Search Results (24,190)

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by persistent joint inflammation and systemic immune dysregulation. While bone marrow activation has been linked to RA pathogenesis, direct access to bone marrow tissue for progenitor analysis remains limited by ethical and technical constraints. Analysis of progenitor cells in peripheral blood can serve as a surrogate reflecting bone marrow activation. In this study, we analysed peripheral blood cells from 12 RA patients and 9 healthy controls using high-dimensional spectral flow cytometry with a nine-marker panel (CD45, CD31, CD235, CD133, CD34, CD105, CD271, CD90, PDPN). Flow Self-Organizing Map (FlowSOM) clustering identified 20 distinct cell populations. Additionally, a complementary flow cytometry panel was used to assess CD31 expression on immune subsets in peripheral mononuclear cells (PBMCs) from 9 RA and 9 healthy donors of this cohort. RA patients showed increased CD45⁺CD31⁻ immune cells, but not their putative progenitors. Conversely, putative CD45⁺CD31^int progenitors and CD45⁺CD31^int mature cells were reduced, along with CD31 expression on T cells. Levels of CD235a⁺ putative erythroid precursors and CD45⁺CD31⁺ progenitors were significantly increased in RA patients. Three putative stromal cell populations were detected in circulation. Together, these findings reveal expanded erythroid precursor populations and reduced CD31 expression on T cells in RA. Our data underscore broad systemic alterations in cellular homeostasis in RA patients. In conclusion, our results suggest that the loss of CD31 expression on immune cell precursors plays a role in age-associated immune remodelling and immune activation in RA and provides the rationale for further studies on erythroblast differentiation and the functional role of erythroblasts in chronic inflammation. Full article

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood–retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues. Full article

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition marked by heterogeneous behavioral symptoms and systemic comorbidities, including immune and gastrointestinal dysfunctions. Emerging studies suggest that glycosylation—a fundamental post-translational modification regulating cellular communication and immune responses—may play a role in ASD pathophysiology, yet its contribution remains underexplored. Methods: In this study, we developed an integrative transcriptomic and network analysis framework to investigate glycosylation-related gene expression changes and their functional associations in ASD. Using publicly available datasets from bulk and single-cell RNA sequencing of brain and blood tissues, we focused on four prior-knowledge gene subsets: glycogenes, extracellular matrix glycoproteins, immune response genes, and autism risk genes. Results: Differential expression and pathway enrichment analyses revealed consistent dysregulation of glycosylation pathways, including mucin-type O-glycan biosynthesis, glycosaminoglycan metabolism, GPI-anchor formation, and sialylation, across ASD tissues. These transcriptional changes were functionally linked to altered immune signaling (e.g., IL-17, Toll-like receptor, and complement pathways) and synaptic development pathways, forming a distinct glyco-immune axis. Network analysis identified key glycogenes such as GALNT10, NEU1, LMAN2L, and CHST1 as central molecular nodes, interacting with immune and neuronal regulators. Linkage disequilibrium analysis further revealed ASD-associated SNPs influencing the expression of these glycogenes in both blood and brain tissues. Conclusions: Together, these findings support a model in which disrupted glycosylation contributes to ASD pathophysiology by mediating immune dysregulation and altered neuronal connectivity. This study offers a systems-level framework to understand the molecular complexity of ASD and highlights glycogenes as potential biomarkers and targets for future therapeutic exploration. Full article

