Search Results (3,018)

Background/Objectives: Although genetic studies have linked immune phenotypes with anxiety, broad Mendelian randomization (MR) screens require explicit multiple-testing control. We reappraised 1753 reported immune-cell-trait-to-anxiety inverse-variance-weighted (IVW) association records available in the analysis tables and assessed the chromosome 20 signal that includes CD40. Methods: The reported records were derived from the 731-trait Sardinian flow-cytometry GWAS of Orrù et al. and were evaluated across one UK Biobank and three FinnGen anxiety phenotypes; outcome-specific Benjamini–Hochberg false-discovery-rate (FDR) correction was applied to the available analysis table. The leading locus was examined using bulk and single-cell expression quantitative trait locus annotations, two-sample MR, summary-data-based MR (SMR), HEIDI tests, and regional colocalization results. Results: Of 1753 tests, 120 were nominally significant, and 21 were retained after outcome-specific FDR correction (14 for UK Biobank anxiety and 7 for FinnGen all anxiety; none for generalized or phobic anxiety). B-cell and regulatory/CD4 T-cell traits were common among retained associations, and several B-cell traits mapped to variants at the CD40 locus. For FinnGen all anxiety disorders, monocyte instruments gave a positive estimate (beta = 0.00418, p = 9.25 × 10⁻⁴), whereas three naïve B-cell instruments gave a negative estimate (beta = −0.0520, p = 2.64 × 10⁻⁴). Monocyte SMR was null (p = 0.542). Naïve B-cell SMR was nominally significant (p = 0.00537), but HEIDI could not be calculated. Regional colocalization was weak in both cell contexts (PP.H4 = 0.0205 and 0.00272). Conclusions: The post-selection locus follow-up prioritizes a chromosome 20 immune locus but does not establish CD40-mediated regulation of anxiety. Because the upstream screen was not regenerated from source GWAS files and complete per-instrument F-statistics were unavailable, all findings are exploratory. CD40 remains a testable candidate for ancestry-matched fine-mapping and cell-state-specific validation. Full article

The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8⁺ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8⁺ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products. Full article

Glucose and lipid metabolism disorders are closely associated with type 2 diabetes mellitus (T2DM), obesity, hyperlipidemia, and metabolic dysfunction-associated steatotic liver disease (MASLD). Gynura divaricata (L.) DC., traditionally consumed as both a food and folk medicine, has attracted increasing attention for its potential regulatory effects on glucose and lipid metabolism. Existing in vitro and in vivo studies suggest that G. divaricata extracts and candidate bioactive constituents, including flavonoids, polysaccharides, phenolic acids, and peptides, may improve metabolic phenotypes such as hyperglycemia, dyslipidemia, and insulin resistance. These effects may involve the regulation of intestinal carbohydrate hydrolysis, insulin signaling, gut microbial homeostasis, pancreatic β-cell function, lipid metabolism, oxidative stress, and chronic inflammation. However, human evidence remains limited, and most studies have investigated compound formulations or combined interventions, which are insufficient to establish the clinical efficacy of G. divaricata as a standalone preparation. This review summarizes the major bioactive constituents of G. divaricata, reviews the current evidence for its glucose-lowering and lipid-regulating effects and related antioxidant and anti-inflammatory mechanisms, and discusses the limitations of existing research. This study aimed to provide a reference for elucidating the mechanisms by which G. divaricata regulates glucose and lipid metabolism and for its future clinical translation. Full article

This study investigated the thyroid effects of azole fungicide mixtures in male rats, addressing the gap in regulatory assessments that typically focus on single chemicals rather than combined exposures. Using a 28-day rat model, binary and ternary mixtures of azole fungicides were tested at high doses, with thyroid hormone levels, liver enzyme activity, and thyroid tissue changes as the key endpoints. The mixtures caused elevated TSH, reduced T4, increased UGT enzyme activity, and thyroid tissue alterations, including follicular cell hypertrophy and hyperplasia. Interestingly, the mechanism observed with single-compound exposures (hepatic metabolism driving secondary TSH elevation) appeared less prominent in the mixture groups. Whether these responses reflect additive, less-than-additive, or more-than-additive interactions could not be determined without formal dose–response modeling. As the tested dose (NOAELx10) is substantially higher than the human realistic exposure levels permitted under the current regulation, direct extrapolation of the present findings to realistic human exposure conditions is limited. However, the current regulatory evaluation with respect to the effect dose was confirmed. While existing approaches appear adequate, a deeper understanding of thyroid-specific endpoints is needed to ensure that mixture risk assessments remain robust and appropriately protective. Full article

