved from specialized mechanistic tools into integrated immune assessment platforms supporting translational immunology, vaccine evaluation, and population-level immune surveillance. These platforms incorporate Fcγ receptor-relevant target cell systems, standardized viral inputs, dilution series-based profiling, quantitative enhancement metrics, and structured quality control frameworks to enable reproducible, comparable, and context-aware functional measurements across cohorts and laboratories. A central concept emerging from these developments is that ADE reflects a dynamic functional immune state rather than an intrinsic property of antibodies or a direct indicator of pathological risk. Accordingly, functional ADE platforms support the contextual interpretation of antibody activity across physiologically relevant conditions, facilitating discrimination between transient functional enhancement and clinically meaningful immunological risk. By integrating functional ADE metrics with serological, cellular, and epidemiological data, these platforms provide a structured framework for interpreting immune profiles in vaccine evaluation, booster strategy design, and population-level risk stratification. This review synthesizes the development, standardization, and global dissemination of functional ADE platforms and discusses key principles governing biological relevance, analytical robustness, and inter-site transferability. Emerging directions integrating functional ADE profiling with systems immunology, immunogenomics, and computational modeling are highlighted as pathways toward predictive, decision-support-oriented frameworks. By positioning ADE platforms as immune assessment infrastructures rather than isolated assays, this review underscores their value for mechanistic inquiry, translational interpretation, and preparedness-oriented responses to emerging viral threats in the absence of definitive correlates of protection. Full article

Extracellular traps (ETs) are immune-derived chromatin networks initially described as antimicrobial barriers but increasingly recognized as modulators of tissue homeostasis and autoimmunity. The oral mucosa, constantly exposed to inflammatory stimuli, is particularly sensitive to ET-mediated remodeling (extracellular traps-mediated remodeling). In this study, we investigated how platelet-rich plasma (PRP), platelet-poor plasma (PPP), and washed platelets (WPT), widely used in regenerative medicine, influence ETosis in monocytes and macrophages, and how these ETs modulate the responses of primary buccal keratinocytes (pBMKs). ETs were induced in monocytes/macrophages using PRP, PPP, and WPT. pBMKs were exposed to ET-rich supernatants, and proliferation was monitored in real time through a live cell imaging system. ETs derived from PRP, PPP, and WPT did not induce either a statistically significant proliferation or morphological changes in buccal keratinocytes. These findings suggest that both platelet-derived products (PRP, PPP, WPT) and ETs play a crucial role in modulating epithelial biology, thus suggesting their possible role in chronic autoimmune diseases characterized by persistent inflammation and epithelial remodeling. Full article

Background: Extracellular vesicles (EVs) mediate intercellular communication in the central nervous system and are a major source of biomarkers. This study characterizes the EV-derived proteome secreted by human endothelial brain cells (HEBCs), astrocytes, and neurons to identify cell-specific roles in intercellular communication in the brain. Methods: Mass spectrometry analyses of EVs and corresponding parent cells were performed to identify differentially enriched proteins. Gene Ontology (GO) analysis of statistically significant, abundantly expressed proteins between EVs and parent cells (log₂ fold-change ≥ 2.0, p < 0.05) was performed to assess cell-specific functions. Results: Proteome analysis identified on average 932 proteins in astrocyte EVs (versus 1725 in parent cells), 1040 in HEBC EVs (versus 5451 in parent cells), and 470 in neuronal EVs (versus 578 in parent cells). The analysis indicated that astrocytes had the highest number of significantly abundant proteins (118), followed by HEBCs (24) and neurons (25). Astrocyte EVs were enriched in lipoproteins, complement factors, and protease inhibitors; HEBCs EVs in tight junction proteins, adhesion molecules, and protease regulators; and neuronal EVs in chromatin-associated histones, tubulin isoforms, and RNA-binding proteins. Conclusions: The proteomic signatures of EVs from different neurovascular unit cells suggest specialized roles in blood–brain barrier homeostasis, immune regulation, and synaptic and epigenetic signaling under healthy conditions. These baseline signatures provide a framework for future studies to investigate how brain cell-derived EVs may contribute to neurodegenerative disorders. Full article