Depression is one of the most prevalent psychiatric disorders worldwide, with a steadily increasing incidence and complex, multifactorial pathophysiology. Beyond classical neurochemical mechanisms, growing evidence points to the role of systemic low-grade inflammation and immuno-metabolic disturbances in its development. Gut microbiota dysbiosis has emerged as a key factor linking metabolic, immune, and neuroendocrine pathways, potentially exacerbating neuroinflammation and contributing to the onset and progression of depressive symptoms. Immune activation, which is a result of gut dysbiosis, may play a crucial role in the pathogenesis of immuno-metabolic depression. Thyroid dysfunction appears to be an important, yet insufficiently understood component of this network. Thyroid hormones play a crucial role in regulating metabolism, immune responses, and central nervous system function. Alterations in thyroid function, even within subclinical ranges, have been associated with mood disturbances and may share common inflammatory and metabolic pathways with depression. Furthermore, emerging data suggest that gut microbiota may influence thyroid hormone metabolism, including deiodinase activity, linking dysbiosis with thyroid axis dysregulation. Despite these insights, the integrated interactions between thyroid function, gut microbiota, metabolic syndrome, and inflammation in depression remain largely unexplored. This review explores current evidence to highlight gaps in existing research and synthesizes current knowledge, aiming to clarify mechanisms underlying immuno-metabolic depression. Understanding these relationships may provide a rationale for redefining depression as an immuno-metabolic disorder and support the development of more integrative therapeutic strategies targeting not only the brain, but also the gut-thyroid axis. Full article

Evidence from recent large-scale disruptions indicates that efficiency-centered supply chain designs struggle to sustain operation under persistent and systemic uncertainty. This study introduces the Response and Adaptive Immune-Inspired Supply Chain Immune System (RAIE–SCIS), a continuous-time dynamic framework that extends existing viability and resilience approaches by explicitly modeling inter-temporal adaptation and operational memory within a control-theoretic structure. The framework represents supply chains as multi-layer control systems where structural protection, adaptive regulation, and memory mechanisms jointly shape system response over time. Viability is assessed using time-dependent indicators, including performance trajectories, recovery time, and an adaptation-based viability index. The model is applied to a carbon capture, utilization, and storage (CCUS) supply chain under heterogeneous disruption scenarios. Results show that immune-enabled configurations increase minimum performance levels by 15–30% and reduce recovery times by up to 25% compared to non-adaptive configurations. These improvements are not uniform across scenarios and depend on disturbance structure and recurrence. The analysis reveals that adaptive regulation introduces a trade-off between recovery speed and variability, while memory mechanisms shape recovery dynamics under recurrent disruptions—effects not captured by static or purely reactive models. Their effects become more pronounced when disturbances accumulate or propagate. Full article

Plant metabolism is essential for coordinating growth, development, and defense under changing environmental conditions. Plants continuously adjust their metabolic pathways to balance resource allocation between growth and immune responses. Under stress, metabolic reprogramming redirects energy and resources toward the production of defense compounds and activation of immune signaling pathways. These changes involve complex interactions among primary metabolism, specialised metabolites, and regulatory networks, including calcium signaling, reactive oxygen species, and phytohormones. Advances in metabolomics and multi-omics technologies have improved understanding of the metabolic control of plant immunity; however, knowledge remains fragmented, and an integrated framework linking metabolism, development, and defense is still emerging. This review examines plant immunometabolism by highlighting the dynamic relationships between metabolic networks and immune functions during development and stress. It discusses pathways that influence growth, stress-induced metabolic shifts linked to defense, and how signaling interacts with metabolism. Progress in metabolomics, transcriptomics, proteomics, and computational modeling that supports systems-level analysis of plant metabolism is also summarized. In addition, potential applications in agriculture and biotechnology, including metabolic engineering, genome editing, and metabolomics-based breeding, are considered in relation to crop resilience. By integrating metabolism, signaling, and systems biology, this review provides a broad perspective on how metabolic reprogramming shapes the growth–defense trade-off in plants and outlines future directions for developing climate-resilient crops. Full article