Diabetes mellitus and periodontitis are bidirectionally associated chronic disorders linked through metabolic dysregulation, host inflammation, microbial dysbiosis, and impaired tissue remodeling. This review summarizes clinical, molecular, cellular, genomic, epigenomic, transcriptomic, and microbial evidence concerning the mechanisms underlying this relationship and their potential translational relevance. Chronic hyperglycemia is associated with advanced glycation end product signaling through the receptor for advanced glycation end products, mitogen-activated protein kinase/nuclear factor-κB activation, reactive oxygen species production, oxidative stress, and NLR family pyrin domain-containing 3 inflammasome activation, which may contribute to enhanced cytokine responses and periodontal tissue injury. Diabetes is also associated with altered neutrophil and macrophage function, increased T helper 17/interleukin-17 signaling, and an elevated receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, thereby favoring osteoclastogenesis and alveolar bone loss. Conversely, periodontal inflammation and microbial products may contribute to systemic low-grade inflammation, insulin resistance, and metabolic dysregulation. Multi-omics studies have identified shared susceptibility loci, regulatory networks, and disease-associated cell states, although their causal and clinical significance remains incompletely defined. These findings suggest potential roles for integrated medical–dental care, glycemic screening in dental settings, periodontal inflammation control, host-modulatory therapies, and regenerative biomaterials. Further longitudinal and experimental studies are needed to determine their clinical applicability. Full article

Viral infections are a widely recognized cause of mortality. Recently it has been demonstrated that vitamin D plays an important immuno-modulatory role in both innate and adaptive immune responses against infections, by reducing excessive inflammation and enhancing defense mechanisms. Specifically, exacerbation of infections may cause sepsis, characterized by a dysregulated immune response with hyperinflammation and immune exhaustion. Vitamin D can modulate these processes through various mechanisms, such as enhancing antiviral protection, promoting anti-inflammatory responses, protecting endothelial barriers, and modulating T-cells. This has been demonstrated for various viral infections, including influenza viruses, respiratory syncytial virus, and severe acute respiratory syndrome coronavirus. Although vitamin D deficiency has been associated with increased susceptibility to viral infections and immune cells of infected patients are highly responsive to vitamin D, the clinical benefits of its supplementation to vitamin D-deficient infected individuals are uncertain and, most importantly, direct evidence linking vitamin D to viral sepsis specifically remains particularly limited, with most mechanistic inference extrapolated from non-septic viral infection and bacterial sepsis literature. Based on these assumptions, this review will outline the present understanding about vitamin D regulatory effects on immune system and the possible connection between its serum levels and viral infections, while also addressing controversial issues. Full article

Background: Cystic fibrosis (CF) is an inherited multisystemic disease. Despite advances in treatment, many patients still experience progressive lung dysfunction. Dental follicle-derived mesenchymal stem cells (DF-MSCs) possess significant immunomodulatory potential in inflammatory airway diseases. We evaluated the effects of DF-MSCs on lymphocyte proliferation, CD4⁺CD25⁺FoxP3⁺ regulatory T cell (Treg) frequency, and cytokine responses in peripheral blood mononuclear cells (PBMCs) from CF patients. Methods: PBMCs from 20 CF patients and 20 matched healthy controls were isolated by density gradient centrifugation, stimulated with a CD3/CD28 T-cell-activating antibody cocktail (CD-mix), and co-cultured ex vivo with cryopreserved DF-MSCs. Lymphocyte proliferation was assessed by carboxyfluorescein succinimidyl ester (CFSE)-based flow cytometry, and Tregs were analyzed by flow cytometry. Cytokine levels in culture supernatants were quantified using a multiplex immunoassay. Results: DF-MSC co-culture significantly suppressed lymphocyte proliferation in CF PBMCs. Treg frequency significantly increased in the stimulated CF samples following MSC co-culture. Following co-culture, levels of tumor necrosis factor-alpha (TNF-α), interleukin-8 (IL-8), and IL-23 decreased. In CF samples, levels of interferon-alpha 2 (IFN-α2), monocyte chemotactic protein-1 (MCP-1), interleukin-12 (IL-12), interleukin-18 (IL-18), and interleukin-33 (IL-33) were elevated. Conclusions: DF-MSCs reduced lymphocyte proliferation, increased Treg frequency, and regulated cytokine levels in CF, supporting their potential to restore immune balance. Full article

The major histocompatibility complex (MHC) represents a critical genetic locus that orchestrates adaptive immune responses through antigen presentation and T cell activation, characterized by exceptional polymorphism and species-specific diversity. In herbivores, MHC polymorphisms constitute fundamental determinants of resistance to parasitic, viral, and bacterial infections while serving as crucial indicators of genetic diversity and breeding value in animal populations. Recent advances in high-throughput sequencing technologies, single-cell omics, and population genetics have substantially advanced understanding of MHC gene structure, allelic polymorphism, evolutionary patterns, and associations with disease susceptibility and vaccine responsiveness. This comprehensive review systematically examines the structural characteristics and regulatory mechanisms of MHC genes, their associations with infectious disease resistance, their role in vaccine responses, and their practical applications in molecular breeding programs, conservation genetics, and immunological research. We identify current technical limitations and outline future research directions to establish a robust theoretical foundation for disease resistance breeding and immune regulation strategies in herbivore populations. Full article

Background: The immune landscape in head and neck squamous cell carcinoma (HNSCC) has been widely investigated. However, the crucial role played by the lymph node microenvironment in metastatic and non-metastatic HNSCC remains unknown. This systematic review aims to discuss the immunological crosstalk between the tumor and the nodal microenvironment and to describe the distribution of immune cells in metastatic and non-metastatic lymph nodes. Methods: A systematic review was conducted according to the PRISMA guidelines. PubMed, Scopus, and the Cochrane Library were searched for studies published between 1990 and 2025, with the final search performed in December 2025. Prospective and retrospective studies evaluating immune cell infiltration in metastatic and non-metastatic cervical lymph nodes were included, whereas studies focusing exclusively on non-cellular biomarkers and non-English publications were excluded. The risk of bias was assessed using the Newcastle–Ottawa Scale. The results were synthesized narratively, and no meta-analysis was performed. Results: The screening process identified 608 articles, of which 27 met our predefined inclusion criteria. These studies focused on macrophages, dendritic cells, neutrophils, natural killer cells, T helper cells, cytotoxic T cells, regulatory T cells, B cells, total lymphocytes, and surface markers. This systematic review provides a well-structured analysis of current knowledge on the impact of the innate and adaptive immune systems on the response against cancer cells and the recruitment of immune cells in lymph nodes. The most significant findings highlight the crucial role of antigen presentation in the antitumor response, particularly through the recruitment and activation of dendritic cells and subcapsular sinus macrophages in tumor-draining lymph nodes. It also presents in a fairly comprehensible manner that the density of mature dendritic cells, cytotoxic T cells, and B cells is higher in non-metastatic lymph nodes. Discussion: The lymph node microenvironment is highly enriched with immune cell infiltration, and their distribution between metastatic and non-metastatic lymph nodes can contribute to a better understanding of the underlying pathological processes. Particular attention should be given to the innate immune system cells and their implication in antigen presentation. Our findings suggest that identifying immunological profiles of lymph nodes may provide a rationale for treatment de-escalation protocols and raise the question of lymph node preservation in antitumor immune responses. However, the heterogeneity and bias assessment of the included studies warrant a cautious interpretation of these findings. Another important limitation is the limited number of studies comparing the immune microenvironment of primary tumors and lymph nodes. Full article