The Mediterranean Diet (MD) is recognized for promoting longevity and reducing the risk of chronic disease, yet the mechanisms underlying these benefits remain uncharacterized. This review highlights the diverse nutritional and phytoactive constituents of the MD and research exploring its complex network of polyphenols. It discusses data evaluating MD-derived constituents formulated into a dietary supplement capsule developed using a systems and network biology framework. Component selection was based on their actions on enzyme systems involved in senescence-related pathways and health preservation. This review highlights how MD components synergistically modulate pathways central to antioxidant activity, cognitive health, and aging. Liquid chromatography–mass spectrometry identified phytochemically diverse constituents in capsules (supplied by DailyColors™, Warwickshire, UK and Sebastopol, CA, USA) derived from primary color groups in sixteen Mediterranean plants. These constituents were mapped to bioactive networks targeting enzymes linked to inflammation, metabolic regulation, and cellular senescence. Preclinical studies demonstrated the modulation of mitochondrial and metabolic health markers, with complementary effects on cytokine inhibition and glucose sensitivity. Two clinical studies confirmed broad proteomic and epigenetic effects on pathways governing immunity, skeletal muscle, cognition, and inflammation. Therefore, this review advances a novel perspective that MD polyphenols act through synergistic, multi-pathway interactions that link dietary patterns to coordinated regulation of longevity and healthy aging. Full article

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune dysregulation that leads to widespread inflammation and damage across multiple organs. B lymphocytes play a vital role in SLE, with abnormal development and activation leading to autoreactive antibody production and immune complex formation, which damages tissues. Methods: The PPARα agonist WY14643 has anti-inflammatory effects in various inflammatory conditions, including CNS diseases. We investigated whether WY14643 decreases inflammatory mediator production in CD45R⁺ cells in the MRL/lpr mouse model of SLE. Flow cytometry was used to evaluate WY14643’s impact on the expression of IFN-γ, IL-6, iNOS, MCP-1, IL-1α, IL-2, Notch-1, Notch-3, GITR, and NF-κB p65 in splenic CD45R⁺ B cells. Additionally, we assessed the effect of WY14643 on the mRNA levels of these markers in the kidney using RT-PCR. Results: WY14643 decreased inflammatory markers such as CD45R⁺IFN-γ⁺, CD45R⁺IL-6⁺, CD45R⁺iNOS⁺, CD45R⁺MCP-1⁺, CD45R⁺IL-1α⁺, CD45R⁺IL-2⁺, CD45R⁺Notch1⁺, CD45R⁺Notch3⁺, CD45R⁺GITR⁺, and CD45R⁺NF-κB p65⁺ in splenic cells from MRL/lpr mice. Furthermore, WY14643 also lowered mRNA expression of IFN-γ, IL-6, iNOS, MCP-1, IL-2, IL-1α, Notch-1, Notch-3, GITR, and NF-κB p65 in the kidney. Conclusions: This study shows that WY14643 inhibits the production of inflammatory mediators and significantly reduces autoimmune features, including kidney inflammation, in MRL/lpr mice. Our results indicate that WY14643, a PPAR-α agonist, could be a potential therapy for lupus nephritis. Full article

Autoimmune diseases arise from the failure of self-tolerance. The recognition of self-antigen peptide–MHC (pMHC) complexes by the T-cell receptor (TCR) is the fundamental event triggering autoimmune pathogenesis. While traditional immunosuppressants provide broad systemic effects, they often compromise global immunity. Emerging molecular strategies aim to selectively disrupt the trimolecular complex—comprising the TCR, the antigenic peptide, and the MHC molecule—to induce antigen-specific tolerance. This review highlights the pMHC–TCR interaction as the primary molecular checkpoint for antigen-specific intervention. We discuss the structural basis of these interactions and their potential to redefine the therapeutic landscape for autoimmune diseases (ADs). We examine the molecular drivers of tolerance breakdown—including genetic susceptibility, molecular mimicry, post-translational modifications (PTMs), and ectopic MHC II expression—that shape the autoreactive T-cell landscape. This review examines current advancements in biological and pharmacological interventions, such as pMHC-decorated nanoparticles and soluble pMHC, to reprogram pathogenic T-cell response. We also explored CAR-T therapy strategies for autoimmune diseases, such as CAR-Treg, designed to precisely modulate pMHC-TCR signaling. Collectively, these precision interventions in immunological synapse assembly during autoimmune response are considered the basis for safer, antigen-specific immunotherapy capable of restoring self-tolerance without global immunosuppression. Full article