Despite significant therapeutic advances, T2DM remains a global public health challenge that leads to multiple complications, including cardiovascular, renal, hepatic, and neurodegenerative disorders. Mitochondrial dysfunction and impaired mitophagy remain fundamental, yet incompletely understood, mechanisms driving pancreatic β-cell failure, chronic inflammation, insulin resistance and diabetic complications. Emerging evidence indicates that noncoding RNAs (including microRNAs, long noncoding RNAs, and circular RNAs) are critical regulators of mitophagy and mitochondrial quality control mechanisms across metabolically active tissues. This review comprehensively examines the interplay between mitochondrial dysfunction, mitophagy impairment, and T2DM pathophysiology. It provides an overview of recent mechanistic insights into mitophagy–noncoding RNA interactions in T2DM, emphasizing tissue-specific effects, and highlights the translational potential of mitophagy-associated proteins and regulatory ncRNAs as diagnostic biomarkers and therapeutic targets. By bridging fundamental molecular biology with translational and clinical perspectives, further it provides a comprehensive framework to guide future research, accelerate biomarker discovery, and support the development of personalized interventions aimed at reducing the growing worldwide burden of T2DM and its complications. Full article

Cardiovascular diseases are increasingly recognized as immune-inflammatory disorders in which adaptive immunity shapes tissue injury, repair, and long-term remodeling. T cells are central to these processes because they integrate antigen recognition, lineage-defining transcriptional programs, tissue trafficking, cytokine production, and immunological memory. In this Review, we synthesize current evidence on the Krüppel-like factor (KLF) family as a transcriptional framework linking T-cell biology to cardiovascular disease. KLF2 primarily regulates T-cell quiescence and trafficking, KLF10 supports regulatory T-cell suppressive function and immune-metabolic fitness, KLF4 contributes to inflammatory effector differentiation, and KLF13 regulates delayed inflammatory chemokine expression and, in thymocyte models, exerts a survival-restraining effect through apoptosis-related pathways. Across atherosclerosis, myocardial infarction, myocarditis, hypertension, and heart failure, these KLF-dependent programs may influence the balance between pathogenic effector responses and protective regulatory mechanisms. The strongest direct disease-specific evidence currently supports a role for KLF10 within the CD4⁺ T-cell lineage in experimental atherosclerosis, with complementary functional evidence implicating Treg–macrophage interactions, whereas the roles of KLF-dependent T-cell programs in other cardiovascular settings remain mechanistically compelling but less fully validated. Future progress will require disease-specific T-cell-restricted models, spatially resolved immune analyses, and cell-selective translational strategies to define the therapeutic relevance of the KLF–T-cell axis. Full article

Background/Objectives: Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in haematological malignancies but has shown limited efficacy against solid tumours. Key barriers include inadequate tumour trafficking, immunosuppressive tumour microenvironments, poor selectivity and heterogeneity of antigen expression, and challenges related to safety and manufacturing. Biomaterial-based technologies have emerged as a potential strategy to address many of these limitations. This review aims to critically evaluate biomaterial approaches designed to enhance CAR-T cell therapy of solid tumours and assess their translational potential. Methods: A narrative review of recent pre-clinical translational studies was conducted, focussing on biomaterial platforms developed to improve CAR-T cell delivery, persistence, functionality, safety control, and manufacturing efficiency in solid-tumour settings. Approaches were analysed according to their mechanisms of action, therapeutic benefits, and stage of translational readiness. Results: Biomaterial strategies, including nanoparticles, injectable and implantable hydrogels, scaffolds, and hybrid delivery systems, have improved CAR-T infiltration, survival, and therapeutic efficacy in several solid-tumour models. Localised delivery of cytokines and other immunomodulatory cues enabled improved spatio-temporal control of CAR-T activation, reducing systemic toxicity, and increasing persistence. Additional applications include amplified ex vivo CAR-T expansion and support for non-viral or in vivo CAR-T generation. However, increased material complexity was frequently associated with challenges in scalability, regulatory approval, and long-term safety. Conclusions: Biomaterial-enabled approaches offer a versatile toolkit to address key biological and translational barriers limiting CAR-T cell therapy of solid tumours. Strategies based on clinically familiar materials and simplified designs appear most suitable for near-term clinical translation, emphasising the need to balance engineering innovation with safety, scalability, and integration into existing clinical workflows. Full article

Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies. Full article

Autoimmune rheumatic diseases are still treated predominantly through broad or targeted suppression of inflammatory pathways, yet durable restoration of self-tolerance remains a central unmet therapeutic goal. This narrative review examines restoration of immune tolerance as an emerging translational framework in rheumatology, integrating checkpoint agonism, antigen-specific immunotherapy, regulatory cell-based strategies, and immune-reset approaches within a unified therapeutic perspective. Rather than treating these strategies as isolated innovations, the review evaluates how each attempts to restore, reinforce, or reconfigure immune restraint at distinct biological levels, spanning inhibitory receptor signaling, antigen-selective non-responsiveness, dominant regulatory control, and deeper reconfiguration of pathogenic immune architecture. Their relevance is considered across rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and systemic sclerosis, with emphasis on mechanistic rationale, translational maturity, disease-specific therapeutic fit, biomarkers, therapeutic timing, and major barriers to clinical implementation. Collectively, these approaches suggest a shift in rheumatology from repeated control of inflammatory consequences toward more selective and potentially durable recalibration of autoreactive immunity. Although the field remains biologically and clinically immature, restoration of immune tolerance is emerging as an important organizing principle for the development of more precise and potentially disease-modifying therapies in autoimmune rheumatic disease. Full article

Winter rapeseed suffers severe damage under cold stress, which seriously restricts its growth and yield. However, differences among cultivars in leaf starch and soluble sugar, as well as their underlying molecular regulatory mechanisms under low-temperature stress, remain poorly understood. We hypothesized that winter rapeseed cultivars with differences in cold tolerance would vary in starch accumulation, soluble sugar contents, and expression of the starch and sugar metabolism-related genes under cold stress. This study aimed to investigate differences in starch accumulation, soluble sugar content, and the gene expression patterns involved in the starch and sugar metabolism pathway in the leaves of winter rapeseed (Brassica napus L.) cultivars with contrasting cold tolerance under cold stress. In this study, two winter rapeseed cultivars, cold-tolerant L88 and cold-sensitive T2288, received 24 h cold treatments at 22 °C (control), 4 °C, 0 °C, and −4 °C. Plant morphology and leaf ultrastructure were observed, iodine–potassium iodide (I₂-KI) staining was performed, and the starch, soluble sugar contents (sucrose, fructose, glucose, and maltose) were analyzed for each temperature regime. Transcriptome sequencing was performed exclusively at −4 °C (0 h versus 24 h). Under −4 °C stress, the two cultivars showed the greatest differences in plant phenotype and leaf ultrastructure, with the cold-sensitive cultivar Tianyou 2288 suffering more severe freezing injury. In Longyou 88, chloroplasts in mesophyll cells were swollen and contained fewer starch granules, whereas in Tianyou 2288 some chloroplasts disintegrated and large numbers of starch granules remained undegraded. As the treatment temperature decreased, leaf starch content declined in both cultivars. At −4 °C, starch content in Longyou 88 was 3.84 mg/g lower than in Tianyou 2288. The contents of soluble sugars, sucrose, glucose, and maltose in leaves increased continuously in both cultivars as stress temperature decreased and reached their maximum values at −4 °C. However, fructose content showed cultivar-specific changes. In Longyou 88, fructose content reached its maximum value of 12.59 mg/g at −4 °C, whereas in Tianyou 2288 it peaked at 7.54 mg/g at 4 °C. At −4 °C, fructose content was 6.69 mg/g higher in Longyou 88 than in Tianyou 2288. Transcriptome analysis revealed that after 24 h of −4 °C stress, Longyou 88 had more upregulated differentially expressed genes (DEGs) than Tianyou 2288, whereas the number of downregulated DEGs in Tianyou 2288 was approximately twice that in Longyou 88. The genes BAM1, BAM3, SUS1, SCRK1, TPS9, and E1314, which were involved in the starch and sucrose metabolism pathway, were upregulated in both cultivars, whereas BGL44 was downregulated. These findings indicate that cold-tolerance winter rapeseed is associated with enhanced starch degradation, maintenance of chloroplast structural integrity in mesophyll cells, and increased soluble sugar accumulation, providing potential physiological indicators for cold-tolerance evaluation. Full article