Alphaviruses are mosquito-borne viruses that can infect the central nervous system (CNS) and cause encephalomyelitis, which is a rare but dangerous complication from infection. In mice, this can be studied in a model of infection with Sindbis virus (SINV), which infects neurons and causes neurological disease. Due to the non-renewable nature of neurons, the immune response in the CNS is specialized to prevent neuronal damage or death, even if they are infected. Therefore, insights into the nuances of antiviral immunity in the CNS provide a better understanding of disease pathogenesis and mechanisms of recovery. Type I interferons (IFNs) are critically important for survival; they are an innate antiviral defense mechanism that consists mainly of IFNα and IFNβ. Although both use the same receptor, type-specific differences between IFNα and IFNβ have been described in other contexts. To this end, Ifnb^−/− mice were used to elucidate the role of IFNβ in recovery from alphavirus encephalomyelitis. IFNβ-deficient mice have intact IFNα expression and downstream signaling, but symptomatic disease occurs earlier and is more severe. This is accompanied by increased virus replication in the early stages of infection. Microgliosis is reduced in Ifnb^−/− mice compared to wildtype, but inflammatory cytokine/chemokine levels are higher and associated with alterations in monocyte and NK cell recruitment into the CNS. Ifnb^−/− mice have no deficiencies in the expression of factors known to be required for viral clearance. Therefore, IFNβ modulates the early stages of the immune response and facilitates restriction of virus replication, contributing to delayed disease onset. Full article

Neuropsychiatric conditions constitute a major and growing global health burden, with prevalence rates that continue to rise worldwide. Although these disorders have traditionally been studied primarily from a neuronal perspective, accumulating evidence indicates that immune dysregulation and inflammatory processes play a central role in their pathophysiology. In this review, we advance the hypothesis that nitric oxide (NO)-mediated alterations in blood–brain barrier (BBB) integrity represent a critical mechanistic link between inflammation and central nervous system dysfunction in neuropsychiatric disorders. NO is a gaseous multifunctional signaling molecule involved in vascular homeostasis and immune responses, and its dysregulated production, together with aberrant protein S-nitrosylation, has been implicated in several neuropsychiatric conditions. However, the specific mechanisms by which NO signaling contributes to BBB dysfunction remain incompletely defined. Here, we synthesize current evidence supporting a role for NO-dependent vascular and inflammatory pathways in BBB disruption and discuss how these processes may contribute to the onset and progression of neuropsychiatric conditions. Clarifying these mechanisms may provide novel insights into disease pathogenesis and identify therapeutic targets aimed at preserving BBB integrity and limiting neuroinflammation. Full article

Male reproductive aging is increasingly recognized as a systemic process in which inflammaging drives progressive dysfunction of urogenital tissues. Key mechanisms include immune–metabolic alterations, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, as well as epigenetic remodeling. Evidence from experimental and clinical studies suggests that these processes are often investigated independently, and integrative models in humans remain limited. Here, we propose a conceptual framework linking the prostate, testis, and skeletal muscle, in which oxidative stress may act as a mediator amplifying systemic dysregulation at different levels during the aging process. Lifestyle and metabolic interventions, including caloric restriction, resistance exercise, and selected nutraceuticals, may act as key modulators of inflammaging pathways, thus highlighting new potential targets for precision medicine approaches. Full article

Epigenetic regulation plays a central role in modulating plant immune responses and interactions with beneficial microbes. In this study, we investigated the contribution of RNA-directed DNA methylation (RdDM) components—DCL3; AGO9; DCL1; and the de novo DNA methyltransferases CMT3, DRM1, and DRM2—to the interaction between Arabidopsis thaliana, Trichoderma atroviride, and foliar pathogens. We show that DCL3 and AGO9 differentially regulate basal and inducible immunity, negatively affecting resistance to the necrotrophic fungus Botrytis cinerea, while promoting defense against the hemibiotrophic bacterium Pseudomonas syringae pv. tomato DC3000. Transcriptional analyses revealed that RdDM components modulate the balance between jasmonic acid/ethylene (JA/ET) and salicylic acid (SA) signaling pathways, influencing the amplitude and coordination of defense responses. In addition, DCL3 and DCL1 appear to be required for the full expression of T. atroviride-mediated systemic resistance, whereas AGO9 and DNA methyltransferases contribute to efficient root colonization. Notably, mutants in these pathways displayed enhanced basal resistance but impaired responsiveness to beneficial microbial signals, revealing a trade-off between constitutive defense activation and inducible systemic protection. Consistent with this, alterations in RdDM components were also associated with changes in plant growth dynamics under specific conditions, supporting a role for epigenetic regulation in coordinating growth–defense trade-offs. Together, our findings support a model in which epigenetic regulation controls defense responsiveness, enabling plants to balance immune activation, growth and compatibility toward beneficial microbes. Full article

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier dysfunction, immune dysregulation, and gut–skin axis imbalance. While probiotics show promise, the therapeutic potential and mechanisms of topical postbiotics in modulating the gut–skin axis remain understudied. Here, we investigated the efficacy of Schleiferilactobacillus harbinensis JNDM-derived cell-free supernatant (CFS) and lysate (ShL) in a DNFB-induced AD mouse model. Topical application of both CFS and ShL significantly attenuated AD-like symptoms, reduced epidermal thickening, and restored the expression of the barrier protein filaggrin. Immunologically, treatment suppressed the Th2-dominant inflammatory cascade (IL-4, IL-5, IL-13, IL-33, TSLP) and reduced serum IgE and IFN-γ levels. Notably, ShL exhibited superior systemic efficacy, significantly inhibiting mast cell infiltration and reducing the spleen index. 16S rRNA sequencing revealed that topical intervention remotely remodeled the gut microbiota, specifically reversing the depletion of the beneficial genus Alistipes and suppressing the compensatory increase in Odoribacter. This microbial restructuring was accompanied by distinct metabolic changes: ShL treatment resulted in an approximately 4-fold elevation in fecal butyrate concentrations compared with the model group. Correlation analysis further validated a strong positive axis linking Alistipes abundance and butyrate levels to skin barrier integrity. Collectively, our findings demonstrate that S. harbinensis postbiotics—particularly the lysate—ameliorate AD through a dual mechanism of local barrier repair and systemic metabolic modulation via the gut–skin axis, presenting a promising non-steroidal therapeutic strategy. Full article

Exercise adaptation depends on overload that is resolved by recovery, yet the same biology becomes maladaptive when immune, endocrine, metabolic, and muscle-centered stress signals fail to normalize. Exercise-induced maladaptation represents a systems-level failure of biological resolution, with direct relevance to disease-like dysregulation. Functional overreaching, non-functional overreaching, and overtraining syndrome remain difficult to diagnose because no single biomarker provides adequate specificity, temporal stability, or clinical portability. This narrative review synthesizes human and mechanistic evidence across proteomics, transcriptomics, metabolomics, endocrine profiling, extracellular vesicles, and mitochondrial quality-control biology to define the molecular architecture most relevant to athlete monitoring. Across these layers, the most coherent signatures cluster in immune-acute-phase activation, redox-buffering strain, endocrine drift, altered substrate availability, excitation–contraction dysfunction, integrated stress-response signaling, and defects in autophagy–mitophagy and lysosomal remodeling. Three translational elements emerge from this synthesis: a systems-convergence model of recovery failure, a staged biomarker deployment hierarchy, and a provisional recovery failure index. The practical priority is therefore not a solitary marker, but serial phenotype-anchored multimarker panels that connect circulating signals with muscle-centered biology and support decision-making before prolonged recovery failure becomes entrenched. Full article